Simultaneous administration of mRNA COVID-19 bivalent booster and influenza vaccines
The U.S. Food and Drug Administration authorized use of mRNA COVID-19 bivalent booster vaccines on August 31, 2022. Currently, CDC’s clinical guidance states that COVID-19 and other vaccines may be administered simultaneously. At time of authorization and recommendations, limited data existed describing simultaneous administration of COVID-19 bivalent booster and other vaccines. We describe simultaneous influenza and mRNA COVID-19 bivalent booster vaccine administration between August 31-December 31, 2022, among persons aged ≥6 months in the Vaccine Safety Datalink (VSD) by COVID-19 bivalent booster vaccine type, influenza vaccine type, age group, sex, and race and ethnicity. Of 2,301,876 persons who received a COVID-19 bivalent booster vaccine, 737,992 (32.1%) received simultaneous influenza vaccine, majority were female (53.1%), aged ≥18 years (91.4%), and non-Hispanic White (55.7%). These findings can inform future VSD studies on simultaneous influenza and COVID-19 bivalent booster vaccine safety and coverage, which may have implications for immunization service delivery.
Authors: Kenigsberg, Tat'Yana A;Lewis, Ned;Weintraub, Eric S;et al.
Vaccine. 2023 Sep 07;41(39):5678-5682. Epub 2023-08-19.
Influenza Vaccination Among Pregnant People Before and During the Coronavirus Disease 2019 (COVID-19) Pandemic
There are limited data on influenza vaccination coverage among pregnant people in the United States during the coronavirus disease 2019 (COVID-19) pandemic. Within the Vaccine Safety Datalink, we conducted a retrospective cohort study to examine influenza vaccination coverage during the 2016-2017 through the 2021-2022 influenza seasons among pregnant people aged 18-49 years. Using influenza vaccines administered through March each season, we assessed crude coverage by demographic and clinical characteristics. Annual influenza vaccination coverage increased from the 2016-2017 season (63.0%) to a high of 71.0% in the 2019-2020 season. After the start of the COVID-19 pandemic, it decreased to a low of 56.4% (2021-2022). In each of the six seasons, coverage was lowest among pregnant people aged 18-24 years and among non-Hispanic Black pregnant people. The 2021-2022 season had the lowest coverage across all age and race and ethnicity groups. The recent decreases highlight the need for continued efforts to improve coverage among pregnant people.
Authors: Irving, Stephanie A;Kharbanda, Elyse;Klein, Nicola P;Naleway, Allison L;et al.
Obstet Gynecol. 2023 Sep 01;142(3):636-639. Epub 2023-08-03.
Clinical epidemiology and risk factors for critical outcomes among vaccinated and unvaccinated adults hospitalized with COVID-19-VISION Network, 10 States, June 2021-March 2023
The epidemiology of COVID-19 continues to develop with emerging variants, expanding population-level immunity, and advances in clinical care. We describe changes in the clinical epidemiology of hospitalized COVID-19 and risk factors for critical outcomes over time. We included adults aged ≥18 years from 10 states hospitalized with COVID-19 June 2021-March 2023 when multiple SARS-CoV-2 variants or sub-lineages predominated. We evaluated changes in baseline demographic and clinical characteristics and critical outcomes (intensive care unit admission and/or death) and used regression models to evaluate critical outcomes risk factors (risk ratios) stratified by COVID-19 vaccination status. 60,488 COVID-19-associated hospitalizations were included in the analysis. Among those hospitalized, from Delta period (June-December 2021) to the Omicron post-BA.4/BA.5 period (September 2022-March 2023), median age increased from 60 to 75 years, proportion vaccinated increased from 18.2% to 70.1%, while critical outcomes declined from 24.8% to 19.4% (all p < 0.001). Compared to all hospitalization events, those with critical outcomes had a higher proportion of four or more categories of medical conditions categories assessed (32.8% critical versus 23.0% all hospitalized). Critical outcome risk factors were similar for unvaccinated and vaccinated populations; presence of ≥4 medical condition categories was most strongly associated with risk of critical outcomes regardless of vaccine status (unvaccinated aRR 2.27 [95% CI: 2.14-2.41]; vaccinated aRR 1.73 [95% CI: 1.56-1.92]) across periods. The proportion of adults hospitalized with COVID-19 who experienced critical outcomes decreased with time and median patient age increased with time. Multimorbidity was mostly strongly associated with critical outcomes.
Authors: Griggs, Eric P;McEvoy, Charlene;Konatham, Deepika;Hansen, John;Tenforde, Mark W;et al.
Clin Infect Dis. 2023 Aug 26.
Effectiveness of COVID-19 vaccines at preventing emergency department or urgent care encounters and hospitalizations among immunocompromised adults: An observational study of real-world data across 10 US states from August-December 2021
Immunocompromised (IC) persons are at increased risk for severe COVID-19 outcomes and are less protected by 1-2 COVID-19 vaccine doses than are immunocompetent (non-IC) persons. We compared vaccine effectiveness (VE) against medically attended COVID-19 of 2-3 mRNA and 1-2 viral-vector vaccine doses between IC and non-IC adults. Using a test-negative design among eight VISION Network sites, VE against laboratory-confirmed COVID-19-associated emergency department (ED) or urgent care (UC) events and hospitalizations from 26 August-25 December 2021 was estimated separately among IC and non-IC adults and among specific IC condition subgroups. Vaccination status was defined using number and timing of doses. VE for each status (versus unvaccinated) was adjusted for age, geography, time, prior positive test result, and local SARS-CoV-2 circulation. We analyzed 8,848 ED/UC events and 18,843 hospitalizations among IC patients and 200,071 ED/UC events and 70,882 hospitalizations among non-IC patients. Among IC patients, 3-dose mRNA VE against ED/UC (73% [95% CI: 64-80]) and hospitalization (81% [95% CI: 76-86]) was lower than that among non-IC patients (ED/UC: 94% [95% CI: 93-94]; hospitalization: 96% [95% CI: 95-97]). Similar patterns were observed for viral-vector vaccines. Transplant recipients had lower VE than other IC subgroups. During B.1.617.2 (Delta) variant predominance, IC adults received moderate protection against COVID-19-associated medical events from three mRNA doses, or one viral-vector dose plus a second dose of any product. However, protection was lower in IC versus non-IC patients, especially among transplant recipients, underscoring the need for additional protection among IC adults.
Authors: Embi, Peter J;Dunne, Margaret M;Stenehjem, Edward;Weber, Zachary A;Naleway, Allison L;et al.
Vaccine. 2023 Aug 23;41(37):5424-5434. Epub 2023-05-22.
Effectiveness of Monovalent and Bivalent mRNA Vaccines in Preventing COVID-19-Associated Emergency Department and Urgent Care Encounters Among Children Aged 6 Months-5 Years – VISION Network, United States, July 2022-June 2023
On June 19, 2022, the original monovalent mRNA COVID-19 vaccines were approved as a primary series for children aged 6 months-4 years (Pfizer-BioNTech) and 6 months-5 years (Moderna) based on safety, immunobridging, and limited efficacy data from clinical trials. On December 9, 2022, CDC expanded recommendations for use of updated bivalent vaccines to children aged ≥6 months. mRNA COVID-19 vaccine effectiveness (VE) against emergency department or urgent care (ED/UC) encounters was evaluated within the VISION Network during July 4, 2022-June 17, 2023, among children with COVID-19-like illness aged 6 months-5 years. Among children aged 6 months-5 years who received molecular SARS-CoV-2 testing during August 1, 2022-June 17, 2023, VE of 2 monovalent Moderna doses against ED/UC encounters was 29% (95% CI = 12%-42%) ≥14 days after dose 2 (median = 100 days after dose 2; IQR = 63-155 days). Among children aged 6 months-4 years with a COVID-19-like illness who received molecular testing during September 19, 2022-June 17, 2023, VE of 3 monovalent Pfizer-BioNTech doses was 43% (95% CI = 17%-61%) ≥14 days after dose 3 (median = 75 days after dose 3; IQR = 40-139 days). Effectiveness of ≥1 bivalent dose, comparing children with at least a complete primary series and ≥1 bivalent dose to unvaccinated children, irrespective of vaccine manufacturer, was 80% (95% CI = 42%-96%) among children aged 6 months-5 years a median of 58 days (IQR = 32-83 days) after the dose. All children should stay up to date with recommended COVID-19 vaccines, including initiation of COVID-19 vaccination immediately when they are eligible.
Authors: Link-Gelles, Ruth;Rowley, Elizabeth A K;Irving, Stephanie A;Weber, Zachary A;Fleming-Dutra, Katherine E;et al.
MMWR Morb Mortal Wkly Rep. 2023 Aug 18;72(33):886-892. Epub 2023-08-18.
Safety of simultaneous vaccination with COVID-19 vaccines in the Vaccine Safety Datalink
Safety data on simultaneous vaccination (SV) with primary series monovalent COVID-19 vaccines and other vaccines are limited. We describe SV with primary series COVID-19 vaccines and assess 23 pre-specified health outcomes following SV among persons aged ≥5 years in the Vaccine Safety Datalink (VSD). We utilized VSD’s COVID-19 vaccine surveillance data from December 11, 2020-May 21, 2022. Analyses assessed frequency of SV. Rate ratios (RRs) were estimated by Poisson regression when the number of outcomes was ≥5 across both doses, comparing outcome rates between COVID-19 vaccinees receiving SV and COVID-19 vaccinees receiving no SV in the 1-21 days following COVID-19 vaccine dose 1 and 1-42 days following dose 2 by SV type received (“All SV”, “Influenza SV”, “Non-influenza SV”). SV with COVID-19 vaccines was not common practice (dose 1: 0.7 % of 8,455,037 persons, dose 2: 0.3 % of 7,787,013 persons). The most frequent simultaneous vaccines were influenza, HPV, Tdap, and meningococcal. Outcomes following SV with COVID-19 vaccines were rare (total of 56 outcomes observed after dose 1 and dose 2). Overall rate of outcomes among COVID-19 vaccinees who received SV was not statistically significantly different than the rate among those who did not receive SV (6.5 vs. 6.8 per 10,000 persons). Statistically significant elevated RRs were observed for appendicitis (2.09; 95 % CI, 1.06-4.13) and convulsions/seizures (2.78; 95 % CI, 1.10-7.06) in the “All SV” group following dose 1, and for Bell’s palsy (2.82; 95 % CI, 1.14-6.97) in the “Influenza SV” group following dose 2. Combined pre-specified health outcomes observed among persons who received SV with COVID-19 vaccine were rare and not statistically significantly different compared to persons who did not receive SV with COVID-19 vaccine. Statistically significant adjusted rate ratios were observed for some individual outcomes, but the number of outcomes was small and there was no adjustment for multiple testing.
Authors: Kenigsberg, Tat'Yana A;Hanson, Kayla E;Klein, Nicola P;Weintraub, Eric S;et al.
Vaccine. 2023 Jul 19;41(32):4658-4665. Epub 2023-06-15.
Medically Attended Acute Adverse Events in Pregnant People After Coronavirus Disease 2019 (COVID-19) Booster Vaccination
In this multisite, observational, matched cohort study of more than 80,000 pregnant people, receipt of an mRNA monovalent coronavirus disease 2019 (COVID-19) booster vaccination in pregnancy was not associated with increased risk for thrombocytopenia, myocarditis, venous thromboembolism, ischemic stroke, or other serious adverse events within 21 or 42 days after booster vaccination. The mRNA monovalent COVID-19 booster in pregnancy was associated with an increased risk for medically attended malaise or fatigue within 7 days of vaccination (adjusted rate ratio [aRR] 3.64, 95% CI 2.42-5.48) and lymphadenopathy or lymphadenitis within 21 days (aRR 3.25, 95% CI 1.67-6.30) or 42 days (aRR 2.18, 95% CI 1.33-3.58) of vaccination. Our findings are consistent with prior evaluations of the primary COVID-19 vaccine series and are reassuring with respect to COVID-19 booster vaccination in pregnancy.
Authors: DeSilva, Malini B;Williams, Joshua T B;Kharbanda, Elyse O;et al.
Obstet Gynecol. 2023 Jul 01;142(1):125-129. Epub 2023-05-09.
Safety and Tolerability of V114 Pneumococcal Vaccine in Infants: A Phase 3 Study
Disease caused by Streptococcus pneumoniae is associated with considerable morbidity and mortality in children. Pneumococcal conjugate vaccines (PCVs) are well tolerated and effective at reducing pneumococcal disease caused by vaccine serotypes. VAXNEUVANCE (V114) is a 15-valent PCV containing 13 serotypes in Prevnar 13 (PCV13), plus serotypes 22F and 33F. This large phase 3 study evaluated safety and tolerability of V114 in infants. In total, 2409 infants were randomized to receive V114 or PCV13 at 2, 4, 6, and 12 to 15 months of age. Safety was evaluated as the proportion of participants with adverse events (AEs). Solicited and unsolicited injection-site and systemic AEs were collected for 14 days after each study vaccination, and serious AEs up to 6 months after the last PCV dose. The proportions of participants with injection-site, systemic, vaccine-related, and serious AEs were generally comparable between recipients of V114 and PCV13. The most frequently reported AEs were solicited, with irritability and somnolence being the most frequent in both groups. Although the incidence of some AEs was higher in the V114 group, the between-group differences were small. The majority of experienced AEs were of mild-to-moderate intensity and lasted ≤3 days. There were 2 vaccine-related serious AEs of pyrexia in the V114 group, and 2 nonvaccine-related deaths, 1 in each group. No participant discontinued study vaccine because of AEs. V114 is well tolerated and has a generally comparable safety profile to that of PCV13. These study results support routine use of V114 in infants.
Authors: Banniettis, Natalie;Oberdorfer, Peninnah;V114-031 (PNEU-LINK) study group,;et al.
Pediatrics. 2023 Jul 01;152(1).
Safety of COVID-19 mRNA Vaccination Among Young Children in the Vaccine Safety Datalink
Authors: Goddard, Kristin;Donahue, James G;Lewis, Ned;Hanson, Kayla E;Weintraub, Eric S;Fireman, Bruce;Klein, Nicola P
Pediatrics. 2023 Jul 01;152(1).
Estimates of Bivalent mRNA Vaccine Durability in Preventing COVID-19-Associated Hospitalization and Critical Illness Among Adults with and Without Immunocompromising Conditions – VISION Network, September 2022-April 2023
Authors: Link-Gelles, Ruth;Irving, Stephanie A;Rogerson, Colin;Tenforde, Mark W;et al.
Am J Transplant. 2023 Jul;23(7):1062-1076.
Evaluation of clinical case definitions for respiratory syncytial virus lower respiratory tract infection in young children
Various case definitions of respiratory syncytial virus lower respiratory tract infection (RSV-LRTI) are currently proposed. We assessed the performance of 3 clinical case definitions against the World Health Organization definition recommended in 2015 (WHO 2015). In this prospective cohort study conducted in 8 countries, 2401 children were followed up for 2 years from birth. Suspected LRTIs were detected via active and passive surveillance, followed by in-person clinical evaluation including single timepoint respiratory rate and oxygen saturation (by pulse oximetry) assessment, and nasopharyngeal sampling for RSV testing by polymerase chain reaction. Agreement between case definitions was evaluated using Cohen’s κ statistics. Of 1652 suspected LRTIs, 227 met the WHO 2015 criteria for RSV-LRTI; 73 were classified as severe. All alternative definitions were highly concordant with the WHO 2015 definition for RSV-LRTI (κ: 0.95-1.00), but less concordant for severe RSV-LRTI (κ: 0.47-0.82). Tachypnea was present for 196/226 (86.7%) WHO 2015 RSV-LRTIs and 168/243 (69.1%) LRTI/bronchiolitis/pneumonia cases, clinically diagnosed by nonstudy physicians. Low oxygen saturation levels were observed in only 55/226 (24.3%) WHO 2015 RSV-LRTIs. Three case definitions for RSV-LRTI showed high concordance with the WHO 2015 definition, while agreement was lower for severe RSV-LRTI. In contrast to increased respiratory rate, low oxygen saturation was not a consistent finding in RSV-LRTIs and severe RSV-LRTIs. This study demonstrates that current definitions are highly concordant for RSV-LRTIs, but a standard definition is still needed for severe RSV-LRTI. NCT01995175.
Authors: Englund, Janet A;Jose, Lisa;Dieussaert, Ilse;et al.
J Pediatric Infect Dis Soc. 2023 May 31;12(5):273-281.
Estimates of Bivalent mRNA Vaccine Durability in Preventing COVID-19-Associated Hospitalization and Critical Illness Among Adults with and Without Immunocompromising Conditions – VISION Network, September 2022-April 2023
On September 1, 2022, CDC’s Advisory Committee on Immunization Practices (ACIP) recommended a single bivalent mRNA COVID-19 booster dose for persons aged ≥12 years who had completed at least a monovalent primary series. Early vaccine effectiveness (VE) estimates among adults aged ≥18 years showed receipt of a bivalent booster dose provided additional protection against COVID-19-associated emergency department and urgent care visits and hospitalizations compared with that in persons who had received only monovalent vaccine doses (1); however, insufficient time had elapsed since bivalent vaccine authorization to assess the durability of this protection. The VISION Network* assessed VE against COVID-19-associated hospitalizations by time since bivalent vaccine receipt during September 13, 2022-April 21, 2023, among adults aged ≥18 years with and without immunocompromising conditions. During the first 7-59 days after vaccination, compared with no vaccination, VE for receipt of a bivalent vaccine dose among adults aged ≥18 years was 62% (95% CI = 57%-67%) among adults without immunocompromising conditions and 28% (95% CI = 10%-42%) among adults with immunocompromising conditions. Among adults without immunocompromising conditions, VE declined to 24% (95% CI = 12%-33%) among those aged ≥18 years by 120-179 days after vaccination. VE was generally lower for adults with immunocompromising conditions. A bivalent booster dose provided the highest protection, and protection was sustained through at least 179 days against critical outcomes, including intensive care unit (ICU) admission or in-hospital death. These data support updated recommendations allowing additional optional bivalent COVID-19 vaccine doses for certain high-risk populations. All eligible persons should stay up to date with recommended COVID-19 vaccines.
Authors: Link-Gelles, Ruth;Irving, Stephanie A;Rogerson, Colin;Tenforde, Mark W;et al.
MMWR Morb Mortal Wkly Rep. 2023 May 26;72(21):579-588. Epub 2023-05-26.
Tdap vaccination during pregnancy and risk of chorioamnionitis and related infant outcomes
An increased risk of chorioamnionitis in people receiving tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine during pregnancy has been reported. The importance of this association is unclear as additional study has not demonstrated increased adverse infant outcomes associated with Tdap vaccination in pregnancy. We conducted a retrospective observational cohort study of pregnant people ages 15-49 years with singleton pregnancies ending in live birth who were members of 8 Vaccine Safety Datalink (VSD) sites during October 2016-September 2018. We used a time-dependent covariate Cox model with stabilized inverse probability weights applied to evaluate associations between Tdap vaccination during pregnancy and chorioamnionitis and preterm birth outcomes. We used Poisson regression with robust variance with stabilized inverse probability weights applied to evaluate the association of Tdap vaccination with adverse infant outcomes. We performed medical record reviews on a random sample of patients with ICD-10-CM-diagnosed chorioamnionitis to determine positive predictive values (PPV) of coded chorioamnionitisfor “probable clinical chorioamnionitis,” “possible clinical chorioamnionitis,” or “histologic chorioamnionitis.” We included 118,211 pregnant people; 103,258 (87%) received Tdap vaccine during pregnancy; 8098 (7%) were diagnosed with chorioamnionitis. The adjusted hazard ratio for chorioamnionitis in the Tdap vaccine-exposed group compared to unexposed was 0.96 (95% CI 0.90-1.03). There was no association between Tdap vaccine and preterm birth or adverse infant outcomes associated with chorioamnionitis. Chart reviews were performed for 528 pregnant people with chorioamnionitis. The PPV for clinical (probable or possible clinical chorioamnionitis) was 48% and 59% for histologic chorioamnionitis. The PPV for the combined outcome of clinical or histologic chorioamnionitis was 81%. Tdap vaccine exposure during pregnancy was not associated with chorioamnionitis, preterm birth, or adverse infant outcomes. ICD-10 codes for chorioamnionitis lack specificity for clinical chorioamnionitis and should be a recognized limitation when interpreting results.
Authors: Greenberg, Victoria;Fu Tseng, Hung;DeSilva, Malini B;et al.
Vaccine. 2023 May 22;41(22):3429-3435. Epub 2023-04-26.
Effectiveness of BNT162b2 COVID-19 Vaccination in Children and Adolescents
We assessed BNT162b2 vaccine effectiveness (VE) against mild to moderate and severe coronavirus disease 2019 (COVID-19) in children and adolescents through the Omicron BA.4/BA.5 period. Using VISION Network records from April 2021 to September 2022, we conducted a test-negative, case-control study assessing VE against COVID-19-associated emergency department/urgent care (ED/UC) encounters and hospitalizations using logistic regression, conditioned on month and site, adjusted for covariates. We compared 9800 ED/UC cases with 70 232 controls, and 305 hospitalized cases with 2612 controls. During Delta, 2-dose VE against ED/UC encounters at 12 to 15 years was initially 93% (95% confidence interval 89 to 95), waning to 77% (69% to 84%) after ≥150 days. At ages 16 to 17, VE was initially 93% (86% to 97%), waning to 72% (63% to 79%) after ≥150 days. During Omicron, VE at ages 12 to 15 was initially 64% (44% to 77%), waning to 13% (3% to 23%) after ≥150 days; at ages 16 to 17 VE was 31% (10% to 47%) during days 60 to 149, waning to 7% (-8 to 20%) after 150 days. A monovalent booster increased VE to 54% (40% to 65%) at ages 12 to 15 and 46% (30% to 58%) at ages 16 to 17. At ages 5 to 11, 2-dose VE was 49% (33% to 61%) initially and 41% (29% to 51%) after 150 days. During Delta, VE against hospitalizations at ages 12 to 17 was high (>97%), and at ages 16 to 17 remained 98% (73% to 100%) beyond 150 days; during Omicron, hospitalizations were too infrequent to precisely estimate VE. BNT162b2 protected children and adolescents against mild to moderate and severe COVID-19. VE was lower during Omicron predominance including BA.4/BA.5, waned after dose 2 but increased after a monovalent booster. Children and adolescents should receive all recommended COVID-19 vaccinations.
Authors: Klein, Nicola P;Dalton, Alexandra F;Patel, Palak;Link-Gelles, Ruth;et al.
Pediatrics. 2023 May 01;151(5).
COVID-19 Booster Vaccination in Early Pregnancy and Surveillance for Spontaneous Abortion
Adherence to COVID-19 booster vaccine recommendations has lagged in pregnant and nonpregnant adult populations. One barrier to booster vaccination is uncertainty regarding the safety of booster doses among pregnant people. To evaluate whether there is an association between COVID-19 booster vaccination during pregnancy and spontaneous abortion. This observational, case-control, surveillance study evaluated people aged 16 to 49 years with pregnancies at 6 to 19 weeks’ gestation at 8 health systems in the Vaccine Safety Datalink from November 1, 2021, to June 12, 2022. Spontaneous abortion cases and ongoing pregnancy controls were evaluated during consecutive surveillance periods, defined by calendar time. Primary exposure was receipt of a third messenger RNA (mRNA) COVID-19 vaccine dose within 28 days before spontaneous abortion or index date (midpoint of surveillance period in ongoing pregnancy controls). Secondary exposures were third mRNA vaccine doses in a 42-day window or any COVID-19 booster in 28- and 42-day windows. Spontaneous abortion cases and ongoing pregnancy controls were identified from electronic health data using a validated algorithm. Cases were assigned to a single surveillance period based on pregnancy outcome date. Eligible ongoing pregnancy time was assigned to 1 or more surveillance periods as an ongoing pregnancy-period control. Generalized estimating equations were used to estimate adjusted odds ratios (AOR) with gestational age, maternal age, antenatal visits, race and ethnicity, site, and surveillance period as covariates and robust variance estimates to account for inclusion of multiple pregnancy periods per unique pregnancy. Among 112 718 unique pregnancies included in the study, the mean (SD) maternal age was 30.6 (5.5) years. Pregnant individuals were Asian, non-Hispanic (15.1%); Black, non-Hispanic (7.5%); Hispanic (35.6%); White, non-Hispanic (31.2%); and of other or unknown (10.6%); and 100% were female. Across eight 28-day surveillance periods, among 270 853 ongoing pregnancy-period controls, 11 095 (4.1%) had received a third mRNA COVID-19 vaccine in a 28-day window; among 14 226 cases, 553 (3.9%) had received a third mRNA COVID-19 vaccine within 28 days of the spontaneous abortion. Receipt of a third mRNA COVID-19 vaccine was not associated with spontaneous abortion in a 28-day window (AOR, 0.94; 95% CI, 0.86-1.03). Results were consistent when using a 42-day window (AOR, 0.97; 95% CI, 0.90-1.05) and for any COVID-19 booster in a 28-day (AOR, 0.94; 95% CI, 0.86-1.02) or 42-day (AOR, 0.96; 95% CI, 0.89-1.04) exposure window. In this case-control surveillance study, COVID-19 booster vaccination in pregnancy was not associated with spontaneous abortion. These findings support the safety of recommendations for COVID-19 booster vaccination, including in pregnant populations.
Authors: Kharbanda, Elyse O;Irving, Stephanie A;Vazquez-Benitez, Gabriela;et al.
JAMA Netw Open. 2023 May 01;6(5):e2314350. Epub 2023-05-01.
Immunogenicity and Safety of a Third COVID-19 BNT162b2 mRNA Vaccine Dose in 5-11-Year-Olds
In this ongoing study, substantially increased ancestral SARS-CoV-2 neutralizing responses were observed 1 month after a third 10-µg BNT162b2 dose given to 5 to 11-year olds versus neutralizing responses post-dose 2. After dose 3, increased neutralizing responses against Omicron BA.1 and BA.4/BA.5 strains were also observed. The safety/tolerability profile was acceptable. (NCT04816643).
Authors: Simões, Eric A F; Klein, Nicola P; C4591007 Clinical Trial Group,; et al.
J Pediatric Infect Dis Soc. 2023 Apr 28;12(4):234-238.
Protection of 2 and 3 mRNA Vaccine Doses Against Severe Outcomes Among Adults Hospitalized with COVID-19 – VISION Network, August 2021 – March 2022
We assessed coronavirus disease 2019 (COVID-19) vaccination impact on illness severity among adults hospitalized with COVID-19, August 2021-March 2022. We evaluated differences in intensive care unit (ICU) admission, in-hospital death, and length of stay among vaccinated (2 or 3 mRNA vaccine doses) versus unvaccinated patients aged ≥18 years hospitalized for ≥24 hours with COVID-19-like illness and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) molecular testing. We calculated odds ratios (ORs) for ICU admission and death and subdistribution hazard ratios (SHR) for time to hospital discharge adjusted for age, geographic region, calendar time, and local virus circulation. We included 27 149 SARS-CoV-2-positive hospitalizations. During both Delta- and Omicron-predominant periods, protection against ICU admission was strongest among 3-dose vaccinees compared with unvaccinated patients (Delta OR, 0.52 [95% CI, .28-.96]; Omicron OR, 0.69 [95% CI, .54-.87]). During both periods, risk of in-hospital death was lower among vaccinated compared with unvaccinated patients but ORs overlapped across vaccination strata. We observed SHR >1 across all vaccination strata in both periods indicating faster discharge for vaccinated patients. COVID-19 vaccination was associated with lower rates of ICU admission and in-hospital death in both Delta and Omicron periods compared with being unvaccinated.
Authors: DeSilva, Malini B; Klein, Nicola P; Zerbo, Ousseny; Fireman, Bruce; Gaglani, Manjusha; et al.
J Infect Dis. 2023 Apr 18;227(8):961-969.
Safety of measles, mumps, and rubella vaccine in adolescents and adults in the vaccine safety Datalink
Measles, mumps, and rubella vaccine (MMR) is routinely administered to children; however, adolescents and adults may receive MMR for various reasons. Safety studies in adolescents and adults are limited. We report on safety of MMR in this age group in the Vaccine Safety Datalink. We included adolescents (aged 9-17 years) and adults (aged ≥ 18 years) who received ≥ 1 dose of MMR from January 1, 2010-December 31, 2018. Pre-specified outcomes were identified by diagnosis codes. Clinically serious outcomes included anaphylaxis, encephalitis/myelitis, Guillain-Barré syndrome, immune thrombocytopenia, meningitis, and seizure. Non-serious outcomes were allergic reaction, arthropathy, fever, injection site reaction, lymphadenopathy, non-specific reaction, parotitis, rash, and syncope. All serious outcomes underwent medical record review. Outcome-specific incidence was calculated in pre-defined post-vaccination windows. A self-controlled risk interval design was used to determine the relative risk of each outcome in a risk window after vaccination compared to a more distal control window. During the study period, 276,327 MMR doses were administered to adolescents and adults. Mean age of vaccinees was 34.8 years; 65.8 % were female; 53.2 % of doses were administered simultaneously with ≥ 1 other vaccine. Serious outcomes were rare, with incidence ≤ 6 per 100,000 doses for each outcome assessed, and none had a significant elevation in incidence during the risk window compared to the control window. Incidence of non-serious outcomes per 100,000 doses ranged from 3.4 for parotitis to 263.0 for arthropathy. Other common outcomes included injection site reaction and rash (157.0 and 112.9 per 100,000 doses, respectively). Significantly more outcomes were observed during the risk window compared to the control window for all non-serious outcomes except parotitis. Some variability was observed by sex and age group. Serious outcomes after MMR are rare in adolescents and adults, but vaccinees should be counseled regarding anticipated local and systemic non-serious adverse events.
Authors: Hanson, Kayla E; Klein, Nicola P; McLean, Huong Q; et al.
Vaccine X. 2023 Apr;13:100268. Epub 2023-02-04.
Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults – VISION Network, Nine States, September-November 2022
During June-October 2022, the SARS-CoV-2 Omicron BA.5 sublineage accounted for most of the sequenced viral genomes in the United States, with further Omicron sublineage diversification through November 2022.* Bivalent mRNA vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the Omicron BA.4/BA.5 sublineages. On September 1, 2022, a single bivalent booster dose was recommended for adults who had completed a primary vaccination series (with or without subsequent booster doses), with the last dose administered ≥2 months earlier (1). During September 13-November 18, the VISION Network evaluated vaccine effectiveness (VE) of a bivalent mRNA booster dose (after 2, 3, or 4 monovalent doses) compared with 1) no previous vaccination and 2) previous receipt of 2, 3, or 4 monovalent-only mRNA vaccine doses, among immunocompetent adults aged ≥18 years with an emergency department/urgent care (ED/UC) encounter or hospitalization for a COVID-19-like illness.† VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated ED/UC encounters was 56% compared with no vaccination, 32% compared with monovalent vaccination only with last dose 2-4 months earlier, and 50% compared with monovalent vaccination only with last dose ≥11 months earlier. VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated hospitalizations was 59% compared with no vaccination, 42% compared with monovalent vaccination only with last dose 5-7 months earlier, and 48% compared with monovalent vaccination only with last dose ≥11 months earlier. Bivalent vaccines administered after 2, 3, or 4 monovalent doses were effective in preventing medically attended COVID-19 compared with no vaccination and provided additional protection compared with past monovalent vaccination only, with relative protection increasing with time since receipt of the last monovalent dose. All eligible persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose. Persons should also consider taking additional precautions to avoid respiratory illness this winter season, such as masking in public indoor spaces, especially in areas where COVID-19 community levels are high.
Authors: Tenforde, Mark W; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Link-Gelles, Ruth; et al.
MMWR Morb Mortal Wkly Rep. 2023 Mar 17;71(53):1637-1646. Epub 2023-03-17.
COVID-19 Vaccine Safety Surveillance in Early Pregnancy in the United States: Design Factors Affecting the Association Between Vaccine and Spontaneous Abortion
In the Vaccine Safety Datalink (VSD), we previously reported no association between COVID-19 vaccination in early pregnancy and spontaneous abortion (SAB). The current study aims to understand how time since vaccine roll-out or other methodologic factors could affect results. Using a case-control design and generalized estimating equations, we estimated the odds ratios (OR) of COVID-19 vaccination in the 28 days before a SAB or last date of the surveillance period (index date) in ongoing pregnancies and occurrence of SAB, across cumulative 4-week periods from December 2020 through June 2021. Using data from a single site, we evaluated alternate methodologic approaches: increasing the exposure window to 42 days, modifying the index date from the last day to the midpoint of the surveillance period, and constructing a cohort design with a time-dependent exposure model. A protective effect (OR 0.78; 95% Confidence Interval (CI): 0.69-0.89), observed with 3-cumulative periods ending March 8, 2021, was attenuated when surveillance extended to June 28, 2021 (OR: 1.02; 95% CI: 0.96-1.08). We observed a lower OR for a 42-day as compared to a 28-day window. The time-dependent model showed no association. Timing of the surveillance appears to be an important factor affecting the observed vaccine-SAB association.
Authors: Vazquez-Benitez, Gabriela; Klein, Nicola P; Kharbanda, Elyse O; et al.
Am J Epidemiol. 2023 Mar 16.
Safety of 9-valent human papillomavirus vaccine administered to males and females in routine use
The nine-valent human papillomavirus vaccine (HPV9, Gardasil®9) was licensed in the USA in December 2014. This study was a multiyear post-licensure study to assess HPV9 safety following routine administration. This retrospective cohort study compared the risk of emergency department visits and hospitalizations during the interval soon after vaccination with risk during a later interval. Kaiser Permanente Northern California (KPNC) members aged ≥ 9 years who received ≥ 1 HPV9 dose between 10/1/2015-9/30/2017 were included. Outcomes were grouped into predefined diagnostic categories. We compared the odds of events in postvaccination risk intervals (days 0-14, days 1-60) with odds of events during control intervals (days 61-75, days 61-120) using conditional logistic regression. We characterized prespecified events on the day of vaccination (allergic reaction and syncope) and all deaths in the study period. The study included 215,965 individuals receiving ≥ 1 dose of HPV9, of whom 140,628 had no prior HPV vaccination. We observed similar numbers of males and females and racial/ethnic diversity consistent with the underlying population. At first dose median age was 12-13 years and 77% received ≥ 1 concomitant vaccine. Eighteen event categories were significantly elevated, including skin disorders (odds ratio [OR] 1.88, 95% confidence interval [CI] 1.00, 3.53) and ill-defined conditions (OR 1.36, 95% CI 1.13, 1.64; category includes abdominal pain, allergic reactions, syncope, etc.). On review, most findings were previously known, preceded vaccination, or had other causes. Allergic reactions and syncope at vaccination were infrequent but many were potentially related. No deaths (n = 37) were considered related to HPV9 and were consistent with the background rate. We did not identify new safety concerns related to HPV9. The results are consistent with the HPV9 safety profile as established from previous studies/surveillance. European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS13151, protocol V503-028).
Authors: Hansen, John;Yee, Arnold;Lewis, Ned;Li, Se;Velicer, Christine;Saddier, Patricia;Klein, Nicola P
Vaccine. 2023 Mar 10;41(11):1819-1825. Epub 2022-11-14.
Estimation of COVID-19 mRNA Vaccine Effectiveness and COVID-19 Illness and Severity by Vaccination Status During Omicron BA.4 and BA.5 Sublineage Periods
Recent SARS-CoV-2 Omicron variant sublineages, including BA.4 and BA.5, may be associated with greater immune evasion and less protection against COVID-19 after vaccination. To evaluate the estimated vaccine effectiveness (VE) of 2, 3, or 4 doses of COVID-19 mRNA vaccination among immunocompetent adults during a period of BA.4 or BA.5 predominant circulation; and to evaluate the relative severity of COVID-19 in hospitalized patients across Omicron BA.1, BA.2 or BA.2.12.1, and BA.4 or BA.5 sublineage periods. This test-negative case-control study was conducted in 10 states with data from emergency department (ED) and urgent care (UC) encounters and hospitalizations from December 16, 2021, to August 20, 2022. Participants included adults with COVID-19-like illness and molecular testing for SARS-CoV-2. Data were analyzed from August 2 to September 21, 2022. mRNA COVID-19 vaccination. The outcomes of interest were COVID-19 ED or UC encounters, hospitalizations, and admission to the intensive care unit (ICU) or in-hospital death. VE associated with protection against medically attended COVID-19 was estimated, stratified by care setting and vaccine doses (2, 3, or 4 doses vs 0 doses as the reference group). Among hospitalized patients with COVID-19, demographic and clinical characteristics and in-hospital outcomes were compared across sublineage periods. During the BA.4 and BA.5 predominant period, there were 82 229 eligible ED and UC encounters among patients with COVID-19-like illness (median [IQR] age, 51 [33-70] years; 49 682 [60.4%] female patients), and 19 114 patients (23.2%) had test results positive for SARS-CoV-2; among 21 007 hospitalized patients (median [IQR] age, 71 [58-81] years; 11 209 [53.4%] female patients), 3583 (17.1 %) had test results positive for SARS-CoV-2. Estimated VE against hospitalization was 25% (95% CI, 17%-32%) for receipt of 2 vaccine doses at 150 days or more after receipt, 68% (95% CI, 50%-80%) for a third dose 7 to 119 days after receipt, and 36% (95% CI, 29%-42%) for a third dose 120 days or more (median [IQR], 235 [204-262] days) after receipt. Among patients aged 65 years or older who had received a fourth vaccine dose, VE was 66% (95% CI, 53%-75%) at 7 to 59 days after vaccination and 57% (95% CI, 44%-66%) at 60 days or more (median [IQR], 88 [75-105] days) after vaccination. Among hospitalized patients with COVID-19, ICU admission or in-hospital death occurred in 21.4% of patients during the BA.1 period vs 14.7% during the BA.4 and BA.5 period (standardized mean difference: 0.17). In this case-control study of COVID-19 vaccines and illness, VE associated with protection against medically attended COVID-19 illness was lower with increasing time since last dose; estimated VE was higher after receipt of 1 or 2 booster doses compared with a primary series alone.
Authors: Link-Gelles, Ruth; Klein, Nicola P; Zerbo, Ousseny; Fireman, Bruce; Tenforde, Mark W; et al.
JAMA Netw Open. 2023 Mar 01;6(3):e232598. Epub 2023-03-01.
Maternal SARS-CoV-2 vaccination and infant protection against SARS-CoV-2 during the first six months of life
We examined the effectiveness of maternal vaccination against SARS-CoV-2 infection in 30,311 infants born at Kaiser Permanente Northern California from December 15, 2020, to May 31, 2022. Using Cox regression, the effectiveness of ≥2 doses of COVID-19 vaccine received during pregnancy was 84% (95% confidence interval [CI]: 66, 93), 62% (CI: 39, 77) and 56% (CI: 34,71) during months 0-2, 0-4 and 0- 6 of a child’s life, respectively, in the Delta variant period. In the Omicron variant period, the effectiveness of maternal vaccination in these three age intervals was 21% (CI: -21,48), 14% (CI: -9,32) and 13% (CI: -3,26), respectively. Over the entire study period, the incidence of hospitalization for COVID-19 was lower during the first 6 months of life among infants of vaccinated mothers compared with infants of unvaccinated mothers (21/100,000 person-years vs. 100/100,000 person-years). Maternal vaccination was protective, but protection was lower during Omicron than during Delta. Protection during both periods decreased as infants aged.
Authors: Zerbo, Ousseny; Ray, G Thomas; Fireman, Bruce; Layefsky, Evan; Goddard, Kristin; Lewis, Edwin; Ross, Pat; Omer, Saad; Greenberg, Mara; Klein, Nicola P
Nat Commun. 2023 Feb 28;14(1):894. Epub 2023-02-28.
Active Post-Licensure Safety Surveillance for Recombinant Zoster Vaccine Using Electronic Health Record Data
Recombinant zoster vaccine (RZV) (Shingrix; GlaxoSmithKline, Brentford, United Kingdom) is an adjuvanted glycoprotein vaccine that was licensed in 2017 to prevent herpes zoster (shingles) and its complications in older adults. In this prospective, postlicensure Vaccine Safety Datalink study using electronic health records, we sequentially monitored a real-world population of adults aged ≥50 years who received care in multiple US Vaccine Safety Datalink health systems to identify potentially increased risks of 10 prespecified health outcomes, including stroke, anaphylaxis, and Guillain-Barré syndrome (GBS). Among 647,833 RZV doses administered from January 2018 through December 2019, we did not detect a sustained increased risk of any monitored outcome for RZV recipients relative to either historical (2013-2017) recipients of zoster vaccine live, a live attenuated virus vaccine (Zostavax; Merck & Co., Inc., Kenilworth, New Jersey), or contemporary non-RZV vaccine recipients who had an annual well-person visit during the 2018-2019 study period. We confirmed prelicensure trial findings of increased risks of systemic and local reactions following RZV. Our study provides additional reassurance about the overall safety of RZV. Despite a large sample, uncertainty remains regarding potential associations with GBS due to the limited number of confirmed GBS cases that were observed.
Authors: Nelson, Jennifer C; Klein, Nicola P; Jackson, Lisa A; et al.
Am J Epidemiol. 2023 Feb 01;192(2):205-216.
Vaccine effectiveness against influenza-associated urgent care, emergency department, and hospital encounters during the 2021-2022 season, VISION Network
Following historically low influenza activity during the 2020-2021 season, the United States saw an increase in influenza circulating during the 2021-2022 season. Most viruses belonged to the influenza A(H3N2) 3C.2a1b 2a.2 subclade. We conducted a test-negative case-control analysis among adults ≥18 years of age at three sites within the VISION Network. Encounters included emergency department/urgent care (ED/UC) visits or hospitalizations with ≥1 acute respiratory illness (ARI) discharge diagnosis codes and molecular testing for influenza. Vaccine effectiveness (VE) was calculated by comparing the odds of influenza vaccination ≥14 days before the encounter date between influenza-positive cases (type A) and influenza-negative and SARS-CoV-2-negative controls, applying inverse probability-to-be-vaccinated weights, and adjusting for confounders. 86,732 ED/UC ARI-associated encounters (7,696 [9%] cases) and 16,805 hospitalized ARI-associated encounters (649 [4%] cases) were included. VE against influenza-associated ED/UC encounters was 25% (95% confidence interval (CI): 20-29%) and 25% (95%CI: 11-37%) against influenza-associated hospitalizations. VE against ED/UC encounters was lower in adults ≥65 years of age (7%; CI: -5-17%) or with immunocompromising conditions (4%, CI:-45-36%). During an influenza A(H3N2)-predominant influenza season, modest VE was observed. These findings highlight the need for improved vaccines, particularly for A(H3N2) viruses that are historically associated with lower VE.
Authors: Tenforde, Mark W; Fireman, Bruce; Zerbo, Ousseny; Klein, Nicola P; et al.
J Infect Dis. 2023 Jan 23.
A safety study evaluating non-COVID-19 mortality risk following COVID-19 vaccination
The safety of COVID-19 vaccines plays an important role in addressing vaccine hesitancy. We conducted a large cohort study to evaluate the risk of non-COVID-19 mortality after COVID-19 vaccination while adjusting for confounders including individual-level demographics, clinical risk factors, health care utilization, and community-level socioeconomic risk factors. The retrospective cohort study consisted of members from seven Vaccine Safety Datalink sites from December 14, 2020 through August 31, 2021. We conducted three separate analyses for each of the three COVID-19 vaccines used in the US. Crude non-COVID-19 mortality rates were reported by vaccine type, age, sex, and race/ethnicity. The counting process model for survival analyses was used to analyze non-COVID-19 mortality where a new observation period began when the vaccination status changed upon receipt of the first dose and the second dose. We used calendar time as the basic time scale in survival analyses to implicitly adjust for season and other temporal trend factors. A propensity score approach was used to adjust for the potential imbalance in confounders between the vaccinated and comparison groups. For each vaccine type and across age, sex, and race/ethnicity groups, crude non-COVID-19 mortality rates among COVID-19 vaccinees were lower than those among comparators. After adjusting for confounders with the propensity score approach, the adjusted hazard ratios (aHRs) were 0.46 (95% confidence interval [CI], 0.44-0.49) after dose 1 and 0.48 (95% CI, 0.46-0.50) after dose 2 of the BNT162b2 vaccine, 0.41 (95% CI, 0.39-0.44) after dose 1 and 0.38 (95% CI, 0.37-0.40) after dose 2 of the mRNA-1273 vaccine, and 0.55 (95% CI, 0.51-0.59) after receipt of Ad26.COV2.S. While residual confounding bias remained after adjusting for several individual-level and community-level risk factors, no increased risk was found for non-COVID-19 mortality among recipients of three COVID-19 vaccines used in the US.
Authors: Xu, Stanley; Klein, Nicola P; Fireman, Bruce; Qian, Lei; et al.
Vaccine. 2023 Jan 16;41(3):844-854. Epub 2022-12-20.
Characterization of parental intention to vaccinate elementary school aged children in the state of California
In October 2021, Emergency Use Authorization of Coronavirus Disease 2019 (COVID-19) vaccines was granted for children aged 5-11. To ensure vaccine uptake in children upon approval, California will implement a state-wide executive order mandating COVID-19 vaccination for school children following full US FDA approval. This study uses survey data collected between November 6th, 2020 and December 14th, 2020 (n = 2091) to identify how sociodemographic characteristics and attitudes towards childhood vaccines among California parents were associated with their intentions to vaccinate their child against COVID-19. About one quarter (26 %) of surveyed California parents did not intend to vaccinate their child, suggesting skepticism towards the COVID-19 vaccine for children and the potential for pushback to a COVID-19 vaccine school-entry mandate. However, 17 % were unsure of their decision, suggesting the potential for public health messaging to make a positive impact on COVID-19 vaccine confidence and uptake. This study identifies characteristics of hesitant parents in California to prioritize for research and outreach. These data also provide a baseline for parental attitudes towards vaccinating children against COVID-19 in California, which will be useful for characterizing changes in attitudes towards childhood COVID-19 vaccination over time.
Authors: Dudley, Matthew Z; Klein, Nicola P; Salmon, Daniel A; et al.
Vaccine. 2023 Jan 16;41(3):630-635. Epub 2022-12-19.
All Older Adults Benefit From Pneumococcal Vaccinations-The Case for Evaluating Vaccine Effectiveness Using All-Cause Pneumonia
Authors: Hsiao, Amber; Klein, Nicola P
JAMA Intern Med. 2023 Jan 01;183(1):48-49.
Association Between Aluminum Exposure From Vaccines Before Age 24 Months and Persistent Asthma at Age 24 to 59 Months
To assess the association between cumulative aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months. A retrospective cohort study was conducted in the Vaccine Safety Datalink (VSD). Vaccination histories were used to calculate cumulative vaccine-associated aluminum in milligrams (mg). The persistent asthma definition required one inpatient or 2 outpatient asthma encounters, and ?2 long-term asthma control medication dispenses. Cox proportional hazard models were used to evaluate the association between aluminum exposure and asthma incidence, stratified by eczema presence/absence. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) per 1 mg increase in aluminum exposure were calculated, adjusted for birth month/year, sex, race/ethnicity, VSD site, prematurity, medical complexity, food allergy, severe bronchiolitis, and health care utilization. The cohort comprised 326,991 children, among whom 14,337 (4.4%) had eczema. For children with and without eczema, the mean (standard deviation [SD]) vaccine-associated aluminum�exposure was�4.07�mg (SD�0.60) and 3.98�mg (SD�0.72), respectively. Among children with and without eczema, 6.0% and 2.1%, respectively, developed persistent asthma. Among children with eczema, vaccine-associated aluminum was positively associated with persistent asthma (aHR 1.26 per 1 mg increase in aluminum, 95% CI 1.07, 1.49); a positive association was also detected among children without eczema (aHR 1.19, 95% CI 1.14, 1.25). In a large observational study, a positive association was found between vaccine-related aluminum exposure and persistent asthma. While recognizing the small effect sizes identified and the potential for residual confounding, additional investigation of this hypothesis appears warranted.
Authors: Daley, Matthew F; Klein, Nicola P; DeStefano, Frank; et al.
Acad Pediatr. 2023 Jan-Feb;23(1):37-46. Epub 2022-09-28.
Extended surveillance to assess safety of 9-valent human papillomavirus vaccine
The safety of 9-valent HPV vaccine (9vHPV) has been established with regard to common and uncommon adverse events. However, investigation of rare and severe adverse events requires extended study periods to capture rare outcomes. This observational cohort study investigated the occurrence of three rare and serious adverse events following 9-valent human papillomavirus (9vHPV) vaccination compared to other vaccinations, in US individuals 9-26?years old, using electronic health record data from the Vaccine Safety Datalink (VSD). We searched for occurrences of Guillain-Barr� syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and stroke following 9vHPV vaccination from October 4, 2015, through January 2, 2021. We compared the risks of GBS, CIDP, and stroke following 9vHPV vaccination to risks of those outcomes following comparator vaccines commonly given to this age group (Td, Tdap, MenACWY, hepatitis A, and varicella vaccines) from January 1, 2007, through January 2, 2021. We observed 1.2 cases of stroke, 0.3 cases of GBS, and 0.1 cases of CIDP per 100,000 doses of 9vHPV vaccine. After observing more than 1.8 million doses of 9vHPV, we identified no statistically significant increase in risks associated with 9vHPV vaccination for any of these adverse events, either combined or stratified by age (9-17?years of age vs. 18-26?years of age) and sex (males vs. females). Our findings provide additional evidence supporting 9vHPV vaccine safety, over longer time frames and for more serious and rare adverse events.
Authors: Sundaram, Maria E; Klein, Nicola P; Donahue, James G; et al.
Hum Vaccin Immunother. 2022 Dec 30;18(7):2159215. Epub 2022-12-28.
Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults – VISION Network, Nine States, September-November 2022
During June-October 2022, the SARS-CoV-2 Omicron BA.5 sublineage accounted for most of the sequenced viral genomes in the United States, with further Omicron sublineage diversification through November 2022.* Bivalent mRNA vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the Omicron BA.4/BA.5 sublineages. On September 1, 2022, a single bivalent booster dose was recommended for adults who had completed a primary vaccination series (with or without subsequent booster doses), with the last dose administered ≥2 months earlier (1). During September 13-November 18, the VISION Network evaluated vaccine effectiveness (VE) of a bivalent mRNA booster dose (after 2, 3, or 4 monovalent doses) compared with 1) no previous vaccination and 2) previous receipt of 2, 3, or 4 monovalent-only mRNA vaccine doses, among immunocompetent adults aged ≥18 years with an emergency department/urgent care (ED/UC) encounter or hospitalization for a COVID-19-like illness.† VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated ED/UC encounters was 56% compared with no vaccination, 31% compared with monovalent vaccination only with last dose 2-4 months earlier, and 50% compared with monovalent vaccination only with last dose ≥11 months earlier. VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated hospitalizations was 57% compared with no vaccination, 38% compared with monovalent vaccination only with last dose 5-7 months earlier, and 45% compared with monovalent vaccination only with last dose ≥11 months earlier. Bivalent vaccines administered after 2, 3, or 4 monovalent doses were effective in preventing medically attended COVID-19 compared with no vaccination and provided additional protection compared with past monovalent vaccination only, with relative protection increasing with time since receipt of the last monovalent dose. All eligible persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose. Persons should also consider taking additional precautions to avoid respiratory illness this winter season, such as masking in public indoor spaces, especially in areas where COVID-19 community levels are high.
Authors: Tenforde, Mark W; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Link-Gelles, Ruth; et al.
MMWR Morb Mortal Wkly Rep. 2022 Dec 30;71(5152):1616-1624. Epub 2022-12-30.
Kawasaki Disease Following the 13-valent Pneumococcal Conjugate Vaccine and Rotavirus Vaccines
Temporal associations between Kawasaki disease (KD) and childhood vaccines have been reported. Limited data on KD following 13-valent pneumococcal conjugate (PCV13) and rotavirus vaccines are available. We conducted a self-controlled risk interval study using Vaccine Safety Datalink electronic health record data to investigate the risk of KD following PCV13 and rotavirus vaccines in children <2 years of age who were born from 2006 to 2017. All hospitalized KD cases identified by International Classification of Diseases diagnosis codes that fell within predefined risk (days 1-28 postvaccination) and control (days 29-56 for doses 1 and 2, and days 43-70 for doses 3 and 4) intervals were confirmed by manual chart review. During the study period, 655 cases of KD were identified by International Classification of Diseases codes. Of these, 97 chart-confirmed cases were within risk or control intervals. In analyses, the age-adjusted relative risk for KD following any dose of PCV13 was 0.75 (95% confidence interval, 0.47-1.21). Similarly, the age-adjusted relative risk for KD following any dose of rotavirus vaccine was 0.66 (95% CI, 0.40-1.09). Overall, there was no evidence of an elevated risk of KD following PCV13 or rotavirus vaccines by dose. In addition, no statistically significant temporal clustering of KD cases was identified during days 1 to 70 postvaccination. PCV13 and rotavirus vaccination were not associated with an increased risk of KD in children <2 years of age. Our findings provide additional evidence for the overall safety of PCV13 and rotavirus vaccines.
Authors: Kamidani, Satoshi; Zerbo, Ousseny; Weintraub, Eric S; et al.
Pediatrics. 2022 Dec 01;150(6).
Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalizations Among Immunocompromised Adults During SARS-CoV-2 Omicron Predominance – VISION Network, 10 States, December 2021-August 2022
Persons with moderate-to-severe immunocompromising conditions might have reduced protection after COVID-19 vaccination, compared with persons without immunocompromising conditions (1-3). On August 13, 2021, the Advisory Committee on Immunization Practices (ACIP) recommended that adults with immunocompromising conditions receive an expanded primary series of 3 doses of an mRNA COVID-19 vaccine. ACIP followed with recommendations on September 23, 2021, for a fourth (booster) dose and on September 1, 2022, for a new bivalent mRNA COVID-19 vaccine booster dose, containing components of the BA.4 and BA.5 sublineages of the Omicron (B.1.1.529) variant (4). Data on vaccine effectiveness (VE) of monovalent COVID-19 vaccines among persons with immunocompromising conditions since the emergence of the Omicron variant in December 2021 are limited. In the multistate VISION Network,§ monovalent 2-, 3-, and 4-dose mRNA VE against COVID-19-related hospitalization were estimated among adults with immunocompromising conditions¶ hospitalized with COVID-19-like illness,** using a test-negative design comparing odds of previous vaccination among persons with a positive or negative molecular test result (case-patients and control-patients) for SARS-CoV-2 (the virus that causes COVID-19). During December 16, 2021-August 20, 2022, among SARS-CoV-2 test-positive case-patients, 1,815 (36.3%), 1,387 (27.7%), 1,552 (31.0%), and 251 (5.0%) received 0, 2, 3, and 4 mRNA COVID-19 vaccine doses, respectively. Among test-negative control-patients during this period, 6,928 (23.7%), 7,411 (25.4%), 12,734 (43.6%), and 2,142 (7.3%) received these respective doses. Overall, VE against COVID-19-related hospitalization among adults with immunocompromising conditions hospitalized for COVID-like illness during Omicron predominance was 36% ≥14 days after dose 2, 69% 7-89 days after dose 3, and 44% ≥90 days after dose 3. Restricting the analysis to later periods when Omicron sublineages BA.2/BA.2.12.1 and BA.4/BA.5 were predominant and 3-dose recipients were eligible to receive a fourth dose, VE was 32% ≥90 days after dose 3 and 43% ≥7 days after dose 4. Protection offered by vaccination among persons with immunocompromising conditions during Omicron predominance was moderate even after a 3-dose monovalent primary series or booster dose. Given the incomplete protection against hospitalization afforded by monovalent COVID-19 vaccines, persons with immunocompromising conditions might benefit from updated bivalent vaccine booster doses that target recently circulating Omicron sublineages, in line with ACIP recommendations. Further, additional protective recommendations for persons with immunocompromising conditions, including the use of prophylactic antibody therapy, early access to and use of antivirals, and enhanced nonpharmaceutical interventions such as well-fitting masks or respirators, should also be considered.
Authors: Britton, Amadea; Klein, Nicola P; Zerbo, Ousseny; Fireman, Bruce; Tenforde, Mark W; et al.
MMWR Morb Mortal Wkly Rep. 2022 Oct 21;71(42):1335-1342. Epub 2022-10-21.
Maternal SARS-CoV-2 Vaccination and Infant Protection Against SARS-CoV-2 During the First 6 Months of Life
We examined the effectiveness of maternal vaccination against SARS-CoV-2 infection in 30,288 infants born at Kaiser Permanente Northern California from December 15, 2020, to May 31, 2022. Using Cox regression, the effectiveness of maternal vaccination was 85% (95% confidence interval [CI]: 67, 93), 64% (CI: 43, 78) and 57% (CI: 36,71) during the first 2, 4 and 6 months of life, respectively, in the Delta variant period. In the Omicron variant period, the effectiveness of maternal vaccination in these three age intervals was 22% (CI: -18,48), 14% (CI: -10,32) and 12% (CI: -4,26), respectively. Over the entire study period, the incidence of hospitalization for COVID-19 was lower during the first 6 months of life among infants of vaccinated mothers compared with infants of unvaccinated mothers (21/100,000 person-years vs. 100/100,000 person-years). Maternal vaccination was protective, but protection was lower during Omicron than during Delta. Protection during both periods decreased as infants aged.
Authors: Zerbo, Ousseny; Ray, G Thomas; Fireman, Bruce; Layefsky, Evan; Goddard, Kristin; Lewis, Edwin; Ross, Pat; Omer, Saad; Greenberg, Mara; Klein, Nicola
Res Sq. 2022 Oct 18.
Waning of vaccine effectiveness against moderate and severe covid-19 among adults in the US from the VISION network: test negative, case-control study
To estimate the effectiveness of mRNA vaccines against moderate and severe covid-19 in adults by time since second, third, or fourth doses, and by age and immunocompromised status. Test negative case-control study. Hospitals, emergency departments, and urgent care clinics in 10 US states, 17 January 2021 to 12 July 2022. 893 461 adults (≥18 years) admitted to one of 261 hospitals or to one of 272 emergency department or 119 urgent care centers for covid-like illness tested for SARS-CoV-2. The main outcome was waning of vaccine effectiveness with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine during the omicron and delta periods, and the period before delta was dominant using logistic regression conditioned on calendar week and geographic area while adjusting for age, race, ethnicity, local virus circulation, immunocompromised status, and likelihood of being vaccinated. 45 903 people admitted to hospital with covid-19 (cases) were compared with 213 103 people with covid-like illness who tested negative for SARS-CoV-2 (controls), and 103 287 people admitted to emergency department or urgent care with covid-19 (cases) were compared with 531 168 people with covid-like illness who tested negative for SARS-CoV-2. In the omicron period, vaccine effectiveness against covid-19 requiring admission to hospital was 89% (95% confidence interval 88% to 90%) within two months after dose 3 but waned to 66% (63% to 68%) by four to five months. Vaccine effectiveness of three doses against emergency department or urgent care visits was 83% (82% to 84%) initially but waned to 46% (44% to 49%) by four to five months. Waning was evident in all subgroups, including young adults and individuals who were not immunocompromised; although waning was morein people who were immunocompromised. Vaccine effectiveness increased among most groups after a fourth dose in whom this booster was recommended. Effectiveness of mRNA vaccines against moderate and severe covid-19 waned with time after vaccination. The findings support recommendations for a booster dose after a primary series and consideration of additional booster doses.
Authors: Ferdinands, Jill M; Klein, Nicola P; Zerbo, Ousseny; Fireman, Bruce; et al.
BMJ. 2022 10 03;379:e072141. Epub 2022-10-03.
Estimation of COVID-19 mRNA Vaccine Effectiveness Against Medically Attended COVID-19 in Pregnancy During Periods of Delta and Omicron Variant Predominance in the United States
Pregnant people are at high risk for severe COVID-19 but were excluded from mRNA vaccine trials; data on COVID-19 vaccine effectiveness (VE) are needed. To evaluate the estimated effectiveness of mRNA vaccination against medically attended COVID-19 among pregnant people during Delta and Omicron predominance. This test-negative, case-control study was conducted from June 2021 to June 2022 in a network of 306 hospitals and 164 emergency department and urgent care (ED/UC) facilities across 10 US states, including 4517 ED/UC encounters and 975 hospitalizations among pregnant people with COVID-19-like illness (CLI) who underwent SARS-CoV-2 molecular testing. Two doses (14-149 and ≥150 days prior) and 3 doses (7-119 and ≥120 days prior) of COVID-19 mRNA vaccine (≥1 dose received during pregnancy) vs unvaccinated. Estimated VE against laboratory-confirmed COVID-19-associated ED/UC encounter or hospitalization, based on the adjusted odds ratio (aOR) for prior vaccination; VE was calculated as (1 - aOR) × 100%. Among 4517 eligible CLI-associated ED/UC encounters and 975 hospitalizations, 885 (19.6%) and 334 (34.3%) were SARS-CoV-2 positive, respectively; the median (IQR) patient age was 28 (24-32) years and 31 (26-35) years, 537 (12.0%) and 118 (12.0%) were non-Hispanic Black and 1189 (26.0%) and 240 (25.0%) were Hispanic. During Delta predominance, the estimated VE against COVID-19-associated ED/UC encounters was 84% (95% CI, 69% to 92%) for 2 doses within 14 to 149 days, 75% (95% CI, 5% to 93%) for 2 doses 150 or more days prior, and 81% (95% CI, 30% to 95%) for 3 doses 7 to 119 days prior; estimated VE against COVID-19-associated hospitalization was 99% (95% CI, 96% to 100%), 96% (95% CI, 86% to 99%), and 97% (95% CI, 79% to 100%), respectively. During Omicron predominance, for ED/UC encounters, the estimated VE of 2 doses within 14 to 149 days, 2 doses 150 or more days, 3 doses within 7 to 119 days, and 3 doses 120 or more days prior was 3% (95% CI, -49% to 37%), 42% (95% CI, -16% to 72%), 79% (95% CI, 59% to 89%), and -124% (95% CI, -414% to 2%), respectively; for hospitalization, estimated VE was 86% (95% CI, 41% to 97%), 64% (95% CI, -102% to 93%), 86% (95% CI, 28% to 97%), and -53% (95% CI, -1254% to 83%), respectively. In this study, maternal mRNA COVID-19 vaccination, including booster dose, was associated with protection against medically attended COVID-19. VE estimates were higher against COVID-19-associated hospitalization than ED/UC visits and lower against the Omicron variant than the Delta variant. Protection waned over time, particularly during Omicron predominance.
Authors: Schrag, Stephanie J; Zerbo, Ousseny; Klein, Nicola P; Fireman, Bruce; Naleway, Allison L; et al.
JAMA Netw Open. 2022 09 01;5(9):e2233273. Epub 2022-09-01.
Risk of myocarditis and pericarditis following BNT162b2 and mRNA-1273 COVID-19 vaccination
Evidence indicates that mRNA COVID-19 vaccination is associated with risk of myocarditis and possibly pericarditis, especially in young males. It is not clear if risk differs between mRNA-1273 versus BNT162b2. We assessed if risk differs using comprehensive health records on a diverse population. Members 18-39 years of age at eight integrated healthcare-delivery systems were monitored using data updated weekly and supplemented with medical record review of myocarditis and pericarditis cases. Incidence of myocarditis and pericarditis events that occurred among vaccine recipients 0 to 7 days after either dose 1 or 2 of a messenger RNA (mRNA) vaccine was compared with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22 to 42 days earlier. Rate ratios (RRs) were estimated by conditional Poisson regression, adjusted for age, sex, race and ethnicity, health plan, and calendar day. Head-to-head comparison directly assessed risk following mRNA-1273 versus BNT162b2 during 0-7 days post-vaccination. From December 14, 2020 – January 15, 2022 there were 41 cases after 2,891,498 doses of BNT162b2 and 38 cases after 1,803,267 doses of mRNA-1273. Cases had similar demographic and clinical characteristics. Most were hospitalized for ≤1 day; none required intensive care. During days 0-7 after dose 2 of BNT162b2, the incidence was 14.3 (CI: 6.5-34.9) times higher than the comparison interval, amounting to 22.4 excess cases per million doses; after mRNA-1273 the incidence was 18.8 (CI: 6.7-64.9) times higher than the comparison interval, amounting to 31.2 excess cases per million doses. In head-to-head comparisons 0-7 days after either dose, risk was moderately higher after mRNA-1273 than after BNT162b2 (RR: 1.61, CI 1.02-2.54). Both vaccines were associated with increased risk of myocarditis and pericarditis in 18-39-year-olds. Risk estimates were modestly higher after mRNA-1273 than after BNT162b2.
Authors: Goddard, Kristin; Fireman, Bruce; Zerbo, Ousseny; Klein, Nicola P; et al.
Vaccine. 2022 Aug 19;40(35):5153-5159. Epub 2022-07-12.
Adults hospitalized with breakthrough COVID-19 have lower mortality than matched unvaccinated adults
Coronavirus disease 2019 (COVID-19) breakthrough infections are common. Evaluate in-hospital mortality of patients with COVID-19 by vaccination status using retrospective cohort study. We generated propensity scores for receipt of full vaccination in adults requiring supplemental oxygen hospitalized at Kaiser Permanente Northern California (1 April 2021 to 30 November 2021) with positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction tests. Optimal matching of fully vaccinated/unvaccinated patients was performed comparing in-hospital mortality. Of 7305 patients, 1463 (20.0%) were full, 138 (1.9%) were partial, and 5704 (78.1%) were unvaccinated. Fully vaccinated were older than partial or unvaccinated (71.0, 63.0, and 54.0 years, respectively, p < 0.001) with more comorbidities (Comorbidity Point Scores 33.0, 22.0, and 10.0, p < 0.001) and immunosuppressant (11.5%, 8.7%, and 3.0%, p < 0.001) or chemotherapy exposure (2.8%, 0.7%, and 0.4%, p < 0.001). Fewer fully vaccinated patients died compared to matched unvaccinated (9.0% vs. 16.3%, p < 0.0001). Fully vaccinated patients are less likely to die compared to matched unvaccinated patients.
Authors: Myers, Laura C; Kipnis, Patricia; Greene, John; Lawson, Brian; Escobar, Gabriel J; Fireman, Bruce H; Klein, Nicola P; Liu, Vincent X
J Intern Med. 2022 08;292(2):377-384. Epub 2022-05-17.
Effectiveness of 2, 3, and 4 COVID-19 mRNA Vaccine Doses Among Immunocompetent Adults During Periods when SARS-CoV-2 Omicron BA.1 and BA.2/BA.2.12.1 Sublineages Predominated – VISION Network, 10 States, December 2021-June 2022
The Omicron variant (B.1.1.529) of SARS-CoV-2, the virus that causes COVID-19, was first identified in the United States in November 2021, with the BA.1 sublineage (including BA.1.1) causing the largest surge in COVID-19 cases to date. Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases.* Estimates of COVID-19 vaccine effectiveness (VE) can be reduced by newly emerging variants or sublineages that evade vaccine-induced immunity (1), protection from previous SARS-CoV-2 infection in unvaccinated persons (2), or increasing time since vaccination (3). Real-world data comparing VE during the periods when the BA.1 and BA.2/BA.2.12.1 predominated (BA.1 period and BA.2/BA.2.12.1 period, respectively) are limited. The VISION network† examined 214,487 emergency department/urgent care (ED/UC) visits and 58,782 hospitalizations with a COVID-19-like illness§ diagnosis among 10 states during December 18, 2021-June 10, 2022, to evaluate VE of 2, 3, and 4 doses of mRNA COVID-19 vaccines (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) compared with no vaccination among adults without immunocompromising conditions. VE against COVID-19-associated hospitalization 7-119 days and ≥120 days after receipt of dose 3 was 92% (95% CI = 91%-93%) and 85% (95% CI = 81%-89%), respectively, during the BA.1 period, compared with 69% (95% CI = 58%-76%) and 52% (95% CI = 44%-59%), respectively, during the BA.2/BA.2.12.1 period. Patterns were similar for ED/UC encounters. Among adults aged ≥50 years, VE against COVID-19-associated hospitalization ≥120 days after receipt of dose 3 was 55% (95% CI = 46%-62%) and ≥7 days (median = 27 days) after a fourth dose was 80% (95% CI = 71%-85%) during BA.2/BA.2.12.1 predominance. Immunocompetent persons should receive recommended COVID-19 booster doses to prevent moderate to severe COVID-19, including a first booster dose for all eligible persons and second booster dose for adults aged ≥50 years at least 4 months after an initial booster dose. Booster doses should be obtained immediately when persons become eligible.¶.
Authors: Link-Gelles, Ruth; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Tenforde, Mark W; et al.
MMWR Morb Mortal Wkly Rep. 2022 Jul 22;71(29):931-939. Epub 2022-07-22.
Safety of Live-Attenuated Vaccines in Children Exposed to Biologic Response Modifiers in Utero
Authors: Zerbo, Ousseny; Klein, Nicola P; et al.
Pediatrics. 2022 07 01;150(1).
Lessons from a mature acellular pertussis vaccination program and strategies to overcome suboptimal vaccine effectiveness
Despite high vaccination coverage among children and adolescents, pertussis remains a public health problem, with large outbreaks occurring periodically in the US and other developed countries. We examine lessons learned more than 20 years after implementation of programs which use only acellular pertussis vaccines and propose avenues for possible effective use of acellular pertussis vaccine to prevent large outbreaks. Acellular pertussis vaccines were introduced more than 20 years ago, yet the incidence of pertussis has been increasing over the past decade, with periodic large outbreaks marked by notable shifts in disease burden from infants and young children toward fully vaccinated adolescents and young adults. This age shift is mainly driven by the waning of vaccine immunity. To better protect adolescents against pertussis, modification of the current acellular pertussis vaccination schedule or adoption of new vaccination strategies should be considered. For infants not yet eligible to be vaccinated, maternal vaccination against pertussis during pregnancy is an effective way to protect infants from infection, severe disease and death. Implementation of maternal vaccination programs should be encouraged in countries without one or efforts to improve coverage should be supported in countries with existing program.
Authors: Zerbo, Ousseny; Fireman, Bruce; Klein, Nicola P
Expert Rev Vaccines. 2022 07;21(7):899-907. Epub 2021-10-08.
Effect of Electronic and Mail Outreach From Primary Care Physicians for COVID-19 Vaccination of Black and Latino Older Adults: A Randomized Clinical Trial
COVID-19 morbidity is highest in Black and Latino older adults. These racial and ethnic groups initially had lower vaccination uptake than others, and rates in Black adults continue to lag. To evaluate the effect of outreach via electronic secure messages and mailings from primary care physicians (PCPs) on COVID-19 vaccination uptake among Black and Latino older adults and to compare the effects of culturally tailored and standard PCP messages. This randomized clinical trial was conducted from March 29 to May 20, 2021, with follow-up surveys through July 31, 2021. Latino and Black individuals aged 65 years and older from 4 Kaiser Permanente Northern California (KPNC) service areas were included. Data were analyzed from May 27, 2021, to September 28, 2021. Individuals who had not received COVID-19 vaccination after previous outreach were randomized to electronic secure message and/or mail outreach from their PCP, similar outreach with additional culturally tailored content, or usual care. Outreach groups were sent a secure message or letter in their PCP’s name, followed by a postcard to those still unvaccinated after 4 weeks. The primary outcome was time to receipt of COVID-19 vaccination during the 8 weeks after initial study outreach. KPNC data were supplemented with state data from external sources. Intervention effects were evaluated via proportional hazards regression. Of 8287 included individuals (mean [SD] age, 72.6 [7.0] years; 4665 [56.3%] women), 2434 (29.4%) were Black, 3782 (45.6%) were Latino and preferred English-language communications, and 2071 (25.0%) were Latino and preferred Spanish-language communications; 2847 participants (34.4%) had a neighborhood deprivation index at the 75th percentile or higher. A total of 2767 participants were randomized to culturally tailored PCP outreach, 2747 participants were randomized to standard PCP outreach, and 2773 participants were randomized to usual care. Culturally tailored PCP outreach led to higher COVID-19 vaccination rates during follow-up compared with usual care (664 participants [24.0%] vs 603 participants [21.7%]; adjusted hazard ratio (aHR), 1.22; 95% CI, 1.09-1.37), as did standard PCP outreach (635 participants [23.1%]; aHR, 1.17; 95% CI, 1.04-1.31). Individuals who were Black (aHR, 1.19; 95% CI, 1.06-1.33), had high neighborhood deprivation (aHR, 1.17; 95% CI, 1.03-1.33), and had medium to high comorbidity scores (aHR, 1.19; 95% CI, 1.09-1.31) were more likely to be vaccinated during follow-up. This randomized clinical trial found that PCP outreach using electronic and mailed messages increased COVID-19 vaccination rates among Black and Latino older adults. ClinicalTrials.gov Identifier: NCT05096026.
Authors: Lieu, Tracy A; Klein, Nicola P; Quesenberry, Charles P; Chen, Yi-Fen Irene; et al.
JAMA Netw Open. 2022 Jun 01;5(6):e2217004. Epub 2022-06-01.
Changes in incidence rates of outcomes of interest in vaccine safety studies during the COVID-19 pandemic
The COVID-19 pandemic caused an abrupt drop in in-person health care (inpatient, Emergency Department, outpatient) and an increase in telehealth care, which poses challenges in vaccine safety studies that identify outcomes from in-person encounters. We examined the changes in incidence rates of selected encounter-based outcomes during the COVID-19 pandemic. We assembled a cohort of members from 8 Vaccine Safety Datalink sites from January 1, 2017 through December 31, 2020. Using ICD-10 diagnosis codes or laboratory criteria, we identified 21 incident outcomes in traditional in-person settings and all settings. We defined 4 periods in 2020: January-February (pre-pandemic), April-June (early pandemic), July-September (middle pandemic), and October-December (late pandemic). We defined four corresponding periods in each year during 2017-2019. We calculated incidence rates, conducted difference in difference (DiD) analyses, and reported ratios of incidence rate ratios (RRR) to examine changes in rates from pre-pandemic to early, middle, and late pandemic in 2020, after adjusting for changes across similar periods in 2017-2019. Among > 10 million members, regardless of setting and after adjusting for changes during 2017-2019, we found that incidence rates of acute disseminated encephalomyelitis, encephalitis/myelitis/encephalomyelitis/meningoencephalitis, and thrombotic thrombocytopenic purpura did not significantly change from the pre-pandemic to early, middle or late pandemic periods (p-values ≥ 0.05). Incidence rates decreased from the pre-pandemic to early pandemic period during 2020 for acute myocardial infarction, anaphylaxis, appendicitis, Bell’s palsy, convulsions/seizures, Guillain-Barré syndrome, immune thrombocytopenia (ITP), narcolepsy/cataplexy, hemorrhagic stroke, ischemic stroke, and venous thromboembolism (p-values < 0.05). Incidence rates of Bell's palsy, ITP, and narcolepsy/cataplexy were higher in all settings than in traditional in-person settings during the three pandemic periods (p-values < 0.05). Rates of some clinical outcomes during the pandemic changed and should not be used as historical background rates in vaccine safety studies. Inclusion of telehealth visits should be considered for vaccine studies involving Bell's palsy, ITP, and narcolepsy/cataplexy.
Authors: Xu, Stanley; Zerbo, Ousseny; Qian, Lei; et al.
Vaccine. 2022 05 20;40(23):3150-3158. Epub 2022-04-18.
Safety and Efficacy of a Third Dose of BNT162b2 Covid-19 Vaccine
Active immunization with the BNT162b2 vaccine (Pfizer-BioNTech) has been a critical mitigation tool against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (Covid-19) pandemic. In light of reports of waning protection occurring 6 months after the primary two-dose vaccine series, data are needed on the safety and efficacy of offering a third (booster) dose in persons 16 years of age or older. In this ongoing, placebo-controlled, randomized, phase 3 trial, we assigned participants who had received two 30-μg doses of the BNT162b2 vaccine at least 6 months earlier to be injected with a third dose of the BNT162b2 vaccine or with placebo. We assessed vaccine safety and efficacy against Covid-19 starting 7 days after the third dose. A total of 5081 participants received a third BNT162b2 dose and 5044 received placebo. The median interval between dose 2 and dose 3 was 10.8 months in the vaccine group and 10.7 months in the placebo group; the median follow-up was 2.5 months. Local and systemic reactogenicity events from the third dose were generally of low grade. No new safety signals were identified, and no cases of myocarditis or pericarditis were reported. Among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated, Covid-19 with onset at least 7 days after dose 3 was observed in 6 participants in the vaccine group and in 123 participants in the placebo group, which corresponded to a relative vaccine efficacy of 95.3% (95% confidence interval, 89.5 to 98.3). A third dose of the BNT162b2 vaccine administered a median of 10.8 months after the second dose provided 95.3% efficacy against Covid-19 as compared with two doses of the BNT162b2 vaccine during a median follow-up of 2.5 months. (Funded by BioNTech and Pfizer; C4591031 ClinicalTrials.gov number, NCT04955626.).
Authors: Moreira, Edson D; Klein, Nicola P; C4591031 Clinical Trial Group,; et al.
N Engl J Med. 2022 05 19;386(20):1910-1921. Epub 2022-03-23.
Incidence of Guillain-Barré Syndrome After COVID-19 Vaccination in the Vaccine Safety Datalink
Postauthorization monitoring of vaccines in a large population may detect rare adverse events not identified in clinical trials such as Guillain-Barré syndrome (GBS), which has a background rate of 1 to 2 per 100 000 person-years. To describe cases and incidence of GBS following COVID-19 vaccination and assess the risk of GBS after vaccination for Ad.26.COV2.S (Janssen) and mRNA vaccines. This cohort study used surveillance data from the Vaccine Safety Datalink at 8 participating integrated health care systems in the United States. There were 10 158 003 participants aged at least 12 years. Data analysis was performed from November 2021 to February 2022. Ad.26.COV2.S, BNT162b2 (Pfizer-BioNTech), or mRNA-1273 (Moderna) COVID-19 vaccine, including mRNA vaccine doses 1 and 2, December 13, 2020, to November 13, 2021. GBS with symptom onset in the 1 to 84 days after vaccination, confirmed by medical record review and adjudication. Descriptive characteristics of confirmed cases, GBS incidence rates during postvaccination risk intervals after each type of vaccine compared with the background rate, rate ratios (RRs) comparing GBS incidence in the 1 to 21 vs 22 to 42 days postvaccination, and RRs directly comparing risk of GBS after Ad.26.COV2.S vs mRNA vaccination, using Poisson regression adjusted for age, sex, race and ethnicity, site, and calendar day. From December 13, 2020, through November 13, 2021, 15 120 073 doses of COVID-19 vaccines were administered to 7 894 989 individuals (mean [SE] age, 46.5 [0.02] years; 8 138 318 doses received [53.8%] by female individuals; 3 671 199 doses received [24.3%] by Hispanic or Latino individuals, 2 215 064 doses received [14.7%] by Asian individuals, 6 266 424 doses received [41.4%] by White individuals), including 483 053 Ad.26.COV2.S doses, 8 806 595 BNT162b2 doses, and 5 830 425 mRNA-1273 doses. Eleven cases of GBS after Ad.26.COV2.S were confirmed. The unadjusted incidence rate of GBS per 100 000 person-years in the 1 to 21 days after Ad.26.COV2.S was 32.4 (95% CI, 14.8-61.5), significantly higher than the background rate, and the adjusted RR in the 1 to 21 vs 22 to 42 days following Ad.26.COV2.S was 6.03 (95% CI, 0.79-147.79). Thirty-six cases of GBS after mRNA vaccines were confirmed. The unadjusted incidence rate per 100 000 person-years in the 1 to 21 days after mRNA vaccines was 1.3 (95% CI, 0.7-2.4) and the adjusted RR in the 1 to 21 vs 22 to 42 days following mRNA vaccines was 0.56 (95% CI, 0.21-1.48). In a head-to-head comparison of Ad.26.COV2.S vs mRNA vaccines, the adjusted RR was 20.56 (95% CI, 6.94-64.66). In this cohort study of COVID-19 vaccines, the incidence of GBS was elevated after receiving the Ad.26.COV2.S vaccine. Surveillance is ongoing.
Authors: Hanson, Kayla E; Fireman, Bruce; Klein, Nicola P; et al.
JAMA Netw Open. 2022 Apr 01;5(4):e228879. Epub 2022-04-01.
Effectiveness of Homologous and Heterologous COVID-19 Booster Doses Following 1 Ad.26.COV2.S (Janssen [Johnson & Johnson]) Vaccine Dose Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults – VISION Network, 10 States, December 2021-March 2022
CDC recommends that all persons aged ≥18 years receive a single COVID-19 vaccine booster dose ≥2 months after receipt of an Ad.26.COV2.S (Janssen [Johnson & Johnson]) adenovirus vector-based primary series vaccine; a heterologous COVID-19 mRNA vaccine is preferred over a homologous (matching) Janssen vaccine for booster vaccination. This recommendation was made in light of the risks for rare but serious adverse events following receipt of a Janssen vaccine, including thrombosis with thrombocytopenia syndrome and Guillain-Barré syndrome† (1), and clinical trial data indicating similar or higher neutralizing antibody response following heterologous boosting compared with homologous boosting (2). Data on real-world vaccine effectiveness (VE) of different booster strategies following a primary Janssen vaccine dose are limited, particularly during the period of Omicron variant predominance. The VISION Network§ determined real-world VE of 1 Janssen vaccine dose and 2 alternative booster dose strategies: 1) a homologous booster (i.e., 2 Janssen doses) and 2) a heterologous mRNA booster (i.e., 1 Janssen dose/1 mRNA dose). In addition, VE of these booster strategies was compared with VE of a homologous booster following mRNA primary series vaccination (i.e., 3 mRNA doses). The study examined 80,287 emergency department/urgent care (ED/UC) visits¶ and 25,244 hospitalizations across 10 states during December 16, 2021-March 7, 2022, when Omicron was the predominant circulating variant.** VE against laboratory-confirmed COVID-19-associated ED/UC encounters was 24% after 1 Janssen dose, 54% after 2 Janssen doses, 79% after 1 Janssen/1 mRNA dose, and 83% after 3 mRNA doses. VE for the same vaccination strategies against laboratory-confirmed COVID-19-associated hospitalizations were 31%, 67%, 78%, and 90%, respectively. All booster strategies provided higher protection than a single Janssen dose against ED/UC visits and hospitalizations during Omicron variant predominance. Vaccination with 1 Janssen/1 mRNA dose provided higher protection than did 2 Janssen doses against COVID-19-associated ED/UC visits and was comparable to protection provided by 3 mRNA doses during the first 120 days after a booster dose. However, 3 mRNA doses provided higher protection against COVID-19-associated hospitalizations than did other booster strategies during the same time interval since booster dose. All adults who have received mRNA vaccines for their COVID-19 primary series vaccination should receive an mRNA booster dose when eligible. Adults who received a primary Janssen vaccine dose should preferentially receive a heterologous mRNA vaccine booster dose ≥2 months later, or a homologous Janssen vaccine booster dose if mRNA vaccine is contraindicated or unavailable. Further investigation of the durability of protection afforded by different booster strategies is warranted.
Authors: Natarajan, Karthik; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Dixon, Brian E; et al.
MMWR Morb Mortal Wkly Rep. 2022 Apr 01;71(13):495-502. Epub 2022-04-01.
Effectiveness of COVID-19 Pfizer-BioNTech BNT162b2 mRNA Vaccination in Preventing COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Nonimmunocompromised Children and Adolescents Aged 5-17 Years – VISION Network, 10 States, April 2021-January 2022
The efficacy of the BNT162b2 (Pfizer-BioNTech) vaccine against laboratory-confirmed COVID-19 exceeded 90% in clinical trials that included children and adolescents aged 5-11, 12-15, and 16-17 years (1-3). Limited real-world data on 2-dose mRNA vaccine effectiveness (VE) in persons aged 12-17 years (referred to as adolescents in this report) have also indicated high levels of protection against SARS-CoV-2 (the virus that causes COVID-19) infection and COVID-19-associated hospitalization (4-6); however, data on VE against the SARS-CoV-2 B.1.1.529 (Omicron) variant and duration of protection are limited. Pfizer-BioNTech VE data are not available for children aged 5-11 years. In partnership with CDC, the VISION Network* examined 39,217 emergency department (ED) and urgent care (UC) encounters and 1,699 hospitalizations† among persons aged 5-17 years with COVID-19-like illness across 10 states during April 9, 2021-January 29, 2022,§ to estimate VE using a case-control test-negative design. Among children aged 5-11 years, VE against laboratory-confirmed COVID-19-associated ED and UC encounters 14-67 days after dose 2 (the longest interval after dose 2 in this age group) was 46%. Among adolescents aged 12-15 and 16-17 years, VE 14-149 days after dose 2 was 83% and 76%, respectively; VE ≥150 days after dose 2 was 38% and 46%, respectively. Among adolescents aged 16-17 years, VE increased to 86% ≥7 days after dose 3 (booster dose). VE against COVID-19-associated ED and UC encounters was substantially lower during the Omicron predominant period than the B.1.617.2 (Delta) predominant period among adolescents aged 12-17 years, with no significant protection ≥150 days after dose 2 during Omicron predominance. However, in adolescents aged 16-17 years, VE during the Omicron predominant period increased to 81% ≥7 days after a third booster dose. During the full study period, including pre-Delta, Delta, and Omicron predominant periods, VE against laboratory-confirmed COVID-19-associated hospitalization among children aged 5-11 years was 74% 14-67 days after dose 2, with wide CIs that included zero. Among adolescents aged 12-15 and 16-17 years, VE 14-149 days after dose 2 was 92% and 94%, respectively; VE ≥150 days after dose 2 was 73% and 88%, respectively. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations, including a booster dose for those aged 12-17 years.
Authors: Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Verani, Jennifer R; et al.
MMWR Morb Mortal Wkly Rep. 2022 Mar 04;71(9):352-358. Epub 2022-03-04.
Incidence and Estimated Vaccine Effectiveness Against Hospitalizations for All-Cause Pneumonia Among Older US Adults Who Were Vaccinated and Not Vaccinated With 13-Valent Pneumococcal Conjugate Vaccine
Following routine use of 13-valent pneumococcal conjugate vaccine (PCV13) in children in 2010, invasive pneumococcal disease rates have decreased substantially in children and adults. In 2014, the Advisory Committee for Immunization Practices recommended routine use of PCV13 among adults aged 65 years or older; previously only 23-valent pneumococcal polysaccharide vaccine (PPV23) was recommended. To estimate the association between the incidence of hospitalized all-cause pneumonia and lower respiratory tract infections (LRTI) and PCV13 vaccination among older adults at Kaiser Permanente Northern California (KPNC). This retrospective cohort study included adults at KPNC aged 65 years or older between July 1, 2015, and June 30, 2018, born after 1936 with no known history of PPV23 or PCV13 receipt before age 65. The study took place at an integrated health care system with an annual membership more than 4 million individuals, approximately 15% of whom are 65 years or older and broadly representative of the region. Data analysis took place from July 2018 to December 2021, and data collection took place from November 2016 to June 2018. PCV13 vaccination status was ascertained from the electronic medical record (EMR). Individuals were considered vaccinated 14 days following immunization. First hospitalized all-cause pneumonia was identified in the EMR using primary/secondary discharge diagnosis International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. First hospitalized LRTI was identified using pneumonia codes and acute bronchitis codes. Relative risk (RR) of first pneumonia or LRTI hospitalization of individuals who were PCV13 vaccinated vs PCV13 unvaccinated was estimated using Poisson regressions adjusted for sex, race, ethnicity, age, influenza vaccine receipt, PPV23 receipt since age 65, pneumonia risk factors, health care use, and season. Vaccine effectiveness (VE) was estimated as (1-RR) × 100%. Of 192 061 adults, 107 957 (56%) were female and 139 024 (72%) were White individuals. PCV13 coverage increased from 0 in 2014 to 135 608 (76.9%) by 2018. There were 3488 individuals with 3766 pneumonia hospitalizations and 3846 individuals with 4173 LRTI hospitalizations. PCV13 was associated with an adjusted VE of 10.0% (95% CI, 2.4-17.0; P = .01) against hospitalized pneumonia and 9.4% (95% CI, 2.1-16.1; P = .01) against hospitalized LRTI. In the context of a robust pediatric PCV13 immunization program, PCV13 vaccination of adults aged 65 years or older was associated with significant reductions in hospitalizations for all-cause pneumonia and LRTI. Vaccinating older adults with PCVs may provide broader public health benefit against pneumonia hospitalizations.
Authors: Hsiao, Amber; Hansen, John; Timbol, Julius; Lewis, Ned; Isturiz, Raul; Alexander-Parrish, Ronika; McLaughlin, John M; Gessner, Bradford D; Klein, Nicola P
JAMA Netw Open. 2022 03 01;5(3):e221111. Epub 2022-03-01.
A decade of data: Adolescent vaccination in the vaccine safety datalink, 2007 through 2016
Between May 2005 and March 2007, three vaccines were recommended by the Advisory Committee on Immunization Practices for routine use in adolescents in the United States: quadrivalent meningococcal conjugate vaccine (MenACWY), tetanus, diphtheria and acellular pertussis vaccine (Tdap), and human papillomavirus vaccine (HPV). Understanding historical adolescent vaccination patterns may inform future vaccination coverage efforts for these and emerging adolescent vaccines, including COVID-19 vaccines. This was a descriptive, retrospective cohort study. All vaccines administered to adolescents aged 11 through 18 years in the Vaccine Safety Datalink population between January 1, 2007 and December 31, 2016 were examined. Vaccination coverage was assessed by study year for ≥1 dose Tdap or Td, ≥1 dose Tdap, ≥1 dose MenACWY, ≥1 dose HPV, and ≥3 dose HPV. The proportion of vaccine visits with concurrent vaccination (≥2 vaccines administered at the same visit) was calculated by sex and study year. The most common vaccine combinations administered in the study population were described by sex for two time periods: 2007-2010 and 2011-2016. The number of 11-18-year-olds in the study population averaged 522,565 males and 503,112 females per study year. Between January 2007 and December 2016 there were 4,884,553 vaccine visits in this population (45% among males). The overall proportion of concurrent vaccine visits among males was 43% (33-61% by study year). Among females, 39% of all vaccine visits included concurrent vaccination (32-48% by study year). Vaccine coverage for Tdap, MenACWY, and 1- and 3-dose HPV increased across the study period. A wide variety of vaccine combinations were administered among both sexes and in both time periods. The high vaccine uptake and multitude of vaccine combinations administered concurrently in the adolescent population of the Vaccine Safety Datalink provide historical patterns with which to compare future adolescent vaccination campaigns.
Authors: Irving, Stephanie A; Klein, Nicola P; Stokley, Shannon; et al.
Vaccine. 2022 02 23;40(9):1246-1252. Epub 2022-02-04.
Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance – VISION Network, 10 States, August 2021-January 2022
CDC recommends that all persons aged ≥12 years receive a booster dose of COVID-19 mRNA vaccine ≥5 months after completion of a primary mRNA vaccination series and that immunocompromised persons receive a third primary dose.* Waning of vaccine protection after 2 doses of mRNA vaccine has been observed during the period of the SARS-CoV-2 B.1.617.2 (Delta) variant predominance† (1-5), but little is known about durability of protection after 3 doses during periods of Delta or SARS-CoV-2 B.1.1.529 (Omicron) variant predominance. A test-negative case-control study design using data from eight VISION Network sites§ examined vaccine effectiveness (VE) against COVID-19 emergency department/urgent care (ED/UC) visits and hospitalizations among U.S. adults aged ≥18 years at various time points after receipt of a second or third vaccine dose during two periods: Delta variant predominance and Omicron variant predominance (i.e., periods when each variant accounted for ≥50% of sequenced isolates).¶ Persons categorized as having received 3 doses included those who received a third dose in a primary series or a booster dose after a 2 dose primary series (including the reduced-dosage Moderna booster). The VISION Network analyzed 241,204 ED/UC encounters** and 93,408 hospitalizations across 10 states during August 26, 2021-January 22, 2022. VE after receipt of both 2 and 3 doses was lower during the Omicron-predominant than during the Delta-predominant period at all time points evaluated. During both periods, VE after receipt of a third dose was higher than that after a second dose; however, VE waned with increasing time since vaccination. During the Omicron period, VE against ED/UC visits was 87% during the first 2 months after a third dose and decreased to 66% among those vaccinated 4-5 months earlier; VE against hospitalizations was 91% during the first 2 months following a third dose and decreased to 78% ≥4 months after a third dose. For both Delta- and Omicron-predominant periods, VE was generally higher for protection against hospitalizations than against ED/UC visits. All eligible persons should remain up to date with recommended COVID-19 vaccinations to best protect against COVID-19-associated hospitalizations and ED/UC visits.
Authors: Ferdinands, Jill M; Klein, Nicola P; Zerbo, Ousseny; Fireman, Bruce; et al.
MMWR Morb Mortal Wkly Rep. 2022 Feb 18;71(7):255-263. Epub 2022-02-18.
Safety of recombinant quadrivalent influenza vaccine compared to inactivated influenza vaccine in Chinese adults: An observational study
Recombinant influenza vaccine (RIV) has been in use in US adults since 2013. This study evaluated the safety of quadrivalent recombinant influenza vaccine (RIV4, Flublok® Quadrivalent, Sanofi Pasteur) compared with standard-dose quadrivalent inactivated influenza vaccine (SD-IIV4) in self-identified Chinese adults at Kaiser Permanente Northern California (KPNC). This study evaluated adults aged 18-64 years within KPNC during the 2018-2019 influenza season who self-identified as Chinese (NCT03694392). We compared the rates of prespecified diagnoses of interest in the emergency department and inpatient settings as done in prior influenza studies, for three risk intervals: 0-2 days, 0-13 days, and 0-41 days following influenza vaccination, as well as number of deaths within 0-180 days after vaccination. We estimated the odds ratios (ORs) and 95% confidence intervals using logistic regression adjusted for sex, age group, presence of comorbidities, and same-day concomitant vaccination. Comparing 15,574 adults who received RIV4 with 27,110 who received SD-IIV4, there was no statistically significant difference in the prespecified diagnoses of interest and deaths between the 2 groups. There were 35 deaths total, none of which were considered to be related to influenza vaccination. This study did not identify any safety concerns regarding RIV4 use among 18-64-year-olds who self-identified as Chinese. This study supports the safety of RIV4 vaccine in this population.
Authors: Hsiao, Amber; Hansen, John; Nunley, Karen Valdez; Lewis, Ned; Selmani, Alex; Inamdar, Ajinkya; Mallett-Moore, Tamala; Izikson, Ruvim; Rudin, Deborah; Klein, Nicola P
Vaccine. 2022 01 31;40(5):774-779. Epub 2022-01-06.
Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance – VISION Network, 10 States, August 2021-January 2022
Estimates of COVID-19 mRNA vaccine effectiveness (VE) have declined in recent months (1,2) because of waning vaccine induced immunity over time,* possible increased immune evasion by SARS-CoV-2 variants (3), or a combination of these and other factors. CDC recommends that all persons aged ≥12 years receive a third dose (booster) of an mRNA vaccine ≥5 months after receipt of the second mRNA vaccine dose and that immunocompromised individuals receive a third primary dose.† A third dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine increases neutralizing antibody levels (4), and three recent studies from Israel have shown improved effectiveness of a third dose in preventing COVID-19 associated with infections with the SARS-CoV-2 B.1.617.2 (Delta) variant (5-7). Yet, data are limited on the real-world effectiveness of third doses of COVID-19 mRNA vaccine in the United States, especially since the SARS-CoV-2 B.1.1.529 (Omicron) variant became predominant in mid-December 2021. The VISION Network§ examined VE by analyzing 222,772 encounters from 383 emergency departments (EDs) and urgent care (UC) clinics and 87,904 hospitalizations from 259 hospitals among adults aged ≥18 years across 10 states from August 26, 2021¶ to January 5, 2022. Analyses were stratified by the period before and after the Omicron variant became the predominant strain (>50% of sequenced viruses) at each study site. During the period of Delta predominance across study sites in the United States (August-mid-December 2021), VE against laboratory-confirmed COVID-19-associated ED and UC encounters was 86% 14-179 days after dose 2, 76% ≥180 days after dose 2, and 94% ≥14 days after dose 3. Estimates of VE for the same intervals after vaccination during Omicron variant predominance were 52%, 38%, and 82%, respectively. During the period of Delta variant predominance, VE against laboratory-confirmed COVID-19-associated hospitalizations was 90% 14-179 days after dose 2, 81% ≥180 days after dose 2, and 94% ≥14 days after dose 3. During Omicron variant predominance, VE estimates for the same intervals after vaccination were 81%, 57%, and 90%, respectively. The highest estimates of VE against COVID-19-associated ED and UC encounters or hospitalizations during both Delta- and Omicron-predominant periods were among adults who received a third dose of mRNA vaccine. All unvaccinated persons should get vaccinated as soon as possible. All adults who have received mRNA vaccines during their primary COVID-19 vaccination series should receive a third dose when eligible, and eligible persons should stay up to date with COVID-19 vaccinations.
Authors: Thompson, Mark G; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Ong, Toan C; et al.
MMWR Morb Mortal Wkly Rep. 2022 Jan 21;71(4):139-145. Epub 2022-01-21.
Effectiveness of two-dose vaccination with mRNA COVID-19 vaccines against COVID-19-associated hospitalizations among immunocompromised adults-Nine States, January-September 2021
Authors: Embi, Peter J; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; DeSilva, Malini B; et al.
Am J Transplant. 2022 01;22(1):306-314.
Association of the COVID-19 Pandemic With Routine Childhood Vaccination Rates and Proportion Up to Date With Vaccinations Across 8 US Health Systems in the Vaccine Safety Datalink
The COVID-19 pandemic has affected routine vaccine delivery in the US and globally. The magnitude of these disruptions and their association with childhood vaccination coverage are unclear. To compare trends in pediatric vaccination before and during the pandemic and to evaluate the proportion of children up to date (UTD) with vaccinations by age, race, and ethnicity. This surveillance study used a prepandemic-postpandemic control design with data from 8 health systems in California, Oregon, Washington, Colorado, Minnesota, and Wisconsin in the Vaccine Safety Datalink. Children from age groups younger than 24 months and 4 to 6, 11 to 13, and 16 to 18 years were included if they had at least 1 week of health system enrollment from January 5, 2020, through October 3, 2020, over periods before the US COVID-19 pandemic (January 5, 2020, through March 14, 2020), during age-limited preventive care (March 15, 2020, through May 16, 2020), and during expanded primary care (May 17, 2020, through October 3, 2020). These individuals were compared with those enrolled during analogous weeks in 2019. This study evaluated UTD status among children reaching specific ages in February, May, and September 2020, compared with those reaching these ages in 2019. Weekly vaccination rates for routine age-specific vaccines and the proportion of children UTD for all age-specific recommended vaccines. Of 1 399 708 children in 2019 and 1 402 227 in 2020, 1 371 718 were female (49.0%) and 1 429 979 were male (51.0%); 334 216 Asian individuals (11.9%), 900 226 were Hispanic individuals (32.1%), and 201 619 non-Hispanic Black individuals (7.2%). Compared with the prepandemic period and 2019, the age-limited preventive care period was associated with lower weekly vaccination rates, with ratios of rate ratios of 0.82 (95% CI, 0.80-0.85) among those younger than 24 months, 0.18 (95% CI, 0.16-0.20) among those aged 4 to 6 years, 0.16 (95% CI, 0.14-0.17) among those aged 11 to 13 years, and 0.10 (95% CI, 0.08-0.13) among those aged 16 to 18 years. Vaccination rates during expanded primary care remained lower for most ages (ratios of rate ratios: <24 months, 0.96 [95% CI, 0.93-0.98]; 11-13 years, 0.81 [95% CI, 0.76-0.86]; 16-18 years, 0.57 [95% CI, 0.51-0.63]). In September 2020, 74% (95% CI, 73%-76%) of infants aged 7 months and 57% (95% CI, 56%-58%) of infants aged 18 months were UTD vs 81% (95% CI, 80%-82%) and 61% (95% CI, 60%-62%), respectively, in September 2019. The proportion UTD was lowest in non-Hispanic Black children across most age groups, both during and prior to the COVID-19 pandemic (eg, in May 2019, 70% [95% CI, 64%-75%] of non-Hispanic Black infants aged 7 months were UTD vs 82% [95% CI, 81%-83%] in all infants aged 7 months combined). As of September 2020, childhood vaccination rates and the proportion who were UTD remained lower than 2019 levels. Interventions are needed to promote catch-up vaccination, particularly in populations at risk for underimmunization.
Authors: DeSilva, Malini B; Klein, Nicola P; Kharbanda, Elyse O; et al.
JAMA Pediatr. 2022 01 01;176(1):68-77.
A multi-country investigation of influenza vaccine coverage in pregnant individuals, 2010-2016
Many countries recommend influenza vaccination during pregnancy. Despite this recommendation, influenza vaccine among pregnant individuals remains under-utilized and uptake varies by country. Factors associated with influenza vaccine uptake during pregnancy may also vary across countries. As members of the Pregnancy Influenza Vaccine Effectiveness Network (PREVENT), five sites from four countries (Australia, Canada, Israel, and the United States) retrospectively identified cohorts of individuals aged 18-50 years who were pregnant during pre-defined influenza seasons. Influenza vaccine coverage estimates were calculated for the 2010-11 through 2015-16 northern hemisphere and the 2012 through 2015 southern hemisphere influenza seasons, by site. Sites used electronic health records, administrative data, and immunization registries to collect information on pregnancy, health history, demographics, and vaccination status. Each season, vaccination coverage was calculated as the percentage of individuals who received influenza vaccine among the individuals in the cohort that season. Characteristics were compared between those vaccinated and unvaccinated, by site. More than two million pregnancies were identified over the study period. Influenza vaccination coverage ranged from 5% to 58% across sites and seasons. Coverage increased consistently over the study period at three of the five sites (Western Australia, Alberta, and Israel), and was highest in all seasons at the United States study site (39-58%). Associations with vaccination varied by country and across seasons; where available, parity >0, presence of a high-risk medical condition, and urban residence were consistently associated with increased likelihood of vaccination. Though increasing, uptake of influenza vaccine among pregnant individuals remains lower than recommended. Coverage varied substantially by country, suggesting an ongoing need for targeted strategies to improve influenza vaccine uptake in this population.
Authors: Irving, Stephanie A; Klein, Nicola P; PREVENT study team,; et al.
Vaccine. 2021 12 20;39(52):7598-7605. Epub 2021-11-19.
Laboratory-Confirmed COVID-19 Among Adults Hospitalized with COVID-19-Like Illness with Infection-Induced or mRNA Vaccine-Induced SARS-CoV-2 Immunity – Nine States, January-September 2021
Previous infection with SARS-CoV-2 (the virus that causes COVID-19) or COVID-19 vaccination can provide immunity and protection from subsequent SARS-CoV-2 infection and illness. CDC used data from the VISION Network* to examine hospitalizations in adults with COVID-19-like illness and compared the odds of receiving a positive SARS-CoV-2 test result, and thus having laboratory-confirmed COVID-19, between unvaccinated patients with a previous SARS-CoV-2 infection occurring 90-179 days before COVID-19-like illness hospitalization, and patients who were fully vaccinated with an mRNA COVID-19 vaccine 90-179 days before hospitalization with no previous documented SARS-CoV-2 infection. Hospitalized adults aged ≥18 years with COVID-19-like illness were included if they had received testing at least twice: once associated with a COVID-19-like illness hospitalization during January-September 2021 and at least once earlier (since February 1, 2020, and ≥14 days before that hospitalization). Among COVID-19-like illness hospitalizations in persons whose previous infection or vaccination occurred 90-179 days earlier, the odds of laboratory-confirmed COVID-19 (adjusted for sociodemographic and health characteristics) among unvaccinated, previously infected adults were higher than the odds among fully vaccinated recipients of an mRNA COVID-19 vaccine with no previous documented infection (adjusted odds ratio [aOR] = 5.49; 95% confidence interval [CI] = 2.75-10.99). These findings suggest that among hospitalized adults with COVID-19-like illness whose previous infection or vaccination occurred 90-179 days earlier, vaccine-induced immunity was more protective than infection-induced immunity against laboratory-confirmed COVID-19. All eligible persons should be vaccinated against COVID-19 as soon as possible, including unvaccinated persons previously infected with SARS-CoV-2.
Authors: Bozio, Catherine H; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Stenehjem, Edward; et al.
MMWR Morb Mortal Wkly Rep. 2021 Nov 05;70(44):1539-1544. Epub 2021-11-05.
Effectiveness of 2-Dose Vaccination with mRNA COVID-19 Vaccines Against COVID-19-Associated Hospitalizations Among Immunocompromised Adults – Nine States, January-September 2021
Immunocompromised persons, defined as those with suppressed humoral or cellular immunity resulting from health conditions or medications, account for approximately 3% of the U.S. adult population (1). Immunocompromised adults are at increased risk for severe COVID-19 outcomes (2) and might not acquire the same level of protection from COVID-19 mRNA vaccines as do immunocompetent adults (3,4). To evaluate vaccine effectiveness (VE) among immunocompromised adults, data from the VISION Network* on hospitalizations among persons aged ≥18 years with COVID-19-like illness from 187 hospitals in nine states during January 17-September 5, 2021 were analyzed. Using selected discharge diagnoses,† VE against COVID-19-associated hospitalization conferred by completing a 2-dose series of an mRNA COVID-19 vaccine ≥14 days before the index hospitalization date§ (i.e., being fully vaccinated) was evaluated using a test-negative design comparing 20,101 immunocompromised adults (10,564 [53%] of whom were fully vaccinated) and 69,116 immunocompetent adults (29,456 [43%] of whom were fully vaccinated). VE of 2 doses of mRNA COVID-19 vaccine against COVID-19-associated hospitalization was lower among immunocompromised patients (77%; 95% confidence interval [CI] = 74%-80%) than among immunocompetent patients (90%; 95% CI = 89%-91%). This difference persisted irrespective of mRNA vaccine product, age group, and timing of hospitalization relative to SARS-CoV-2 (the virus that causes COVID-19) B.1.617.2 (Delta) variant predominance in the state of hospitalization. VE varied across immunocompromising condition subgroups, ranging from 59% (organ or stem cell transplant recipients) to 81% (persons with a rheumatologic or inflammatory disorder). Immunocompromised persons benefit from mRNA COVID-19 vaccination but are less protected from severe COVID-19 outcomes than are immunocompetent persons, and VE varies among immunocompromised subgroups. Immunocompromised persons receiving mRNA COVID-19 vaccines should receive 3 doses and a booster, consistent with CDC recommendations (5), practice nonpharmaceutical interventions, and, if infected, be monitored closely and considered early for proven therapies that can prevent severe outcomes.
Authors: Embi, Peter J; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; DeSilva, Malini B; et al.
MMWR Morb Mortal Wkly Rep. 2021 Nov 05;70(44):1553-1559. Epub 2021-11-05.
The Adjuvanted Recombinant Zoster Vaccine in Adults Aged ≥65 Years Previously Vaccinated With a Live-Attenuated Herpes Zoster Vaccine
Efficacy of the live-attenuated herpes zoster (HZ) vaccine (ZVL) wanes substantially over time. We evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) in previous ZVL recipients. Adults aged ≥65 years who were previously vaccinated with ZVL ≥5 years earlier (n = 215) were group-matched with ZVL-naive individuals (n = 215) and vaccinated with RZV. Glycoprotein E (gE)-specific humoral and cell-mediated immune responses and the correlation between them, polyfunctional gE-specific CD4 T-cell responses, safety, and confirmed HZ cases were assessed. Through 12 months after dose 2, anti-gE antibody concentrations, gE-specific CD4 T-cell frequencies, and activation marker profiles were similar between groups. Safety outcomes were also similar. No HZ episodes were confirmed. RZV induced strong humoral and polyfunctional cell-mediated immune responses that persisted above prevaccination levels through 1 year after dose 2 in adults aged ≥65 years irrespective of previous ZVL vaccination. The RZV safety profile was not affected. NCT02581410.
Authors: Dagnew AF; Klein NP; Hervé C; Kalema G; Di Paolo E; Peterson J; Salaun B; Schuind A
J Infect Dis. 2021 10 13;224(7):1139-1146.
Effectiveness of Covid-19 Vaccines in Ambulatory and Inpatient Care Settings
There are limited data on the effectiveness of the vaccines against symptomatic coronavirus disease 2019 (Covid-19) currently authorized in the United States with respect to hospitalization, admission to an intensive care unit (ICU), or ambulatory care in an emergency department or urgent care clinic. We conducted a study involving adults (≥50 years of age) with Covid-19-like illness who underwent molecular testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We assessed 41,552 admissions to 187 hospitals and 21,522 visits to 221 emergency departments or urgent care clinics during the period from January 1 through June 22, 2021, in multiple states. The patients’ vaccination status was documented in electronic health records and immunization registries. We used a test-negative design to estimate vaccine effectiveness by comparing the odds of a positive test for SARS-CoV-2 infection among vaccinated patients with those among unvaccinated patients. Vaccine effectiveness was adjusted with weights based on propensity-for-vaccination scores and according to age, geographic region, calendar time (days from January 1, 2021, to the index date for each medical visit), and local virus circulation. The effectiveness of full messenger RNA (mRNA) vaccination (≥14 days after the second dose) was 89% (95% confidence interval [CI], 87 to 91) against laboratory-confirmed SARS-CoV-2 infection leading to hospitalization, 90% (95% CI, 86 to 93) against infection leading to an ICU admission, and 91% (95% CI, 89 to 93) against infection leading to an emergency department or urgent care clinic visit. The effectiveness of full vaccination with respect to a Covid-19-associated hospitalization or emergency department or urgent care clinic visit was similar with the BNT162b2 and mRNA-1273 vaccines and ranged from 81% to 95% among adults 85 years of age or older, persons with chronic medical conditions, and Black or Hispanic adults. The effectiveness of the Ad26.COV2.S vaccine was 68% (95% CI, 50 to 79) against laboratory-confirmed SARS-CoV-2 infection leading to hospitalization and 73% (95% CI, 59 to 82) against infection leading to an emergency department or urgent care clinic visit. Covid-19 vaccines in the United States were highly effective against SARS-CoV-2 infection requiring hospitalization, ICU admission, or an emergency department or urgent care clinic visit. This vaccine effectiveness extended to populations that are disproportionately affected by SARS-CoV-2 infection. (Funded by the Centers for Disease Control and Prevention.).
Authors: Thompson, Mark G; Fireman, Bruce; Zerbo, Ousseny; Klein, Nicola P; et al.
N Engl J Med. 2021 10 07;385(15):1355-1371. Epub 2021-09-08.
Interim Estimates of COVID-19 Vaccine Effectiveness Against COVID-19-Associated Emergency Department or Urgent Care Clinic Encounters and Hospitalizations Among Adults During SARS-CoV-2 B.1.617.2 (Delta) Variant Predominance – Nine States, June-August 2021
Data on COVID-19 vaccine effectiveness (VE) since the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, became the predominant circulating strain in the United States are limited (1-3). CDC used the VISION Network* to examine medical encounters (32,867) from 187 hospitals and 221 emergency departments (EDs) and urgent care (UC) clinics across nine states during June-August 2021, beginning on the date the Delta variant accounted for >50% of sequenced isolates in each medical facility’s state. VISION Network methods have been published (4).
Authors: Grannis, Shaun J; Rowley, Elizabeth A; Ong, Toan C; Stenehjem, Edward; Klein, Nicola P; DeSilva, Malini B; Naleway, Allison L; Natarajan, Karthik; Thompson, Mark G; VISION Network,
MMWR Morb Mortal Wkly Rep. 2021 Sep 17;70(37):1291-1293. Epub 2021-09-17.
A phase 3, randomized, double-blind study to evaluate the immunogenicity and safety of 3 lots of 20-valent pneumococcal conjugate vaccine in pneumococcal vaccine-naive adults 18 through 49 years of age
Introduction of pneumococcal conjugate vaccines (PCVs), including the 13-valent PCV (PCV13), has considerably reduced pneumococcal disease burden. However, additional serotypes not in PCV13 continue to present a substantial disease burden. The 20-valent PCV (PCV20) was developed to expand protection against pneumococcal disease beyond PCV13. As part of the phase 3 clinical development program, the current study assessed consistency of immune responses across 3 lots of PCV20 and described the safety profile of PCV20. This phase 3, randomized, multicenter, double-blind study of pneumococcal vaccine-naive adults 18-49 years of age randomized 1710 participants in a 2:2:2:1 ratio to receive 1 of 3 lots of PCV20 or PCV13. Immunogenicity was assessed through serotype-specific opsonophagocytic activity (OPA) titers before and approximately 1 month (28-42 days) after vaccination. Reported local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 30 days, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination were evaluated. Equivalence in immune responses (OPA geometric mean titers) for all 20 vaccine serotypes was demonstrated across the 3 PCV20 lots. Robust responses, assessed by OPA geometric mean fold rises, percentage of participants achieving ≥4-fold rises, and percentage of participants with OPA titers ≥lower limit of quantitation, were observed after PCV20. Reported rates of local reactions, systemic events, and AEs were similar between the pooled PCV20 lots and PCV13; most events were mild or moderate. Reported rates of SAEs and NDCMCs were low and similar between the PCV20 and PCV13 groups. Three different lots of PCV20 demonstrated robust and consistent immunogenicity. The safety and tolerability of PCV20 was acceptable and similar to that of PCV13. (Clinicaltrials.gov: NCT03828617).
Authors: Klein, Nicola P; Peyrani, Paula; Yacisin, Kari; Caldwell, Nicole; Xu, Xia; Scully, Ingrid L; Scott, Daniel A; Jansen, Kathrin U; Gruber, William C; Watson, Wendy
Vaccine. 2021 09 07;39(38):5428-5435. Epub 2021-07-24.
Use of COVID-19 Vaccines After Reports of Adverse Events Among Adult Recipients of Janssen (Johnson & Johnson) and mRNA COVID-19 Vaccines (Pfizer-BioNTech and Moderna): Update from the Advisory Committee on Immunization Practices – United States, July 2021
In December 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for Pfizer-BioNTech and Moderna COVID-19 vaccines, and in February 2021, FDA issued an EUA for the Janssen (Johnson & Johnson) COVID-19 vaccine. After each EUA, the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for vaccine use; currently Pfizer-BioNTech is authorized and recommended for persons aged ≥12 years and Moderna and Janssen for persons aged ≥18 years (1-3). Both Pfizer-BioNTech and Moderna vaccines, administered as 2-dose series, are mRNA-based COVID-19 vaccines, whereas the Janssen COVID-19 vaccine, administered as a single dose, is a recombinant replication-incompetent adenovirus-vector vaccine. As of July 22, 2021, 187 million persons in the United States had received at least 1 dose of COVID-19 vaccine (4); close monitoring of safety surveillance has demonstrated that serious adverse events after COVID-19 vaccination are rare (5,6). Three medical conditions have been reported in temporal association with receipt of COVID-19 vaccines. Two of these (thrombosis with thrombocytopenia syndrome [TTS], a rare syndrome characterized by venous or arterial thrombosis and thrombocytopenia, and Guillain-Barré syndrome [GBS], a rare autoimmune neurologic disorder characterized by ascending weakness and paralysis) have been reported after Janssen COVID-19 vaccination. One (myocarditis, cardiac inflammation) has been reported after Pfizer-BioNTech COVID-19 vaccination or Moderna COVID-19 vaccination, particularly after the second dose; these were reviewed together and will hereafter be referred to as mRNA COVID-19 vaccination. ACIP has met three times to review the data associated with these reports of serious adverse events and has comprehensively assessed the benefits and risks associated with receipt of these vaccines. During the most recent meeting in July 2021, ACIP determined that, overall, the benefits of COVID-19 vaccination in preventing COVID-19 morbidity and mortality outweigh the risks for these rare serious adverse events in adults aged ≥18 years; this balance of benefits and risks varied by age and sex. ACIP continues to recommend COVID-19 vaccination in all persons aged ≥12 years. CDC and FDA continue to closely monitor reports of serious adverse events and will present any additional data to ACIP for consideration. Information regarding risks and how they vary by age and sex and type of vaccine should be disseminated to providers, vaccine recipients, and the public.
Authors: Rosenblum, Hannah G; Klein, Nicola P; Oliver, Sara E; et al.
MMWR Morb Mortal Wkly Rep. 2021 Aug 13;70(32):1094-1099. Epub 2021-08-13.
Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents
Until very recently, vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had not been authorized for emergency use in persons younger than 16 years of age. Safe, effective vaccines are needed to protect this population, facilitate in-person learning and socialization, and contribute to herd immunity. In this ongoing multinational, placebo-controlled, observer-blinded trial, we randomly assigned participants in a 1:1 ratio to receive two injections, 21 days apart, of 30 μg of BNT162b2 or placebo. Noninferiority of the immune response to BNT162b2 in 12-to-15-year-old participants as compared with that in 16-to-25-year-old participants was an immunogenicity objective. Safety (reactogenicity and adverse events) and efficacy against confirmed coronavirus disease 2019 (Covid-19; onset, ≥7 days after dose 2) in the 12-to-15-year-old cohort were assessed. Overall, 2260 adolescents 12 to 15 years of age received injections; 1131 received BNT162b2, and 1129 received placebo. As has been found in other age groups, BNT162b2 had a favorable safety and side-effect profile, with mainly transient mild-to-moderate reactogenicity (predominantly injection-site pain [in 79 to 86% of participants], fatigue [in 60 to 66%], and headache [in 55 to 65%]); there were no vaccine-related serious adverse events and few overall severe adverse events. The geometric mean ratio of SARS-CoV-2 50% neutralizing titers after dose 2 in 12-to-15-year-old participants relative to 16-to-25-year-old participants was 1.76 (95% confidence interval [CI], 1.47 to 2.10), which met the noninferiority criterion of a lower boundary of the two-sided 95% confidence interval greater than 0.67 and indicated a greater response in the 12-to-15-year-old cohort. Among participants without evidence of previous SARS-CoV-2 infection, no Covid-19 cases with an onset of 7 or more days after dose 2 were noted among BNT162b2 recipients, and 16 cases occurred among placebo recipients. The observed vaccine efficacy was 100% (95% CI, 75.3 to 100). The BNT162b2 vaccine in 12-to-15-year-old recipients had a favorable safety profile, produced a greater immune response than in young adults, and was highly effective against Covid-19. (Funded by BioNTech and Pfizer; C4591001 ClinicalTrials.gov number, NCT04368728.).
Authors: Frenck, Robert W; Klein, Nicola P; C4591001 Clinical Trial Group,; et al.
N Engl J Med. 2021 07 15;385(3):239-250. Epub 2021-05-27.
School-level perceptions and enforcement of the elimination of nonmedical exemptions to vaccination in California
In 2015, California passed Senate Bill 277 eliminating all nonmedical exemptions to school vaccinations. We aimed to explore school-level modes of SB277 enforcement, characterize vaccination knowledge, attitudes, and beliefs of school officials, and identify whether school vaccination policies are associated with medical exemptions being granted. Surveys were mailed to a stratified random sample of 1,450 schools in California. School personnel (n = 752) reported their medical training, vaccination beliefs, enforcement of vaccination policies, and school rates of medical exemptions. Multiple logistic regression was used to assess whether school policies are associated with the likelihood of medical exemption requests being granted. Nurses were more likely than non-nurses to hold beliefs recognizing the importance of vaccination. A school where the survey respondent was a nurse was more likely to have granted a medical exemption request compared to a school where the respondent was not a nurse (OR 2.11, 95% CI 1.34-3.36). The training of school officials and school-level practices may impact the enforcement of medical exemptions. Equipping school officials as competent sources of vaccine information for concerned parents will be valuable in improving parental vaccine uptake.
Authors: Holroyd, Taylor A; Howa, Amanda C; Proveaux, Tina M; Delamater, Paul L; Klein, Nicola P; Buttenheim, Alison M; Limaye, Rupali J; Omer, Saad B; Salmon, Daniel A
Hum Vaccin Immunother. 2021 07 03;17(7):1986-1993. Epub 2021-01-25.
Incidence of pediatric inflammatory bowel disease within the Vaccine Safety Datalink network and evaluation of association with rotavirus vaccination
Recent studies have reported an increase in Inflammatory bowel disease (IBD) incidence in young children, highlighting the need to better understand risk factors for the development of IBD. Licensed for use in infants in 2006, the oral, live-attenuated rotavirus vaccine has biologic plausibility for instigating inflammation of the gut mucosa as a pathway to immune dysregulation. Over a ten-year period, we evaluated incidence of IBD within a cohort of children under the age of ten, enrolled in seven integrated healthcare delivery systems. We conducted a nested case-control study to evaluate the association between rotavirus vaccination and IBD using conditional logistic regression. Cases were confirmed via medical record review and matched to non-IBD controls on date of birth, sex, and study site. Among 2.4 million children under the age of 10 years, 333 cases of IBD were identified with onset between 2007 and 2016. The crude incidence of IBD increased slightly over the study period (p-value for trend = 0.046). Of the 333 cases, 227 (68%) were born prior to 2007. Forty-two cases born in 2007 or later, with continuous enrollment since birth were included in the case-control study and matched to 210 controls. The adjusted odds ratio for any rotavirus vaccination in IBD cases, compared to matched controls, was 0.72 (95% confidence interval 0.19-2.65). Data from this large pediatric cohort demonstrate a small overall increase in IBD incidence in young children over a ten-year period. The data suggest that rotavirus vaccination is not associated with development of IBD.
Authors: Liles, Elizabeth; Klein, Nicola P; Naleway, Allison L; et al.
Vaccine. 2021 06 16;39(27):3614-3620. Epub 2021-05-26.
Genetic associations with a fever after measles-containing vaccines
Children have elevated fever risk 1 to 2 weeks after the first dose of a measles-containing vaccine (MCV), which is likely affected by genetic, immunologic, and clinical factors. Fever after MCV is associated with febrile seizures, though may also be associated with higher measles antibody titers. This exploratory study investigated genetic and immunologic associations with a fever after MCV. Concurrent with a randomized Phase 3 clinical trial of 12-15-month-olds who received their first measles-mumps-rubella (MMR) vaccine in which parents recorded post-vaccination temperatures daily, we consented a subset to collect additional blood and performed human leukocyte antigens (HLA) typing. Association between fever 5-12 days after MMR (“MMR-associated”) and HLA type was assessed using logistic regression. We compared 42-day post-vaccination geometric mean titers (GMT) to measles between children who did and did not have fever using a t-test. We enrolled 86 children and performed HLA typing on 82; 13 (15.1%) had MMR-associated fever. Logistic regressions identified associations between MMR-associated fever and HLA Class I loci A-29:02 (P = .036), B-57:01 (P = .018), C-06:02 (P = .006), C-14:02 (P = .022), and Class II loci DRB1-15 (P = .045). However, Bonferroni’s adjustment for multiple comparisons suggests that these associations could have been due to chance. Ninety-eight percent of children had protective antibody titers to measles; however, GMT was higher among those with fever compared with children without fever (P = .006). Fever after the measles vaccine correlated with genetic factors and higher immune response. This study suggests a possible genetic susceptibility to MMR-associated fever.
Authors: Klein, Nicola P; Zerbo, Ousseny; Goddard, Kristin; Wang, Weiqi; Fohner, Alison E; Wiesner, Amy; Shokoohi, Vida; Coller, John; Bok, Karin; Gans, Hayley A
Hum Vaccin Immunother. 2021 06 03;17(6):1763-1769. Epub 2020-12-22.
Parental vaccine attitudes, beliefs, and practices: initial evidence in California after a vaccine policy change
Senate Bill 277 (SB277) eliminated nonmedical exemptions for school-entry vaccines in California, but the impact of parental vaccine knowledge, attitudes, and beliefs on vaccine decision-making has not been extensively examined within the post-SB277 context. This study generates preliminary understanding and discussion of the vaccination knowledge, attitudes, and beliefs among a pilot population of parents of kindergarten students in California after the implementation of SB277. School officials administered a cross-sectional survey to parents of kindergarten children in California from April to July 2019. Parents reported their perceptions of diseases and vaccines, key immunization beliefs, and confidence in different sources of vaccine information. Most parents (92%) had fully vaccinated their children post-SB277 and generally perceived vaccines to be safe and effective, but about 44% reported they were hesitant about childhood vaccines. The majority of parents (87%) rated vaccine information from their doctor as highly credible. This pilot group of kindergarten parents was generally supportive of vaccination and had fully vaccinated their children, but most parents still harbored concerns and misconceptions about vaccines and about public health authorities. This indicates a disconnect between parental vaccine compliance and confidence, and suggests that educational interventions could impact parental vaccine behavior and decision-making.
Authors: Holroyd, Taylor A; Howa, Amanda C; Delamater, Paul L; Klein, Nicola P; Buttenheim, Alison M; Limaye, Rupali J; Proveaux, Tina M; Omer, Saad B; Salmon, Daniel A
Hum Vaccin Immunother. 2021 06 03;17(6):1675-1680. Epub 2020-11-24.
Association of Inadvertent 9-Valent Human Papillomavirus Vaccine in Pregnancy With Spontaneous Abortion and Adverse Birth Outcomes
The 9-valent human papillomavirus (9vHPV) vaccine is recommended for individuals through age 26 years and may be administered to women up to age 45 years. Data on 9vHPV vaccine exposures during pregnancy are limited. To evaluate the associations between 9vHPV vaccine exposures during pregnancy or peripregnancy and selected pregnancy and birth outcomes (spontaneous abortion [SAB], preterm birth, small-for-gestational age [SGA] birth, and major structural birth defect). This cohort study analyzed data from 7 participating health systems in the Vaccine Safety Datalink. The cohort comprised pregnancies among girls and women aged 12 to 28 years that ended between October 26, 2015, and November 15, 2018. Singleton pregnancies that ended in a live birth, stillbirth, or SAB were included. Vaccine exposure windows were distal (9vHPV or 4vHPV vaccine administered from 22 to 16 weeks before last menstrual period [LMP]), peripregnancy (9vHPV vaccine administered from 42 days before LMP until LMP), and during pregnancy (9vHPV vaccine administered from LMP to 19 completed weeks’ gestation). Primary comparisons were (1) girls and women with 9vHPV vaccine exposures during pregnancy vs those with 4vHPV or 9vHPV distal vaccine exposures, (2) girls and women with vaccine exposures peripregnancy vs those with 4vHPV or 9vHPV distal vaccine exposures, and (3) girls and women with 9vHPV vaccine exposures during pregnancy or peripregnancy vs those with 4vHPV or 9vHPV distal vaccine exposure. Spontaneous abortions were confirmed based on medical record review and adjudication. Preterm and SGA births were identified from electronic health record and birth data. Major structural birth defects were based on diagnostic codes using a validated algorithm. Inverse probability weighting was used to balance the covariates. Time-dependent covariate Cox proportional hazards regression models and Poisson regression were used to estimate the associations between 9vHPV vaccine exposures and pregnancy and birth outcomes. The final cohort included 1493 pregnancies among girls and women with a mean (SD) maternal age of 23.9 (2.9) years. Of these pregnancies, 445 (29.8%) had exposures to the 9vHPV vaccine during pregnancy, 496 (33.2%) had exposures to the 9vHPV vaccine peripregnancy, and 552 (37.0%) had 4vHPV or 9vHPV distal vaccine exposures. The 9vHPV vaccine administered during pregnancy was not associated with increased risk for SAB (hazard ratio, 1.12; 95% CI, 0.66-1.93) compared with distal vaccine exposures. Findings were similar for 9vHPV vaccine exposures peripregnancy (relative risk [RR], 0.72; 95% CI, 0.42-1.24). Among live births (n = 1409), 9vHPV vaccine exposures during pregnancy were not associated with increased risks for preterm birth (RR, 0.73; 95% CI, 0.44-1.20) or SGA birth (RR, 1.31; 95% CI, 0.78-2.20). Results were similar regarding the association between 9vHPV vaccine exposures peripregnancy and preterm birth (RR, 0.72; 95% CI, 0.45-1.17) and SGA birth (RR, 1.10; 95% CI, 0.65-1.88). Birth defects were rare in all exposure groups, occurring in about 1% of live births with available infant data. This study found that 9vHPV vaccine exposures during or around the time of pregnancy were uncommon and not associated with SABs or selected adverse birth outcomes. These findings can inform counseling for inadvertent 9vHPV vaccine exposures.
Authors: Kharbanda, Elyse O; Klein, Nicola P; Lipkind, Heather S; et al.
JAMA Netw Open. 2021 04 01;4(4):e214340. Epub 2021-04-01.
Studying attitudes towards vaccine hesitance and California law SB 277 in online discourse: A dataset and methodology
This article presents data that are further analyzed and interpreted in “Shouting at Each Other into the Void: A Semantic Network Analysis of Vaccine Hesitance and Support in Online Discourse Regarding California Law SB277” [1]. This research modified snowball sampling, a technique usually used to generate chains of informants that illuminate the structure of social networks, to collect digital documents following a chain of web links and recommendations, thus illuminating the underlying social, technical, and linguistic structure of online discourse. The resulting documents were manually coded according to the attitude towards vaccines they represented and/or the position they took with regard to California Senate Bill 277, a vaccine mandate policy that banned all nonmedical exemptions from school immunization requirements. Each attitude category, as well as the dataset as a whole, was subjected to quantitative linguistic analysis to identify key words and phrases in the data according to the frequency with which they appeared. A combination of that technique and semantic network analysis were used to generate clusters of related words that could be used for qualitative and narrative analysis, as detailed in the companion paper. The data collection and analysis processes described here will be of use to researchers conducting mixed-method analysis of online discourse who want their data to reflect the potential information and digital resources available to individuals who attempt to inform themselves about a particular topic using Internet searches. The data presented here could be useful for anyone seeking deeper insight into the linguistic and narrative patterns surrounding online debates about vaccination, controversial government policies, or both.
Authors: DeDominicis, Kali; Buttenheim, Alison M; Howa, Amanda C; Delamater, Paul L; Salmon, Daniel; Klein, Nicola P; Omer, Saad B
Data Brief. 2021 Apr;35:106841. Epub 2021-02-24.
Concomitant administration of a liquid formulation of human rotavirus vaccine (porcine circovirus-free) with routine childhood vaccines in infants in the United States: Results from a phase 3, randomized trial
In response to the detection of porcine circovirus type 1 (PCV-1) in the human rotavirus vaccine (HRV), a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the detection limit of tests used) was developed. Liquid (Liq) PCV-free HRV previously showed immunogenicity and safety profiles comparable to lyophilized (Lyo) HRV. This was a phase 3a, randomized, single-blind study (NCT03207750) conducted in the United States. Healthy infants aged 6-12 weeks received 2 doses (0, 2 months) of either Liq PCV-free HRV or Lyo HRV with routine vaccines (0, 2, 4 months): diphtheria-tetanus-acellular pertussis, hepatitis B and inactivated poliovirus combination vaccine (DTaP-HBV-IPV), monovalent tetanus toxoid-conjugated vaccine against Haemophilus influenzae type b (Hib-TT), and 13-valent pneumococcal conjugate vaccine. Co-primary objectives were: (i) to assess non-inferiority of immune responses to routine vaccine antigens 1 month post-dose 3 following co-administration with Liq PCV-free HRV compared to Lyo HRV; (ii) to rule out a 10% decrease in seroresponse to pertussis antigens after dose 3. Other objectives were to evaluate immunogenicity and safety of HRV vaccines. Of 1272 vaccinated infants, 990 (489 in Liq PCV-free HRV and 501 in Lyo HRV group) were included in the per-protocol set. All statistical criteria were met, thus co-primary objectives were demonstrated. Seroprotection/seropositivity rates in both groups were high: 100% for diphtheria/tetanus, ≥99.3% for HBV, ≥99.8% for polio, ≥99.8% for each pertussis antigen, ≥90.8% for all pneumococcal serotypes except serotype 3 (≥69.1%), and ≥ 97.4% for Hib. Most infants seroconverted for anti-RV antibodies (76.3% of Liq PCV-free HRV and 78.9% of Lyo HRV recipients). Geometric mean concentrations/titers were comparable between groups. Incidences of adverse events and serious adverse events were similar between groups. Routine pediatric vaccines co-administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles to those following co-administration with Lyo HRV.
Authors: Abu-Elyazeed, Remon; Klein, Nicola P; Moerman, Leentje; Povey, Michael; Pruitt, Anthony; Senders, Shelly; Silas, Peter; Bi, Dan; Rota-090 Study Group,
Vaccine. 2021 03 05;39(10):1534-1543. Epub 2020-10-17.
Vaccine Safety Datalink infrastructure enhancements for evaluating the safety of maternal vaccination
Identifying pregnancy episodes and accurately estimating their beginning and end dates are imperative for observational maternal vaccine safety studies using electronic health record (EHR) data. We modified the Vaccine Safety Datalink (VSD) Pregnancy Episode Algorithm (PEA) to include both the International Classification of Disease, ninth revision (ICD-9 system) and ICD-10 diagnosis codes, incorporated additional gestational age data, and validated this enhanced algorithm with manual medical record review. We also developed the new Dynamic Pregnancy Algorithm (DPA) to identify pregnancy episodes in real time. Around 75% of the pregnancy episodes identified by the enhanced VSD PEA were live births, 12% were spontaneous abortions (SABs), 10% were induced abortions (IABs), and 0.4% were stillbirths (SBs). Gestational age was identified for 99% of live births, 89% of SBs, 69% of SABs, and 42% of IABs. Agreement between the PEA-assigned and abstractor-identified pregnancy outcome and outcome date was 100% for live births, but was lower for pregnancy losses. When gestational age was available in the medical record, the agreement was higher for live births (97%), but lower for pregnancy losses (75%). The DPA demonstrated strong concordance with the PEA and identified pregnancy episodes ⩾6 months prior to the outcome date for 89% of live births. The enhanced VSD PEA is a useful tool for identifying pregnancy episodes in EHR databases. The DPA improves the timeliness of pregnancy identification and can be used for near real-time maternal vaccine safety studies. Improving identification of pregnancies in the Vaccine Safety Datalink electronic medical record databases to allow for better and faster monitoring of vaccination safety during pregnancy Introduction: It is important to monitor of the safety of vaccines after they have been approved and licensed by the Food and Drug Administration, especially among women vaccinated during pregnancy. The Vaccine Safety Datalink (VSD) monitors vaccine safety through observational studies within large databases of electronic medical records. Since 2012, VSD researchers have used an algorithm called the Pregnancy Episode Algorithm (PEA) to identify the medical records of women who have been pregnant. Researchers then use these medical records to study whether receiving a particular vaccine is linked to any negative outcomes for the woman or her child.Methods: The goal of this study was to update and enhance the PEA to include the full set of medical record diagnostic codes [both from the older International Classification of Disease, ninth revision (ICD-9 system) and the newer ICD-10 system] and to incorporate additional sources of data about gestational age. To ensure the validity of the PEA following these enhancements, we manually reviewed medical records and compared the results with the algorithm. We also developed a new algorithm, the Dynamic Pregnancy Algorithm (DPA), to identify women earlier in pregnancy, allowing us to conduct more timely vaccine safety assessments.Results: The new version of the PEA identified 2,485,410 pregnancies in the VSD database. The enhanced algorithm more precisely estimated the beginning of pregnancies, especially those that did not result in live births, due to the new sources of gestational age data.Conclusion: Our new algorithm, the DPA, was successful at identifying pregnancies earlier in gestation than the PEA. The enhanced PEA and the new DPA will allow us to better evaluate the safety of current and future vaccinations administered during or around the time of pregnancy.
Authors: Naleway, Allison L; Klein, Nicola P; Zerbo, Ousseny; Kharbanda, Elyse O; et al.
Ther Adv Drug Saf. 2021;12:20420986211021233. Epub 2021-06-14.
Evaluating the Association of Stillbirths After Maternal Vaccination in the Vaccine Safety Datalink
To evaluate whether the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommended influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccinations in pregnancy are associated with increased risk of stillbirth. We performed a case-control study in the Vaccine Safety Datalink that was matched 1:4 on site, month, and year of last menstrual period, comparing the odds of vaccination in pregnancies that ended in stillbirth (defined as fetal loss at or after 20 weeks of gestation) compared with those that ended in live birth from January 1, 2012, to September 30, 2015. We included patients with singleton pregnancies that ended in stillbirth or live birth who had at least one prenatal care visit, pregnancy dating information, and continuous health plan enrollment for the duration of pregnancy. Medical records for all stillbirths were reviewed. We were statistically powered to detect an odds ratio (OR) of 1.37 when evaluating the association between influenza or Tdap vaccination and stillbirth. We also examined stillbirth rates in pregnant patients aged 14-49 years in the Vaccine Safety Datalink between 2007 and 2015. In our matched analysis of 795 confirmed stillbirths in the case group and 3,180 live births in the control group, there was no significant association between influenza vaccination during pregnancy and stillbirth (343/795 [43.1%] stillbirths in the case group vs 1,407/3,180 [44.3%] live births in the control group, OR 0.94, adjusted OR 0.95, 95% CI 0.79-1.14, P=.54) and no significant association between Tdap vaccination during pregnancy and stillbirth (184/795 [23.1%] stillbirths in the case group vs 746/3,180 [23.5%] live births in the control group, OR 0.97, aOR 0.96, 95% CI 0.76-1.28, P=.91). From 2007 to 2015, the stillbirth rate in the Vaccine Safety Datalink was 5.2 per 1,000 live births and stillbirths. No association was found between vaccination during pregnancy and the odds of stillbirth. These findings support the safety of ACIP recommendations for vaccination during pregnancy.
Authors: Panagiotakopoulos, Lakshmi; Klein, Nicola P; Weintraub, Eric S; et al.
Obstet Gynecol. 2020 12;136(6):1086-1094.
Shouting at each other into the void: A linguistic network analysis of vaccine hesitance and support in online discourse regarding California law SB277
In 2015, California passed Senate Bill 277 and became the third state in the United States to ban all nonmedical exemptions from school immunization requirements, effectively prohibiting religious and personal belief exemptions. This attracted grassroots opposition and considerable debate among vaccine hesitant factions online. This mixed-methods study used quantitative linguistic analysis, semantic network analysis, and content analysis techniques to examine 2424 online documents drawn from newspapers, blogs, health websites, government information pages, web forums, personal websites, Facebook groups, among others. The study examined which words and phrases were used most frequently by vaccine skeptics, vaccine defenders, and more neutral media accounts to illuminate how groups with different attitudes towards vaccination discuss and disseminate information about vaccines and vaccine policy online. We proposed an innovative methodology for examining online discourse surrounding vaccine hesitance, as well as for studying the online dissemination of misinformation about vaccines. Our findings highlighted discrepancies in the narratives between what vaccine supporters believe causes vaccine skepticism and the issues that vaccine skeptics actually discuss within their own digital spaces. For example, in these exchanges, the importance of parental rights overshadowed that of children’s rights; supporters of vaccines brought up autism in more distinct documents than skeptics do; distrust of government regulators and researchers seemed to unite vaccine skeptics and defenders; and politicians, doctors, and even celebrities often served as proxies in heated exchanges about factual evidence, believability, and the importance of expertise in public discourse.
Authors: DeDominicis, Kali; Buttenheim, Alison M; Howa, Amanda C; Delamater, Paul L; Salmon, Daniel; Omer, Saad B; Klein, Nicola P
Soc Sci Med. 2020 12;266:113216. Epub 2020-08-28.
Identification and description of mumps cases in a non-outbreak setting and evaluation of the effectiveness of mumps-containing vaccines over time
Mumps outbreaks among previously vaccinated young adults raise concerns regarding waning vaccine immunity. This study identified, described and assessed the changing incidence of mumps cases following mumps-containing vaccination (MMR/MMRV) in a non-mumps outbreak setting. Potential cases between 1996 and 2018 were identified by the international classification of disease codes or by mumps laboratory test orders among Kaiser Permanente Northern California members. Medical charts were reviewed to confirm diagnoses, timing relative to vaccination and clinical characteristics. Among 474 potential cases, 257 (54.2%) were confirmed after chart review. A third of the cases were <10 years old at diagnosis and 48% were over 25 years. Most cases (92.2%) had parotitis and 5% of males had orchitis. Mumps rates decreased from 8.5 to 1.8/1,000,000 person-years as time since the second MMR/MMRV dose increased from <2 years to ≥10 years. Similarly, rates decreased from 16.3 to 3/1,000,000 person-years after at least 1 dose of MMR/MMRV. Mumps rates were higher among children aged ≤10 years compared with older age groups. In conclusion, in the context of a non-outbreak setting, this study suggests that waning of vaccine immunity to mumps appeared to have minimal clinical impact.
Authors: Zerbo O; Modaressi S; Glanternik JR; Goddard K; Ross P; Lewis N; Klein NP
Hum Vaccin Immunother. 2020 12 01;16(12):3098-3102. Epub 2020-05-13.
Individual and Neighborhood Factors Associated with Failure to Vaccinate against Influenza during Pregnancy
Uptake of influenza vaccine among pregnant women remains low. We investigated whether unvaccinated pregnant women were clustered geographically and determined factors associated with failure to vaccinate using spatial and multivariate logistic regression analyses. Pregnant women who were members of Kaiser Permanente Northern California in 2015 or 2016 were included in the study. More than half (53%) of the 77,607 included pregnant women were unvaccinated. Spatial analysis identified 5 clusters with a high prevalence of unvaccinated pregnant women. The proportion of unvaccinated women ranged from 57% to 75% within clusters as compared with 51% outside clusters. In covariate-adjusted analyses, residence in a cluster was associated with a 41% increase in the odds of being unvaccinated (odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.36, 1.46). The odds of being unvaccinated were greater for Black women (OR = 1.58, 95% CI: 1.49, 1.69), Hispanic women (OR = 1.15, 95% CI: 1.05, 1.25), women with subsidized health insurance (OR = 1.18, 95% CI: 1.11, 1.24), women with fewer than 5 prenatal-care visits (OR = 1.85, 95% CI: 1.60, 2.16), and neighborhoods with a high deprivation index (fourth quartile vs. first: OR = 1.14, 95% CI: 1.07, 1.21). In conclusion, unvaccinated pregnant women were clustered geographically and by key sociodemographic factors. These findings suggest that interventions to increase influenza vaccine coverage among pregnant women are needed, particularly in vulnerable populations.
Authors: Zerbo, Ousseny; Ray, G Thomas; Zhang, Lea; Goddard, Kristin; Fireman, Bruce; Adams, Alyce; Omer, Saad; Kulldorff, Martin; Klein, Nicola P
Am J Epidemiol. 2020 11 02;189(11):1379-1388.
Determining Which of Several Simultaneously Administered Vaccines Increase Risk of an Adverse Event
Childhood immunization schedules often involve multiple vaccinations per visit. When increased risk of an adverse event is observed after simultaneous (same-day) vaccinations, it can be difficult to ascertain which triggered the adverse event. This methods paper discusses a systematic process to determine which of the simultaneously administered vaccine(s) are most likely to have caused an observed increase in risk of an adverse event. We use an example from the literature where excess risk of seizure was observed 1 day after vaccination, but same-day vaccination patterns made it difficult to discern which vaccine(s) may trigger the adverse event. We illustrate the systematic identification process using a simulation that retained the observed pattern of simultaneous vaccination in an empirical cohort of vaccinated children. We simulated “true” effects for diphtheria-tetanus-acellular pertussis (DTaP) and pneumococcal conjugate (PCV) on risk of seizure the day after vaccination. We varied the independent and interactive effects of vaccines (on the multiplicative scale). After applying the process to simulated data, we evaluated risk of seizure 1 day after vaccination in the empirical cohort. In all simulations, we were able to determine which vaccines contributed to excess risk. In the empirical data, we narrowed the association with seizure from all vaccines in the schedule to three likely candidates, DTaP, PCV, and/or Haemophilus influenzae type B (HiB) (p < 0.01, attributable risk when all three were administered together: five per 100,000). Disentangling their associations with seizure would require a larger sample or more variation in the combinations administered. When none of these three were administered, no excess risk was observed. The process outlined could provide valuable information on the magnitude of potential risk from individual and simultaneousvaccinations. Associations should be further investigated with independent data as well as biologically based, statistically independent hypotheses.
Authors: Wang SV; Stefanini K; Lewis E; Newcomer SR; Fireman B; Daley MF; Glanz JM; Duffy J; Weintraub E; Kulldorff M
Drug Saf. 2020 10;43(10):1057-1065.
Evaluation of a Vaccine-Communication Tool for Physicians
To evaluate a Kaiser Permanente Northern California physician training tool entitled “Effective Communication without Confrontation” aimed at improving communication with vaccine-hesitant parents, building trust, and alleviating physician stress surrounding vaccination visits. Trainings were held May to July 2015. Pre- and post-training surveys assessed physician comfort and perceived effectiveness in communicating with vaccine-hesitant parents. We measured vaccination coverage at the 2-, 4-, and 6-month well-child visits, and days undervaccinated at 9 months of age. We compared vaccination rates before and after the training. Of 415 physicians who received training, 249 completed post-training surveys. Physicians reported that the training helped them feel “much more or more” comfortable talking with parents who are unsure (72.3%), want to delay (73.9%), or refuse (63.5%) vaccinations and “much more or more” effective at persuading parents who are unsure (67.5%) or want to delay vaccinations (61.4%). They reported feeling “the same or less” effective persuading parents who refuse vaccinations (66.3%). Vaccine coverage remained unchanged and high from before to after the training (95%-96%), as did parent satisfaction with his or her child’s provider (4.73/5.00). The Effective Communication without Confrontation training did not increase vaccine coverage, but did improve physicians’ comfort and perceived effectiveness communicating with most vaccine-hesitant parents and may help to ease potentially stressful vaccination visits.
Authors: Glanternik JR; McDonald JC; Yee AH; Howell Ba A; Saba KN; Mellor RG; Fireman B; Klein NP
J Pediatr. 2020 09;224:72-78.e1. Epub 2020-06-06.
Overcoming Waning Immunity in Pertussis Vaccines: Workshop of the National Institute of Allergy and Infectious Diseases
Despite high vaccine coverage in many parts of the world, pertussis is resurging in a number of areas in which acellular vaccines are the primary vaccine administered to infants and young children. This is attributed in part to the suboptimal and short-lived immunity elicited by acellular pertussis vaccines and to their inability to prevent nasal colonization and transmission of the etiologic agent Bordetella pertussis In response to this escalating public health concern, the National Institute of Allergy and Infectious Diseases held the workshop “Overcoming Waning Immunity in Pertussis Vaccines” in September 2019 to identify issues and possible solutions for the defects in immunity stimulated by acellular pertussis vaccines. Discussions covered aspects of the current problem, gaps in knowledge and possible paths forward. This review summarizes presentations and discussions of some of the key points that were raised by the workshop.
Authors: Damron, F Heath; Lu, Kristina; Harvill, Eric T; et al.
J Immunol. 2020 08 15;205(4):877-882.
Safety of Recombinant Influenza Vaccine Compared to Inactivated Influenza Vaccine in Adults: An Observational Study
Recombinant trivalent influenza vaccine (RIV3) was initially licensed in 2013 and approved for all adults ≥18 in 2014. This study evaluated the safety of RIV3 compared with trivalent standard-dose, inactivated influenza vaccine (IIV3) in Kaiser Permanente Northern California (KPNC). This Phase 4 observational, postmarketing safety study included persons ≥18 years vaccinated with RIV3 or IIV3 in KPNC during the 2015-2016 influenza season. We compared (1) the rates of prespecified diagnoses of interest (Guillain-Barré Syndrome, pericarditis, pleural effusion, narcolepsy/cataplexy, asthma, acute hypersensitivity reactions, and fever) during various postvaccination risk intervals as well as (2) all-cause hospitalization and mortality 0-180 days after vaccination. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression analyses adjusted for age, sex, race/ethnicity, month of vaccination, and concomitant receipt of other vaccinations. Comparing the 21 976 persons who received RIV3 with the 283 683 who received IIV3, there were statistically significant differences in the prespecified diagnoses of interest between the 2 groups. Specifically, RIV3 vaccination was associated with fewer fever diagnoses during the 0-41 days postvaccination (OR, 0.38; 95% CI, 0.14-0.86). Also, RIV3 was associated with fewer all-cause hospitalizations during the 0-180 days postvaccination (OR, 0.66; 95% CI, 0.61-0.73), which was mostly related to pregnancy-related hospitalizations in IIV3 recipients. There were no serious adverse events or deaths related to RIV3. This study did not identify any safety concerns regarding the use of RIV3 in adults.
Authors: Hansen J; Goddard K; Timbol J; Zhang L; Lewis N; Dunkle L; Izikson R; Klein NP
Open Forum Infect Dis. 2020 Jun;7(6):ofaa179. Epub 2020-05-20.
Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Invasive Pneumococcal Disease After Introduction Into Routine Pediatric Use
In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced 7-valent PCV (PCV7) for protection against invasive pneumococcal disease (IPD). This study used laboratory surveillance data to examine the effect of PCV13 on IPD before and after PCV13 introduction among children aged 6 weeks to
Authors: Baxter R; Aukes L; Pelton SI; Yee A; Klein NP; Gruber WC; Scott DA; Center KJ
J Pediatric Infect Dis Soc. 2020 May 16.
Immunogenicity and Safety of a Measles-Mumps-Rubella Vaccine Administered as a First Dose to Children Aged 12 to 15 Months: A Phase III, Randomized, Noninferiority, Lot-to-Lot Consistency Study
MMR II (M-M-R II [Merck & Co, Inc.]) is currently the only measles, mumps, and rubella (MMR) vaccine licensed in the United States. A second MMR vaccine would mitigate the potential risk of vaccine supply shortage or delay. In this study, we assessed the immunogenicity and safety of another MMR vaccine (MMR-RIT [Priorix, GlaxoSmithKline]) compared with those of the MMR II in 12- to 15-month-old children who received it as a first dose. In this phase III, observer-blinded, noninferiority, lot-to-lot consistency clinical trial (ClinicalTrials.gov identifier NCT01702428), 5003 healthy children were randomly assigned to receive 1 dose of MMR-RIT (1 of 3 production lots) or MMR II along with other age-recommended routine vaccines. We evaluated the immunogenicity of all vaccines in terms of antibody concentrations (by using an enzyme-linked immunosorbent assay or electrochemiluminescence assay) and/or seroresponse rates 43 days after vaccination. We also assessed the reactogenicity and safety of the vaccines. Immunoresponses after vaccination with MMR-RIT were robust and noninferior to those after vaccination with the MMR II. Immunogenicity of the 3 production lots of MMR-RIT was consistent; more than 97% of the children had a seroresponse to MMR components. The coadministered vaccines elicited similar immunoresponses in the MMR-RIT and MMR II groups. Both MMR vaccines resulted in comparable reactogenicity profiles, and no safety concerns were detected. If licensed, the MMR-RIT could provide a valid option for the prevention of measles, mumps, and rubella in children in the United States and would reduce potential risks of a vaccine shortage.
Authors: Klein NP; Henry O; et al.
J Pediatric Infect Dis Soc. 2020 Apr 30;9(2):194-201.
If Influenza Vaccines Wane Can We Delay Vaccination Without Compromising Coverage?
Authors: Klein NP; Fireman B
Clin Infect Dis. 2020 04 10;70(8):1560-1561.
Parental Risk Factors for Fever in their Children 7-10 Days After the First Dose of Measles-Containing Vaccines
We evaluated whether parental clinical conditions were associated with fever after a first dose of measles-containing vaccine (MCV) in the child in a cohort study including 244,125 children born in Kaiser Permanente Northern California between 2009 and 2016 who received MCV between ages 1 and 2 years. Each child was linked with his/her mother and father when possible. Parental clinical conditions present before and after their child’s birth were identified. We defined fever in the children as clinic and emergency department visits with a fever code 7-10 days after a first dose of MCV (“MCV-associated fever”). We evaluated parental clinical conditions associated with MCV-associated fever using multivariate logistic regression analyses. After adjusting for multiple factors, including healthcare utilization, maternal fever [odds ratio (OR) = 1.19, 95% confidence interval (CI) 1.06-1.32], fever after MCV (OR = 5.90, 95% CI 1.35-25.78), respiratory infections (OR = 1.20, 95% CI 1.10-1.31), migraine (OR = 1.14, 95% CI 1.05-1.24), syncope (OR 1.14, 95% CI 1.01-1.27), and essential thrombocythemia (OR = 1.93, 95% CI 1.15-3.25) were significantly associated with MCV-associated fever. Paternal respiratory infections (OR = 1.15, 95% CI 1.05-1.27), fever associated with respiratory infections (OR = 1.47, 95% CI 1.23-1.76), and vitiligo (OR = 1.63, 95% CI 1.06-2.53) were significantly associated with MCV-associated fever. Parental clinical conditions, specifically fever alone and fever associated with respiratory infection, are associated with fever in their child 7-10 days after MCV.
Authors: Zerbo O; Modaressi S; Goddard K; Lewis E; Bok K; Gans H; Klein NP
Hum Vaccin Immunother. 2020 04 02;16(4):875-880. Epub 2019-11-08.
Depletion of Susceptibles Bias in Analyses of Intra-season Waning of Influenza Vaccine Effectiveness
Bias arises in studies of waning vaccine effectiveness when higher-risk individuals are depleted from the at-risk population at different rates between study groups. We examined how this bias arises and how to avoid it. A reanalysis of data from California confirmed a finding of intra-season waning of influenza vaccine effectiveness.
Authors: Ray GT; Lewis N; Klein NP; Daley MF; Lipsitch M; Fireman B
Clin Infect Dis. 2020 03 17;70(7):1484-1486.
Human Papillomavirus Vaccine Effectiveness Against HPV Infection: Evaluation of One, Two, and Three Doses
Highly effective human papillomavirus (HPV) vaccines are used in many national programs in 3- or 2-dose schedules. We examined HPV vaccine effectiveness against HPV prevalence by number of doses. We collected residual liquid-based cytology samples from US women aged 20-29 years who were screened for cervical cancer. Women continuously enrolled from 2006 through the specimen collection date were analyzed. Specimens were tested using the Linear Array assay. We analyzed prevalence of quadrivalent HPV vaccine (4vHPV) types (HPV 6,11,16,18) and other HPV-type categories and determined prevalence ratios (PRs) and 95% confidence intervals (CIs) for 1, 2, and 3 compared with no vaccine doses. Among 4269 women, 1052 (24.6%) were unvaccinated, 2610 (61.1%) received 3 doses, 304 (7.1%) received 2 doses, and 303 (7.1%) received 1 dose. The 4vHPV-type prevalence was 7.4% among unvaccinated women compared with 1.7%, 1.0%, and 1.0% among 1-, 2-, and 3-dose recipients. Among women vaccinated at ≤18 years, adjusted PRs for 1, 2, and 3 doses were 0.06 (95% CI, 0.01-0.42), 0.05 (95% CI, 0.01-0.39), and 0.06 (95% CI, 0.04-0.12). Among women who received their first dose at age ≤18, estimated HPV vaccine effectiveness was high regardless of number of doses.
Authors: Markowitz LE; Klein NP; Unger ER; et al.
J Infect Dis. 2020 03 02;221(6):910-918.
Order of Live and Inactivated Vaccines and Risk of Non-vaccine-targeted Infections in US Children 11-23 Months of Age
Some findings from observational studies have suggested that recent receipt of live vaccines may be associated with decreased non-vaccine-targeted infection risk and mortality. Our objective was to estimate risk of non-vaccine-targeted infections based on most recent vaccine type (live vaccines only, inactivated vaccines only or both concurrently) received in US children 11-23 months of age. We conducted a retrospective cohort study within the Vaccine Safety Datalink. We examined electronic health record and immunization data from children born in 2003-2013 who received 3 diphtheria-tetanus-acellular pertussis vaccines before their first birthday. We modeled vaccine type as a time-varying exposure and estimated risk of non-vaccine-targeted infections identified in emergency department and inpatient settings, adjusting for multiple confounders. Among 428,608 children, 48.9% were female, 4.9% had ≥1 immunization visit with live vaccines only and 10.3% had a non-vaccine-targeted infection. In males, lower risk of non-vaccine-targeted infections was observed following last receipt of live vaccines only or live and inactivated vaccines concurrently as compared with last receipt of inactivated vaccines only [live vaccines-only adjusted hazard ratio (aHR) = 0.83, 95% confidence interval (CI): 0.72-0.94; live and inactivated vaccines concurrently aHR: 0.91, 95% CI: 0.88-0.94]. Among females, last receipt of live and inactivated vaccines concurrently was significantly associated with non-vaccine-targeted infection risk (aHR = 0.94, 95% CI: 0.91-0.97 vs. last receipt of inactivated vaccines only). We observed modest associations between live vaccine receipt and non-vaccine-targeted infections. In this observational study, multiple factors, including healthcare-seeking behavior, may have influenced results.
Authors: Newcomer SR; Zerbo O; Glanz JM; et al.
Pediatr Infect Dis J. 2020 03;39(3):247-253.
Trivalent inactivated influenza vaccine (IIV3) during pregnancy and six-month infant development
Despite recommendations by professional organizations that all pregnant women receive inactivated influenza vaccine, safety concerns remain a barrier. Our objective was to assess the effect of trivalent influenza vaccines (IIV3) during pregnancy on parent report 6-month infant development. We conducted a multi-site prospective birth cohort study during the 2010-2011 influenza season and followed pregnant women and their newborns through 6 months of age. Information on IIV3 during pregnancy was ascertained from the EHR and self-report. The Ages and Stages Questionnaire-3 (ASQ-3) was completed by the mother to assess 6-month infant neurodevelopment in five domains (communication, gross motor, fine motor, problem-solving, and personal adaptive skills). Scores for each domain above the cut-off point indicating typical development were categorized as “on schedule” while scores in the zones indicating the need for either monitoring or further assessment were categorized as “not on schedule”. Multivariable logistic regression was conducted. Of the 1225 infant-mother pairs, 65% received IIV3 during pregnancy. In bivariate analysis, infants of women who received IIV3 during pregnancy were moderately-less likely to need monitoring or further assessment in the personal social domain compared with infants of unvaccinated women (10.0% vs. 14.1%, p = 0.033; crude OR (cOR): 0.68(95%CI:0.48,0.97)). However, after controlling for potential confounders, the findings were no longer statistically significant (aOR:0.72,95%CI: 0.49,1.06,p = 0.46). No significant unadjusted or adjusted associations emerged in any other ASQ-3 domain. There was no significant association between IIV3 exposure during pregnancy and 6-month infant development. Studies of IIV3 during pregnancy to assess longer-term developmental outcomes are indicated.
Authors: Avalos LA; Zerbo O; Li DK; et al.
Vaccine. 2020 02 28;38(10):2326-2332. Epub 2020-02-05.
Survey of influenza vaccine knowledge, attitudes, and beliefs among pregnant women in the 2016-17 season
Influenza vaccination coverage among pregnant women in the United States is suboptimal. We surveyed women who were pregnant during the 2016-17 influenza season to assess knowledge and attitudes regarding influenza vaccination. We identified and sampled pregnant women to include approximately equal numbers of vaccinated and unvaccinated women from strata defined by vaccination status and trimester from four integrated health systems in the Vaccine Safety Datalink (VSD). Potential participants were contacted via mail and telephone to complete a standardized survey. Characteristics and responses of women vaccinated and unvaccinated during pregnancy were compared. The survey was completed by 510 (48%) of 1062 contacted women; 500 were included in the analysis. Vaccine receipt while pregnant was associated with primigravida status (p = 0.02), college degree (p = 0.01), employment in health care (p < 0.01), and history of routine annual influenza vaccination (p < 0.01). Among 330 vaccinated women, the primary reasons for vaccination included protection of self and baby from influenza (n = 233, 71%), and medical professional recommendation (n = 46, 14%). Multiple reasons were given for nonvaccination, but concern about 'negative effects' was cited most often (n = 44, 29%). Vaccinated women were significantly more likely to believe that influenza vaccines are safe and effective, and to recognize the potential for harm from influenza infection. Nearly all women reported receiving at least one influenza vaccination recommendation from a healthcare provider. Vaccinated pregnant women were more likely to receive routine annual influenza vaccine compared to those not vaccinated. Recommendations by obstetric providers should be supplemented with efforts to encourage women of childbearing age to receive annual vaccination.
Authors: King JP; Hanson KE; Donahue JG; Glanz JM; Klein NP; Naleway AL; DeStefano F; Weintraub E; Belongia EA
Vaccine. 2020 02 24;38(9):2202-2208. Epub 2020-01-25.
Homeschooling parents in California: Attitudes, beliefs and behaviors associated with child’s vaccination status
Senate Bill 277 (SB277) banned nonmedical exemptions from school-entry vaccination requirements for children attending classroom-based schools in California, but excluded homeschooled children from vaccination requirements. Thus, it was hypothesized that more parents would choose to homeschool to avoid vaccination requirements in response to SB277. There is limited literature on the vaccine attitudes, beliefs, and behaviors among the homeschooling population in the US, despite an overall increase in homeschooling nationwide and documented vaccine-preventable disease outbreaks within the homeschooled child population. Between November 2018 and January 2019, we conducted a cross-sectional online survey among homeschooling parents with at least one child in grades K-8 who is currently enrolled in one of the legally-acceptable mechanisms to homeschool in California: (1) home-based private school satellite program (PSP), or (2) public or charter independent study program (ISP) with no classroom-based instruction. Among 140 homeschooling parents from 8 schools in California, 71% reported that their youngest child in grade K-8 was up-to-date on immunizations at kindergarten-entry and 56% reported that they made the decision to homeschool their child after the implementation of SB277. Compared to homeschooling parents whose child was up-to-date at kindergarten entry, homeschooling parents whose child was not up-to-date at kindergarten entry reported higher concerns over vaccine safety and effectiveness, more frequently cited immunization mandates as a reason to homeschool, and were more likely to report having considered moving out of California due to immunization mandates. There was variation in vaccine attitudes and beliefs within the homeschooling population in this sample. Immunization mandates were a factor in the decision to homeschool for some parents in this sample, supporting the hypothesis that vaccine-hesitant parents considered homeschooling as a way to avoid immunization mandates such as SB277. Future studies should explore the complexities around vaccine attitudes, beliefs and behaviors among homeschooling populations.
Authors: Mohanty S; Joyce CM; Delamater PL; Klein NP; Salmon D; Omer SB; Buttenheim AM
Vaccine. 2020 02 18;38(8):1899-1905. Epub 2020-01-22.
Vaccine effectiveness of cell-culture relative to egg-based inactivated influenza vaccine during the 2017-18 influenza season
There is concern that influenza vaccine effectiveness (VE) may be attenuated by passage in eggs during manufacture. We compared quadrivalent cell-culture vaccine with egg-based vaccines, most of which were trivalent, against influenza A and B during 2017-2018 when A(H3N2) and B/Yamagata (present only in quadrivalent vaccines) predominated. We retrospectively examined risk of PCR-confirmed influenza A and B in members of Kaiser Permanente Northern California aged 4-64 years. We estimated the relative VE (rVE) of cell-culture vaccine versus egg-based vaccines, and the absolute VE (aVE) of each vaccine comparing vaccinated to unvaccinated individuals. Analyses used Cox regression with a calendar timeline, stratified by birth year, and adjusted for demographics, co-morbidities and utilization. One-third (1,016,965/3,053,248) of the population was vaccinated; 932,545 (91.7% of vaccinees) received egg-based and 84,420 (8.3%) received cell-culture vaccines. The rVE against influenza A was 8.0% (95% CI: -10, 23); aVE was 31.7% (CI: 18.7, 42.6) for cell-culture and 20.1% (CI: 14.5, 25.4) for egg-based vaccines. The rVE against influenza B was 39.6% (CI: 27.9, 49.3); aVE was 40.9% (CI: 30, 50.1) for cell-culture and 9.7% (CI 3.5, 15.6) for egg-based trivalent vaccines. Inclusion of the B/Yamagata lineage in the quadrivalent cell-based vaccine provided better protection against influenza B but vaccine effectiveness against influenza A was low for both the cell-culture vaccine and the egg-based vaccines. Improving influenza vaccines requires ongoing comparative vaccine effectiveness monitoring.
Authors: Klein NP; Fireman B; Goddard K; Zerbo O; Asher J; Zhou J; King J; Lewis N
PLoS One. 2020;15(2):e0229279. Epub 2020-02-26.
Chorioamnionitis: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data
Authors: Kachikis A; Klein NP; Brighton Collaboration Chorioamnionitis Working Group; et al.
Vaccine. 2019 12 10;37(52):7610-7622.
Near Real-Time Surveillance to Assess the Safety of the 9-Valent Human Papillomavirus Vaccine
Human papillomavirus is the most common sexually transmitted infection in the United States and causes certain anogenital and oropharyngeal cancers. The 9-valent human papillomavirus vaccine (9vHPV) provides protection against additional types not included in the quadrivalent vaccine. We conducted near real-time vaccine safety surveillance for 24 months after the vaccine became available in the Vaccine Safety Datalink. Immunizations and adverse events were extracted weekly from October 2015 to October 2017 from standardized data files for persons 9 to 26 years old at 6 Vaccine Safety Datalink sites. Prespecified adverse events included anaphylaxis, allergic reaction, appendicitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, injection site reaction, pancreatitis, seizure, stroke, syncope, and venous thromboembolism. The observed and expected numbers of events after 9vHPV were compared weekly by using sequential methods. Both historical and concurrent comparison groups were used to identify statistical signals for adverse events. Unexpected signals were investigated by medical record review and/or additional analyses. During 105 weeks of surveillance, 838 991 doses of 9vHPV were administered. We identified unexpected statistical signals for 4 adverse events: appendicitis among boys 9 to 17 years old after dose 3; pancreatitis among men 18 to 26 years old; and allergic reactions among girls 9 to 17 years old and women 18 to 26 years old after dose 2. On further evaluation, which included medical record review, temporal scan analysis, and additional epidemiological analyses, we did not confirm signals for any adverse events. After 2 years of near real-time surveillance of 9vHPV and several prespecified adverse events, no new safety concerns were identified.
Authors: Donahue JG; Klein NP; Belongia EA; et al.
Pediatrics. 2019 12;144(6). Epub 2019-11-18.
Assessment of Exemptions From Vaccination in California, 2015 to 2027
Authors: Delamater PL; Buttenheim AM; Klein NP; Mohanty S; Salmon DA; Omer SB
Ann Intern Med. 2019 Nov 05.
Uptake and safety of hepatitis A vaccination during pregnancy: A Vaccine Safety Datalink study
Infection with hepatitis A virus (HAV) during pregnancy, although uncommon, is associated with gestational complications and pre-term labor. Hepatitis A vaccine (HepA) is recommended for anyone at increased risk for contracting hepatitis A, including women at risk who are also pregnant. Limited data are available on the safety of maternal HepA vaccination. Assess the frequency of maternal HepA receipt and evaluate the potential association between maternal vaccination and pre-specified maternal and infant safety outcomes. A retrospective cohort of pregnancies in the Vaccine Safety Datalink (VSD) resulting in live births from 2004 through 2015 was included. Pregnancies with HepA exposure were compared to those with other vaccine exposures, and to those with no vaccine exposures. Risk factors for contracting hepatitis A were identified up to one-year prior to or during the pregnancy using ICD-9 codes. Maternal and fetal adverse events were evaluated according to maternal HepA exposure status. Adjusted odds ratio (OR) were used to describe the association. Among 666,233 pregnancies in the study period, HepA was administered at a rate of 1.7 per 1000 (n = 1140), most commonly within the first six weeks of pregnancy. Less than 3% of those exposed to HepA during pregnancy had an ICD-confirmed risk factor. There were no significant associations between HepA exposure during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, cesarean delivery, pre-term delivery, and low birthweight. There was a statistically significant association between HepA exposure during pregnancy and small-for-gestational age (SGA) infants (aOR 1.32, [95% CI 1.09, 1.60], p = 0.004). The rate of maternal HepA vaccination was low and rarely due to documented risk factors for vaccination. HepA vaccination during pregnancy was not associated with an increased risk for a range of adverse events examined among pregnancies resulting in live births, but an identified association between maternal HepA and SGA infant outcomes, while likely due to unmeasured confounding, warrants further exploration.
Authors: Groom HC; Klein NP; Naleway AL; et al.
Vaccine. 2019 10 16;37(44):6648-6655. Epub 2019-09-20.
Inactivated influenza vaccine and spontaneous abortion in the Vaccine Safety Datalink in 2012-13, 2013-14, and 2014-15
A recent study reported an association between inactivated influenza vaccine (IIV) and spontaneous abortion (SAB), but only among women who had also been vaccinated in the previous influenza season. We sought to estimate the association between IIV administered in three recent influenza seasons and SAB among women who were and were not vaccinated in the previous influenza season. We conducted a case-control study over three influenza seasons (2012-13, 2013-14, 2014-15) in the Vaccine Safety Datalink (VSD). Cases (women with SAB) and controls (women with live births) were matched on VSD site, date of last menstrual period, age group, and influenza vaccination status in the previous influenza season. Of 1908 presumptive cases identified from the electronic record, 1236 were included in the main analysis. Administration of IIV was documented in several risk windows, including 1-28, 29-56, and >56 days before the SAB date. Among 627 matched pairs vaccinated in the previous season, no association was found between vaccination in the 1-28 day risk window and SAB (adjusted odds ratio (aOR) 0.9; 95% confidence interval (CI) 0.6-1.5). The season-specific aOR ranged from 0.5 to 1.7 with all CIs including the null value of 1.0. Similarly, no association was found among women who were not vaccinated in the previous season; the season-specific aOR in the 1-28 day risk window ranged from 0.6 to 0.7 and the 95% CI included 1.0 in each season. There was no association found between SAB and influenza vaccination in the other risk windows, or when vaccine receipt was analyzed relative to date of conception. During these seasons we found no association between IIV and SAB, including among women vaccinated in the previous season. These findings lend support to current recommendations for influenza vaccination at any time during pregnancy, including the first trimester.
Authors: Donahue JG; Klein NP; Belongia EA; et al.
Vaccine. 2019 10 16;37(44):6673-6681. Epub 2019-09-17.
Prevalence of human papillomavirus (HPV)-vaccine types by race/ethnicity and sociodemographic factors in women with high-grade cervical intraepithelial neoplasia (CIN2/3/AIS), Alameda County, California, United States
We evaluated racial/ethnic differences in prevalence of oncogenic HPV types targeted by the quadrivalent HPV vaccine (16/18) and nonavalent HPV vaccine (31/33/45/52/58) in women diagnosed with CIN2/3/AIS after quadrivalent HPV vaccine introduction (2008-2015). Typing data from 1810 cervical tissue specimen from HPV-IMPACT (Alameda County, California, US), a population-based CIN2/3/AIS surveillance effort, were analyzed. Using log-binomial regression, we calculated adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) comparing type prevalence by race/ethnicity, adjusted for health insurance, age, CIN2/3/AIS grade, and time period, overall and in the "early vaccine era" (2008-2011) and "later vaccine era" (2012-2015). Overall, oncogenic HPV16/18 prevalence was significantly lower among black (43%) and Hispanic (43%) women compared with white (52%) women (aPR (95% CI): 0.80 (0.70, 0.93) and 0.80 (0.70, 0.91), respectively). In 2008-2011, proportion of HPV16/18 detected was significantly lower in black (47%), Hispanic (46%), and Asian (42%) women compared to white (58%) women (aPR (95% CI): 0.80 (0.67, 0.96), 0.75 (0.63, 0.90), and 0.73 (0.58, 0.90), respectively). There were no significant differences in 2012-2015. Between the two eras, HPV16/18 prevalence declined in white (-11%), black (-9%), and Hispanic (-6%) women, and increased in Asian women (12%). Decreasing HPV 16/18 prevalence in CIN2/3/AIS lesions in white, black, and Hispanic women may suggest benefit from quadrivalent vaccination. In our unadjusted analysis of HPV31/33/45/52/58, prevalence did not differ significantly by race/ethnicity, but was significantly higher among Hispanic women (32%) compared to white women (27%) after adjustment (aPR (95%CI): 1.22 (1.02, 1.47). Prevalence was also non-significantly higher among black (32%) and Asian (33%) women. This analysis suggests that the nonavalent vaccine’s potential for impact against cervical precancers will not be lower in women of color compared to white women. These data underscore the importance of equitable vaccination in facilitating continued declines of vaccine-preventable HPV types among all women.
Authors: Saadeh K; Park I; Gargano JW; Whitney E; Querec TD; Hurley L; Silverberg M
Vaccine. 2019 Oct 11.
Long-term effectiveness of zoster vaccine live for postherpetic neuralgia prevention
Postherpetic neuralgia (PHN) occurs in 5-30% of individuals with herpes zoster (HZ) and is characterized by long-lasting pain. Zoster vaccine live (ZVL) is licensed for people 50 years and older to prevent HZ and PHN. This study evaluated vaccine effectiveness (VE) of ZVL against PHN. We conducted an open cohort study within Kaiser Permanente Northern California with continuous accrual of people as they became age-eligible for ZVL. We defined PHN using a PHN diagnosis between 90 and 365 days after an incident episode of HZ. We estimated VE against PHN using Cox regression with a calendar timeline stratified by year of birth and adjusted for sex, race, influenza vaccination, outpatient visit frequency, comorbidities, and immune compromise status. From 2007 to 2016, 1·5 million people entered the study population and 33% received ZVL. During 7·6 million person-years of follow-up, there were 62,205 HZ cases, 4150 (6·7%) of which went on to develop PHN. Overall VE for PHN was 64·8% (95% CI 61·3, 68). VE was 82·8% (95% CI 77·6, 86·7) during the first year after vaccination, 58·3% (95% CI 50.1, 65.2) during the third year, and then waned more gradually to 48·7% (95% CI 30·2, 62·3) during the eighth year. VE in persons vaccinated when aged 80 years or older was similar to VE in younger vaccinees. VE in persons vaccinated when immune compromised was similar to VE in immune competent. Overall, ZVL was 65% effective against PHN. It was effective in all age groups and provided moderate protection through 8 years.
Authors: Klein NP; Bartlett J; Fireman B; Marks MA; Hansen J; Lewis E; Aukes L; Saddier P
Vaccine. 2019 08 23;37(36):5422-5427. Epub 2019-07-10.
Antibody persistence and booster response following MenACWY-CRM vaccination in children as assessed by two different assay methods
The quadrivalent meningococcal conjugate vaccine MenACWY-CRM has been shown to be immunogenic and well-tolerated in infants and toddlers. We evaluated antibody persistence for up to 4 years after vaccination with MenACWY-CRM in the first years of life and response to a booster dose administered at 60 months of age. This was phase 3b, open-label, multicenter extension trial (NCT01148017). We assessed by hSBA and rSBA the persistence of antibody responses to serogroups ACWY in 203 healthy 60-month-olds receiving 4 doses of MenACWY-CRM during infancy (ACWY-4 group), or 2 doses at 12/13 and 15 months or 1 dose at 18 months of age (ACWY-2 group). We administered a MenACWY-CRM dose to 224 primed and 45 naïve 60-month-olds and evaluated safety and antibody response 1 month later. Antibody persistence measured by both assays was higher in primed than naïve 60-month-olds. The percentages of primed children with hSBA titers ≥8 was low for serogroup A (6-25%) and moderate for serogroups C (27-43%), Y (69-74%) and W (56-69%). For all serogroups, hSBA antibody geometric mean titers (GMTs) tended to be higher in the ACWY-2 than the ACWY-4 group. Post-booster/single dose, ≥96% of primed and ≥73% of naïve children had hSBA titers ≥8 against each serogroup, and hSBA GMTs were higher in primed children. The booster dose was well-tolerated and no safety concern was identified. We further assessed persistence using rSBA across different age groups and detected no overall correlation between rSBA and hSBA titers. Primary vaccination of infants/toddlers with MenACWY-CRM resulted in moderate antibody persistence against serogroups C, W and Y for up to 4 years after the last priming dose. Regardless of priming schedule, a MenACWY-CRM booster dose at 60 months of age induced a robust immune response against all serogroups and was well-tolerated in all children.
Authors: Klein NP; Block SL; Essink B; Barbi S; Smolenov I; Keshavan P
Vaccine. 2019 07 26;37(32):4460-4467. Epub 2019-07-03.
The impact of reactogenicity after the first dose of recombinant zoster vaccine upon the physical functioning and quality of life of older adults: an open phase III trial
Herpes zoster and its related complications are associated with significant medical burden, which negatively affects quality of life and daily functioning of the patients. The recently licensed recombinant zoster vaccine (RZV) offers high efficacy but is associated with local and systemic reactions. This study assessed the impact of RZV on the quality of life and daily functioning of participants and implications for caregivers. Four hundred and one adults aged 50 years or older received single RZV doses at 0 and 2 months in this open-label, single-arm, multicenter study (NCT02979639). Change in mean SF-36 Physical Functioning score following first-dose administration, quality of life, reactogenicity, safety, productivity loss, and health care resource utilization was assessed. The current analysis was performed post-vaccine dose-1; safety follow-up will continue until 1 year post-dose-2. The most common solicited local symptoms were injection-site pain (77.5%), redness (23.0%), and swelling (13.3%); the most frequent solicited systemic reactions were fatigue (33.5%), headache (28.3%), and myalgia (26.8%). Grade 3 reactogenicity occurred in 9.5% of participants and was associated with a transient clinically important decrease in SF-36 Physical Functioning score (affecting activities such as walking, carrying groceries, climbing stairs) on Days 1 and 2 post-first vaccination. No clinically meaningful reductions in mean SF-36 Physical Functioning scale scores from pre- to post-RZV dose-1 were observed (mean +1.9 points, primary end point), and no overall quality-adjusted-life-year loss was recorded post-dose-1. Five participants reported lost workdays; caregiver workload was not increased. Overall, the physical functioning and quality of life of older adults were not affected by a first RZV dose. The observed reactogenicity was consistent with previous studies.
Authors: Schmader KE; Klein NP; Curran D; et al.
J Glaucoma. 2019 05;28(5):473-480.
Associations of Statewide Legislative and Administrative Interventions With Vaccination Status Among Kindergartners in California
California implemented 3 interventions to increase uptake of vaccines. In 2014, Assembly bill 2109 tightened requirements for obtaining a personal belief exemption. A 2015 campaign provided educational materials to school staff on the proper application of conditional admission for kindergartners who were not up to date on required vaccinations. In 2016, Senate bill 277 eliminated personal belief exemptions. Prior research has not evaluated these 3 interventions together with regard to the vaccination status of students. To assess the changes in the yearly rates of kindergartners who were not up to date on required vaccinations who were entering school during the period of the interventions, by focusing on geographic clustering and the potential contacts of these kindergartners. Observational study that used cross-sectional school-entry data from 2000-2017 to calculate the rates of kindergartners attending California schools who were not up to date on required vaccinations. Assembly bill 2109, a conditional admission education program, and Senate bill 277. The primary outcome was the yearly rate of kindergartners without up-to-date vaccination status. The secondary outcomes were (1) the modified aggregation index, which was used to assess the potential within-school contacts among kindergartners without up-to-date vaccination status, (2) the number of geographic clusters of schools with rates for kindergartners without up-to-date vaccination status that were higher than the rates for schools located outside the cluster, and (3) the number of schools located inside the geographic clusters. In California between 2000 and 2017, 9 323 315 children started attending kindergarten and 721 593 were not up to date on required vaccinations. Prior to the interventions, the statewide rate of kindergartners without up-to-date status for required vaccinations increased from 7.80% during 2000 to 9.84% during 2013 and then decreased after the interventions to 4.87% during 2017. The percentage chance for within-school contact among kindergartners without up-to-date vaccination status decreased from 26.02% during 2014 to 4.56% (95% CI, 4.21%-4.99%) during 2017. During 2012-2013, there were 124 clusters that contained 3026 schools with high rates of kindergartners without up-to-date vaccination status. During 2014-2015, there were 93 clusters that contained 2290 schools with high rates of kindergartners without up-to-date vaccination status. During 2016-2017, there were 110 clusters that contained 1613 (95% CI, 1565-1691) schools. In California, statewide legislative and educational interventions were associated with a decrease in the yearly rates of kindergartners without up-to-date vaccination status. These interventions also were associated with reductions in the number of schools inside the clusters with high rates of kindergartners without up-to-date vaccination status and the potential for contact among these kindergartners.
Authors: Pingali SC; Delamater PL; Buttenheim AM; Salmon DA; Klein NP; Omer SB
JAMA. 2019 07 02;322(1):49-56.
Incidence of Herpes Zoster Among Children: 2003-2014
After the 1996 introduction of routine varicella vaccination in the United States, most studies evaluating pediatric herpes zoster (HZ) incidence reported lower incidence over time, with varying degrees of decline. Using the combined databases of 6 integrated health care organizations, we examined HZ incidence in children over a 12-year period in the varicella vaccine era. This study included children aged 0 through 17 years from 2003 through 2014. Using electronic medical records, we identified HZ cases through International Classification of Diseases, Ninth Revision diagnosis code 053. We calculated HZ incidence rates per 100 000 person years of health plan membership for all children and among children who were vaccinated versus unvaccinated. We calculated rates for the 12-year period and examined temporal trends. Among children who were vaccinated, we compared HZ rates by month and year of age at vaccination. The study included 6 372 067 children with ≥1 month of health plan membership. For the 12-year period, the crude HZ incidence rate for all subjects was 74 per 100 000 person years, and the rate among children who were vaccinated was 38 per 100 000 person years, which was 78% lower than that among children who were unvaccinated (170 per 100 000 person years; P < .0001). Overall HZ incidence declined by 72% (P < .0001) from 2003 through 2014. Annual rates in children who were vaccinated were consistently lower than in children who were unvaccinated. With this population-based study, we confirm the decline in pediatric HZ incidence and the significantly lower incidence among children who are vaccinated, reinforcing the benefit of routine varicella vaccination to prevent pediatric HZ.
Authors: Weinmann S; Klein NP; Chun C; et al.
Pediatrics. 2019 07;144(1). Epub 2019-06-10.
Acellular Pertussis Vaccine Effectiveness Over Time
To determine pertussis risk by diphtheria-tetanus-acellular pertussis (DTaP) vaccination status and time since last DTaP dose. Children born at Kaiser Permanente Northern California between 1999 and 2016 were followed from 3 months of age until they tested positive for pertussis; disenrolled from Kaiser Permanente Northern California; received the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed vaccine; turned 11 years of age, or the end of the study period. DTaP vaccination status was categorized on the basis of the number of doses received in relation to the number of doses expected according to the Advisory Committee on Immunization Practice-recommended ages. Among 469 982 children ages 3 months to 11 years, we identified 738 pertussis cases. A total of 99 cases were unvaccinated, 36 were undervaccinated, 515 were fully vaccinated, and 88 were fully vaccinated plus 1 dose. Pertussis risk was 13 times higher among unvaccinated (adjusted hazard ratio [aHR] = 13.53; 95% confidence interval [CI] 10.64-17.21) compared with fully vaccinated children and 1.9 times higher (aHR = 1.86; 95% CI 1.32-2.63) among undervaccinated children. Among vaccinated children ages 19 to <84 months, pertussis risk was 5 times higher (aHR = 5.04; 95% CI 1.84-13.80) ≥3 years vs <1 year after vaccination. Among children ages 84 to 132 months, risk was 2 times higher (aHR = 2.32; 95% CI 0.97-5.59) ≥6 years vs <3 years after vaccination. Undervaccinated and especially unvaccinated children were at greater risk of pertussis. However, most pertussis cases occurred among children age-appropriately vaccinated who were further away from their last DTaP dose, suggesting that suboptimal vaccine effectiveness played a major role in recent pertussis epidemics.
Authors: Zerbo O; Bartlett J; Goddard K; Fireman B; Lewis E; Klein NP
Pediatrics. 2019 07;144(1). Epub 2019-06-10.
Elimination of Nonmedical Immunization Exemptions in California and School-Entry Vaccine Status
California implemented Senate Bill 277 (SB277) in 2016, becoming the first state in nearly 30 years to eliminate nonmedical exemptions from immunization requirements for schoolchildren. Our objectives were to determine (1) the impacts of SB277 on the percentage of kindergarteners entering school not up-to-date on vaccinations and (2) if geographic patterns of vaccine refusal persisted after the implementation of the new law. At the state level, we analyzed the magnitude and composition of the population of kindergarteners not up-to-date on vaccinations before and after the implementation of SB277. We assessed correlations between previous geographic patterns of nonmedical exemptions and patterns of the remaining entry mechanisms for kindergarteners not up-to-date after the law’s implementation. In the first year after SB277 was implemented, the percentage of kindergartners entering school not up-to-date on vaccinations decreased from 7.15% to 4.42%. The conditional entrance rate fell from 4.43% to 1.91%, accounting for much of this decrease. Other entry mechanisms for students not up-to-date, including medical exemptions and exemptions for independent study or homeschooled students, largely replaced the decrease in the personal belief exemption rate from 2.37% to 0.56%. In the second year, the percentage of kindergartners not up-to-date increased by 0.45%, despite additional reductions in conditional entrants and personal belief exemptions. The correlational analysis revealed that previous geographic patterns of vaccine refusal persisted after the law’s implementation. Although the percentage of incoming kindergarteners up-to-date on vaccinations in California increased after the implementation of SB277, we found evidence for a replacement effect.
Authors: Delamater PL; Pingali SC; Buttenheim AM; Salmon DA; Klein NP; Omer SB
Pediatrics. 2019 06;143(6). Epub 2019-05-21.
Vaccine safety in HIV-infected adults within the Vaccine Safety Datalink Project
We evaluate safety of routine vaccination among adults infected with human immunodeficiency virus (HIV) in five healthcare organizations in the United States. We conducted a retrospective cohort study of HIV-infected adults who received inactivated influenza vaccines, hepatitis B vaccines, pneumococcal vaccines, or tetanus, diphtheria, and acellular pertussis vaccines between 2002 and 2013. We conducted self-controlled case series analysis to estimate the relative risk (RR) for 11 pre-specified adverse events (AEs) requiring medical attention. Among 20,417 HIV-infected adults (90.2% male), a total of 137,674 vaccine doses were administered. Based on ICD-9 codes, we detected an increased risk of cellulitis and infection (RR: 1.18, 95% CI: 1.03-1.35) among all patients, and an increased risk of stroke/cerebrovascular diseases among patients with an HIV viral load >10,000 copies/ml (adjusted RR: 3.94, 95% CI: 1.32-11.72). Further analyses on chart confirmed cases of stroke/cerebrovascular diseases indicated no statistically significant increased risk (adjusted RR: 1.72, 95% CI: 0.41-7.24). There was no evidence of increased risk for other AEs following routine vaccination in HIV-infected adults. Routinely administered vaccines are generally safe for HIV-infected adults.
Authors: Hechter RC; Qian L; Tartof SY; Sy LS; Klein NP; Weintraub E; Mercado C; Naleway A; McLean HQ; Jacobsen SJ
Vaccine. 2019 May 31;37(25):3296-3302. Epub 2019-05-04.
Intra-season Waning of Influenza Vaccine Effectiveness
In the United States, it is recommended that healthcare providers offer influenza vaccination by October, if possible. However, if the vaccine’s effectiveness soon begins to wane, the optimal time for vaccination may be somewhat later. We examined whether the effectiveness of influenza vaccine wanes during the influenza season with increasing time since vaccination. We identified persons who were vaccinated with inactivated influenza vaccine from 1 September 2010 to 31 March 2017 and who were subsequently tested for influenza and respiratory syncytial virus (RSV) by a polymerase chain reaction test. Test-confirmed influenza was the primary outcome and days-since-vaccination was the predictor of interest in conditional logistic regression. Models were adjusted for age and conditioned on calendar day and geographic area. RSV was used as a negative-control outcome. Compared with persons vaccinated 14 to 41 days prior to being tested, persons vaccinated 42 to 69 days prior to being tested had 1.32 (95% confidence interval [CI], 1.11 to 1.55) times the odds of testing positive for any influenza. The odds ratio (OR) increased linearly by approximately 16% for each additional 28 days since vaccination. The OR was 2.06 (95% CI, 1.69 to 2.51) for persons vaccinated 154 or more days prior to being tested. No evidence of waning was found for RSV. Our results suggest that effectiveness of inactivated influenza vaccine wanes during the course of a single season. These results may lead to reconsideration of the optimal timing of seasonal influenza vaccination.
Authors: Ray GT; Lewis N; Klein NP; Daley MF; Wang SV; Kulldorff M; Fireman B
Clin Infect Dis. 2019 05 02;68(10):1623-1630.
Influenza Vaccine Effectiveness in Preventing Influenza-associated Hospitalizations During Pregnancy: A Multi-country Retrospective Test Negative Design Study, 2010-2016
To date, no study has examined influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza-associated hospitalizations during pregnancy. The Pregnancy Influenza Vaccine Effectiveness Network (PREVENT) consisted of public health or healthcare systems with integrated laboratory, medical, and vaccination records in Australia, Canada (Alberta and Ontario), Israel, and the United States (California, Oregon, and Washington). Sites identified pregnant women aged 18 through 50 years whose pregnancies overlapped with local influenza seasons from 2010 through 2016. Administrative data were used to identify hospitalizations with acute respiratory or febrile illness (ARFI) and clinician-ordered real-time reverse transcription polymerase chain reaction (rRT-PCR) testing for influenza viruses. Overall IVE was estimated using the test-negative design and adjusting for site, season, season timing, and high-risk medical conditions. Among 19450 hospitalizations with an ARFI discharge diagnosis (across 25 site-specific study seasons), only 1030 (6%) of the pregnant women were tested for influenza viruses by rRT-PCR. Approximately half of these women had pneumonia or influenza discharge diagnoses (54%). Influenza A or B virus infections were detected in 598/1030 (58%) of the ARFI hospitalizations with influenza testing. Across sites and seasons, 13% of rRT-PCR-confirmed influenza-positive pregnant women were vaccinated compared with 22% of influenza-negative pregnant women; the adjusted overall IVE was 40% (95% confidence interval = 12%-59%) against influenza-associated hospitalization during pregnancy. Between 2010 and 2016, influenza vaccines offered moderate protection against laboratory-confirmed influenza-associated hospitalizations during pregnancy, which may further inform the benefits of maternal influenza vaccination programs.
Authors: Thompson MG; Klein NP; PREVENT Workgroup; et al.
Clin Infect Dis. 2019 04 24;68(9):1444-1453.
Safety and Immunogenicity of a Full-Dose Split-Virion Inactivated Quadrivalent Influenza Vaccine in Healthy Children 6 to 35 Months of Age: A Randomized Controlled Clinical Trial
For children <3 years of age, a half dose of inactivated influenza vaccine (7.5 μg hemagglutinin per strain) has been used for more than 30 years, but several studies indicate that a full dose (15 μg hemagglutinin per strain) can be used in this population without increasing the rate of fever or other reactions. Here, we compare the safety and immunogenicity of full and half doses of quadrivalent, split-virion, inactivated influenza vaccine (IIV4) in children 6-35 months of age. In this phase IV, randomized, observer-blinded, multi-center study, healthy children 6-35 months of age were randomized 1:1 to be vaccinated with a half or full dose of IIV4 (NCT02915302). The primary objective was to demonstrate that the rate of any fever (≥38.0°C) up to 7 days after a full dose of IIV4 was noninferior to the rate of fever after a half dose. The study included 1950 children. Noninferiority in the rate of fever was demonstrated for the full dose versus the half dose of IIV4 (difference in rate = 0.84%; 95% confidence interval, -2.13% to 3.80%). Solicited reactions and unsolicited adverse events were similar between the dose groups. No vaccine-related serious adverse events were reported. Noninferiority of both hemagglutination inhibition geometric mean titers and seroconversion rates was demonstrated for all 4 vaccine strains for the full dose versus the half dose. In children 6-35 months of age, a full dose of IIV4 was immunogenic and had a safety profile comparable to that of a half dose, with no new safety concerns observed.
Authors: Robertson CA; Mercer M; Selmani A; Klein NP; Jeanfreau R; Greenberg DP
Pediatr Infect Dis J. 2019 03;38(3):323-328.
Exploring California’s new law eliminating personal belief exemptions to childhood vaccines and vaccine decision-making among homeschooling mothers in California
California’s Senate Bill 277 (SB-277) law eliminated the personal belief exemption to school immunization requirements. A potential consequence may be that parents choose homeschooling to avoid immunization. Vaccine attitudes and behaviors have not been well studied among the home-schooling population. This study explored the effect of SB-277 and vaccine decision-making among California home schoolers. Purposive and snowball sampling were used recruit home-schooling parents through home-schooling Facebook groups based on home school type in high-exemption regions in California for in-depth interviews. Participants had to have a child in a legalized form of homeschooling in California in grades kindergarten-twelfth grade. Twenty-four mothers were interviewed. Participants were categorized based on self-reported vaccine attitudes and behavior into three groups: Confident and Accepting, Hesitant and Accepting, and Skeptical and Refusing. All reported the belief that SB-277 is an infringement on parental rights but was not currently impacting them. Confident and Accepting mothers (n?=?10) generally believed vaccinations were safe, effective, and posed a lower risk than vaccine preventable disease (VPD). Hesitant and Accepting mothers (n?=?5) expressed varying confidence levels in the belief that vaccinations were safe and effective, were not confident in the belief that vaccination posed lower risks than VPD risk, and risk perception affected vaccine decision-making. Skeptical and Refusing mothers (n?=?9) generally believed that vaccinations were unsafe and ineffective, refused select vaccines, believed that vaccination posed a more serious risk than VPD risks, and belief of vaccine harm was a salient factor in vaccine decision-making. Home-schooling mothers were concerned about SB-277 but did not report that it was directly impacting their children, their vaccine decisions, or reason to home school. Vaccine attitudes and beliefs among homeschooling mothers broadly fell into categories similar to parents of non-home-schooled children. Future quantitative studies should measure vaccine hesitancy and refusal prevalence and potential confounders.
Authors: McDonald P; Limaye RJ; Omer SB; Buttenheim AM; Mohanty S; Klein NP; Salmon DA
Value Health. 2019 06;22(6):648-655. Epub 2019-05-17.
Estimating Vaccine Effectiveness Against Hospitalized Influenza During Pregnancy: Multicountry Protocol for a Retrospective Cohort Study
Although pregnant women are believed to have elevated risks of severe influenza infection and are targeted for influenza vaccination, no study to date has examined influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza-associated hospitalizations during pregnancy, primarily because this outcome poses many methodological challenges. The Pregnancy Influenza Vaccine Effectiveness Network (PREVENT) was formed in 2016 as an international collaboration with the Centers for Disease Control and Prevention; Abt Associates; and study sites in Australia, Canada, Israel, and the United States. The primary goal of this collaboration is to estimate IVE in preventing acute respiratory or febrile illness (ARFI) hospitalizations associated with laboratory-confirmed influenza virus infection during pregnancy. Secondary aims include (1) describing the incidence, clinical course, and severity of influenza-associated ARFI hospitalization during pregnancy; (2) comparing the characteristics of ARFI-hospitalized pregnant women who were tested for influenza with those who were not tested; (3) describing influenza vaccination coverage in pregnant women; and (4) comparing birth outcomes among women with laboratory-confirmed influenza-associated hospitalization versus other noninfluenza ARFI hospitalizations. For an initial assessment of IVE, sites identified a retrospective cohort of pregnant women aged from 18 to 50 years whose pregnancies overlapped with local influenza seasons from 2010 to 2016. Pregnancies were defined as those that ended in a live birth or stillbirth of at least 20 weeks gestation. The analytic sample for the primary IVE analysis was restricted to pregnant women who were hospitalized for ARFI during site-specific influenza seasons and clinically tested for influenza virus infection using real-time reverse transcription polymerase chain reaction. We identified approximately 2 million women whose pregnancies overlapped with influenza seasons; 550,344 had at least one hospitalization during this time. After restricting to women who were hospitalized for ARFI and tested for influenza, the IVE analytic sample included 1005 women. In addition to addressing the primary question about the effectiveness of influenza vaccination, PREVENT data will address other important knowledge gaps including understanding the incidence, clinical course, and severity of influenza-related hospitalizations during pregnancy. The data infrastructure and international partnerships created for these analyses may be useful and informative for future influenza studies. DERR1-10.2196/11333.
Authors: Naleway AL; Klein NP; Thompson MG; et al.
JMIR Res Protoc. 2019 Jan 21;8(1):e11333. Epub 2019-01-21.
Similar relative risks of seizures following measles containing vaccination in children born preterm compared to full-term without previous seizures or seizure-related disorders
Febrile seizures are associated with the first dose of measles-containing vaccines and the risk increases with chronologic age during the second year of life. We used the Vaccine Safety Datalink (VSD) to determine if the relative increase in risk of seizures following receipt of measles-containing vaccine differs by gestational age at birth. Children were eligible if they received their first dose of measles-containing vaccine at age 12 through 23?months from January 2003 through September 2015. Children were excluded if they had a history of seizure or conditions strongly related to seizure prior to 12?months of age. Seizures were identified by diagnostic codes in the inpatient or emergency department settings. Using risk-interval analysis, we estimated the incidence rate ratio (IRR) for seizures in the 7 through 10?days (risk period) vs 15 through 42?days (control period) following receipt of measles-containing vaccines in children born preterm (<37?weeks gestation age) and those born full-term (?37?weeks). There were 532,375 children (45,343 preterm and 487,032 full-term) who received their first dose of measles-containing vaccine at age 12 through 23?months. The IRRs of febrile seizures 7 through 10?days compared with 15 through 42?days after receipt of measles-containing vaccine were 3.9 (95% CI: 2.5-6.0) in preterm children and 3.2 (2.7-3.7) in full-term children; the ratio of IRRs: was 1.2 (0.76-1.9), p?=?0.41. IRRs were also similar across gestational age groups, by vaccine type received (measles-mumps-rubella [MMR] or measles-mumps-rubella-varicella [MMRV]) and age at vaccination (12-15 or 16-23?months). Vaccination with a measles-containing vaccine in the second year of life is associated with a similar relative risk of a first seizure in children born preterm as in those who were born full-term.
Authors: McClure DL; Jacobsen SJ; Klein NP; Naleway AL; Kharbanda EO; Glanz JM; Jackson LA; Weintraub ES; McLean HQ
Vaccine. 2019 01 03;37(1):76-79. Epub 2018-11-23.
Impact of an electronic medical record reminder on hepatitis B vaccine initiation and completion rates among insured adults with diabetes mellitus
The Advisory Committee on Immunization Practices recommends Hepatitis B (HepB) vaccine for previously unvaccinated adults <60 years with diabetes mellitus. This observational retrospective cohort study assessed the impact of implementing electronic provider reminders on HepB vaccine initiation and 3-dose series completion rates among insured adults with diabetes aged 19-59 years old. Difference-in-difference (DID) analyses compared changes in vaccine initiation and completion rates (ratio of the rate ratio [RRR] and 95% confidence interval [CI]) during 12 months pre- and post-implementation between intervention and control sites. We examined trends in vaccine initiation and completion rates by plotting monthly rates during the study period. We also calculated the overall HepB vaccine coverage rates with 95% CI among all adults with diabetes aged 19-59 years old at the start and end date of the study period. Baseline HepB vaccine initiation and completion rates were similar at both the intervention and control sites. Gender, age, and race/ethnicity distributions within both sites were similar during the 12 months pre- and post-implementation. DID analyses demonstrated statistically significant differences in the changes of the annual vaccine initiation rates (RRR: 70.7, 95% CI: 62.8-79.6) and the third dose completion rates (RRR = 18.7, 95% CI: 14.2-24.8) between the two sites. The coverage increased significantly at the intervention site while it remained low at the control site. Use of provider reminders is highly effective in increasing both HepB vaccine initiation and series completion rates among adults with diabetes.
Authors: Hechter RC; Klein NP; Tseng HF; et al.
Vaccine. 2019 01 03;37(1):195-201. Epub 2018-06-27.
Evaluation of two frailty indices, with practical application in a vaccine clinical trial
Frail older adults are at increased risk of poor clinical outcomes. Frailty assessment is therefore important in clinical trials to understand the benefits and harms of interventions. However, consensus is lacking on how frailty should be assessed.We developed a prospectively specified index using a battery of formal tests and instruments and a retrospectively generated index using medical comorbidities and patient reported outcomes (PROs) within an adjuvanted recombinant zoster vaccine (RZV) trial (NCT02979639). For both frailty indices (FIs), a total deficit score was calculated as the accumulation of deficits and participants were categorized as non-frail, pre-frail and frail. We assessed (1) the feasibility and validity of both FIs; (2) the impact of RZV vaccine reactogenicity by frailty status on Short Form-36 [SF-36] physical functioning (PF) scores.Of 401 participants, aged ≥50 years, 236 (58.9%) were categorized non-frail, 143 (35.7%), pre-frail, and 22 (5.5%) frail using the prospective FI. Corresponding numbers for the retrospective FI were 192 (47.9%), 169 (42.1%) and 40 (10.0%), respectively. Strong concordance was observed between the frailty status assessments (P < .001). The proportion defined as frail increased from 1.5%, to 10.4% in participants aged 50-59, and ≥70 years, respectively, for the prospective FI. Corresponding numbers for the retrospective FI were 3.7%, and 17.2%, respectively. RZV vaccination was associated with a transient, non-clinically meaningful, decrease on the SF-36 PF score in frail participants.Both frailty indices provided similar results. The retrospectively generated FI offers the advantage of being easier to incorporate into vaccine clinical trials of older adults.
Authors: Curran D; Andrew MK; Levin MJ; Turriani E; Matthews S; Fogarty C; Klein NP; Grupping K; Oostvogels L; Schmader KE
Hum Vaccin Immunother. 2019;15(12):2960-2968. Epub 2019-06-21.
Immunogenicity and safety following primary and booster vaccination with a hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and Haemophilus influenzae type b vaccine: a randomized trial in the United States
Combined hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis and Haemophilus influenzae type b vaccine (DTaP-HBV-IPV/Hib) can further reduce the number of injections in pediatric immunization schedules of countries currently using pentavalent DTaP combination vaccines. This open-label, randomized, multicenter study (NCT02096263) conducted in the United States evaluated the immunogenicity and safety of DTaP-HBV-IPV/Hib vaccine compared with concomitant administration of DTaP-HBV-IPV and HibA or DTaP-IPV/Hib and HBV vaccines. We randomized (1:1:1) infants to receive 3-dose priming with DTaP-HBV-IPV/Hib boosted with DTaP+ HibB, DTaP-HBV-IPV+ HibA boosted with DTaP+ HibA, or DTaP-IPV/Hib+ HBV boosted with DTaP-IPV/Hib, at 2, 4, 6, and 15-18 months of age. We enrolled and vaccinated 585 participants, 486 received a booster, and 476 completed the study. Of these, 466 participants were included in the primary and 408 in the booster according-to-protocol cohorts for immunogenicity. We demonstrated non-inferiority of DTaP-HBV-IPV/Hib vaccine to DTaP-HBV-IPV+ HibA co-administered vaccines in terms of geometric mean concentrations for pertussis antibodies post-primary vaccination. Post-primary vaccination, seroprotection/seropositivity rates for all vaccine antigens were similarly high between DTaP-HBV-IPV/Hib (? 94.8%), DTaP-HBV-IPV+ HibA (? 98.1%) or DTaP-IPV/Hib+ HBV (? 97.8%) groups. We observed robust immune responses post-booster, indicating effective priming by the 3 regimens. Reactogenicity was similar in the 3 groups. Twenty-eight serious adverse events were reported during the study; 3 were considered related to vaccination and resolved by the end of the study. These results confirm that DTaP-HBV-IPV/Hib could be a valuable additional source of pediatric DTaP, IPV, HBV, and Hib-containing vaccine in countries that currently use multivalent vaccines.
Authors: Klein NP; Abu-Elyazeed R; Cheuvart B; Janssens W; Mesaros N
Hum Vaccin Immunother. 2019;15(4):809-821. Epub 2019-01-04.
Coadministration of 13-valent pneumococcal conjugate and quadrivalent inactivated influenza vaccines in adults previously immunized with polysaccharide pneumococcal vaccine 23: a randomized clinical trial
Immune responses to 13-valent pneumococcal conjugate vaccine (PCV13) and quadrivalent inactivated influenza vaccine (QIV) in older adults may vary with coadministration and previous pneumococcal polysaccharide vaccination. This study assessed safety and noninferiority of immune responses to coadministered PCV13 and QIV compared with each vaccine given alone. Adults ?50 years old preimmunized with ?1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) ?1 year before enrollment were randomized 1:1 to receive PCV13+QIV then placebo 1 month later or placebo+QIV then PCV13 1 month later. Administration of PCV13 and placebo was blinded; QIV was administered open-label. Pneumococcal serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) 1 month after PCV13, and influenza hemagglutination inhibition assay GMTs 1 month after QIV were measured. Prespecified noninferiority was demonstrated by a lower bound of the 2-sided 95% CI for geometric mean ratios >0.5. Safety endpoints included proportions of subjects with adverse and serious adverse events. Of 882 randomized subjects, 846 comprised the evaluable immunogenicity population. Immune responses to all 13 pneumococcal serotypes and all 4 influenza strains 1 month after PCV13+QIV were noninferior to responses 1 month after each vaccine given alone. No safety concerns were identified. Immune responses to coadministered PCV13 and QIV were noninferior to responses after each vaccine given alone, although generally lower for coadministered PCV13. PCV13 and QIV can be administered concomitantly to adults ?50 years of age preimmunized with PPSV23.
Authors: Thompson AR; Klein NP; Schmöele-Thoma B; et al.
Hum Vaccin Immunother. 2019;15(2):444-451. Epub 2018-10-25.
Immunogenicity and safety of the Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine co-administered with human rotavirus, hepatitis A and 13-valent pneumococcal conjugate vaccines: results from a phase III, randomized, multicenter study in infants
This phase III, open-label, randomized study (NCT01978093) evaluated the immunogenicity and safety of co-administered Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (Hib-MenCY-TT) with human rotavirus vaccine (HRV), hepatitis A vaccine (HAV) and 13-valent pneumococcal conjugate vaccine (PCV13). We randomized 600 infants (1:1) to receive 4 doses of Hib-MenCY-TT at 2, 4, 6 and 12-15 months of age or 3 doses of Hib vaccine conjugated to N. meningitidis outer membrane protein complex (Hib-OMP) at 2, 4 and 12-15 months of age. All infants received HRV at 2 and 4 months of age, PCV13 at 2, 4, 6 and 12-15 months of age, HAV at 12-15 and 18-21 months of age, and diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine at 2, 4 and 6 months of age. We measured immune responses against HRV, HAV and Hib with enzyme-linked immunosorbent assays, and against MenC/MenY with serum bactericidal assays using human complement. The 4-dose vaccination series with Hib-MenCY-TT induced a robust immune response against Hib, which was non-inferior to that induced by a 3-dose vaccination series with Hib-OMP, and against MenC and MenY. Hib-MenCY-TT did not interfere with immune responses to concomitantly administered HRV, PCV13 and HAV. We did not identify any safety concern. In conclusion, we showed that 4-dose vaccination series with Hib-MenCY-TT during infancy did not interfere with immune responses of co-administered HRV, PCV13 and HAV, induced robust immune responses against Hib, MenC and MenY, and had a clinically acceptable safety profile.
Authors: Klein NP; Abu-Elyazeed R; Baine Y; Cheuvart B; Silerova M; Mesaros N
Hum Vaccin Immunother. 2019;15(2):327-338. Epub 2018-10-05.
Respiratory Syncytial Virus Hospitalization during Pregnancy in Four High-income Countries, 2010-2016
Few studies have addressed respiratory syncytial virus (RSV) infection during pregnancy. Among 846 pregnant women hospitalized with respiratory illness and tested for RSV, 21 (2%) were RSV positive, of whom 8 (38%) were diagnosed with pneumonia. Despite study limitations, these data can help inform decisions about RSV prevention strategies.
Authors: Regan AK; Klein NP; PREVENT Group; et al.
Clin Infect Dis. 2018 11 28;67(12):1915-1918.
A framework for research on vaccine effectiveness
The need for a systematic approach to research on vaccine effectiveness (VE) is increasing with growing numbers of vaccines and complexity of immunization programs. The diverse scientific fields that investigate how vaccines work and why they fail continue to evolve, yet definitions related to such advances have not kept pace. Researchers in disciplines ranging from basic science through immunopathology, clinical and epidemiological research, and mathematical modelling need more precise definitions to promote communication and interdisciplinary VE research to ensure that studies are designed to appropriately address relevant questions. To meet these aims, we suggest standardized definitions, consider models of vaccine failure, and offer general approaches for incorporation into study design. We further propose a framework for conducting VE research that builds on the traditional epidemiological triad of host, pathogen and environment, and also includes additional elements such as characteristics of both the vaccine and vaccinee, the effect of time on likelihood of exposure and protection, and the impact of environment and pathogen, as well as how outcomes of interest and study design may impact observed vaccine effectiveness. The framework is relevant to researchers in all disciplines who investigate the effectiveness of vaccines and vaccination programs and why they may fail. Stronger research in this field will help policy makers optimise decision-making on vaccination programs, ensuring we maximize the health benefits of vaccines. It is also important for clinicians communicating the benefits of vaccines to the public.
Authors: Crowcroft NS; Klein NP
Vaccine. 2018 11 19;36(48):7286-7293. Epub 2018-10-26.
Uptake and safety of Hepatitis B vaccination during pregnancy: A Vaccine Safety Datalink study
Hepatitis B virus (HBV) infection acquired during pregnancy can pose a risk to the infant at birth that can lead to significant and lifelong morbidity. Hepatitis B vaccine (HepB) is recommended for anyone at increased risk for contracting HBV infection, including pregnant women. Limited data are available on the safety of HepB administration during pregnancy. To assess the frequency of maternal HepB receipt among pregnant women and evaluate the potential association between maternal vaccination and pre-specified maternal and infant safety outcomes. We examined a retrospective cohort of pregnancies in the Vaccine Safety Datalink (VSD) resulting in live birth outcomes from 2004 through 2015. Eligible pregnancies in women aged 12-55 years who were continuously enrolled from 6 months pre-pregnancy to 6 weeks postpartum in VSD integrated health systems were included. We compared pregnancies with HepB exposure to those with other vaccine exposures, and to those with no vaccine exposures. High-risk conditions for contracting HBV infection were identified up to one-year prior to or during the pregnancy using ICD-9 codes. Maternal and fetal adverse events were also evaluated according to maternal HepB exposure status. Among over 650,000 pregnancies in the study period, HepB was administered at a rate of 2.1 per 1000 pregnancies (n = 1399), commonly within the first 5 weeks of pregnancy. Less than 3% of the HepB-exposed group had a high-risk ICD-9 code indicating need for HepB; this was similar to the rate among HepB unvaccinated groups. There were no significant associations between HepB exposure during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, cesarean delivery, pre-term delivery, low birthweight or small for gestational age infants. Most women who received maternal HepB did not have high-risk indications for vaccination. No increased risk for the adverse events that were examined were observed among women who received maternal HepB or their offspring.
Authors: Groom HC; Klein NP; Naleway AL; et al.
Vaccine. 2018 10 01;36(41):6111-6116. Epub 2018-09-05.
Factors Affecting Vaccination in Children and Their Siblings After Autism Spectrum Disorder Diagnosis-Reply
Authors: Zerbo O; Klein NP
JAMA Pediatr. 2018 10 01;172(10):985-986.
Assessing Potential Confounding and Misclassification Bias When Studying the Safety of the Childhood Immunization Schedule
Some parents are concerned the childhood immunization schedule could increase risk for allergic disorders, including asthma. To inform future safety studies of this speculated association, a parent survey was conducted to examine the risk of misclassification of vaccination status in electronic health record data, and to assess the potential for confounding if asthma risk factors varied by vaccination status. A survey was conducted among parents of children 19 to 35 months old at 6 medical organizations within the Vaccine Safety Datalink. Parents of children in 4 vaccination groups were surveyed: 1) no vaccines by 12 months of age and a diagnosis of parental vaccine refusal; 2) consistent vaccine limiting (≤2 vaccines per visit); 3) not consistently vaccine limiting but otherwise undervaccinated with a vaccine refusal diagnosis; and 4) fully vaccinated with no delays and no vaccine refusal. Parents were surveyed about their child’s vaccination status and whether asthma risk factors existed. Among a survey sample of 2043 parents, 1209 responded (59.2%). For receiving no vaccines, the observed agreement between parent report and electronic health record data was 94.0% (κ = 0.79); for receiving all vaccines with no delays, the observed agreement was 87.3% (κ = 0.73). Although most asthma risk factors (allergic rhinitis, eczema, food allergies, family asthma history) reported by parents did not differ significantly between children in the vaccination groups studied, several factors (aeroallergen sensitivity, breastfeeding) differed significantly between groups. Measurement and control of disease risk factors should be carefully considered in observational studies of the safety of the immunization schedule.
Authors: Daley MF; Shoup JA; Newcomer SR; Jackson ML; Groom HC; Jacobsen SJ; McLean HQ; Klein NP; Weintraub ES; McNeil MM; Glanz JM
Acad Pediatr. 2018 Sep - Oct;18(7):754-762. Epub 2018-03-28.
Effectiveness of catch-up human papillomavirus vaccination on incident cervical neoplasia in a US health-care setting: a population-based case-control study
The population effectiveness of human papillomavirus (HPV) catch-up vaccination, defined in the USA as first vaccination at ages 13-26 years, has not been studied extensively. We aimed to assess the risk of cervical intraepithelial neoplasia (CIN) 2, CIN3, adenocarcinoma in situ, or cancer (CIN2+ and CIN3+) by prior HPV vaccination status, age at first dose, and number of doses in women participating in a screening programme within a large integrated health-care system. We performed a nested case-control study of women enrolled in Kaiser Permanente Northern California (an integrated health-care delivery system in California, USA). Cases were women with CIN2+ or CIN3+ confirmed by histology between Jan 1, 1995, and June 30, 2014, and incidence density-selected controls were age-matched women without CIN2+ or CIN3+ at the time each case occurred. For each case, we randomly selected five controls. Cases and controls were aged 26 years or younger when the HPV quadrivalent vaccine became available in 2006. Rate ratios (RRs) from conditional logistic regression were estimated by age at time of first HPV quadrivalent vaccine dose (14-17 years, 18-20 years, and ≥21 years), and number of doses (one, two, and three or more doses) compared with no prior vaccination, with adjustment for smoking, hormonal contraceptive prescription, race or ethnicity, sexually transmitted infections, immunosuppression, parity, and number of outpatient visits. 4357 incident CIN2+ cases and 21 773 matched controls were included in the study. Of these, 1849 were incident CIN3+ cases with 9242 matched controls. The youngest age at time of first vaccination was 14 years. One or more HPV vaccine doses conferred protection against CIN2+ (RR 0·82, 95% CI 0·73-0·93) and CIN3+ (0·77, 0·64-0·94). We found the strongest protection against CIN2+ in women who had received at least three vaccine doses and had received their first dose aged 14-17 years (0·52, 0·36-0·74) or aged 18-20 years (0·65, 0·49-0·88). No significant protection was found in women aged 21 years or older at time of first dose (0·94, 0·81-1·09). Inferences were similar for CIN3+, but with stronger effects for women who received at least three vaccine doses and had received their first dose aged 14-17 years (0·27, 0·13-0·56) or aged 18-20 years (0·59, 0·36-0·97). Catch-up quadrivalent HPV vaccination with three doses was effective against CIN2+ and CIN3+ in girls and women aged 14-20 years at time of first vaccine dose but not for women aged 21 years and older at first dose. US National Cancer Institute.
Authors: Silverberg MJ; Leyden WA; Lam JO; Gregorich SE; Huchko MJ; Kulasingam S; Kuppermann M; Smith-McCune KK; Sawaya GF
Lancet Child Adolesc Health. 2018 Oct;2(10):707-714. Epub 2018-08-08.
Safety of repeated doses of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine in adults and adolescents
In light of waning immunity to pertussis following receipt of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine, maintaining protection may require repeated Tdap vaccination. We evaluated the safety of repeated doses of tetanus-containing vaccine in 68 915 nonpregnant adolescents and adults in the Vaccine Safety Datalink population who had received an initial dose of Tdap. Compared with 7521 subjects who received a subsequent dose of tetanus toxoid, reduced diphtheria (Td) vaccine, the 61 394 subjects who received a subsequent dose of Tdap did not have significantly elevated risk of medical visits for seizure, cranial nerve disorders, limb swelling, pain in limb, cellulitis, paralytic syndromes, or encephalopathy/encephalitis/meningitis. These results suggest that repeated Tdap vaccination has acceptable safety relative to Tdap vaccination followed by Td vaccination.
Authors: Jackson ML; Yu O; Nelson JC; Nordin JD; Tartof SY; Klein NP; Donahue JG; Irving SA; Glanz JM; McNeil MM; Jackson LA
Pharmacoepidemiol Drug Saf. 2018 08;27(8):921-925. Epub 2018-06-03.
Pneumococcal Conjugate Vaccine Safety in Elderly Adults
The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) were both recommended to adults aged ≥65 years. The study examines adults ≥65 years for risk of adverse events (AEs) requiring medical attention following vaccination with PCV13 as compared with vaccination with PPSV23, a long-standing vaccine with a satisfactory safety profile. The cohort study included 6 Vaccine Safety Datalink sites. The exposed person-time included follow-up time of the first PCV13 received by subjects age ≥65 years from January 1 to August 15, 2015. The comparator person-time included follow-up time after the first PPSV23 received by subjects of the same age during Janaury 1 to August 15 of each year of 2011-2015. The prespecified AEs included cardiovascular events, Bell’s palsy, Guillain-Barré syndrome, syncope, erythema multiforme, thrombocytopenia, cellulitis and infection, allergic reaction, and anaphylaxis. Inverse probability of treatment weighting-adjusted Poisson regression models was used to estimate the relative risk (RR) of each AE. A total of 313 136 doses of PCV13 and 232 591 doses of PPSV23 were included. The adjusted RRs comparing the incidence of AEs following PCV13 vs PPSV23 were all <1, except for anaphylaxis, which was insignificant with an RR of 1.32 (95% confidence interval, 0.30-5.79). Only 1 patient who received PCV13 and 4 other vaccines concomitantly was confirmed by medical chart review as having experienced anaphylaxis after vaccination. These data do not support an increased rate of adverse events following PCV13 administration in elders compared with PPSV23 and should provide reassurance regarding continued use of PCV13.
Authors: Tseng HF; Klein NP; Jacobsen SJ; et al.
Open Forum Infect Dis. 2018 Jun;5(6):ofy100. Epub 2018-05-02.
Birth outcomes following immunization of pregnant women with pandemic H1N1 influenza vaccine 2009-2010
Following the H1N1 influenza pandemic in 2009, pregnant women were recommended to receive both seasonal (TIV) and H1N1 influenza vaccines. This study presents incidence of adverse birth and pregnancy outcomes among a population of pregnant women immunized with TIV and H1N1 vaccines at Kaiser Permanente Northern California during 2009-2010. We telephone surveyed pregnant Kaiser Permanente Northern California members to assess non-medically-attended reactions following H1N1, TIV or both vaccines during 2009-2010 (n=5365) in a separate study. Here we assessed preterm birth (<37weeks), very preterm birth (<32weeks), low birth weight (<2500 g, LBW), very low birth weight (<1500g), small for gestational age, spontaneous abortions, stillbirths and congenital anomalies among this cohort by comparing incidence and 95% confidence intervals between the following immunization groups: TIV only, H1N1 only, H1N1 prior to TIV immunization, TIV prior to H1N1 and both immunizations given at the same time. Results did not vary significantly between groups. Comparing H1N1 with TIV, incidence were similar for preterm births (6.37vs 6.28/100 births), very preterm births (5.30vs 8.29/1000 births), LBW (4.19vs 2.90/100 births), very LBW (4.54vs 5.52/1000 births), small for gestational age (9.99vs 9.24/1000 births), spontaneous abortion (7.10vs 6.83/1000 pregnancies), stillbirths (7.10vs 4.57/1000 pregnancies), and congenital anomalies (2.66vs 2.43/100 births). Although constrained by small sample size, complex vaccine groups, and differential vaccine availability during 2009-2010, this study found no difference in adverse birth outcomes between H1N1 vaccine and TIV.
Authors: Eaton A; Lewis N; Fireman B; Hansen J; Baxter R; Gee J; Klein NP
Vaccine. 2018 05 03;36(19):2733-2739. Epub 2017-09-13.
Vaccination Patterns in Children After Autism Spectrum Disorder Diagnosis and in Their Younger Siblings
In recent years, rates of vaccination have been declining. Whether this phenomenon disproportionately affects children with autism spectrum disorder (ASD) or their younger siblings is unknown. To investigate if children after receiving an ASD diagnosis obtain their remaining scheduled vaccines according to the Advisory Committee on Immunization Practices (ACIP) recommendations and to compare the vaccination patterns of younger siblings of children with ASD with the vaccination patterns of younger siblings of children without ASD. This investigation was a retrospective matched cohort study. The setting was 6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink. Participants were children born between January 1, 1995, and September 30, 2010, and their younger siblings born between January 1, 1997, and September 30, 2014. The end of follow-up was September 30, 2015. Recommended childhood vaccines between ages 1 month and 12 years. The proportion of children who received all of their vaccine doses according to ACIP recommendations. The study included 3729 children with ASD (676 [18.1%] female), 592 907 children without ASD, and their respective younger siblings. Among children without ASD, 250 193 (42.2%) were female. For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD (adjusted rate ratio, 0.87; 95% CI, 0.85-0.88). Within each age category, vaccination rates were significantly lower among younger siblings of children with ASD compared with younger siblings of children without ASD. The adjusted rate ratios varied from 0.86 for siblings younger than 1 year to 0.96 for those 11 to 12 years old. Parents who had a child with ASD were more likely to refuse at least 1 recommended vaccine for that child’s younger sibling and to limit the number of vaccines administered during the younger sibling’s first year of life. Children with ASD and their younger siblings were undervaccinated compared with the general population. The results of this study suggest that children with ASD and their younger siblings are at increased risk of vaccine-preventable diseases.
Authors: Zerbo O; Fireman BH; Klein NP; et al.
JAMA Pediatr. 2018 05 01;172(5):469-475.
Live Attenuated Influenza Vaccination Prior To Age 3 Years and Subsequent Development of Asthma: A 14-Year Follow-Up Study
Live-attenuated influenza vaccines (LAIVs) are not licensed in children younger than 2 years of age because of a wheezing safety signal that has not been fully elucidated. In 2000, the Kaiser Permanente Vaccine Study Center conducted a placebo-controlled randomized clinical trial (RCT) of LAIV in children. As many of these children were still enrolled in Kaiser Permanente in 2014, we could assess the possible long-term association between LAIV and subsequent asthma diagnosis. We identified all children who were originally enrolled into the LAIV RCT at younger than 3 years of age. We followed up subjects until disenrollment from the health plan, a first diagnosis of asthma, or through the end of the study period in 2014. Asthma was defined by a first International Classification of Diseases, 9th revision, Clinical Modification code (493.*) assigned at an outpatient or emergency department encounter. We performed a survival analysis of time to first asthma diagnosis among children receiving LAIV or placebo with a Cox proportional hazards model. We identified 1151 children in the original RCT who were 12 through 35 months of age at the time of enrollment and who had received 2 doses of LAIV or placebo. A total of 767 (66.7%) RCT participants were still Kaiser Permanente Northern California members in 2014. There was no evidence of differential dropout by treatment group. The hazard ratio for new-onset asthma for LAIV recipients compared with placebo was 1.1 (95% confidence interval: 0.88-1.41; P = 0.38). We found no evidence of increased risk of subsequent asthma diagnosis among children younger than 3 years of age who received LAIV compared with placebo.
Authors: Baxter RP; Lewis N; Fireman B; Hansen J; Klein NP; Ortiz JR
Pediatr Infect Dis J. 2018 05;37(5):383-386.
Immunogenicity and safety of the quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT) in splenectomized or hyposplenic children and adolescents: Results of a phase III, open, non-randomized study
Individuals with functional or anatomic asplenia are at high risk for meningococcal disease. We evaluated the immunogenicity and safety of 1 and 2 doses of the quadrivalent meningococcal serogroups A, C, W, Y tetanus toxoid-conjugate vaccine (MenACWY-TT) in this high-risk population. This phase III, open-label, controlled, non-randomized study (NCT01641042) enrolled 1-17-year-olds with impaired splenic activity (high-risk group) and age-matched healthy controls (control group). We measured immune responses to MenACWY-TT by serum bactericidal activity assays using rabbit (rSBA) and human (hSBA) complement and in terms of antibodies against polysaccharides of the 4 vaccine serogroups. We evaluated vaccine response rates (VRRs) as 4-fold increases from pre-vaccination levels or titers ≥1:32 (rSBA)/≥1:8 (hSBA). We recorded solicited and unsolicited adverse events (AEs) during 4 and 31 days post-vaccination, and serious AEs (SAEs) and new onset of chronic illnesses (NOCIs) throughout the study. The according-to-protocol cohort for immunogenicity included 40 participants per group. In both groups, the first MenACWY-TT dose induced rSBA VRRs of 92.5-100% and hSBA VRRs of 55.6-77.1% across vaccine serogroups. Following the second MenACWY-TT dose, all participants had high responses, with rSBA and hSBA VRRs of 73.0-100% across vaccine serogroups. rSBA and hSBA geometric mean titers for each serogroup increased in both groups (with different magnitudes, but ≥13.1-fold) compared with baseline levels. Polysaccharide antibody concentrations ≥2.0 μg/ml were detected in ≥84.4% of participants and were similar between groups. Incidences of solicited and unsolicited AEs were comparable between groups. We recorded SAEs in 4/43 participants in the high-risk group and 1/43 participants in the control group (none vaccine-related). No NOCIs were reported. In this descriptive study, MenACWY-TT induced similar functional and humoral immune responses and had a clinically acceptable safety profile in children and adolescents with impaired splenic activity and in healthy controls.
Authors: Klein NP; Habanec T; Kosina P; Shah NR; Kolhe D; Miller JM; Hezareh M; Van der Wielen M
Vaccine. 2018 04 19;36(17):2356-2363. Epub 2018-03-22.
Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children
Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.
Authors: Hansen J; Zhang L; Eaton A; Baxter R; Robertson CA; Decker MD; Greenberg DP; Bassily E; Klein NP
Vaccine. 2018 04 12;36(16):2133-2138. Epub 2018-03-14.
Meningococcal conjugate vaccine safety surveillance in the Vaccine Safety Datalink using a tree-temporal scan data mining method
The objective of our study was to conduct a data mining analysis to identify potential adverse events (AEs) following MENACWY-D using the tree-temporal scan statistic in the Vaccine Safety Datalink population and demonstrate the feasibility of this method in a large distributed safety data setting. Traditional pharmacovigilance techniques used in vaccine safety are generally geared to detecting AEs based on pre-defined sets of conditions or diagnoses. Using a newly developed tree-temporal scan statistic data mining method, we performed a pilot study to evaluate the safety profile of the meningococcal conjugate vaccine Menactra® (MenACWY-D), screening thousands of potential AE diagnoses and diagnosis groupings. The study cohort included enrolled participants in the Vaccine Safety Datalink aged 11 to 18 years who had received MenACWY-D vaccination(s) between 2005 and 2014. The tree-temporal scan statistic was employed to identify statistical associations (signals) of AEs following MENACWY-D at a 0.05 level of significance, adjusted for multiple testing. We detected signals for 2 groups of outcomes: diseases of the skin and subcutaneous tissue, fever, and urticaria. Both groups are known AEs following MENACWY-D vaccination. We also identified a statistical signal for pleurisy, but further examination suggested it was likely a false signal. No new MENACWY-D safety concerns were raised. As a pilot study, we demonstrated that the tree-temporal scan statistic data mining method can be successfully applied to screen broadly for a wide range of vaccine-AE associations within a large health care data network.
Authors: Li R; Weintraub E; McNeil MM; Kulldorff M; Lewis EM; Nelson J; Xu S; Qian L; Klein NP; Destefano F
Pharmacoepidemiol Drug Saf. 2018 04;27(4):391-397. Epub 2018-02-15.
Association Between Estimated Cumulative Vaccine Antigen Exposure Through the First 23 Months of Life and Non-Vaccine-Targeted Infections From 24 Through 47 Months of Age
Some parents are concerned that multiple vaccines in early childhood could weaken their child’s immune system. Biological data suggest that increased vaccine antigen exposure could increase the risk for infections not targeted by vaccines. To examine estimated cumulative vaccine antigen exposure through the first 23 months of life in children with and without non-vaccine-targeted infections from 24 through 47 months of age. A nested case-control study was conducted in 6 US health care organizations participating in the Vaccine Safety Datalink. Cases were identified by International Classification of Diseases codes for infectious diseases in the emergency department and inpatient medical settings and then validated by medical record review. Cases of non-vaccine-targeted infection were matched to controls by age, sex, health care organization site, and chronic disease status. Participants were children ages 24 through 47 months, born between January 1, 2003, and September 31, 2013, followed up until December 31, 2015. Cumulative vaccine antigen exposure, estimated by summing the number of antigens in each vaccine dose received from birth through age 23 months. Non-vaccine-targeted infections, including upper and lower respiratory infections and gastrointestinal infections, from 24 through 47 months of age, and the association between these infections and estimated cumulative vaccine exposure from birth through 23 months. Conditional logistic regression was used to estimate matched odds ratios representing the odds of non-vaccine-targeted infections for every 30-unit increase in estimated cumulative number of antigens received. Among the 944 patients (193 cases and 751 controls), the mean (SD) age was 32.5 (6.3) months, 422 (45%) were female, and 61 (7%) had a complex chronic condition. Through the first 23 months, the estimated mean (SD) cumulative vaccine antigen exposure was 240.6 (48.3) for cases and 242.9 (51.1) for controls. The between-group difference for estimated cumulative antigen exposure was -2.3 (95% CI, -10.1 to 5.4; P = .55). Among children with vs without non-vaccine-targeted infections from 24 through 47 months of age, the matched odds ratio for estimated cumulative antigen exposure through age 23 months was not significant (matched odds ratio, 0.94; 95% CI, 0.84 to 1.07). Among children from 24 through 47 months of age with emergency department and inpatient visits for infectious diseases not targeted by vaccines, compared with children without such visits, there was no significant difference in estimated cumulative vaccine antigen exposure through the first 23 months of life.
Authors: Glanz JM; Zerbo O; et al.
JAMA. 2018 03 06;319(9):906-913.
Infant Hospitalizations and Mortality After Maternal Vaccination
The Advisory Committee on Immunization Practices currently recommends pregnant women receive influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines. There are limited studies of the long-term safety in infants for vaccines administered during pregnancy. We evaluate whether maternal receipt of influenza and Tdap vaccines increases the risk of infant hospitalization or death in the first 6 months of life. We included singleton, live birth pregnancies in the Vaccine Safety Datalink between 2004 and 2014. Outcomes were infant hospitalizations and mortality in the first 6 months of life. We performed a case-control study matching case patients and controls 1:1 and used conditional logistic regression to estimate odds ratios for maternal exposure to influenza and/or Tdap vaccines in pregnancy. There were 413 034 live births in our population. Of these, 25 222 infants had hospitalizations and 157 infants died in the first 6 months of life. We found no association between infant hospitalization and maternal influenza (adjusted odds ratio: 1.00; 95% confidence interval [CI]: 0.96-1.04) or Tdap (adjusted odds ratio: 0.94; 95% CI: 0.88-1.01) vaccinations. We found no association between infant mortality and maternal influenza (adjusted odds ratio: 0.96; 95% CI: 0.54-1.69) or Tdap (adjusted odds ratio: 0.44; 95% CI: 0.17-1.13) vaccinations. We found no association between vaccination during pregnancy and risk of infant hospitalization or death in the first 6 months of life. These findings support the safety of current recommendations for influenza and Tdap vaccination during pregnancy.
Authors: Sukumaran L; Klein NP; Weintraub ES; et al.
Pediatrics. 2018 03;141(3). Epub 2018-02-20.
Methods for addressing “innocent bystanders” when evaluating safety of concomitant vaccines
The need to develop methods for studying the safety of childhood immunization schedules has been recognized by the Institute of Medicine and Department of Health and Human Services. The recommended childhood immunization schedule includes multiple vaccines in a visit. A key concern is safety of concomitant (same day) versus separate day vaccination. This paper addresses a methodological challenge for observational studies using a self-controlled design to investigate the safety of concomitant vaccination. We propose a process for distinguishing which of several concomitantly administered vaccines is responsible for increased risk of an adverse event while adjusting for confounding due to relationships between effect modifying risk factors and concomitant vaccine combinations. We illustrate the approach by re-examining the known increase in risk of seizure 7 to 10 days after measles-mumps-rubella (MMR) vaccination and evaluating potential independent or modifying effects of other vaccines. Initial analyses suggested that DTaP had both an independent and potentiating effect on seizure. After accounting for the relationship between age at vaccination and vaccine combination, there was little evidence for increased risk of seizure with same day administration of DTaP and MMR; incidence rate ratio, 95% confidence interval 1.2 (0.9-1.6), P value = θ.226. We have shown that when using a self-controlled design to investigate safety of concomitant vaccination, it can be critically important to adjust for time-invariant effect modifying risk factors, such as age at time of vaccination, which are structurally related to vaccination patterns due to recommended immunization schedules.
Authors: Wang SV; Abdurrob A; Spoendlin J; Lewis E; Newcomer SR; Fireman B; Daley MF; Glanz JM; Duffy J; Weintraub ES; Kulldorff M
Pharmacoepidemiol Drug Saf. 2018 Feb 13.
Postlicensure Safety Surveillance of Congenital Anomaly and Miscarriage Among Pregnancies Exposed to Quadrivalent Human Papillomavirus Vaccine
Limited safety data are available on inadvertent exposure to quadrivalent human papillomavirus vaccine (4vHPV) during pregnancy. We conducted a descriptive observational postlicensure safety surveillance study in Kaiser Permanente Southern California and Northern California to assess congenital anomaly and miscarriage among pregnancies exposed to 4vHPV. Using electronic medical records, we identified women who received a dose of 4vHPV between August 2006 and March 2008 within 30 days preconception or any time during a possible pregnancy. A broad algorithm was developed using diagnostic and procedure codes and laboratory tests to identify pregnancy, congenital anomalies, and miscarriages. Medical records of all potential congenital anomaly cases and a random sample of 100 potential miscarriage cases were reviewed to confirm pregnancy exposure and diagnosis. Results were reviewed by an independent Safety Review Committee (SRC). Among the population of 189,629 females who received at least one dose of 4vHPV during the study period, 2,678 females were identified as possibly having a 4vHPV-exposed pregnancy. Among 170 potential congenital anomalies identified, 44 (26%) were found to be both 4vHPV-exposed and confirmed congenital anomaly cases. Among the 633 potential miscarriages identified, the records of a random sample of 100 cases were reviewed, and 9 cases (9%) were confirmed as 4vHPV-exposed miscarriages. The SRC noted no safety signal for congenital anomaly or miscarriage associated with 4vHPV exposure during pregnancy. The rate of major congenital anomaly (3.6%) was in the range of background estimates from the literature. There was no apparent pattern of timing of 4vHPV exposure among 4vHPV-exposed miscarriages.
Authors: Sy LS; Klein NP; Jacobsen SJ; et al.
Hum Vaccin Immunother. 2018 02 01;14(2):412-419. Epub 2017-12-14.
Bias from outcome misclassification in immunization schedule safety research
The Institute of Medicine recommended conducting observational studies of childhood immunization schedule safety. Such studies could be biased by outcome misclassification, leading to incorrect inferences. Using simulations, we evaluated (1) outcome positive predictive values (PPVs) as indicators of bias of an exposure-outcome association, and (2) quantitative bias analyses (QBA) for bias correction. Simulations were conducted based on proposed or ongoing Vaccine Safety Datalink studies. We simulated 4 studies of 2 exposure groups (children with no vaccines or on alternative schedules) and 2 baseline outcome levels (100 and 1000/100 000 person-years), with 3 relative risk (RR) levels (RR = 0.50, 1.00, and 2.00), across 1000 replications using probabilistic modeling. We quantified bias from non-differential and differential outcome misclassification, based on levels previously measured in database research (sensitivity > 95%; specificity > 99%). We calculated median outcome PPVs, median observed RRs, Type 1 error, and bias-corrected RRs following QBA. We observed PPVs from 34% to 98%. With non-differential misclassification and true RR = 2.00, median bias was toward the null, with severe bias (median observed RR = 1.33) with PPV = 34% and modest bias (median observed RR = 1.83) with PPV = 83%. With differential misclassification, PPVs did not reflect median bias, and there was Type 1 error of 100% with PPV = 90%. QBA was generally effective in correcting misclassification bias. In immunization schedule studies, outcome misclassification may be non-differential or differential to exposure. Overall outcome PPVs do not reflect the distribution of false positives by exposure and are poor indicators of bias in individual studies. Our results support QBA for immunization schedule safety research.
Authors: Newcomer SR; Kulldorff M; Xu S; Daley MF; Fireman B; Lewis E; Glanz JM
Pharmacoepidemiol Drug Saf. 2018 02;27(2):221-228. Epub 2018-01-02.
Effectiveness of Respiratory Syncytial Virus Immunoprophylaxis on Bronchiolitis Hospitalizations among High-risk Infants
We sought to determine the real-world effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis in a population-based cohort to inform policy. The study population included infants born 1996-2008 and enrolled in Kaiser Permanente Northern California. During the RSV season (November-March), RSV immunoprophylaxis administration and the following 30 days were defined as RSV immunoprophylaxis protected period(s), and all other days as unprotected period(s). Bronchiolitis hospitalizations were determined using the International Classification of Diseases Ninth Revision codes during RSV season. We used proportional hazard model to estimate bronchiolitis hospitalization risk comparing infants’ protected period(s) with unprotected period(s). Infants who ever received RSV immunoprophylaxis had a 32% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.68, 95% confidence interval: 0.46, 1.00) when comparing protected periods to unprotected periods. Infants with chronic lung disease (CLD) had a 52% decreased risk in bronchiolitis hospitalization (adjusted hazard ratio = 0.48, 95% confidence interval: 0.25, 0.94). Under the new 2014 American Academy of Pediatrics (AAP) guidelines, 48% of infants eligible based on in-place AAP guidelines at birth would no longer be eligible, but nearly all with CLD remain eligible. RSV immunoprophylaxis is effective in decreasing hospitalization. This association is greatest for infants with CLD, a group still recommended for receipt under the new AAP guidelines.
Authors: Wu P; Escobar GJ; Gebretsadik T; Carroll KN; Li SX; Walsh EM; Mitchel EF; Sloan C; Dupont WD; Yu C; Horner JR; Hartert TV
Am J Epidemiol. 2018 Jan 17.
Long-Term Effectiveness of the Live Zoster Vaccine in Preventing Shingles: A Cohort Study
A live attenuated zoster vaccine was licensed in the United States in 2006 for prevention of shingles in persons aged 60 years or older; the indication was extended in 2011 to cover those aged 50-59 years. We assessed vaccine effectiveness (VE) against shingles for 8 years after immunization at Kaiser Permanente Northern California. VE was estimated by Cox regression with a calendar timeline that was stratified by birth year. We adjusted for demographics and time-varying covariates, including comorbidities and immune compromise. From 2007 to 2014, 1.4 million people entered the study when they became age eligible for vaccination; 392,677 (29%) received the zoster vaccine. During 5.8 million person-years of follow-up, 48,889 cases of shingles were observed, including 5,766 among vaccinees. VE was 49.1% (95% confidence interval (CI): 47.5, 50.6) across all follow-up. VE was 67.5% (95% CI: 65.4, 69.5) during the first year after vaccination, waned to 47.2% (95% CI: 44.1, 50.1) during the second year after vaccination, and then waned more gradually through year 8, when VE was 31.8% (95% CI: 15.1, 45.2). Unexpectedly, VE in persons vaccinated when they were aged 80 years or older was similar to VE in younger vaccinees, and VE in persons vaccinated when immune compromised was similar to VE in persons vaccinated when immune competent.
Authors: Baxter R; Bartlett J; Fireman B; Marks M; Hansen J; Lewis E; Aukes L; Chen Y; Klein NP; Saddier P
Am J Epidemiol. 2018 01 01;187(1):161-169.
The safety of live attenuated influenza vaccine in children and adolescents 2 through 17years of age: A Vaccine Safety Datalink study
To evaluate the safety of live attenuated influenza vaccine (LAIV) in children 2 through 17 years of age. The study was conducted in 6 large integrated health care organizations participating in the Vaccine Safety Datalink (VSD). Trivalent LAIV safety was assessed in children who received LAIV between September 1, 2003 and March 31, 2013. Eighteen pre-specified adverse event groups were studied, including allergic, autoimmune, neurologic, respiratory, and infectious conditions. Incident rate ratios (IRRs) were calculated for each adverse event, using self-controlled case series analyses. For adverse events with a statistically significant increase in risk, or an IRR > 2.0 regardless of statistical significance, manual medical record review was performed to confirm case status. During the study period, 396 173 children received 590 018 doses of LAIV. For 13 adverse event groups, there was no significant increased risk of adverse events following LAIV. Five adverse event groups (anaphylaxis, syncope, Stevens-Johnson syndrome, adverse effect of drug, and respiratory failure) met criteria for manual medical record review. After review to confirm cases, 2 adverse event groups remained significantly associated with LAIV: anaphylaxis and syncope. One confirmed case of anaphylaxis was observed following LAIV, a rate of 1.7 per million LAIV doses. Five confirmed cases of syncope were observed, a rate of 8.5 per million doses. In a study of trivalent LAIV safety in a large cohort of children, few serious adverse events were detected. Anaphylaxis and syncope occurred following LAIV, although rarely. These data provide reassurance regarding continued LAIV use.
Authors: Daley MF; Klein NP; Weintraub E; et al.
Pharmacoepidemiol Drug Saf. 2018 01;27(1):59-68. Epub 2017-11-17.
Respiratory distress in the neonate: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data
Authors: Sweet LR; Klein NP; Brighton Collaboration Respiratory Distress in the Neonate Working Group; et al.
Vaccine. 2017 12 04;35(48 Pt A):6506-6517.
Patterns of childhood immunization and all-cause mortality
Evidence supports the safety of the recommended childhood immunization schedule as a whole. However, additional research is warranted as parents’ refusing or delaying vaccinations has increased in recent years. All-cause mortality has been identified as a priority outcome to study in the context of the recommended immunization schedule. We included children born January 1, 2004 through December 31, 2009, enrolled in the Vaccine Safety Datalink (VSD) from birth through 18 months of age. We examined vaccination patterns during the first 18 months of life among 8 vaccines, and identified deaths occurring between 19 and 48 months of age. We excluded children with complex chronic conditions, contraindications to vaccination, and deaths due to injuries, congenital anomalies, or diseases with onset prior to 19 months of age. We calculated mortality rates among children with different patterns of immunization, and incidence rate ratios (IRR) using the Cox proportional hazards model for children vaccinated according to the schedule versus undervaccinated children, adjusting for outpatient healthcare utilization, influenza vaccination, sex, and VSD site. Among 312,388 children in the study, 199,661 (64%) were vaccinated according to the schedule, and 112,727 (36%) were delayed or not vaccinated for at least one vaccine dose. Of 18 deaths eligible for analysis, 11 occurred in children following the schedule (2.28 per 100,000 person-years), and seven occurred in undervaccinated children (2.57 per 100,000 person-years). Mortality rates among children following the schedule were not significantly different from those of undervaccinated children when excluding deaths with unknown causes (IRR = 1.29, 95% CI = 0.33-4.99), as well as when including deaths with unknown causes (IRR = 0.84, 95% CI = 0.32-2.99). Although there were few deaths, our results do not indicate a difference in risk of all-cause mortality among fully vaccinated versus undervaccinated children. Our findings support the safety of the currently recommended immunization schedule with regard to all-cause mortality.
Authors: McCarthy NL; Sukumaran L; Newcomer S; Glanz J; Daley MF; McClure D; Klein NP; Irving S; Jackson ML; Lewin B; Weintraub E
Vaccine. 2017 12 04;35(48 Pt B):6643-6648. Epub 2017-10-20.
Use of acellular pertussis vaccines in the United States: can we do better?
Despite robust vaccination schedules and high vaccination rates, many countries, including the U.S., have seen large pertussis outbreaks with a shift in recent years in the distribution of disease burden towards adolescents and young adults. Areas covered: This perspective covers problems related to the increased incidence of pertussis among adolescents. Because the Tdap vaccine only protects against pertussis for 1-2 years after vaccination, we propose a new strategy which aims to optimize the benefit of Tdap in adolescents. Expert commentary: Current pertussis vaccination schedules are based on age and have not been effective at protecting adolescents and teenagers from pertussis outbreaks. An alternative to the current practice would be to take advantage of the cyclical nature of pertussis outbreaks. Rather than immunizing children and adolescent solely based on age regardless of risk of pertussis at that moment, perhaps we should consider a ‘timed’ Tdap. The goal would be to administer Tdap to susceptible adolescents and young adults during periods when there is a greater risk of being exposed to pertussis. This approach would optimize the use of an effective, but short-lived vaccine by maximizing protection at the time of increased risk.
Authors: Klein NP; Zerbo O
Expert Rev Vaccines. 2017 12;16(12):1175-1179. Epub 2017-10-20.
Risk of venous thromboembolism following influenza vaccination in adults aged 50years and older in the Vaccine Safety Datalink
Influenza-like illness and inflammation are known risk factors for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). However, few studies have characterized the risk of VTE following influenza vaccination. We examined VTE risk after vaccination in adults 50years old and older within the Vaccine Safety Datalink (VSD). We used the self-controlled case series method to determine the risk of VTE among age-eligible adults who received influenza vaccine (with or without pandemic H1N1) and experienced a VTE during the months of September through December in 2007 through 2012. Presumptive VTE cases were identified among VSD participants using diagnostic codes, diagnostic tests, and oral anticoagulant prescription. Potential cases were validated by medical record review. The VTE incidence rate ratio was calculated among confirmed cases for the risk window 1 to 10days after vaccination relative to all other person-time from September through December. Of the 1,488 presumptive cases identified, 508 were reviewed, of which 492 (97%) were confirmed cases of VTE. The analysis included 396 incident, confirmed cases. Overall, there was no increased risk of VTE in the 1 to 10days after influenza vaccination (IRR=0.89, 95% CI 0.69-1.17) compared to the control period. Results were similar when all person-time was censored before vaccination. A post hoc analysis showed an increased risk among current tobacco smokers (IRR=2.57, 95% CI 1.06-6.23). No clustering of VTE was observed in the 1-42days after vaccination. Overall, there was no evidence that inactivated influenza vaccine was associated with VTE in adults ≥50years old. An increased risk was found among current smokers in a post hoc analysis. These findings are consistent with previous research and support the safety of annual vaccination in this population.
Authors: Vickers ER; McClure DL; Naleway AL; Jacobsen SJ; Klein NP; Glanz JM; Weintraub ES; Belongia EA
Vaccine. 2017 Oct 13;35(43):5872-5877. Epub 2017-09-06.
Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010-11 and 2011-12
Inactivated influenza vaccine is recommended in any stage of pregnancy, but evidence of safety in early pregnancy is limited, including for vaccines containing A/H1N1pdm2009 (pH1N1) antigen. We sought to determine if receipt of vaccine containing pH1N1 was associated with spontaneous abortion (SAB). We conducted a case-control study over two influenza seasons (2010-11, 2011-12) in the Vaccine Safety Datalink. Cases had SAB and controls had live births or stillbirths and were matched on site, date of last menstrual period, and age. Of 919 potential cases identified using diagnosis codes, 485 were eligible and confirmed by medical record review. Exposure was defined as vaccination with inactivated influenza vaccine before the SAB date; the primary exposure window was the 1-28days before the SAB. The overall adjusted odds ratio (aOR) was 2.0 (95% CI, 1.1-3.6) for vaccine receipt in the 28-day exposure window; there was no association in other exposure windows. In season-specific analyses, the aOR in the 1-28days was 3.7 (95% CI 1.4-9.4) in 2010-11 and 1.4 (95% CI 0.6-3.3) in 2011-12. The association was modified by influenza vaccination in the prior season (post hoc analysis). Among women who received pH1N1-containing vaccine in the previous influenza season, the aOR in the 1-28days was 7.7 (95% CI 2.2-27.3); the aOR was 1.3 (95% CI 0.7-2.7) among women not vaccinated in the previous season. This effect modification was observed in each season. SAB was associated with influenza vaccination in the preceding 28days. The association was significant only among women vaccinated in the previous influenza season with pH1N1-containing vaccine. This study does not and cannot establish a causal relationship between repeated influenza vaccination and SAB, but further research is warranted.
Authors: Donahue JG; Klein NP; Belongia EA; et al.
Vaccine. 2017 Sep 25;35(40):5314-5322.
Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine
Menactra� vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55years of age. The aim of this study was to assess the safety of MenACWY-D administered as part of routine clinical care to patients at Kaiser Permanente Northern California (KPNC). This was an observational, retrospective study that included all KPNC members who received MenACWY-D during the study period. We monitored all vaccine recipients for non-elective hospitalizations, emergency department visits, and selected outcomes captured in the clinic setting (Bell’s palsy, seizures, neuritis, Guillain-Barr� syndrome, encephalopathy, encephalitis, epilepsy, transverse myelitis, multiple sclerosis, hypersensitivity reactions, idiopathic thrombocytopenic purpura, diabetes, arthritis, hemolytic anemia, collagen-vascular disease) through 6months after vaccination. Using vaccine recipients as their own controls, we calculated incidence rate ratios (IRRs) of outcomes during the post-vaccination risk interval and compared these with rates during a comparison interval more remote from vaccination. We also compared rates of outcomes in MenACWY-D recipients with those in matched controls who received selected vaccines in the prior year. We reviewed medical records for selected outcomes. From April 2005 through April 2006, 31,561 KPNC patients (>99% of whom were 11-55years of age) received MenACWY-D. Overall, there were 21 outcomes with significantly elevated IRRs and 44 outcomes with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs did not suggest any relationship with MenACWY-D. Two serious adverse events were considered possibly related to vaccination by the study investigator. This study did not detect any safety concerns following MenACWY-D and provides reassurance that MenACWY-D administered as part of routine care was not associated with unexpected safety risks. ClinicalTrials.gov Identifier is NCT00254995.
Authors: Hansen J; Zhang L; Klein NP; Robertson CA; Decker MD; Greenberg DP; Bassily E; Baxter R
Vaccine. 2017 Sep 20.
Rates and Predictors of Vaccinations Among Inflammatory Bowel Disease Patients Receiving Anti-Tumor Necrosis Factor Agents
As an important quality measure, the rates of recommended immunizations among immunocompromised inflammatory bowel disease (IBD) patients in community practice have not been well studied. This study sought to investigate the rates and predictors of recommended immunizations and screening tests among IBD patients receiving anti-tumor necrosis factor (TNF) therapy in a large integrated healthcare organization. We conducted a retrospective cohort study of 1401 IBD patients on anti-TNF therapy between 2010 and 2013 within the Kaiser Permanente Northern California healthcare system. The rates of vaccinations and screening tests were quantified, and the associated predictors were investigated. Vaccination rates for influenza and pneumococcus were 43.5 and 24.1%, respectively. The majority of patients (73.7%) received hepatitis B screening and/or vaccine. Patients receiving infliximab had higher rates of pneumococcal vaccine (P = 0.002), hepatitis B screening (P < 0.001), and tuberculin skin test (P < 0.001) compared with patients receiving adalimumab. Older patient age (≥50 years) was associated with higher likelihood of having HBsAg test (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0, P = 0.002), influenza vaccine (OR 2.6 [2.1-3.4], P < 0.001), and pneumococcal vaccine (OR 4.0 [3.0-5.3], P < 0.001). In contrast, older providers (≥50 years) were associated with significantly lower likelihood of their patients' having hepatitis A and B screening tests, and pneumococcal vaccination. The rates of immunizations for IBD patients receiving anti-TNF treatment were lower than recommended. Structured reminders for vaccinations and education for both patients and providers (older physicians in particular) may prove beneficial in improving immunization rates among immunocompromised IBD patients.
Authors: Pham HV; Hasan I; Udaltsova N; Pham K; Abramson O; Armstrong MA; Postlethwaite D; Li D
Dig Dis Sci. 2017 Aug 23.
Lot-to-lot consistency, safety and immunogenicity of 3 lots of Haemophilus influenzae type b conjugate vaccine: results from a phase III randomized, multicenter study in infants
Vaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination. This phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6months (primary vaccination) and 15-18months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study. Of 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines’ antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5-96.7% and 99.6-100% of participants achieved anti-PRP levels ≥0.15µg/mL, while 78.3-89.8% and 97.9-99.1% had anti-PRP levels ≥1µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related. Hib-TT induced seroprotective antibody concentrations in the majority of participants and was well-tolerated when co-administered with routine pediatric vaccines according to a 3+1 schedule.
Authors: Klein NP; Roy-Ghanta S; et al.
Vaccine. 2017 06 16;35(28):3564-3574. Epub 2017-05-20.
Waning protection following 5 doses of a 3-component diphtheria, tetanus, and acellular pertussis vaccine
The effectiveness of diphtheria, tetanus, and acellular pertussis (DTaP) vaccines wanes substantially after the 5thdose given at ages 4-6years, but has not been described following 5 doses of the same type of DTaP vaccine. We investigated waning effectiveness against pertussis in California over nearly 10years, which included large pertussis outbreaks, following 5 doses of GSK DTaP vaccines (DTaP3). We conducted a case-control study (NCT02447978) of children who received 5 doses of DTaP at Kaiser Permanente Northern California from 01/2006 through 03/2015. We compared time since the 5thdose in confirmed pertussis polymerase chain reaction (PCR)-positive cases with pertussis PCR-negative controls. We used logistic regression adjusted for calendar time, age, sex, race, and service area to estimate the effect of time since the 5thDTaP dose on the odds of pertussis. Our primary analysis evaluated waning after 5 doses of DTaP3. We also examined waning after 5 doses of any type of DTaP vaccines. Our primary analysis compared 340 pertussis cases diagnosed at ages 4-12years with 3841 controls. The any DTaP analysis compared 462 pertussis cases with 5649 controls. The majority of all DTaP doses in the study population were DTaP3(86.8%). Children who were more remote from their 5thdose were less protected than were children whose 5thdose was more recent; the adjusted odds of pertussis increased by 1.27 per year (95% CI 1.10, 1.46) after 5 doses of DTaP3and by 1.30 per year (95% CI 1.15, 1.46) after any 5 DTaP vaccines doses. Waning protection after DTaP3was similar to that following 5 doses of any type of DTaP vaccines. This finding is not unexpected as most of the DTaP vaccines administered were DTaP3.Following 5 doses of DTaP3vaccines, protection from pertussis waned 27% per year on average. NCT number: NCT02447978.
Authors: Klein NP; Bartlett J; Fireman B; Aukes L; Buck PO; Krishnarajah G; Baxter R
Vaccine. 2017 06 08;35(26):3395-3400. Epub 2017-05-12.
No association between influenza vaccination during pregnancy and adverse birth outcomes
Pregnant women are recommended to receive inactivated influenza vaccination anytime during pregnancy. Studies have investigated the impact of influenza vaccination during pregnancy on birth outcomes and results on preterm birth have been inconsistent. We conducted a retrospective cohort study among children born at a gestational age≥24weeks from January 1, 2010 to December 31, 2015 at Kaiser Permanente Northern California facilities (KPNC). We evaluated the association between maternal influenza vaccination during pregnancy and risk of preterm birth, small and large for gestational age, admission to the neonatal intensive care unit (NICU), respiratory distress syndrome, low birth weight, and low Apgar score. We ascertained the dates of maternal influenza vaccination, conception, and delivery, as well as birth outcomes from KPNC inpatient and outpatient databases. Conditional multivariate Cox regression and logistic regression analyses were used to determine the association between maternal vaccination during pregnancy and risk of each birth outcome. The study included 145,869 children. Maternal influenza vaccination during pregnancy was not associated with risk of small or large for gestational age births, preterm birth, need for mechanical ventilation at birth, respiratory distress syndrome, admission to the NICU, low birth weight, or low Apgar score. However, when we did not control for immortal time bias, the risk of preterm birth (odds ratio [OR]=0.69, 95% confidence interval [CI] 0.66-0.72) was lower among infants of vaccinated mothers. We found no association between maternal influenza vaccination during pregnancy and adverse birth outcomes. When investigating preterm birth outcome in association with vaccination during pregnancy, immortal time bias should be taken into account in the analysis.
Authors: Zerbo O; Modaressi S; Chan B; Goddard K; Lewis N; Bok K; Fireman B; Klein NP; Baxter R
Vaccine. 2017 May 31;35(24):3186-3190. Epub 2017-05-05.
Asthma exacerbations among asthmatic children receiving live attenuated versus inactivated influenza vaccines
To investigate whether there is a difference in the risk of asthma exacerbations between children with pre-existing asthma who receive live attenuated influenza vaccine (LAIV) compared with inactivated influenza vaccine (IIV). We identified IIV and LAIV immunizations occurring between July 1, 2007 and March 31, 2014 among Kaiser Permanente Northern California members aged 2 to <18years with a history of asthma, and subsequent asthma exacerbations seen in the inpatient or Emergency Department (ED) setting. We calculated the ratio of the odds (OR) of an exacerbation being in the risk interval (1-14days) versus the comparison interval (29-42days) following immunization, separately for LAIV and IIV, and then examined whether the OR differed between children receiving LAIV and those receiving IIV ("difference-in-differences"). Among 387,633 immunizations, 85% were IIV and 15% were LAIV. Children getting LAIV vs. IIV were less likely to have "current or recent, persistent" asthma (25% vs. 47%), and more likely to have "remote history" of asthma (47% vs. 25%). Among IIV-vaccinated asthmatic children, the OR of an inpatient/ED asthma exacerbation was 0.97 (95% CI: 0.82-1.15). Among LAIV-vaccinated asthmatic children the OR was 0.38 (95% CI: 0.17-0.90). In the difference-in-differences analysis, the odds of asthma exacerbation following LAIV were less than IIV (Ratio of ORs: 0.40, CI: 0.17-0.95, p value: 0.04). Among children ≥2years old with asthma, we found no increased risk of asthma exacerbation following LAIV or IIV, and a decreased risk following LAIV compared to IIV.
Authors: Ray GT; Lewis N; Goddard K; Ross P; Duffy J; DeStefano F; Baxter R; Klein NP
Vaccine. 2017 05 09;35(20):2668-2675. Epub 2017-04-09.
Effectiveness of Vaccination During Pregnancy to Prevent Infant Pertussis
Vaccination against pertussis during pregnancy is recommended to protect newborns, yet there is limited information about the effectiveness of maternal tetanus toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap) vaccine before the first infant dose of diphtheria, tetanus and acellular pertussis (DTaP) vaccine and during the first year of life in infants who have received DTaP. In a retrospective cohort study of infants born at Kaiser Permanente Northern California from 2010 to 2015, we estimated the effectiveness of maternal pertussis vaccination for protecting newborns against pertussis in the first 2 months of life and in the first year of life accounting for each infant DTaP dose. Among 148 981 newborns, the vaccine effectiveness of maternal Tdap was 91.4% (95% confidence interval [CI], 19.5 to 99.1) during the first 2 months of life and 69.0% (95% CI, 43.6 to 82.9) during the entire first year of life. The vaccine effectiveness was 87.9% (95% CI, 41.4 to 97.5) before infants had any DTaP vaccine doses, 81.4% (95% CI, 42.5 to 94.0) between doses 1 and 2, 6.4% (95% CI, -165.1 to 66.9) between doses 2 and 3, and 65.9% (95% CI, 4.5 to 87.8) after infants had 3 DTaP doses. Maternal Tdap vaccination was highly protective against infant pertussis, especially in the first 2 months of life. Even after infant DTaP dosing, there was evidence of additional protection from maternal Tdap vaccination for the first year of life. This study strongly supports the United States’ current recommendation to administer Tdap during each pregnancy.
Authors: Baxter R; Bartlett J; Fireman B; Lewis E; Klein NP
Pediatrics. 2017 May;139(5). Epub 2017-04-03.
Assessing misclassification of vaccination status: Implications for studies of the safety of the childhood immunization schedule
To address public concern about the safety of the childhood immunization schedule, the Institute of Medicine recommended observational studies comparing adverse health outcomes of fully vaccinated children to children under-vaccinated due to parental choice. Misclassification of vaccination status could bias such studies. To assess risk of misclassification of vaccination status within the Vaccine Safety Datalink (VSD). A retrospective cohort study was conducted in three phases. In phase 1, electronic health record (EHR) data were used to identify patterns of under-vaccination during the first 24months of life potentially due to parental choice. In phase 2, a random sample of records of under-vaccinated children was manually reviewed. In phase 3, a separate sample of parents were surveyed to assess whether EHR data accurately reflected their child’s vaccination status. Phases 1 and 2 were conducted at 6 VSD sites, phase 3 at 1 site. The study cohort included 361,901 children born 2004 through 2012. By 24months of age, 198,249 (54.8%) were fully vaccinated with no delays, 84,698 (23.4%) experienced delays but were fully vaccinated by 24months of age, 4865 (1.3%) received no vaccines, 3789 (1.0%) delayed starting vaccination until ≥4months of age, 4781 (1.3%) had consistent vaccine-limiting (≤2 vaccines per visit), and the remaining 65,519 (18.1%) were missing vaccine series or doses. When a diagnosis code for vaccine refusal was present in EHR data, encounter notes confirmed vaccine refusal as the reason for under-vaccination for nearly 100% of sampled records. Parent surveys confirmed these findings. Parents of under-vaccinated children were more likely to report visiting an alternative medical provider than parents of fully vaccinated children. Specific groups of children, under-vaccinated due to parental choice, can be identified with relatively low likelihood of misclassification of vaccination status using EHR-based vaccine data and diagnosis codes.
Authors: Daley MF; Glanz JM; Newcomer SR; Jackson ML; Groom HC; Lugg MM; McLean HQ; Klein NP; Weintraub ES; McNeil MM
Vaccine. 2017 Apr 04;35(15):1873-1878. Epub 2017-03-09.
Identifying birth defects in automated data sources in the Vaccine Safety Datalink
The Vaccine Safety Datalink (VSD), a collaboration between the Centers for Disease Control and Prevention and several large healthcare organizations, aims to monitor safety of vaccines administered in the USA. We present definitions and prevalence estimates for major structural birth defects to be used in studies of maternal vaccine safety. In this observational study, we created and refined algorithms for identifying major structural birth defects from electronic healthcare data, conducted formal chart reviews for severe cardiac defects, and conducted limited chart validation for other defects. We estimated prevalence for selected defects by VSD site and birth year and compared these estimates to those in a US and European surveillance system. We developed algorithms to enumerate >50 major structural birth defects from standardized administrative and healthcare data based on utilization patterns and expert opinion, applying criteria for number, timing, and setting of diagnoses. Our birth cohort included 497 894 infants across seven sites. The period prevalence for all selected major birth defects in the VSD from 2004 to 2013 was 1.7 per 100 live births. Cardiac defects were most common (65.4 per 10 000 live births), with one-fourth classified as severe, requiring emergent intervention. For most major structural birth defects, prevalence estimates were stable over time and across sites and similar to those reported in other population-based surveillance systems. Our algorithms can efficiently identify many major structural birth defects in large healthcare datasets and can be used in studies evaluating the safety of vaccines administered to pregnant women. Copyright © 2017 John Wiley & Sons, Ltd.
Authors: Kharbanda EO; Klein NP; Nordin JD; et al.
Pharmacoepidemiol Drug Saf. 2017 Apr;26(4):412-420. Epub 2017-01-04.
Risk factors and familial clustering for fever 7-10days after the first dose of measles vaccines
Seven to ten days after a first dose of a measles-containing vaccine (MCV; i.e., MMR or MMRV), children have elevated fever risk which can be associated with febrile seizures. This study investigated individual and familial factors associated with fever 7-10days after MCV. Retrospective cohort study among children who were <36months of age at receipt of MCV in six sites of the Vaccine Safety Datalink from 1/1/2000 to 12/31/2012. We evaluated medically-attended clinic or emergency department visits with a code for fever 7-10days after any MCV ("MCV- associated"). We evaluated factors associated with MCV-associated fever using χ2 and multivariable logistic regression analyses. Among 946,806 children vaccinated with MCV, we identified 7480 (0.8%) MCV-associated fever visits. Compared with children without fever after MCV, children with MCV-associated fever were more likely to have received MMRV than MMR (OR 1.3 95% CI 1.2, 1.5), have had medically attended fever both following previous vaccines (OR 1.3 95% CI 1.1, 1.6) and at any other previous time (OR 1.7 95% CI 1.6, 1.8), have had at least 1 prior seizure (OR 2.2 95% CI 1.7, 2.7), and have had >3 medical visits within the 6months before MCV (OR 1.7 95% CI 1.6, 1.8). In families with multiple MCV-immunized children, after adjusting for healthcare seeking behavior care for fever, those whose siblings had MCV-associated fever were more likely to also have MCV-associated fever (OR 3.5 95% CI 2.5, 4.8). Children who received MMRV vaccine or who had prior medically-attended fevers and seizures during the first year of life had increased risk of fever after a first dose of measles vaccine. After adjusting for familial propensity to seek care, MCV-associated fever still clustered within families, suggesting a possible genetic basis for susceptibility to developing fever due to measles vaccines.
Authors: Klein NP; Lewis E; McDonald J; Fireman B; Naleway A; Glanz J; Jackson LA; Donahue JG; Jacobsen SJ; Weintraub E; Baxter R
Vaccine. 2017 Mar 14;35(12):1615-1621. Epub 2017-02-21.
Time to Change Dosing of Inactivated Quadrivalent Influenza Vaccine in Young Children: Evidence From a Phase III, Randomized, Controlled Trial
Children under 3 years of age may benefit from a double-dose of inactivated quadrivalent influenza vaccine (IIV4) instead of the standard-dose. We compared the only United States-licensed standard-dose IIV4 (0.25 mL, 7.5 µg hemagglutinin per influenza strain) versus double-dose IIV4 manufactured by a different process (0.5 mL, 15 µg per strain) in a phase III, randomized, observer-blind trial in children 6-35 months of age (NCT02242643). The primary objective was to demonstrate immunogenic noninferiority of the double-dose for all vaccine strains 28 days after last vaccination. Immunogenic superiority of the double-dose was evaluated post hoc. Immunogenicity was assessed in the per-protocol cohort (N = 2041), and safety was assessed in the intent-to-treat cohort (N = 2424). Immunogenic noninferiority of double-dose versus standard-dose IIV4 was demonstrated in terms of geometric mean titer (GMT) ratio and seroconversion rate difference. Superior immunogenicity against both vaccine B strains was observed with double-dose IIV4 in children 6-17 months of age (GMT ratio = 1.89, 95% confidence interval [CI] = 1.64-2.17, B/Yamagata; GMT ratio = 2.13, 95% CI = 1.82-2.50, B/Victoria) and in unprimed children of any age (GMT ratio = 1.85, 95% CI = 1.59-2.13, B/Yamagata; GMT ratio = 2.04, 95% CI = 1.79-2.33, B/Victoria). Safety and reactogenicity, including fever, were similar despite the higher antigen content and volume of the double-dose IIV4. There were no attributable serious adverse events. Double-dose IIV4 may improve protection against influenza B in some young children and simplifies annual influenza vaccination by allowing the same vaccine dose to be used for all eligible children and adults.
Authors: Jain VK; Klein NP; Innis BL; et al.
J Pediatric Infect Dis Soc. 2017 Mar 01;6(1):9-19.
Lot-to-Lot Consistency, Safety, Tolerability, and Immunogenicity of an Investigational Hexavalent Vaccine in US Infants
This multicenter phase III study (NCT01340937) evaluated the consistency of immune responses to 3 separate lots of diphtheria-tetanus toxoids-acellular pertussis 5, inactivated poliovirus vaccine, Haemophilus influenzae type b, and hepatitis B (DTaP5-IPV-Hib-HepB), an investigational hexavalent vaccine (HV). Healthy infants were randomized (2:2:2:1) to receive HV or Pentacel (Control). Groups 1, 2 and 3 received HV at 2, 4 and 6 months, and Control at 15 months. Group 4 received Control at 2, 4, 6 and 15 months, plus Recombivax HB (HepB) at 2 and 6 months. Concomitant Prevnar 13 was given to all groups at 2, 4, 6 and 15 months; pentavalent rotavirus vaccine (RV5) was given to all groups at 2, 4 and 6 months. Blood specimens (3-5 mL) were collected immediately before administration of dose 1, postdose 3, immediately before toddler dose, and after toddler dose. Adverse events were recorded after each vaccination. The 3 manufacturing lots of HV induced consistent antibody responses to all antigens. Immunogenicity of HV was noninferior to Control for all antibodies, except for pertussis filamentous hemagglutinin geometric mean concentration postdose 3, and pertussis pertactin (PRN) geometric mean concentration after toddler dose. Postdose 3 immunogenicity of concomitantly administered Prevnar 13 was generally similar (except for serotype 6B) when given with HV or Control. Adverse events of HV were similar to Control, except for a higher rate of fever ≥38.0°C [49.2% vs. 35.4%, estimated difference 13.7% (8.4, 18.8)]. HV demonstrated lot-to-lot manufacturing consistency; safety and immunogenicity were comparable with the licensed vaccines. HV provides a new combination vaccine option within the US 2-month, 4-month and 6-month vaccine series.
Authors: Block SL; Klein NP; Lee AW; et al.
Pediatr Infect Dis J. 2017 Feb;36(2):202-208.
Association Between Influenza Infection and Vaccination During Pregnancy and Risk of Autism Spectrum Disorder
Maternal infections and fever during pregnancy are associated with increased risk for autism spectrum disorders (ASDs). To our knowledge, no study has investigated the association between influenza vaccination during pregnancy and ASD. To investigate the association between influenza infection and vaccination during pregnancy and ASD risk. This cohort study included 196 929 children born at Kaiser Permanente Northern California from January 1, 2000 to December 31, 2010, at a gestational age of at least 24 weeks. Data on maternal influenza infection and vaccination from conception date to delivery date, obtained from Kaiser Permanente Northern California inpatient and outpatient databases. Influenza infection was defined by the International Classification of Diseases, Ninth Revision, Clinical Modification codes or positive influenza laboratory test results. Clinical diagnoses of ASDs identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes 299.0, 299.8, or 299.9 recorded in Kaiser Permanente Northern California electronic medical records on at least 2 occasions any time from birth through June 2015. Within this cohort of 196 929 children, influenza was diagnosed in 1400 (0.7%) mothers and 45 231 (23%) received an influenza vaccination during pregnancy. The mean (SD) ages of vaccinated and unvaccinated women were 31.6 (5.2) and 30.4 (5.6) years, respectively. A total number of 3101 (1.6%) children were diagnosed with ASD. After adjusting for covariates, we found that maternal influenza infection (adjusted hazard ratio, 1.04; 95% CI, 0.68-1.58) or influenza vaccination (adjusted hazard ratio, 1.10; 95% CI, 1.00-1.21) anytime during pregnancy was not associated with increased ASD risk. In trimester-specific analyses, first-trimester influenza vaccination was the only period associated with increased ASD risk (adjusted hazard ratio, 1.20; 95% CI, 1.04-1.39). However, this association could be due to chance (P = 0.1) if Bonferroni corrected for the multiplicity of hypotheses tested (n = 8). Maternal influenza vaccination in the second or third trimester was not associated with increased ASD risk. There was no association between maternal influenza infection anytime during pregnancy and increased ASD risk. There was a suggestion of increased ASD risk among children whose mothers received an influenza vaccination in their first trimester, but the association was not statistically significant after adjusting for multiple comparisons, indicating that the finding could be due to chance. These findings do not call for changes in vaccine policy or practice, but do suggest the need for additional studies on maternal influenza vaccination and autism.
Authors: Zerbo O; Qian Y; Yoshida C; Fireman BH; Klein NP; Croen LA
JAMA Pediatr. 2017 Jan 02;171(1):e163609. Epub 2017-01-02.
Acute demyelinating events following vaccines – a case centered analysis
Case reports have suggested that vaccines may trigger transverse myelitis (TM) or acute disseminated encephalomyelitis (ADEM), but the evidence for a causal association is inconclusive. We analyzed the association of immunization and subsequent development of TM or ADEM. We identified all cases of TM and ADEM in the Vaccine Safety Datalink population. Using a case-centered method, we compared vaccination of each case to vaccination of all matched persons in the study population, who received the same type of vaccine, with respect to whether or not their vaccination occurred during a predetermined exposure interval. We calculated a risk difference (excess risk) of TM and ADEM for each vaccine. Following nearly 64 million vaccine doses, only 7 cases of TM and 8 cases of ADEM were vaccinated during the primary exposure window 5-28 days prior to onset. For TM, there was no statistically significant increased risk of immunization. For ADEM, there was no statistically significant increased risk following any vaccine except for Tdap (adolescent and adult tetanus, reduced diphtheria, acellular pertussis) vaccine. Based on 2 exposed cases, the odds ratio for Tdap exposure 5-28 days prior to ADEM onset was 15.8 (95% confidence interval [CI], 1.2-471.6; P = .04), and the estimated excess risk was 0.385 (95% CI, -.04 to 1.16) cases per million doses. We found no association between TM and prior immunization. There was a possible association of ADEM with Tdap vaccine, but the excess risk is not likely to be more than 1.16 cases of ADEM per million vaccines administered.
Authors: Baxter R; Lewis E; Goddard K; Fireman B; Bakshi N; DeStefano F; Gee J; Tseng HF; Naleway AL; Klein NP
Clin Infect Dis. 2016 Dec 01;63(11):1456-1462. Epub 2016-09-01.
Kaiser Permanente Northern California pregnancy database: Description and proof of concept study
We describe the establishment of a dynamic database linking mothers to newborns with the goal of studying vaccine safety in both pregnant women and their children and provide results of a study utilizing this database as a proof of concept. All Kaiser Permanente Northern California (KPNC) live births and their mothers were eligible for inclusion in the pregnancy database. We used the medical record number (MRN), a unique identifier, to retrieve information about events that occurred during the pregnancy and at delivery and linked this same MRN to newborns for post-partum follow up. We conducted a retrospective cohort study to evaluate the association between receipt of tetanus, diphtheria and acellular pertussis (Tdap) vaccine during pregnancy and fever 0-3days after the first dose of diphtheria tetanus and acellular pertussis (DTaP) vaccine in the infant. The study included infants who were born at ⩾37weeks gestation from January 1, 2009 – October 1, 2015 and who received their first DTaP vaccine between 6 and 10weeks of age. We utilized diagnostic codes from inpatient, emergency department, outpatient clinics, and telephone calls. We identified fever using ICD 9 code 780.6, recorded temperature ⩾101 degree Fahrenheit, or parental report. The database contained the starting and ending date of each pregnancy and basic demographic characteristics of mothers and infants. There were 859,699 women and 873,753 children in the database as of January 2016. The proof of concept study included 148,699 infants. In a multivariable logistic regression analysis, Tdap vaccination during pregnancy was not associated with infant fever 0-3daysafter first dose of DTaP (adjusted odds ratio=0.92, 95% CI 0.82-1.04). The KPNC pregnancy database can be used for studies investigating exposure during pregnancy and outcomes in mothers and/or infants, particularly monitoring vaccine safety and effectiveness.
Authors: Zerbo O; Chan B; Goddard K; Lewis N; Bok K; Klein NP; Baxter R
Vaccine. 2016 11 04;34(46):5519-5523. Epub 2016-10-07.
Risk of underlying chronic medical conditions for invasive pneumococcal disease in adults
In the United States, the 13-valent pneumococcal conjugate vaccine is recommended in persons ⩾65years of age, and persons ⩽65years of age with immunocompromising (IC) conditions. For invasive pneumococcal disease (IPD) prevention in those ⩽65 with non-IC medical conditions, the 23-valent polysaccharide vaccine is recommended. This group is at higher risk of IPD than the general population, but the level of risk is not well-quantified. We estimated IPD risk by individual underlying medical conditions, and by total number of conditions, for persons ⩾18years of age. We calculated the relative risks (RR) of various medical conditions, comparing the incident IPD cases to the general study population, and used Poisson regression models to estimate an IPD RR, adjusting for other conditions. We also examined IPD incidence by number of conditions diagnosed in each calendar year, using a risk-stacking model. Underlying medical conditions with the highest adjusted RR for IPD were chronic liver disease (RR 2.1, 95% CI 1.5-2.8) and chronic obstructive pulmonary disease (COPD; RR 2.1, 95% CI 1.8-2.5). IPD risk increased with increasing number of medical conditions: adjusted RR, 2.2 (95% CI 1.9-2.5) 1 condition, 2.9 (2.5-3.5) for 2 conditions, and 5.2 (4.4-6.1) for 3 conditions. For persons with a single, non-IC medical condition, IPD risk was twice that for the general KPNC population. Persons with multiple, non-IC chronic conditions exhibited increased IPD risk with each additional condition. Such information may inform discussions on recommendations for adult pneumococcal immunization and prevention.
Authors: Baxter R; Yee A; Aukes L; Snow V; Fireman B; Atkinson B; Klein NP
Vaccine. 2016 Aug 05;34(36):4293-7. Epub 2016-07-07.
Risk of Preterm or Small-for-Gestational-Age Birth After Influenza Vaccination During Pregnancy: Caveats When Conducting Retrospective Observational Studies
Vaccines are increasingly targeted toward women of reproductive age, and vaccines to prevent influenza and pertussis are recommended during pregnancy. Prelicensure clinical trials typically have not included pregnant women, and when they are included, trials cannot detect rare events. Thus, postmarketing vaccine safety assessments are necessary. However, analysis of observational data requires detailed assessment of potential biases. Using data from 8 Vaccine Safety Datalink sites in the United States, we analyzed the association of monovalent H1N1 influenza vaccine (MIV) during pregnancy with preterm birth (<37 weeks) and small-for-gestational-age birth (birth weight < 10th percentile). The cohort included 46,549 pregnancies during 2009-2010 (40% of participants received the MIV). We found potential biases in the vaccine-birth outcome association that might occur due to variable access to vaccines, the time-dependent nature of exposure to vaccination within pregnancy (immortal time bias), and confounding from baseline differences between vaccinated and unvaccinated women. We found a strong protective effect of vaccination on preterm birth (relative risk = 0.79, 95% confidence interval: 0.74, 0.85) when we ignored potential biases and no effect when accounted for them (relative risk = 0.91; 95% confidence interval: 0.83, 1.0). In contrast, we found no important biases in the association of MIV with small-for-gestational-age birth. Investigators conducting studies to evaluate birth outcomes after maternal vaccination should use statistical approaches to minimize potential biases.
Authors: Vazquez-Benitez G; Klein NP; Nordin JD; et al.
Am J Epidemiol. 2016 Aug 01;184(3):176-86. Epub 2016-07-22.
Safety of DTaP-IPV/Hib vaccine administered routinely to infants and toddlers
The combination DTaP-IPV/Hib vaccine was licensed in the United States in 2008 for children ages 6weeks through 4years with doses administered at 2, 4, 6, and 15-18months of age. The aim of this study was to assess the safety of DTaP-IPV/Hib vaccine routinely administered as part of clinical care to infants at Kaiser Permanente Northern California. This was an observational, retrospective study that included all 2-month-old infants vaccinated with either DTaP-IPV/Hib or another DTaP-containing vaccine. We monitored all subjects for non-elective hospitalizations, emergency department visits and selected outpatient outcomes (seizures, Guillain-Barré Syndrome, encephalopathy, encephalitis, alteration of consciousness, meningitis, hypersensitivity reactions, immune thrombocytopenic purpura, hemolytic anemia, type 1 diabetes, and Kawasaki disease) beginning with their first dose through 6months after a 4th dose or until 24months of age. We calculated incidence rate ratios (IRRs) in the primary analysis by comparing rates of outcomes during the post-vaccination risk interval with rates during a comparison interval more remote from vaccination. Secondary analyses compared outcomes after DTaP-IPV/Hib with those after other DTaP-containing vaccines. We reviewed the medical records of selected outcomes. From October 1, 2008 through July 31, 2010, 14,042 subjects received a first dose of DTaP-IPV/Hib, 13,194 received 2 doses, 12,548 received 3 doses and 6702 received 4 doses. Overall, there were 166 comparisons with significantly elevated IRRs and 165 comparisons with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs in both the primary and secondary analyses did not suggest any relationship with DTaP-IPV/Hib. This study did not detect any safety concerns following DTaP-IPV/Hib and provides reassurance that DTaP-IPV/Hib administered as part of routine care was not associated with unexpected safety risks. ClinicalTrials.gov Identifier: NCT00804284.
Authors: Hansen J; Timbol J; Lewis N; Pool V; Decker MD; Greenberg DP; Klein NP
Vaccine. 2016 Jul 29;34(35):4172-4179. Epub 2016-06-30.
Case centered analysis of Optic Neuritis following vaccines
We evaluated the risk of optic neuritis (ON) after vaccines, using a case-centered analysis, comparing the time since vaccination for the patients with ON with that for all similar vaccinees in a large integrated health plan population. We did not detect any association between ON and receipt of any type of vaccine.
Authors: Baxter R; Lewis E; Fireman B; DeStefano F; Gee J; Klein NP
Clin Infect Dis. 2016 Jul 01;63(1):79-81. Epub 2016-04-10.
Five-Year Antibody Persistence and Booster Response Following One or Two Doses of Meningococcal A, C, W, and Y Tetanus Toxoid Conjugate Vaccine in Healthy Children
We evaluated antibody persistence up to 5 years postvaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT), and subsequent booster responses to MenACWY-TT in healthy US children. In the initial phase II, open, multicenter study (NCT00471081), 349 infants were randomized (1:1) to receive MenACWY-TT (1 or 2 doses). In the follow-up study (NCT00718666), we evaluated antibody persistence at years 1, 3 and 5 by serum bactericidal assay using human complement (hSBA). At year 5, children received a booster dose of MenACWY-TT. We compared their immune responses at 1 month postbooster with those from 100 age-matched, meningococcal naive children, who received a primary MenACWY-TT dose. We recorded solicited adverse events for 4 days and unsolicited adverse events for 31 days, followed by an additional 5-month extended safety follow-up. At year 5, ?64.0% of 1-dose and ?74.6% of 2-dose recipients had hSBA titers ?8 for MenC, MenW and MenY. For MenA, 31.7% of 1-dose and 38.0% of 2-dose recipients had hSBA titers ?8. One month postvaccination, all booster dose recipients and ?78.5% of primary dose recipients exhibited hSBA titers ?8 for all serogroups. Geometric mean titers were higher in primed than in naive children. MenACWY-TT had a clinically acceptable safety profile. With the exception of serogroup W, antibody persistence 5 years after MenACWY-TT vaccination did not differ substantially between children who received 1 or 2 doses in infancy. A booster dose of MenACWY-TT elicited robust anamnestic responses and was well tolerated.
Authors: Klein NP; Baine Y; Kolhe D; Baccarini CI; Miller JM; Van der Wielen M
Pediatr Infect Dis J. 2016 06;35(6):662-72.
Influenza Vaccination During Pregnancy: Influenza Seasons 2002-2012, Vaccine Safety Datalink
Pregnant women are at risk for influenza-related complications and have been recommended for vaccination by the Advisory Committee on Immunization Practices (ACIP) since 1990. Annual rates of influenza coverage of pregnant women have been consistently low. The Vaccine Safety Datalink was used to assess influenza vaccine coverage over 10 consecutive years (2002-2012); assess patterns related to changes in ACIP recommendations; identify predictors of vaccination; and compare the results with those published by national U.S. surveys. Retrospective cohort study of 721,898 pregnancies conducted in 2014. Coverage rates were assessed for all pregnancies and for live births only. Multivariate regression analysis identified predictors associated with vaccination. Coverage increased from 8.8% to 50.9% in 2002-2012. Seasonal coverage rates increased slowly following the 2004 ACIP influenza vaccine recommendation (to remove the first trimester restriction), but spiked significantly during the 2009 H1N1 influenza pandemic. Significant predictors of vaccination during pregnancy included older age; vaccination in a previous season; high-risk conditions in addition to pregnancy; pregnancy during either the 2004-2005 or 2009-2010 seasons; entering the influenza season after the first trimester of pregnancy; and a pregnancy with longer overlap with the influenza season (p<0.001 for each). Influenza vaccination coverage among pregnant women increased between the 2002-2003 and 2011-2012 seasons, although it was still below the developmental Healthy People 2020 goal of 80%. The 2004 ACIP language change positively impacted first-trimester vaccination uptake. Vaccine Safety Datalink data estimates were consistent with U.S. estimates.
Authors: Groom HC; Klein NP; Naleway AL; et al.
Am J Prev Med. 2016 Apr;50(4):480-8. Epub 2015-10-31.
Maternal Tdap vaccination: Coverage and acute safety outcomes in the vaccine safety datalink, 2007-2013
Since October 2012, the combined tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine (Tdap) has been recommended in the United States during every pregnancy. In this observational study from the Vaccine Safety Datalink, we describe receipt of Tdap during pregnancy among insured women with live births across seven health systems. Using a retrospective matched cohort, we evaluated risks for selected medically attended adverse events in pregnant women, occurring within 42 days of vaccination. Using a generalized estimating equation, we calculated adjusted incident rate ratios (AIRR). Our vaccine coverage cohort included 438,487 live births between January 1, 2007 and November 15, 2013. Across the coverage cohort, 14% received Tdap during pregnancy. By 2013, Tdap was administered during pregnancy in 41.7% of live births, primarily in the 3rd trimester. Our vaccine safety cohort included 53,885 vaccinated and 109,253 matched unvaccinated pregnant women. There was no increased risk for a composite outcome of medically attended acute adverse events within 3 days of vaccination. Similarly, across the safety cohort, over a 42 day window, incident neurologic events, thrombotic events, and new onset proteinuria did not differ by maternal receipt of Tdap. Among women receiving Tdap at 20 weeks gestation or later, as compared to their matched controls, there was no increased risk for gestational diabetes or cardiac events while venous thromboembolic events and thrombocytopenia were diagnosed within 42 days of vaccination at slightly decreased rates. Tdap coverage during pregnancy increased from 2007 through 2013, but was still below 50%. No acute maternal safety signals were detected in this large cohort.
Authors: Kharbanda EO; Klein NP; Nordin JD; et al.
Vaccine. 2016 Feb 10;34(7):968-73. Epub 2016-01-04.
Absence of venous thromboembolism risk following quadrivalent human papillomavirus vaccination, Vaccine Safety Datalink, 2008-2011
To investigate concerns about a potential association between quadrivalent human papillomavirus vaccination (HPV4) and venous thromboembolism (VTE), we conducted a self-controlled case series study in adolescents and young adults 9-26 years of age in the Vaccine Safety Datalink. We identified potential VTE cases diagnosed in 2008 through 2011 who had also received at least one HPV4 dose during that period. We confirmed each presumptive diagnosis by medical record review. We calculated incidence rate ratios (IRRs) and 95% confidence intervals (CI) to estimate the risk in the 1-60 day period following HPV4 exposure and in subsets of that period. IRRs were stratified by age, gender, hormonal contraceptive use, and recent surgery or trauma. We identified 313 potential cases of VTE among HPV4 vaccinees, and 291 (93%) had sufficient medical records for review. Of these, we confirmed 156 (54%) cases. VTE was uncommon among males (n=3) and 9-12 year olds (n=4). Nearly all confirmed cases (97%) had at least one known risk factor for VTE, including hormonal contraceptive use, obesity, and hypercoagulability. Sixteen (10%) confirmed cases occurred in the 1-60 days following HPV4 exposure. The risk of VTE varied from 1.47 (95% CI: 0.47-4.64) in the 1-7 days following HPV4 exposure to 0.92 (95% CI: 0.54-1.57) in the 1-60 days following vaccination. It was not possible to calculate a stratified IRR for males due to small sample size; the other risk factors evaluated did not significantly affect the risk of VTE after HPV4 exposure. The risk of developing VTE among 9- to 26-year-olds was not elevated following HPV4 exposure. Sample size limited our ability to rigorously evaluate potential effect modifiers, such as gender, through stratified analysis.
Authors: Naleway AL; Klein NP; Vaccine Safety Datalink; et al.
Vaccine. 2016 Jan 2;34(1):167-71. Epub 2015-Nov-06.
An Overview of Quadrivalent Human Papillomavirus Vaccine Safety – 2006 to 2015
A quadrivalent human papillomavirus (HPV4) type 6/11/16/18 vaccine (GARDASIL/SILGARD®) has been licensed in many countries around the world for the prevention of cervical, vulvar, vaginal, and anal cancers and precancers, as well as external genital warts causally related to HPV types 6/11/16/18. Across 7 phase 3 clinical trials involving more than 29,000 males and females ages 9-45 years, vaccination was generally well tolerated. Because of its expected public health benefit in reducing cervical cancer and other HPV-related diseases, the vaccine has been implemented in the national vaccination programs of several countries, with over 178 million doses distributed worldwide. Extensive efforts to assess the safety of the vaccine in routine practice have been conducted over the past 9 years since licensure, including more than 15 studies in more than 1 million preadolescents, adolescents and adults from various countries. Most have been performed in the general population although there have been some in special populations (pregnant women, HIV-infected individuals and those with systemic lupus erythematosus). We present a summary of the published, postlicensure safety data from active and passive surveillance. Only syncope, and possibly skin infections were associated with vaccination in the postlicensure setting. Serious adverse events, such as adverse pregnancy outcomes, autoimmune diseases (including Guillain-Barre Syndrome and multiple sclerosis), anaphylaxis, venous thromboembolism and stroke, were extensively studied, and no increase in the incidence of these events was found compared with background rates. These results, along with the safety data from the prelicensure clinical trials, confirm that the HPV4 vaccine has a favorable safety profile. Key policy, medical and regulatory organizations around the world have independently reviewed these data and continue to recommend routine HPV vaccination.
Authors: Vichnin M; Klein NP; Kuter BJ; et al.
Pediatr Infect Dis J. 2015 Sep;34(9):983-91.
Differentiating Sepsis From Adverse Events After Immunization in the Neonatal Intensive Care Unit: How Is a Physician to Know?
Authors: Kuzniewicz MW; Klein NP
JAMA Pediatr. 2015 Aug;169(8):718-9.
Safety of Measles-Containing Vaccines in 1-Year-Old Children
All measles-containing vaccines are associated with several types of adverse events, including seizure, fever, and immune thrombocytopenia purpura (ITP). Because the measles-mumps-rubella-varicella (MMRV) vaccine compared with the separate measles-mumps-rubella (MMR) and varicella (MMR + V) vaccine increases a toddler’s risk for febrile seizures, we investigated whether MMRV is riskier than MMR + V and whether either vaccine elevates the risk for additional safety outcomes. Study children were aged 12 to 23 months in the Vaccine Safety Datalink from 2000 to 2012. Nine study outcomes were investigated: 7 main outcomes (anaphylaxis, ITP, ataxia, arthritis, meningitis/encephalitis, acute disseminated encephalomyelitis, and Kawasaki disease), seizure, and fever. Comparing MMRV with MMR + V, relative risk was estimated by using stratified exact binomial tests. Secondary analyses examined post-MMRV or MMR + V risk versus comparison intervals; risk and comparison intervals were then contrasted for MMRV versus MMR+V. We evaluated 123,200 MMRV and 584,987 MMR + V doses. Comparing MMRV with MMR + V, risks for the 7 main outcomes were not significantly different. Several outcomes had few or zero postvaccination events. Comparing risk versus comparison intervals, ITP risk was higher after MMRV (odds ratio [OR]: 11.3 [95% confidence interval (CI): 1.9 to 68.2]) and MMR + V (OR: 10 [95% CI: 4.5 to 22.5]) and ataxia risk was lower after both vaccines (MMRV OR: 0.8 [95% CI: 0.5 to 1]; MMR + V OR: 0.8 [95% CI: 0.7 to 0.9]). Compared with MMR + V, MMRV increased risk of seizure and fever 7 to 10 days after vaccination. This study did not identify any new safety concerns comparing MMRV with MMR + V or after either the MMRV or the MMR + V vaccine. This study provides reassurance that these outcomes are unlikely after either vaccine.
Authors: Klein NP; Fireman B; Baxter R; et al.
Pediatrics. 2015 Feb;135(2):e321-9. Epub 2015-01-05.
Geographic Clusters in Underimmunization and Vaccine Refusal
Parental refusal and delay of childhood vaccines has increased in recent years and is believed to cluster in some communities. Such clusters could pose public health risks and barriers to achieving immunization quality benchmarks. Our aims were to (1) describe geographic clusters of underimmunization and vaccine refusal, (2) compare clusters of underimmunization with different vaccines, and (3) evaluate whether vaccine refusal clusters may pose barriers to achieving high immunization rates. We analyzed electronic health records among children born between 2000 and 2011 with membership in Kaiser Permanente Northern California. The study population included 154,424 children in 13 counties with continuous membership from birth to 36 months of age. We used spatial scan statistics to identify clusters of underimmunization (having missed 1 or more vaccines by 36 months of age) and vaccine refusal (based on International Classification of Diseases, Ninth Revision, Clinical Modification codes). We identified 5 statistically significant clusters of underimmunization among children who turned 36 months old during 2010-2012. The underimmunization rate within clusters ranged from 18% to 23%, and the rate outside them was 11%. Children in the most statistically significant cluster had 1.58 (P < .001) times the rate of underimmunization as others. Underimmunization with measles, mumps, rubella vaccine and varicella vaccines clustered in similar geographic areas. Vaccine refusal also clustered, with rates of 5.5% to 13.5% within clusters, compared with 2.6% outside them. Underimmunization and vaccine refusal cluster geographically. Spatial scan statistics may be a useful tool to identify locations with challenges to achieving high immunization rates, which deserve focused intervention.
Authors: Lieu TA; Ray GT; Klein NP; Chung C; Kulldorff M
Pediatrics. 2015 Feb;135(2):280-9. Epub 2015-01-19.
Childhood vaccines and Kawasaki disease, Vaccine Safety Datalink, 1996-2006
Kawasaki disease is a childhood vascular disorder of unknown etiology. Concerns have been raised about vaccinations being a potential risk factor for Kawasaki disease. Data from the Vaccine Safety Datalink were collected on children aged 0-6 years at seven managed care organizations across the United States. Defining exposure as one of several time periods up to 42 days after vaccination, we conducted Poisson regressions controlling for age, sex, season, and managed care organization to determine if rates of physician-diagnosed and verified Kawasaki disease were elevated following vaccination compared to rates during all unexposed periods. We also performed case-crossover analyses to control for unmeasured confounding. A total of 1,721,186 children aged 0-6 years from seven managed care organizations were followed for a combined 4,417,766 person-years. The rate of verified Kawasaki disease was significantly lower during the 1-42 days after vaccination (rate ratio=0.50, 95% CL=0.27-0.92) and 8-42 days after vaccination (rate ratio=0.45, 95% CL=0.22-0.90) compared to rates during unexposed periods. Breaking down the analysis by vaccination category did not identify a subset of vaccines which was solely responsible for this association. The case-crossover analyses revealed that children with Kawasaki disease had lower rates of vaccination in the 42 days prior to symptom onset for both physician-diagnosed Kawasaki disease (rate ratio=0.79, 95% CL=0.64-0.97) and verified Kawasaki disease (rate ratio=0.38, 95% CL=0.20-0.75). Childhood vaccinations’ studied did not increase the risk of Kawasaki disease; conversely, vaccination was associated with a transient decrease in Kawasaki disease incidence. Verifying and understanding this potential protective effect could yield clues to the underlying etiology of Kawasaki disease.
Authors: Abrams JY; Klein NP; Belay ED; et al.
Vaccine. 2015 Jan 3;33(2):382-7. Epub 2014-11-04.
Does preventing rotavirus infections through vaccination also protect against naturally-occurring intussusception over time?
Authors: Payne DC; Baggs J; Klein NP; Parashar UD
Clin Infect Dis. 2015 Jan 1;60(1):163-4. Epub 2014-09-23.
Evaluation of the association of maternal pertussis vaccination with obstetric events and birth outcomes
In 2010, due to a pertussis outbreak and neonatal deaths, the California Department of Health recommended that the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) be administered during pregnancy. Tdap is now recommended by the Advisory Committee on Immunization Practices for all pregnant women, preferably between 27 and 36 weeks’ gestation. Limited data exist on Tdap safety during pregnancy. To evaluate whether maternal Tdap vaccination during pregnancy is associated with increased risks of adverse obstetric events or adverse birth outcomes. Retrospective, observational cohort study using administrative health care databases from 2 California Vaccine Safety Datalink sites. Of 123,494 women with singleton pregnancies ending in a live birth between January 1, 2010, and November 15, 2012, 26,229 (21%) received Tdap during pregnancy and 97,265 did not. Risks of small-for-gestational-age (SGA) births (<10th percentile), chorioamnionitis, preterm birth (<37 weeks' gestation), and hypertensive disorders of pregnancy were evaluated. Relative risk (RR) estimates were adjusted for site, receipt of another vaccine during pregnancy, and propensity to receive Tdap during pregnancy. Cox regression was used for preterm delivery, and Poisson regression for other outcomes. Vaccination was not associated with increased risks of adverse birth outcomes: crude estimates for preterm delivery were 6.3% of vaccinated and 7.8% of unvaccinated women (adjusted RR, 1.03; 95% CI, 0.97-1.09); 8.4% of vaccinated and 8.3% of unvaccinated had an SGA birth (adjusted RR, 1.00; 95% CI, 0.96-1.06). Receipt of Tdap before 20 weeks was not associated with hypertensive disorder of pregnancy (adjusted RR, 1.09; 95% CI, 0.99-1.20); chorioamnionitis was diagnosed in 6.1% of vaccinated and 5.5% of unvaccinated women (adjusted RR, 1.19; 95% CI, 1.13-1.26). In this cohort of women with singleton pregnancies that ended in live birth, receipt of Tdap during pregnancy was not associated with increased risk of hypertensive disorders of pregnancy or preterm or SGA birth, although a small but statistically significant increased risk of chorioamnionitis diagnosis was observed.
Authors: Kharbanda EO; Klein NP; Nordin JD; et al.
JAMA. 2014 Nov 12;312(18):1897-904.
Receipt of pertussis vaccine during pregnancy across 7 Vaccine Safety Datalink Sites
In response to widespread pertussis outbreaks and infant deaths, in 2010, the California Department of Health (CDPH) and in 2011 the Advisory Committee on Immunization Practices (ACIP) advised that the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine be administered during pregnancy. The goals of this study were to describe Tdap coverage among pregnant women following these recommendations. In this observational cohort study, we utilized electronic medical record and claims data from seven Vaccine Safety Datalink sites to identify pregnancies and Tdap administrations. All Tdap doses were classified as pre-pregnancy, during pregnancy or post-pregnancy/postpartum. For pregnancies ending in a live birth, we evaluated factors associated with Tdap vaccination. Among 289,141 live births at the California VSD sites, receipt of Tdap during pregnancy increased substantially in the years 2010, 2011, and 2012, when coverage was 15.9, 30.0 and 19.5%, respectively. Among 82,398 women with live births at the Oregon, Washington, Colorado, Wisconsin and Minnesota VSD sites, receipt of Tdap during pregnancy first increased in 2012, at 16.0%. Women receiving early prenatal care and other vaccine(s) during pregnancy had higher Tdap coverage. We observed substantial increases in Tdap coverage during pregnancy following CDPH and ACIP recommendations.
Authors: Kharbanda EO; Vazquez-Benitez G; Lipkind H; Naleway AL; Klein NP; Cheetham TC; Hambidge SJ; Vellozzi C; Nordin JD
Prev Med. 2014 Oct;67:316-9. Epub 2014-06-18.
Integrating database knowledge and epidemiological design to improve the implementation of data mining methods that evaluate vaccine safety in large healthcare databases
Large healthcare databases maintained by health plans have been widely used to conduct customized protocol-based epidemiological safety studies as well as targeted routine sequential monitoring of suspected adverse events for newly licensed vaccines. These databases also offer a rich data source to discover vaccine-related adverse events not known prior to licensure using data mining methods, but they remain relatively under-utilized for this purpose. Initial safety applications of data mining methods using big healthcare data are promising, but stronger integration of database expertize, epidemiological design, and statistical analysis strategies are needed to better leverage the available information, reduce bias, and improve reporting transparency. We enumerate major methodological challenges in mining large healthcare databases for vaccine safety research, describe existing strategies that have been used to address these issues, and identify opportunities for methodological advancements that emphasize the importance of adapting techniques used in customized protocol-based vaccine safety assessments. Investment in such research methods and in the development of deeper collaborations between database safety experts and data mining methodologists has great potential to improve existing safety surveillance programs and further increase public confidence in the safety of newly licensed vaccines.
Authors: Nelson JC; Shrotreed SM; Yu O; Peterson D; Baxter R; Fireman B; Lewis N; McClure D; Weintraub E; Xu S; Jackson LA
Stat Anal Data Min. 2014 Oct;7(5):337-51.
The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety
The Vaccine Safety Datalink (VSD) is a collaborative project between the Centers for Disease Control and Prevention (CDC) and 9 health care organizations. Established in 1990, VSD is a vital resource informing policy makers and the public about the safety of vaccines used in the United States. Large linked databases are used to identify and evaluate adverse events in over 9 million individuals annually. VSD generates rapid, important safety assessments for both routine vaccinations and emergency vaccination campaigns. VSD monitors safety of seasonal influenza vaccines in near-real time, and provided essential information on the safety of influenza A (H1N1) 2009 monovalent vaccine during the recent pandemic. VSD investigators have published important studies demonstrating that childhood vaccines are not associated with autism or other developmental disabilities. VSD prioritizes evaluation of new vaccines; searches for possible unusual health events after vaccination; monitors vaccine safety in pregnant women; and has pioneered development of biostatistical research methods.
Authors: McNeil MM; Klein NP; DeStefano F; et al.
Vaccine. 2014 Sep 22;32(42):5390-8. Epub 2014-08-06.
Impact of Vaccination on the Epidemiology of Varicella: 1995-2009
When varicella vaccine was licensed in the United States in 1995, there were concerns that childhood vaccination might increase the number of adolescents susceptible to varicella and shift disease toward older age groups where it can be more severe. We conducted a series of 5 cross-sectional studies in 1994 to 1995 (prevaccine), 2000, 2003, 2006, and 2009 in Kaiser Permanente of Northern California to assess changes in varicella epidemiology in children and adolescents, as well as changes in varicella hospitalization in people of all ages. For each study, information on varicella history and varicella occurrence during the past year was obtained by telephone survey from a sample of ?8000 members 5 to 19 years old; varicella hospitalization rates were calculated for the entire membership. Between 1995 and 2009, the overall incidence of varicella in 5- to 19-year-olds decreased from 25.8 to 1.3 per 1000 person-years, a ?90% to 95% decline in the various age categories (5-9, 10-14, and 15-19 years of age). The proportion of varicella-susceptible children and adolescents also decreased in all age groups, including in 15- to 19-year-olds (from 15.6% in 1995 to 7.6% in 2009). From 1994 to 2009, age-adjusted varicella hospitalization rates in the general member population decreased from 2.13 to 0.25 per 100,000, a ?90% decline. In the 15 years after the introduction of varicella vaccine, a major reduction in varicella incidence and hospitalization was observed with no evidence of a shift in the burden of varicella to older age groups.
Authors: Baxter R; Tran TN; Ray P; Lewis E; Fireman B; Black S; Shinefield HR; Coplan PM; Saddier P
Pediatrics. 2014 Jul;134(1):24-30. Epub 2014-06-09.
Timely Versus Delayed Early Childhood Vaccination and Seizures
Little is known regarding the timing of childhood vaccination and postvaccination seizures. In a cohort of 323?247 US children from the Vaccine Safety Datalink born from 2004 to 2008, we analyzed the association between the timing of childhood vaccination and the first occurrence of seizure with a self-controlled case series analysis of the first doses of individual vaccines received in the first 2 years of life. In infants, there was no association between the timing of infant vaccination and postvaccination seizures. In the second year of life, the incident rate ratio (IRR) for seizures after receipt of the first measles-mumps-rubella vaccine (MMR) dose at 12 to 15 months was 2.65 (95% confidence interval [CI] 1.99-3.55); the IRR after an MMR dose at 16 to 23 months was 6.53 (95% CI 3.15-13.53). The IRR for seizures after receipt of the first measles-mumps-rubella-varicella vaccine (MMRV) dose at 12 to 15 months was 4.95 (95% CI 3.68-6.66); the IRR after an MMRV dose at 16 to 23 months was 9.80 (95% CI 4.35 -22.06). There is no increased risk of postvaccination seizure in infants regardless of timing of vaccination. In year 2, delaying MMR vaccine past 15 months of age results in a higher risk of seizures. The strength of the association is doubled with MMRV vaccine. These findings suggest that on-time vaccination is as safe with regard to seizures as delayed vaccination in the first year of life, and that delayed vaccination in the second year of life is associated with more postvaccination seizures than on-time vaccination.
Authors: Hambidge SJ; Klein NP; DeStefano F; et al.
Pediatrics. 2014 Jun;133(6):e1492-9.
Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine
In 2008, a diphtheria, tetanus, acellular pertussis, and inactivated poliovirus combined vaccine (DTaP-IPV) was licensed for use in children 4 through 6 years of age. While pre-licensure studies did not demonstrate significant safety concerns, the number vaccinated in these studies was not sufficient to examine the risk of uncommon but serious adverse events. To assess the risk of serious adverse events following DTaP-IPV vaccination. The study was conducted from January 2009 through September 2012 in the Vaccine Safety Datalink (VSD) project. In the VSD, electronic vaccination and encounter data are updated and aggregated weekly as part of ongoing surveillance activities. Based on previous reports and biologic plausibility, eight potential adverse events were monitored: meningitis/encephalitis; seizures; stroke; Guillain-Barré syndrome; Stevens-Johnson syndrome; anaphylaxis; serious allergic reactions other than anaphylaxis; and serious local reactions. Adverse event rates in DTaP-IPV recipients were compared to historical incidence rates in the VSD population prior to 2009. Sequential probability ratio testing was used to analyze the data on a weekly basis. During the study period, 201,116 children received DTaP-IPV vaccine. Ninety-seven percent of DTaP-IPV recipients also received other vaccines on the same day, typically measles-mumps-rubella and varicella vaccines. There was no statistically significant increased risk of any of the eight pre-specified adverse events among DTaP-IPV recipients when compared to historical incidence rates. In this safety surveillance study of more than 200,000 DTaP-IPV vaccine recipients, there was no evidence of increased risk for any of the pre-specified adverse events monitored. Continued surveillance of DTaP-IPV vaccine safety may be warranted to monitor for rare adverse events, such as Guillain-Barré syndrome.
Authors: Daley MF; Klein NP; Weintraub E; et al.
Vaccine. 2014 May 23;32(25):3019-24. Epub 2014-03-31.
Live Vaccine Use and Safety in DiGeorge Syndrome
Live vaccines are generally contraindicated in patients with DiGeorge syndrome (DGS), a congenital disorder characterized by cellular immune deficiency. Vaccine utilization and safety in this population are not well described. This study examined vaccination patterns and adverse events following live immunization (AEFLI) in these individuals. A multicenter retrospective cohort study was conducted in subjects with DGS confirmed by fluorescence in situ hybridization assay (chromosome 22q11.2 microdeletion). Live vaccine-preventable illnesses, vaccination coverage and timeliness, and AEFLIs in the 56-day window after live vaccination were examined. Bivariate and multivariable analyses assessed the impact of demographics medical history, timing of diagnostic confirmation, and preceding immune function on vaccination patterns and AEFLIs. Of 194 subjects, 77% and 75% received measles-mumps-rubella (MMR) and varicella vaccines, respectively; 58% completed recommended vaccinations by age 19 to 35 months. Adverse events occurred after 14% and 20% of MMR and varicella vaccine doses, respectively. Most events were minor, few were serious, and no deaths were reported in post-live vaccination windows. Although early diagnostic confirmation negatively affected live vaccination coverage and timeliness (P < .001), baseline CD4% did not differ between subjects who did or did not receive live vaccines by 12 to 18 months. Among varicella vaccine recipients, those with a subsequent adverse event had a lower preceding CD4% (24.8% ± 7.3%) than those without (35.5% ± 11.7%) (P < .05); no CD4% differences were observed with MMR vaccination. Fourteen unvaccinated subjects experienced live vaccine-preventable illnesses. Live vaccines were frequently given and generally well-tolerated among patients with DGS with mild-to-moderate immunosuppression.
Authors: Hofstetter AM; Jakob K; Klein NP; Dekker CL; Edwards KM; Halsey NA; Baxter R; Williams SE; Graham PL; LaRussa P
Pediatrics. 2014 Apr;133(4):e946-54. Epub 2014-03-31.
Risk of Intussusception after Monovalent Rotavirus Vaccination
Although current rotavirus vaccines were not associated with an increased risk of intussusception in large trials before licensure, recent postlicensure data from international settings suggest the possibility of a small increase in risk of intussusception after monovalent rotavirus vaccination. We examined this risk in a population in the United States. Participants were infants between the ages of 4 and 34 weeks who were enrolled in six integrated health care organizations in the Vaccine Safety Datalink (VSD) project. We reviewed medical records and visits for intussusception within 7 days after monovalent rotavirus vaccination from April 2008 through March 2013. Using sequential analyses, we then compared the risk of intussusception among children receiving monovalent rotavirus vaccine with historical background rates. We further compared the risk after monovalent rotavirus vaccination with the risk in a concurrent cohort of infants who received the pentavalent rotavirus vaccine. During the study period, 207,955 doses of monovalent rotavirus vaccine (including 115,908 first doses and 92,047 second doses) were administered in the VSD population. We identified 6 cases of intussusception within 7 days after the administration of either dose of vaccine. For the two doses combined, the expected number of intussusception cases was 0.72, resulting in a significant relative risk of 8.4. For the pentavalent rotavirus vaccine, 1,301,810 doses were administered during the study period, with 8 observed intussusception cases (7.11 expected), for a nonsignificant relative risk of 1.1. The relative risk of chart-confirmed intussusception within 7 days after monovalent rotavirus vaccination, as compared with the risk after pentavalent rotavirus vaccination, was 9.4 (95% confidence interval, 1.4 to 103.8). The attributable risk of intussusception after the administration of two doses of monovalent rotavirus vaccine was estimated to be 5.3 per 100,000 infants vaccinated. In this prospective postlicensure study of more than 200,000 doses of monovalent rotavirus vaccine, we observed a significant increase in the rate of intussusception after vaccination, a risk that must be weighed against the benefits of preventing rotavirus-associated illness. (Funded by the Centers for Disease Control and Prevention.).
Authors: Weintraub ES; Klein NP; DeStefano F; et al.
N Engl J Med. 2014 Feb 6;370(6):513-9. Epub 2014-01-14.
Vaccinations given during pregnancy, 2002-2009: a descriptive study
A number of studies have described influenza vaccination coverage during pregnancy but few publications have described rates of other vaccinations. To describe vaccination rates during pregnancy in the Vaccine Safety Datalink (VSD), with particular focus on vaccinations contraindicated during pregnancy. Pregnancies ending in 2002 through 2009 and vaccinations administered during these pregnancies were identified in the VSD. Vaccination rates per 1000 pregnancies during the study period were calculated by vaccine type, recommendation category, pregnancy year, maternal age, and trimester. Analyses were conducted in 2012-2013. In the VSD, 669,695 pregnancies and 141,389 vaccinations were identified. Trivalent inactivated influenza (TIV) was the most commonly administered vaccination (174.1 doses per 1000 pregnancies) and was most often administered during the 2nd and 3rd trimesters. The most common vaccines in the “consider if indicated” category were tetanus-diphtheria (6.1 per 1000) and hepatitis B (3.7 per 1000). Contraindicated vaccination was infrequent, and the majority of these were measles-mumps-rubella (MMR) (1.2 per 1000); varicella (1.0 per 1000); and live-attenuated influenza vaccine (LAIV) (0.3 per 1000). Both “consider if indicated” and contraindicated vaccines were more frequently administered during early pregnancy. TIV was the most commonly administered vaccine. With the exception of TIV, other vaccines were most frequently administered during early pregnancy and among younger women, suggesting that vaccination may occur when the woman and/or provider are unaware of the pregnancy. Contraindicated vaccines were infrequently administered during pregnancy; however, given that some women received contraindicated vaccines later in pregnancy, clearer recommendations and improved provider education may be needed.
Authors: Naleway AL; Klein NP; Weintraub E; et al.
Am J Prev Med. 2014 Feb;46(2):150-7.
Protective Association Between Rotavirus Vaccination and Childhood Seizures in the Year Following Vaccination in US Children
Rotavirus illness has been linked to childhood seizures. We investigated whether a protective association exists between receipt of rotavirus vaccine and being hospitalized or visiting the emergency department for seizures in the year after vaccination. We retrospectively analyzed a cohort of children born after 28 February 2006 (when rotavirus vaccine was licensed in the United States) and enrolled in the Vaccine Safety Datalink (VSD) through November 2009. Seizure rates from 4 to 55 weeks following last rotavirus vaccination were compared by vaccine exposure status (fully vaccinated and unvaccinated). A time-to-event analysis using a Cox proportional hazards model was performed, accounting for time-varying covariates. We calculated the relative incidence of seizure compared by vaccine exposure status during the postexposure interval. Our cohort contained VSD data on 250 601 infants, including 186 502 children fully vaccinated (74.4%) and 64 099 (25.6%) not vaccinated with rotavirus vaccine. Rates of seizures were associated with rotavirus vaccination status. After adjusting for covariates (VSD site, age at last dose, sex, and calendar month of the index date), a statistically significant protective association was observed between a full course of rotavirus vaccination vs no vaccination for both first-ever seizures (risk ratio [RR] = 0.82; 95% confidence interval [CI], .73-.91) and all seizures (RR = 0.79; 95% CI, .71-.88). A full course of rotavirus vaccination was statistically associated with an 18%-21% reduction in risk of seizure requiring hospitalization or emergency department care in the year following vaccination, compared with unvaccinated children. This reduction in childhood seizures complements the well-documented vaccine-related benefit of preventing US diarrhea hospitalizations.
Authors: Payne DC; Baggs J; Zerr DM; Klein NP; Yih K; Glanz J; Curns AT; Weintraub E; Parashar UD
Clin Infect Dis. 2014 Jan;58(2):173-7. Epub 2013-11-20.
Licensed pertussis vaccines in the United States
The United States switched from whole cell to acellular pertussis vaccines in the 1990s following global concerns with the safety of the whole cell vaccines. Despite high levels of acellular pertussis vaccine coverage, the United States and other countries are experiencing large pertussis outbreaks. The aim of this article is to describe the historical context which led to acellular pertussis vaccine development, focusing on vaccines currently licensed in the US, and to review evidence that waning protection following licensed acellular pertussis vaccines have been significant factors in the widespread reappearance of pertussis.
Authors: Klein NP
Hum Vaccin Immunother. 2014;10(9):2684-90. Epub 2014-11-06.
Effect of Age on the Risk of Fever and Seizures Following Immunization With Measles-Containing Vaccines in Children
IMPORTANCE The first dose of live attenuated measles-containing vaccines is associated with an increased risk of febrile seizures 7 to 10 days following immunization among 12- to 23-month-old children. The combination measles, mumps, rubella, and varicella vaccine is associated with a 2-fold increased risk of febrile seizures 7 to 10 days following immunization compared with the separately administered measles, mumps, and rubella and varicella vaccines. It is unknown whether the magnitude of these increased risks depends on age at immunization. OBJECTIVE To examine the potential modifying effect of age on the risk of fever and seizures following immunization with measles-containing vaccines. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at 8 Vaccine Safety Datalink sites of a total of 840,348 children 12 to 23 months of age who had received a measles-containing vaccine from 2001 through 2011. EXPOSURES Any measles-containing vaccines and measles-containing vaccines by type. MAIN OUTCOMES AND MEASURES Fever and seizure events occurring during a 42-day postimmunization observation period. RESULTS In the analysis of any measles-containing vaccines, the increased risk of seizures during the 7- to 10-day risk interval, using the remainder of the observation period as the control interval, was significantly greater among older children (relative risk, 6.5; 95% CI, 5.3-8.1; attributable risk, 9.5 excess cases per 10,000 doses; 95% CI, 7.6-11.5) than among younger children (relative risk, 3.4; 95% CI, 3.0-3.9; attributable risk?=?4.0 excess cases per 10,000 doses; 95% CI, 3.4-4.6). The relative risk of postimmunization fever was significantly greater among older children than among younger children; however, its attributable risk was not. In the analysis of vaccine type, measles, mumps, rubella, and varicella vaccine was associated with a 1.4-fold increase in the risk of fever and 2-fold increase in the risk of seizures compared with measles, mumps, and rubella vaccine administered with or without varicella vaccine in both younger and older children. CONCLUSIONS AND RELEVANCE Measles-containing vaccines are associated with a lower increased risk of seizures when administered at 12 to 15 months of age. Findings of this study that focused on safety outcomes highlight the importance of timely immunization of children with the first dose of measles-containing vaccines.
Authors: Rowhani-Rahbar A; Fireman B; Klein NP; et al.
JAMA Pediatr. 2013 Dec;167(12):1111-7.
Factors that may explain observed associations between trivalent influenza vaccination and gastrointestinal illness in young children
Previously published studies reported an increased risk of gastrointestinal illness in the 14 days following trivalent influenza vaccination (TIV) in young children. While gastrointestinal illness may be a true adverse effect of TIV, other factors may influence this observed association, such as seasonal illness patterns and children being exposed to gastrointestinal pathogens at medical visits. The objective of this study was to examine factors influencing the association between TIV and gastrointestinal illness. Specifically, using data from a previous influenza vaccine safety study, we examined the association between medical encounters without TIV and gastrointestinal illness. Using electronic health record (EHR) data from 6 managed care organizations (MCOs), we identified medically attended gastrointestinal illness cases among children 24-59 months in the 2002-2006 influenza seasons. We matched each case to four controls on sex, birthdate (month/year), MCO, influenza season, and presence of a chronic condition. We then looked 1-14 days prior to the index date (gastrointestinal illness diagnosis date) to determine whether the child had a medical encounter. We excluded previous medical encounters with gastrointestinal-related diagnoses or TIV. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. We identified 2062 gastrointestinal illness cases and matched them to 8248 controls. We observed increased odds of gastrointestinal illness within 14 days after a medical encounter (odds ratio=1.9; 95% confidence interval [CI]: 1.7-2.2) among children without chronic conditions. Among children with chronic conditions, the odds ratio was 3.9 (95% CI: 2.5-6.2). We demonstrated that another exposure related to vaccination, medical visits, is also associated with increased odds for gastrointestinal illness. This study highlights challenges of interpreting results from observational vaccine safety studies when there are co-occurring exposures, and the importance of investigating confounding in EHR data, which are an essential resource for vaccine safety research.
Authors: Newcomer SR; Hambidge SJ; McClure DL; Daley MF; Klein NP; Glanz JM
Vaccine. 2013 Aug 20;31(37):3894-8. Epub 2013-07-02.
One or Two Doses of Quadrivalent Meningococcal Serogroups A, C, W-135 and Y Tetanus Toxoid Conjugate Vaccine is Immunogenic in 9-12 Month Old Children
The incidence of invasive meningococcal disease is highest in infants. A quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) was evaluated in children 9-12 months of age. We randomized infants (1:1) to receive 1 dose of MenACWY-TT at 12 months of age (ACWY-1 group) or 2 doses at 9 and 12 months (ACWY-2). We measured immunogenicity after each dose and 1 year after completing vaccination using human serum bactericidal antibody (hSBA) assays according to prespecified criteria of ? 1:8. Local and general symptoms were solicited for 8 days after vaccination. Adverse events were recorded for 6 months after the last dose. We enrolled and vaccinated 349 subjects, of whom 248 reenrolled at Year 1 for evaluation of antibody persistence. Percentages of subjects with postvaccination hSBA ? 1:8 in the ACWY-1 group were 79.5%, 94.6%, 50.8% and 56.1% and in the 2-dose group (ACWY-2) were 88.4%, 100%, 99.3% and 99.3% postdose 2 for serogroups A, C, W-135 and Y, respectively. At Year 1, 80.0-99.1% in each group had hSBA ? 1:8, except for serogroup A, for which 20.6% (ACWY-1) and 25.9% (ACWY-2) retained hSBA ?1:8. Both schedules were well-tolerated, with no observed increase in reactogenicity after the second dose. MenACWY-TT was immunogenic when administered as a single dose at 12 months of age, or as 2 doses at 9 and 12 months, and had a clinically acceptable safety profile. Good antibody persistence was observed through 12 months postvaccination after both treatment schedules for serogroups C, W-135, Y.
Authors: Klein NP; Baine Y; Bianco V; Lestrate PR; Naz A; Blatter M; Friedland LR; Miller JM
Pediatr Infect Dis J. 2013 Jul;32(7):760-7.
Lack of Association of Guillain-Barre Syndrome with Vaccinations
Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy, thought to be an autoimmune process. Although cases of GBS have been reported following a wide range of vaccines, a clear association has only been established with the 1976 H1N1 inactivated influenza vaccine. We identified hospitalized GBS cases from Kaiser Permanente Northern California (KPNC) from 1995 through 2006. The medical record of each suspected case was neurologist-reviewed according to the Brighton Collaboration GBS case definition; only confirmed cases were included in the analyses, and cases of Miller Fisher syndrome were excluded. Using a case-centered design, we compared the odds of vaccination in the 6 and 10 weeks prior to onset of GBS to the odds of vaccination during the same time intervals in all vaccinated individuals in the entire KPNC population. We confirmed 415 incident cases of GBS (including Brighton levels 1, 2, and 3) during the study period (>30 million person-years). Incidence peaked during the winter months. The odds ratio of influenza vaccination within a 6-week interval prior to GBS, compared with the prior 9 months, was 1.1 (95% confidence interval [CI], .4-3.1). The risk in the 6-week interval compared to the prior 12 months for tetanus diphtheria combination, 23-valent pneumococcal polysaccharide, and for all vaccines combined was 1.4 (95% CI, .3-4.5), 0.7 (95% CI, .1-2.9), and 1.3 (95% CI, .8-2.3), respectively. In this large retrospective study, we did not find evidence of an increased risk of GBS following vaccinations of any kind, including influenza vaccination.
Authors: Baxter R; Bakshi N; Fireman B; Lewis E; Ray P; Vellozzi C; Klein NP
Clin Infect Dis. 2013 Jul;57(2):197-204. Epub 2013-04-11.
Cervical Intraepithelial Neoplasia Grade 3 and Adenocarcinoma in situ: Comparison of ICD-9 Codes and Pathology Results – Kaiser Permanente, United States, 2000-2005
Cervical intraepithelial neoplasia grade 3+ (CIN3+) and adenocarcinoma in situ incidence will be an important measure of HPV vaccine impact. Integrated healthcare delivery systems, such as Kaiser Permanente, could be used to monitor CIN3+ trends; however, limited evaluations of data from healthcare delivery systems for CIN3+ surveillance exist. We compared CIN3+ diagnoses by ICD-9 code with CIN3+ diagnoses by pathology results among 121,211 females aged 11 to 30 years who were continuously enrolled from 2000 to 2005 in either Kaiser Permanente Northern California or Kaiser Permanente Northwest. We calculated sensitivity and positive predictive value of diagnosis by ICD-9 codes using pathology CIN3+ diagnosis as the gold standard. There were 1,090 women with at least one CIN3+ diagnosis by ICD-9 code 233.1 and 1,200 women with at least one CIN3+ diagnosis by pathology results. The sensitivity of the ICD-9 code for detecting a woman with at least one pathology diagnosis for CIN3+ was 62% (740/1,200); positive predictive value was 68% (740/1,090). Among women with at least one CIN3+ diagnosis by ICD-9 code, 679 (62%) had more than one visit with this code; whereas, among women with at least one CIN3+ diagnosis by pathology, 466 (39%) had more than one CIN3+ pathology result. ICD-9 codes may underestimate the number of women with at least one CIN3+ diagnosis. Pathology results, when available, may provide better estimates of CIN3+ incidence.
Authors: Surie D; Dunne EF; Naleway AL; Weinmann S; Klein NP; Baxter R; Hutchins K; Gee J; Markowitz L
Cancer Epidemiol Biomarkers Prev. 2013 Jun;22(6):1129-32. Epub 2013-04-05.
Comprehensive Assessment of Serious Adverse Events Following Immunization by Health Care Providers
Authors: Williams SE; Klein NP; et al.
J Pediatr. 2013 Jun;162(6):1276-81, 1281.e1. Epub 2013 Feb 26.
Long-term Effectiveness of Varicella Vaccine: A 14-Year, Prospective Cohort Study
BACKGROUND: Varicella vaccine was licensed in the United States in 1995 for individuals >/=12 months of age. A second dose was recommended in the United States in June 2006. Varicella incidence and vaccine effectiveness were assessed in a 14-year prospective study conducted at Kaiser Permanente Northern California. METHODS: A total of 7585 children vaccinated with varicella vaccine in their second year of life in 1995 were followed up prospectively for breakthrough varicella and herpes zoster (HZ) through 2009. A total of 2826 of these children received a second dose in 2006-2009. Incidences of varicella and HZ were estimated and compared with prevaccine era rates. RESULTS: In this cohort of vaccinated children, the average incidence of varicella was 15.9 per 1000 person-years, nine- to tenfold lower than in the prevaccine era. Vaccine effectiveness at the end of the study period was 90%, with no indication of waning over time. Most cases of varicella were mild and occurred early after vaccination. No child developed varicella after a second dose. HZ cases were mild, and rates were lower in the cohort of vaccinated children than in unvaccinated children during the prevaccine era (relative risk: 0.61 [95% confidence interval: 0.43-0.89]). CONCLUSIONS: This study confirmed that varicella vaccine is effective at preventing chicken pox, with no waning noted over a 14-year period. One dose provided excellent protection against moderate to severe disease, and most cases occurred shortly after the cohort was vaccinated. The study data also suggest that varicella vaccination may reduce the risks of HZ in vaccinated children.
Authors: Baxter R; Ray P; Tran TN; Black S; Shinefield HR; Coplan PM; Lewis E; Fireman B; Saddier P
Pediatrics. 2013 May;131(5):e1389-96. Epub 2013 Apr 1.
Prevalence of HPV types in cervical specimens from an integrated healthcare delivery system: baseline assessment to measure HPV vaccine impact
PURPOSE: Two human papillomavirus (HPV) vaccines are available to prevent cervical cancer. One early measure of HPV vaccine impact would be a reduction in vaccine-related HPV types (HPV 6, 11, 16, or 18, or HPV 16, 18) in cervical samples from young women. We aimed to assess feasibility of specimen collection and baseline HPV prevalence in an integrated healthcare delivery system. METHODS: Residual cervical specimens collected during routine cervical cancer screening (2006-2008) were retained consecutively from eligible females aged 11-29 years, stratified by age group. Specimens were evaluated for 37 HPV genotypes using the Roche Linear Array assay. RESULTS: Of 10,124 specimens submitted, 10,103 (99 %) were adequate for HPV testing. Prevalence of HPV 6, 11, 16, or 18 genotype was 11.4 % overall and was the highest in the youngest age group (18.1 % in the 11-19-year-olds, 12.5 % in the 20-24-year-olds, and 7.0 % in the 25-29-year-olds). CONCLUSIONS: HPV types 6, 11, 16, or 18 prevalence could be measured over time to assess early HPV vaccine impact using residual specimens from an integrated healthcare delivery system, particularly if sampling focused on young women.
Authors: Dunne EF; Klein NP; Unger ER; et al.
Cancer Causes Control. 2013 Feb;24(2):403-7. Epub 2013 Jan 5.
Clinical Assessment of Serious Adverse Events in Children Receiving 2009 H1N1 Vaccination
BACKGROUND: Monovalent 2009 H1N1 influenza vaccines were licensed and administered in the United States during the H1N1 influenza pandemic between 2009 and 2013. METHODS: Vaccine Adverse Event Reporting System received reports of adverse events following immunization (AEFI) after H1N1 vaccination. Selected reports were referred to the Centers for Disease Control and Prevention’s Clinical Immunization Safety Assessment network for additional review. We assessed causality using modified World Health Organization criteria. RESULTS: There were 3,928 reports of AEFI in children younger than age 18 years after 2009 H1N1 vaccination received by January 31, 2010. Of these, 214 (5.4%) were classified as serious nonfatal and 109 were referred to Clinical Immunization Safety Assessment for further evaluation. Ninety-nine (91%) had sufficient initial information to begin investigation and are described here. The mean age was 8 years (range, 6 months-17 years) and 38% were female. Median number of days between vaccination and symptom onset was 2 (range, -11 days to +41 days). Receipt of inactivated, live attenuated, or unknown type of 2009 H1N1 vaccines was reported by 68, 26 and 5 cases, respectively. Serious AEFI were categorized as neurologic events in 47 cases, as hypersensitivity in 15 cases and as respiratory events in 10 cases. At the time of evaluation, recovery was described as complete (61), partial (16), no improvement (1), or unknown (21). Causality assessment yielded the following likelihood of association with 2009 H1N1 vaccination: 8 definitely; 8 probably; 21 possibly; 43 unlikely; 17 unrelated; and 2 unclassifiable. CONCLUSIONS: Most AEFI in children evaluated were not causally related to vaccine and resolved without sequelae. Detailed clinical assessment of individual serious AEFI can provide reassurance of vaccine safety.
Authors: Pahud BA; Klein NP; Edwards KM; et al.
Pediatr Infect Dis J. 2013 Feb;32(2):163-8.
Adapting Group Sequential Methods to Observational Postlicensure Vaccine Safety Surveillance: Results of a Pentavalent Combination DTaP-IPV-Hib Vaccine Safety Study
To address gaps in traditional postlicensure vaccine safety surveillance and to promote rapid signal identification, new prospective monitoring systems using large health-care database cohorts have been developed. We newly adapted clinical trial group sequential methods to this observational setting in an original safety study of a combination diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib) conjugate vaccine (DTaP-IPV-Hib) among children within the Vaccine Safety Datalink population. For each prespecified outcome, we conducted 11 sequential Poisson-based likelihood ratio tests during September 2008-January 2011 to compare DTaP-IPV-Hib vaccinees with historical recipients of other DTaP-containing vaccines. No increased risk was detected among 149,337 DTaP-IPV-Hib vaccinees versus historical comparators for any outcome, including medically attended fever, seizure, meningitis/encephalitis/myelitis, nonanaphylactic serious allergic reaction, anaphylaxis, Guillain-Barre syndrome, or invasive Hib disease. In end-of-study prespecified subgroup analyses, risk of medically attended fever was elevated among 1- to 2-year-olds who received DTaP-IPV-Hib vaccine versus historical comparators (relative risk = 1.83, 95% confidence interval: 1.34, 2.50) but not among infants under 1 year old (relative risk = 0.83, 95% confidence interval: 0.73, 0.94). Findings were similar in analyses with concurrent comparators who received other DTaP-containing vaccines during the study period. Although lack of a controlled experiment presents numerous challenges, implementation of group sequential monitoring methods in observational safety surveillance studies is promising and warrants further investigation.
Authors: Nelson JC; Klein NP; Jackson LA; et al.
Am J Epidemiol. 2013 Jan 15;177(2):131-41. Epub 2013 Jan 4.
Kaiser Permanente Vaccine Study Center: Highlights of 2009-2012
The Kaiser Permanente Vaccine Study Center is a specialized research organization in Oakland, California. They have been an active vaccine research group for many years, and have participated in and led a multitude of vaccine studies. This article will review the last three years of research activities.
Authors: Baxter R; Klein NP
Vaccines (Basel). 2013;1(2):139-53. Epub 2013-04-25.
Biologically plausible and evidence-based risk intervals in immunization safety research
In immunization safety research, individuals are considered at risk for the development of certain adverse events following immunization (AEFI) within a specific period of time referred to as the risk interval. These intervals should ideally be determined based on biologic plausibility considering features of the AEFI, presumed or known pathologic mechanism, and the vaccine. Misspecification of the length and timing of these intervals may result in introducing bias in epidemiologic and clinical studies of immunization safety. To date, little work has been done to formally assess and determine biologically plausible and evidence-based risk intervals in immunization safety research. In this report, we present a systematic process to define biologically plausible and evidence-based risk interval estimates for two specific AEFIs, febrile seizures and acute disseminated encephalomyelitis. In addition, we review methodologic issues related to the determination of risk intervals for consideration in future studies of immunization safety.
Authors: Rowhani-Rahbar A; Klein NP; Dekker CL; Edwards KM; Marchant CD; Vellozzi C; Fireman B; Sejvar JJ; Halsey NA; Baxter R; Risk Interval Working Group of the Clinical Immunization Safety Assessment Network
Vaccine. 2012 Dec 17;31(1):271-7. Epub 2012 Jul 24.
Safety of Quadrivalent Human Papillomavirus Vaccine Administered Routinely to Females
OBJECTIVE: To assess the safety of the quadrivalent human papillomavirus vaccine (HPV4) in females following routine administration. DESIGN: In a cohort of vaccinated females, we compared the risk of emergency department visits and hospitalizations during the interval soon after vaccination with risk during a comparison interval more remote from vaccination. SETTING: Kaiser Permanente in California. PARTICIPANTS: All females who received the HPV4 vaccine. MAIN EXPOSURE: One or more doses of HPV4 between August 2006 and March 2008. MAIN OUTCOME MEASURES: Outcomes were emergency department visits and hospitalizations, grouped into predefined diagnostic categories. Within diagnostic groups, we used odds ratios (ORs) to estimate whether each subject had any outcome in postvaccination risk intervals (days 1-60, days 1-14, and day 0), compared with a control interval distant in time from vaccination. RESULTS: One hundred eighty-nine thousand six hundred twenty-nine females received at least 1 dose and 44 001 received 3 HPV4 doses. Fifty categories had significantly elevated ORs during at least 1 risk interval. Medical record review revealed that most diagnoses were present before vaccination or diagnostic workups were initiated at the vaccine visit. Only skin infections during days 1 to 14 (OR, 1.8; 95% CI, 1.3-2.4) and syncope on day of vaccination (OR, 6.0; 95% CI, 3.9-9.2) were noted by an independent Safety Review Committee as likely associations with HPV4. CONCLUSIONS: The quadrivalent human papillomavirus vaccine was associated with same-day syncope and skin infections in the 2 weeks after vaccination. This study did not detect evidence of new safety concerns among females 9 to 26 years of age secondary to vaccination with HPV4.
Authors: Klein NP; Jacobsen SJ; et al.
Arch Pediatr Adolesc Med. 2012 Dec;166(12):1140-8.
Causality assessment of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS)
Adverse events following immunization (AEFI) reported to the national Vaccine Adverse Event Reporting System (VAERS) represent true causally related events, as well as events that are temporally, but not necessarily causally related to vaccine. OBJECTIVE: We sought to determine if the causal relationships between the vaccine and the AEFI reported to VAERS could be assessed through expert review. DESIGN: A stratified random sample of 100 VAERS reports received in 2004 contained 13 fatal cases, 19 cases with non-fatal disabilities, 39 other serious non-fatal cases and 29 non-serious cases. Experts knowledgeable about vaccines and clinical outcomes, reviewed each VAERS report and available medical records. MAIN OUTCOME MEASURES: Modified World Health Organization criteria were used to classify the causal relationship between vaccines and AEFI as definite, probable, possible, unlikely or unrelated. Five independent reviewers evaluated each report. If they did not reach a majority agreement on causality after initial review, the report was discussed on a telephone conference to achieve agreement. RESULTS: 108 AEFIs were identified in the selected 100 VAERS reports. After initial review majority agreement was achieved for 83% of the AEFI and 17% required further discussion. In the end, only 3 (3%) of the AEFI were classified as definitely causally related to vaccine received. Of the remaining AEFI 22 (20%) were classified as probably and 22 (20%) were classified as possibly related to vaccine received; a majority (53%) were classified as either unlikely or unrelated to a vaccine received. CONCLUSIONS: Using VAERS reports and additional documentation, causality could be assessed by expert review in the majority of VAERS reports. Assessment of VAERS reports identified that causality was thought to be probable or definite in less than one quarter of reports, and these were dominated by local reactions, allergic reactions, or symptoms known to be associated with the vaccine administered.
Authors: Loughlin AM; Klein NP; Jakob K; et al.
Vaccine. 2012 Nov 26;30(50):7253-9. Epub 2012 Oct 9.
Safety of Zostavax-A cohort study in a managed care organization
BACKGROUND: Zostavax is a live, attenuated varicella-zoster virus vaccine indicated for the prevention of herpes zoster (shingles). An observational post-licensure (Phase IV) study was conducted at Kaiser Permanente Northern California (KPNC), a US managed care organization, to assess the safety of zoster vaccine in people 60 years of age or older, vaccinated in routine medical care. METHODS: We performed a cohort study, comparing rates of clinical events resulting in hospitalizations or emergency department visits in a 42-day risk time period immediately following vaccination with rates in the same cohort in a subsequent comparison time period. The study data were reviewed and interpreted by an external safety review committee of 3 independent experts. RESULTS: Approximately 29,000 people >/= 60 years of age were vaccinated with zoster vaccine from July 2006 to November 2007. Of the 386 comparisons performed for the main analysis, 4 had an increased relative risk with a nominal p-value
Authors: Baxter R; Tran TN; Hansen J; Emery M; Fireman B; Bartlett J; Lewis N; Saddier P
Vaccine. 2012 Oct 19;30(47):6636-41. Epub 2012 Sep 8.
Waning protection after fifth dose of acellular pertussis vaccine in children
BACKGROUND: In the United States, children receive five doses of diphtheria, tetanus, and acellular pertussis (DTaP) vaccine before 7 years of age. The duration of protection after five doses of DTaP is unknown. METHODS: We assessed the risk of pertussis in children in California relative to the time since the fifth dose of DTaP from 2006 to 2011. This period included a large outbreak in 2010. We conducted a case-control study involving members of Kaiser Permanente Northern California who were vaccinated with DTaP at 47 to 84 months of age. We compared children with pertussis confirmed by a positive polymerase-chain-reaction (PCR) assay with two sets of controls: those who were PCR-negative for pertussis and closely matched controls from the general population of health-plan members. We used logistic regression to examine the risk of pertussis in relation to the duration of time since the fifth DTaP dose. Children who received whole-cell pertussis vaccine during infancy or who received any pertussis-containing vaccine after their fifth dose of DTaP were excluded. RESULTS: We compared 277 children, 4 to 12 years of age, who were PCR-positive for pertussis with 3318 PCR-negative controls and 6086 matched controls. PCR-positive children were more likely to have received the fifth DTaP dose earlier than PCR-negative controls (P<0.001) or matched controls (P=0.005). Comparison with PCR-negative controls yielded an odds ratio of 1.42 (95% confidence interval, 1.21 to 1.66), indicating that after the fifth dose of DTaP, the odds of acquiring pertussis increased by an average of 42% per year. CONCLUSIONS: Protection against pertussis waned during the 5 years after the fifth dose of DTaP. (Funded by Kaiser Permanente).
Authors: Klein NP; Bartlett J; Rowhani-Rahbar A; Fireman B; Baxter R
N Engl J Med. 2012 Sep 13;367(11):1012-9.
Algorithm to assess causality after individual adverse events following immunizations
Assessing individual reports of adverse events following immunizations (AEFI) can be challenging. Most published reviews are based on expert opinions, but the methods and logic used to arrive at these opinions are neither well described nor understood by many health care providers and scientists. We developed a standardized algorithm to assist in collecting and interpreting data, and to help assess causality after individual AEFI. Key questions that should be asked during the assessment of AEFI include: Is the diagnosis of the AEFI correct? Does clinical or laboratory evidence exist that supports possible causes for the AEFI other than the vaccine in the affected individual? Is there a known causal association between the AEFI and the vaccine? Is there strong evidence against a causal association? Is there a specific laboratory test implicating the vaccine in the pathogenesis? An algorithm can assist with addressing these questions in a standardized, transparent manner which can be tracked and reassessed if additional information becomes available. Examples in this document illustrate the process of using the algorithm to determine causality. As new epidemiologic and clinical data become available, the algorithm and guidelines will need to be modified. Feedback from users of the algorithm will be invaluable in this process. We hope that this algorithm approach can assist with educational efforts to improve the collection of key information on AEFI and provide a platform for teaching about causality assessment.
Authors: Halsey NA; Edwards KM; Dekker CL; Klein NP; Baxter R; Larussa P; Marchant C; Slade B; Vellozzi C; Causality Working Group of the Clinical Immunization Safety Assessment network
Vaccine. 2012 Aug 24;30(39):5791-8. Epub 2012 Apr 14.
Underimmunization at discharge from the neonatal intensive care unit
OBJECTIVE: The objectives of this study are to determine immunization rates at discharge from the neonatal intensive care unit (NICU) among infants 2 months of age and above and to evaluate risk factors for underimmunization. STUDY DESIGN: A retrospective cohort study was performed for infants in six NICUs in the Northern California Kaiser Permanente Medical Care Program. Immunization status at discharge was determined for all infants discharged on or after age 60 days. Logistic regression was used to identify risk factors for underimmunization at the time of discharge. RESULT: Of 668 infants discharged on or after age 60 days from the NICU, 51% were up-to-date for routine immunizations. Twenty-seven percent of infants had received no vaccines. Factors associated with higher immunization rates at discharge include history of mechanical ventilation, congenital heart disease and a diagnosis of apnea or bronchopulmonary dysplasia during the NICU stay, whereas surgery was associated with lower immunization rates. CONCLUSION: A significant proportion of infants discharged on or after 2 months of age in the NICU in this health system was unimmunized or underimmunized at discharge. Further efforts should be made to improve immunization rates prior to discharge.
Authors: Navar-Boggan AM; Halsey NA; Escobar GJ; Golden WC; Klein NP
J Perinatol. 2012 May;32(5):363-7. Epub 2011 Aug 11.
Immunogenicity and Safety of Two Tetravalent (Measles, Mumps, Rubella, Varicella) Vaccines Co-Administered with Hepatitis A and Pneumococcal Conjugate Vaccines to Children 12 14 Months of Age
BACKGROUND:: This study compared single-dose tetravalent measles, mumps, rubella, varicella (MMRV) vaccine, Priorix-Tetra, stored refrigerated (GSK+4C) or frozen (GSK 20C), with ProQuad (Merck-20C), when co-administered with hepatitis A vaccine (HAV) and 7-valent pneumococcal conjugate vaccine (PCV7). METHODS:: Multicenter, observer-blind Phase 2 study in 1783 healthy 12-14 month-olds randomized to: GSK+4C (n=705), GSK-20C (n=689) or Merck-20C (n=389), administered concomitantly with HAV (Havrix) and PCV7 (Prevnar). Seroresponse rates and antibody geometric mean concentrations/titers (GMC/GMT) were determined from ELISA and neutralization assays. Reactogenicity and safety were assessed. RESULTS:: Seroresponse rates (Day 42) were >97% for measles and rubella viruses, and >92% for mumps virus, in all groups. Non-inferiority of both GSK+4C and GSK-20C vaccines versus Merck-20C was demonstrated for seroresponse rates to measles, mumps and rubella viruses (lower 97.5% CIs above -5%, -10%, and -5%, respectively). For varicella-zoster virus (VZV), seroresponse rates were 57.1%, 69.8%, and 86.7% in the GSK+4C, GSK-20C, and Merck-20C groups, respectively. Non-inferiority was not shown for either GSK vaccine (lower 97.5% CIs <-15%). GMC ratios for anti-VZV demonstrated non-inferiority (lower 97.5% CI >/=0.5) versus Merck-20C for GSK-20C only. GMC ratios for antibodies to HAV and to PCV7 pneumococcal serotypes also met criteria for non-inferiority for both GSK groups compared with Merck-20C. GSK vaccine safety was observed comparable to Merck-20C. Localized but not generalized measles/rubella-like rash and Grade 3 fever was reported slightly more frequently with GSK vaccines, but antipyretic use was similar. The incidence of subjects experiencing at least one serious adverse event was 2.0%, 2.9% and 1.8% in the GSK+4C, GSK-20C and Merck-20C groups, respectively. CONCLUSIONS:: Non-inferiority of both GSK MMRV vaccines versus Merck-20C was demonstrated for responses to measles, mumps and rubella viruses, but was not fully demonstrated for VZV. The vaccines showed acceptable reactogenicity/safety when co-administered with HAV and PCV7.
Authors: Blatter MM; Klein NP; Innis BL; et al.
Pediatr Infect Dis J. 2012 Aug;31(8):e133-40.
Assessing the safety of influenza vaccination in specific populations: children and the elderly
Comprehensive monitoring of the safety of influenza vaccines remains a public health priority, particularly as immunization coverage increases across different age groups at the global level. In this review, the authors provide state-of-the-art knowledge on the safety of influenza immunization among children and the elderly. The authors review the safety information in each group separately for inactivated and live attenuated influenza vaccines. Adverse events of special concern including febrile seizure, narcolepsy, asthma and Guillain-Barre syndrome are covered under specific considerations. The authors discuss the current status of the field, particularly the use of new technologies for influenza vaccines and their potential safety profile.
Authors: Rowhani-Rahbar A; Klein NP; Baxter R
Expert Rev Vaccines. 2012 Aug;11(8):973-84.
An unmasking phenomenon in an observational post-licensure safety study of adolescent girls and young women
Our recent experience in a post-licensure safety study of autoimmune conditions following the quadrivalent human papillomavirus vaccine in 189,629 girls and young women ages 9-26 years led us to question the adequacy of the exclusion of Day 0 events to prevent the erroneous association of prevalent conditions with vaccination. Of the 18 confirmed cases of Graves’ disease diagnosed in days 1-60 following vaccination, only 6 cases appeared to be truly new onset. Among the remaining 12 cases, 2 cases had abnormal thyroid stimulating hormone or thyroxine labs drawn prior to or on Day 0 but had no documented pre-existing symptoms. The other 10 cases had mention of symptoms of hyperthyroidism referencing a period prior to first HPV-4 dose. This ‘unmasking’ phenomenon, due to health care visits that include vaccination and new workups of preexisting symptoms, may not be adequately controlled through the exclusion of Day 0 events.
Authors: Jacobsen SJ; Sy LS; Ackerson BK; Chao CR; Slezak JM; Cheetham TC; Takhar HS; Velicer CM; Hansen J; Klein NP
Vaccine. 2012 Jun 29;30(31):4585-7. Epub 2012 May 11.
Immunogenicity and safety of a quadrivalent meningococcal conjugate vaccine administered concomitantly with measles, mumps, rubella, varicella vaccine in healthy toddlers
BACKGROUND: Invasive meningococcal disease can have devastating outcomes, especially in high-risk groups such as infants. As infants are recommended to receive multiple vaccines during a single office visit, this phase 3 study assessed the safety and immune response to MenACWY-CRM at alternative visits in older infants and concomitant use with measles, mumps, rubella, varicella vaccine (MMRV) at 12 months of age. METHODS: Two age groups were concurrently enrolled: 7- to 9-month-old infants who received 2 doses of MenACWY-CRM at 7-9 and 12 months and were randomized 1:1 to receive MenACWY-CRM with or without MMRV at 12 months, and 12-month-old infants who received MMRV only at 12 months. Using predefined non-inferiority criteria, immune responses to the antigens in MMRV were compared between those who did and did not receive MenACWY-CRM; immune responses to MenACWY-CRM as measured by the percentage of subjects with human serum bactericidal activity (hSBA) titers >/= 8, were compared between those who did and did not receive concomitant MMRV. Adequacy of the immune response to 2 doses of MenACWY-CRM administered at 7-9 and 12 months was also assessed. Local and systemic reactions, adverse events resulting in withdrawal or requiring medical attention and serious adverse events were monitored. RESULTS: Concomitant administration of MMRV with MenACWY-CRM did not affect the immune response to either vaccine. The 2-dose series of MenACWY-CRM induced adequate immune response to all 4 serogroups. No increased reactogenicity was observed with MenACWY-CRM+MMRV compared with MMRV alone, and there were no study-related serious adverse events. CONCLUSIONS: Concomitant administration of MenACWY-CRM with MMRV vaccinations at 12 months was well-tolerated, without safety concerns. Robust immune responses to all components of both vaccines were produced and all criteria for non-inferiority were met, supporting the use of a 2-dose regimen of MenACWY-CRM in this age group.
Authors: Klein NP; Shepard J; Bedell L; Odrljin T; Dull P
Vaccine. 2012 Jun 6;30(26):3929-36. Epub 2012 Apr 10.
Risk of Confirmed Guillain-Barre Syndrome Following Receipt of Monovalent Inactivated Influenza A (H1N1) and Seasonal Influenza Vaccines in the Vaccine Safety Datalink Project, 2009-2010
An increased risk of Guillain-Barre syndrome (GBS) following administration of the 1976 swine influenza vaccine led to a heightened focus on GBS when monovalent vaccines against a novel influenza A (H1N1) virus of swine origin were introduced in 2009. GBS cases following receipt of monovalent inactivated (MIV) and seasonal trivalent inactivated (TIV) influenza vaccines in the Vaccine Safety Datalink Project in 2009-2010 were identified in electronic data and confirmed by medical record review. Within 1-42 days following vaccination, 9 cases were confirmed in MIV recipients (1.48 million doses), and 8 cases were confirmed in TIV-only recipients who did not also receive MIV during 2009-2010 (1.72 million doses). Five cases following MIV and 1 case following TIV-only had an antecedent respiratory infection, a known GBS risk factor; furthermore, unlike TIV, MIV administration was concurrent with heightened influenza activity. In a self-controlled risk interval analysis comparing GBS onset within 1-42 days following MIV with GBS onset 43-127 days following MIV, the risk difference was 5.0 cases per million doses (95% confidence interval: 0.5, 9.5). No statistically significant increased GBS risk was found within 1-42 days following TIV-only vaccination versus 43-84 days following vaccination (risk difference = 1.1 cases per million doses, 95% confidence interval: -3.1, 5.4). Further evaluation to assess GBS risk following both vaccination and respiratory infection is warranted.
Authors: Greene SK; Fireman BH; Lee GM; et al.
Am J Epidemiol. 2012 Jun 1;175(11):1100-9. Epub 2012 May 11.
Trends and Characteristics of Culture-Confirmed Staphylococcus aureus Infections in a Large U.S. Integrated Health Care Organization
Infections due to Staphylococcus aureus present a significant health problem in the United States. Between 1990 and 2005, there was a dramatic increase in community-associated methicillin-resistant S. aureus (MRSA), but recent reports suggest that MRSA may be declining. We retrospectively identified S. aureus isolates (n = 133,450) that were obtained from patients in a large integrated health plan between 1 January 1998 and 31 December 2009. Trends over time in MRSA were analyzed, and demographic risk factors for MRSA versus methicillin-susceptible S. aureus (MSSA) were identified. The percentage of S. aureus isolates that were MRSA increased from 9% to 20% between 1998 and 2001 and from 25% to 49% between 2002 and 2005 and decreased from 49% to 43% between 2006 and 2009. The increase in MRSA was seen in blood and in other bacteriological specimens and occurred in all age and race/ethnicity groups, though it was most pronounced in persons aged 18 to <50 years and African-Americans. Hospital onset infections were the most likely to be MRSA (odds ratio [OR], 1.58; confidence interval [CI], 1.46 to 1.70, compared to community-associated cases), but the largest increase in MRSA was in community-associated infections. Isolates from African-Americans (OR, 1.73; CI, 1.64 to 1.82) and Hispanics (OR, 1.11; CI, 1.06 to 1.16) were more likely to be MRSA than those from whites. After substantial increases between 1998 and 2005 in the proportion of S. aureus isolates that were MRSA, the proportion decreased between 2006 and 2009. Hospital onset S. aureus infections are disproportionately MRSA, as are those among African-Americans.
Authors: Ray GT; Suaya JA; Baxter R
J Clin Microbiol. 2012 Jun;50(6):1950-7. Epub 2012 Mar 14.
Comparative immunogenicity and safety of different multivalent component pertussis vaccine formulations and a 5-component acellular pertussis vaccine in infants and toddlers: A randomized, controlled, open-label, multicenter study
BACKGROUND: Pentavalent and quadrivalent combination vaccine formulations from the same manufacturer (DTaP-IPV/Hib [PENTA], DTaP-IPV [QUAD]) were investigated as to whether they were sufficiently interchangeable to tailor use to local preference or availability. METHODS: A randomized, controlled, open-label, 4-armed, multicenter study in healthy, full-term infants (42-89 days of age) was conducted in 38 centers across the United States. Participants were randomized 1:1:1:1 to a control vaccine group (3 doses DTaP, IPV, and Hib and at Dose 4 DTaP and Hib) and 3 combination vaccine groups: (1) 3 doses PENTA, then Dose 4 DTaP and Hib; (2) 4 QUAD doses and Hib; (3) 4 PENTA doses. Participants (N=2167) were immunized at 2, 4, and 6 months of age, Dose 4 participants (N=1832) at 15 months of age. Immunogenicity was assessed before Doses 1 and 4 and after Doses 3 and 4. Safety was assessed 30 days after each dose and through 180 days Post-Dose 4. RESULTS: Antibody responses and geometric mean concentrations/geometric mean titers (GMCs/GMTs) elicited by each combination vaccine were noninferior (upper-bound 90% confidence interval of GMC/GMT ratios <1.5) to control vaccines except pertactin GMCs were higher after 4 control DTaP doses (157.46EU/mL) than after Dose 4 with DTaP and Hib (after a PENTA infant series) (111.70EU/mL) and after 4 PENTA doses (98.00EU/mL). Fever rates in the combination vaccine groups were noninferior (upper bound 95% CI of combination vaccine group fever rate minus control vaccine group fever rate <10%) to the control vaccine group except the rate after 4 QUAD and Hib doses (23.5%) was higher than after 4 control DTaP doses (13.9%). CONCLUSIONS: PENTA and QUAD had similar safety profiles and no clinically important differences in immunogenicity compared with separately administered control vaccines. ClinicalTrials.gov (NCT ID: NCT00255047).
Authors: Chatterjee A; O'Keefe C; Varman M; Klein NP; Luber S; Tomovici A; Noriega F
Vaccine. 2012 May 14;30(23):3360-8. Epub 2012 Apr 1.
Safety of Zoster Vaccine in Adults from a Large Managed Care Cohort: A Vaccine Safety Datalink Study
OBJECTIVES: The aim of this study was to examine a large cohort of adults who received the zoster vaccine for evidence of an increased risk of prespecified adverse events requiring medical attention. DESIGN: Two self-comparison approaches, including a case-centred approach and a self-controlled case series (SCCS) analysis were used. SETTING: Eight managed-care organizations participating in the Vaccine Safety Datalink project in the United States. SUBJECTS: A total of 193 083 adults aged 50 and older receiving a zoster vaccine from 1 January 2007 to 31 December 2008 were included. MAIN OUTCOME MEASURES: Prespecified adverse events were identified by aggregated International Classification of Diseases, Ninth Revision (ICD-9) codes in automated health plan datasets. RESULTS: The risk of allergic reaction was significantly increased within 1-7 days of vaccination [relative risk = 2.13, 95% confidence interval (CI): 1.87-2.40 by case-centred method and relative rate = 2.32, 95% CI: 1.85-2.91 by SCCS]. No increased risk was found for the following adverse event groupings: cerebrovascular events; cardiovascular events; meningitis; encephalitis; and encephalopathy; and Ramsay-Hunt syndrome and Bell’s palsy. CONCLUSIONS: The results of this study support the findings from the prelicensure clinical trials, providing reassurance that the zoster vaccine is generally safe and well-tolerated with a small increased risk of allergic reactions in 1-7 days after vaccination.
Authors: Tseng HF; Fireman B; Vaccine Safety Datalink (VSD) Team; et al.
J Intern Med. 2012 May;271(5):510-20. Epub 2011 Nov 22.
Immunization and Bell’s Palsy in Children: A Case-Centered Analysis
Bell’s palsy (BP) is an acute and idiopathic paralysis of the facial nerve, with an estimated incidence ranging from 11.5 per 100,000 person-years to 53.3 per 100,000 person-years in different populations. BP has been reported following immunization with inactivated trivalent influenza vaccine (TIV) and hepatitis B virus (HBV) vaccine. Epidemiologic studies examining this association among children are lacking. From 2001 through 2006, all children aged
Authors: Rowhani-Rahbar A; Klein NP; Lewis N; Fireman B; Ray P; Rasgon B; Black S; Klein JO; Baxter R
Am J Epidemiol. 2012 May 1;175(9):878-85. Epub 2012 Mar 12.
Measles-Containing Vaccines and Febrile Seizures in Children Age 4 to 6 Years
BACKGROUND: In the United States, children receive 2 doses of measles-mumps-rubella vaccine (MMR) and varicella vaccine (V), the first between ages 1 to 2 years and the second between ages 4 to 6 years. Among 1- to 2-year-olds, the risk of febrile seizures 7 to 10 days after MMRV is double that after separate MMR + V. Whether MMRV or MMR + V affects risk for febrile seizure risk among 4- to 6-year-olds has not been reported. METHODS: Among 4- to 6-year-old Vaccine Safety Datalink members, we identified seizures in the emergency department and hospital from 2000 to 2008 and outpatient visits for fever from 2006 to 2008 during days 7 to 10 and 0 to 42 after MMRV and MMR + V. Incorporating medical record reviews, we assessed seizure risk after MMRV and MMR + V. RESULTS: From 2006 through 2008, 86 750 children received MMRV; from 2000 through 2008, 67 438 received same-day MMR + V. Seizures were rare throughout days 0 to 42 without peaking during days 7 to 10. There was 1 febrile seizure 7 to 10 days after MMRV and 0 after MMR + V. Febrile seizure risk was 1 per 86 750 MMRV doses (95% confidence interval, 1 per 3 426 441, 1 per 15 570) and 0 per 67 438 MMR + V doses (1 per 18 282). CONCLUSIONS: This study provides reassurance that MMRV and MMR + V were not associated with increased risk of febrile seizures among 4- to 6-year-olds. We can rule out with 95% confidence a risk greater than 1 febrile seizure per 15 500 MMRV doses and 1 per 18 000 MMR + V doses.
Authors: Klein NP; Lewis E; Baxter R; Weintraub E; Glanz J; Naleway A; Jackson LA; Nordin J; Lieu T; Belongia EA; Fireman B
Pediatrics. 2012 May;129(5):809-14. Epub 2012 Apr 2.
Rowhani-Rahbar et al. Respond to ‘Immunization and Bell’s Palsy in Children’
Authors: Rowhani-Rahbar A; Fireman B; Lewis N; Ray P; Rasgon B; Klein JO; Black S; Klein NP; Baxter R
Am J Epidemiol. 2012 Mar 12.
Recurrent Guillain-Barre Syndrome Following Vaccination
BACKGROUND: Guillain-Barre syndrome (GBS) is an acute polyradiculopathy, thought to be autoimmune, which has been reported following vaccinations. The Advisory Committee on Immunization Practices recommends not administering influenza vaccine to individuals who have had a history of GBS within 6 weeks of a prior influenza vaccination if they are not at high risk of severe complications from influenza illness. METHODS: We identified GBS cases from the Kaiser Permanente Northern California databases from 1995 into 2006 using hospital discharge codes; each medical record was neurologist-reviewed and only GBS-confirmed cases were included for follow-up. We followed confirmed cases through 2008 for vaccinations and recurrent GBS. RESULTS: We identified 550 cases of GBS over 33 million person-years. Following their GBS diagnoses, 989 vaccines were given to 279 of these individuals, including 405 trivalent inactivated influenza vaccines (TIV) administered to 107 individuals with a prior diagnosis of GBS. Among the 550 total cases of GBS, 18 initially had onset within 6 weeks of TIV; of these, 2 were revaccinated with TIV without a recurrence of GBS. Only 6 individuals of 550 (1.1%) had a second (recurrent) diagnosis of GBS. Among these 6 individuals, none had any vaccine exposure at all in the 2 months prior to the second onset of GBS. CONCLUSIONS: In our population of over 3 million members, during an 11-year period, risk of GBS recurrence was low. There were no cases of recurrent GBS after influenza vaccination and none within 6 weeks after any vaccine.
Authors: Baxter R; Lewis N; Bakshi N; Vellozzi C; Klein NP; CISA Network
Clin Infect Dis. 2012 Mar;54(6):800-4. Epub 2012 Jan 19.
Risk of intussusception following administration of a pentavalent rotavirus vaccine in US infants
CONTEXT: Current rotavirus vaccines were not associated with intussusception in large prelicensure trials. However, recent postlicensure data from international settings suggest the possibility of a low-level elevated risk, primarily in the first week after the first vaccine dose. OBJECTIVE: To examine the risk of intussusception following pentavalent rotavirus vaccine (RV5) in US infants. DESIGN, SETTING, AND PATIENTS: This cohort study included infants 4 to 34 weeks of age, enrolled in the Vaccine Safety Datalink (VSD) who received RV5 from May 2006-February 2010. We calculated standardized incidence ratios (SIRs), relative risks (RRs), and 95% confidence intervals for the association between intussusception and RV5 by comparing the rates of intussusception in infants who had received RV5 with the rates of intussusception in infants who received other recommended vaccines without concomitant RV5 during the concurrent period and with the expected number of intussusception visits based on background rates assessed prior to US licensure of the RV5 (2001-2005). MAIN OUTCOME MEASURE: Intussusception occurring in the 1- to 7-day and 1- to 30-day risk windows following RV5 vaccination. RESULTS: During the study period, 786,725 total RV5 doses, which included 309,844 first doses, were administered. We did not observe a statistically significant increased risk of intussusception with RV5 for either comparison group following any dose in either the 1- to 7-day or 1- to 30-day risk window. For the 1- to 30-day window following all RV5 doses, we observed 21 cases of intussusception compared with 20.9 expected cases (SIR, 1.01; 95% CI, 0.62-1.54); following dose 1, we observed 7 cases compared with 5.7 expected cases (SIR, 1.23; 95% CI, 0.5-2.54). For the 1- to 7-day window following all RV5 doses, we observed 4 cases compared with 4.3 expected cases (SIR, 0.92; 95% CI, 0.25-2.36); for dose 1, we observed 1 case compared with 0.8 expected case (SIR, 1.21; 95% CI, 0.03-6.75). The upper 95% CI limit of the SIR (6.75) from the historical comparison translates to an upper limit for the attributable risk of 1 intussusception case per 65,287 RV5 dose-1 recipients. CONCLUSION: Among US infants aged 4 to 34 weeks who received RV5, the risk of intussusception was not increased compared with infants who did not receive the rotavirus vaccine.
Authors: Shui IM; Baggs J; Patel M; Parashar UD; Rett M; Belongia EA; Hambidge SJ; Glanz JM; Klein NP; Weintraub E
JAMA. 2012 Feb 8;307(6):598-604.
Surveillance of Autoimmune Conditions following Routine Use of Quadrivalent Human Papillomavirus Vaccine
OBJECTIVE: An observational safety study of the quadrivalent human papillomavirus vaccine (HPV4) in women was conducted. This report presents findings from autoimmune surveillance. Design. Subjects were followed for 180days after each HPV4 dose for new diagnoses of 16 prespecified autoimmune conditions. SETTING: Two managed care organizations in California. Subjects. Number of 189,629 women who received >/=1 dose of HPV4 between 08/2006 and 03/2008. OUTCOME: Potential new-onset autoimmune condition cases amongst HPV4 recipients were identified by electronic medical records. Medical records of those with >/=12-month health plan membership prior to vaccination were reviewed by clinicians to confirm the diagnosis and determine the date of disease onset. The incidence of each autoimmune condition was estimated for unvaccinated women at one study site using multiple imputations and compared with that observed in vaccinated women. Incidence rate ratios (IRR) were calculated. Findings were reviewed by an independent Safety Review Committee (SRC). RESULTS: Overall, 1014 potential new-onset cases were electronically identified; 719 were eligible for case review; 31-40% were confirmed as new onset. Of these, no cluster of disease onset in relation to vaccination timing, dose sequence or age was found for any autoimmune condition. None of the estimated IRR was significantly elevated except Hashimoto’s disease [IRR=1.29, 95% confidence interval: 1.08-1.56]. Further investigation of temporal relationship and biological plausibility revealed no consistent evidence for a safety signal for autoimmune thyroid conditions. The SRC and the investigators identified no autoimmune safety concerns in this study. CONCLUSIONS: No autoimmune safety signal was found in women vaccinated with HPV4.
Authors: Chao C; Klein NP; Jacobsen SJ; et al.
J Intern Med. 2012 Feb;271(2):193-203. Epub 2011 Nov 15.
An open-label, randomized, multi-center study of the immunogenicity and safety of DTaP-IPV (Kinrix) co-administered with MMR vaccine with or without varicella vaccine in healthy pre-school age children
BACKGROUND: In the US, it is recommended that 4-6 year old children receive diphtheria-tetanus-acellular pertussis (DTaP), inactivated poliovirus (IPV), measles-mumps-rubella (MMR), varicella (V), and influenza vaccines. Data relating to the concomitant administration of combination DTaP-IPV vaccine (Kinrix; GlaxoSmithKline Biologicals) and influenza or V vaccines are currently limited. This study was undertaken to evaluate the immunogenicity and reactogenicity of Kinrix when co-administered with MMR (M-M-RII((R)), Merck & Co.) and Varivax (Merck & Co.) in 4-6 year old children. METHODS: Phase IIIb, open-label, non-inferiority study (NCT00871117). We randomized (1:1) healthy 4-6 year olds to receive Kinrix+MMR+V on day 0 (Group 1), or Kinrix+MMR on day 0, followed by V at month 1 (Group 2). We measured DTaP-IPV immunogenicity before and 1 month post-vaccination (prior to V vaccination in Group 2). We collected local and general solicited symptoms within 4 days after vaccination and serious adverse events (SAEs) through 6 months post-vaccination. RESULTS: We enrolled 478 subjects. One month post-vaccination, >95% of subjects in both groups had booster responses to diphtheria, tetanus and pertussis antigens and all subjects had seroprotective anti-poliovirus antibody titers. Immune responses in Group 1 were non-inferior to Group 2 for responses to DTaP-IPV antigens according to pre-specified criteria. Reporting of solicited local events at the DTaP-IPV site appeared to be similar between the two vaccine groups, as was reporting of solicited general adverse events within 4 days of vaccination; no vaccine related SAEs were reported. CONCLUSION: Concomitant administration of varicella vaccine with Kinrix and MMR did not impact the immunogenicity of diphtheria, tetanus, pertussis or poliovirus antigens. Both vaccine regimens were well tolerated. These results support the co-administration of DTaP-IPV, MMR, and V vaccines in 4-6-year-old children, providing protection against multiple diseases in a timely and efficient manner.
Authors: Klein NP; Weston WM; Kuriyakose S; Kolhe D; Howe B; Friedland LR; Van Der Meeren O
Vaccine. 2012 Jan 11;30(3):668-74. Epub 2011 Nov 4.
Lack of association between childhood immunizations and encephalitis in California, 1998-2008
OBJECTIVE: A number of new and combination vaccines have been introduced for children in the past two decades. Encephalitis cases occurring within defined time windows following administration of pertussis- or measles-containing vaccines are eligible for compensation by the Vaccine Injury Compensation Program. Due to increased parental concerns about vaccine safety and potential neurologic adverse events following immunization with new and multiple vaccines administered at the same visit, our aim was to determine whether immunizations are associated with an increased risk of encephalitis within defined risk windows. METHODS: We reviewed immunization records from 246 pediatric encephalitis cases referred to the California Encephalitis Project between July 1998 and December 2008. We included data on 110 cases who had been immunized in the year prior to the onset of encephalitis (observation period) and had complete immunization records. We used the case-centered method to test whether cases were more likely to have developed encephalitis in defined risk windows-42, 30 and 21 days after any vaccination, 3 days after pertussis-containing vaccines and 5-15 days after measles-virus containing vaccines-compared with the rest of the observation period. RESULTS: All vaccines recommended in the current immunization schedule were represented in our sample. No increased risk of encephalitis was seen following administration of pertussis-containing vaccines, measles-containing vaccines or any number of vaccines administered in a single visit (vaccine episode); the odds ratios and 95% confidence intervals for encephalitis after a vaccine episode were: 1.0 (0.6-1.8) in a 42-day risk window, 0.9 (0.5-1.6) in a 30-day risk window and 1.2 (0.7-2.2) in a 21-day risk window. CONCLUSION: No association between receipt of currently recommended immunizations and subsequent development of encephalitis was observed in this study.
Authors: Pahud BA; Rowhani-Rahbar A; Glaser C; Gavali S; Salibay CJ; Fireman B; Dekker CL
Vaccine. 2012 Jan 5;30(2):247-53. Epub 2011 Nov 12.
Safety and Immunogenicity of a Novel Quadrivalent Meningococcal CRM-Conjugate Vaccine Given Concomitantly With Routine Vaccinations in Infants
BACKGROUND: In phase II studies, MenACWY-CRM elicited robust immunologic responses in young infants. We now present results from our pivotal phase III infant immunogenicity/safety study. METHODS: In this open-label phase III study, we randomized full-term 2-month-old infants to 4 doses of MenACWY-CRM coadministered with routine vaccines at 2, 4, 6, and 12 months of age or with routine vaccines alone. We monitored for local and systemic reactions and serious adverse events among all study participants and evaluated for sufficiency of the immune responses to MenACWY-CRM through serum bactericidal activity assay with human complement. RESULTS: Bactericidal antibodies were present in 94% to 100% of subjects against each of the serogroups in MenACWY-CRM after the 4-dose series and were 67% to 97% after the first 3 doses. Geometric mean titers were higher after the fourth dose of MenACWY-CRM compared with a single dose of MenACWY-CRM at 12 months of age for all serogroups (range of ratios, 4.5-38). Responses to 3 doses of routine vaccines coadministered with MenACWY-CRM were noninferior to routine vaccinations alone, except for small differences in pneumococcal serotype 6B responses after dose 3 but not dose 4 and pertactin after dose 3. Inclusion of MenACWY-CRM did not affect the safety or reactogenicity profiles of the routine infant vaccine series. CONCLUSIONS: A 4-dose series of MenACWY-CRM was highly immunogenic and well tolerated in young infants, and it can be coadministered with routine infant vaccines. Substantial immunity was conferred after the first 3 doses administered at 2, 4, and 6 months of age.
Authors: Klein NP; Reisinger KS; Johnston W; Odrljin T; Gill CJ; Bedell L; Dull P
Pediatr Infect Dis J. 2012 Jan;31(1):64-71.
Epidemiologic and Clinical Features of Bell’s Palsy among Children in Northern California
BACKGROUND: Bell’s palsy (BP) is an acute, idiopathic, and usually unilateral paralysis of the facial nerve. Large population-based studies of BP among children are lacking. We determined epidemiologic and clinical features of BP among children enrolled in a large integrated health care delivery system. METHODS: From 2001 through 2006, all children
Authors: Rowhani-Rahbar A; Baxter R; Rasgon B; Ray P; Black S; Klein JO; Klein NP
Neuroepidemiology. 2012;38(4):252-8. Epub 2012 Jun 5.
Developing the next generation of vaccinologists
Authors: Klein NP; DeStefano F; et al.
Vaccine. 2011 Nov 21;29(50):9296-7. Epub 2011 Apr 19.
Causality assessment of serious neurologic adverse events following 2009 H1N1 vaccination
BACKGROUND: Adverse events occurring after vaccination are routinely reported to the Vaccine Adverse Event Reporting System (VAERS). We studied serious adverse events (SAEs) of a neurologic nature reported after receipt of influenza A (H1N1) 2009 monovalent vaccine during the 2009-2010 influenza season. Investigators in the Clinical Immunization Safety Assessment (CISA) network sought to characterize these SAEs and to assess their possible causal relationship to vaccination. METHODS: Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) physicians reviewed all SAE reports (as defined by the Code of Federal Regulations, 21CFR section sign314.80) after receipt of H1N1 vaccine reported to VAERS between October 1, 2009 and March 31, 2010. Non-fatal SAE reports with neurologic presentation were referred to CISA investigators, who requested and reviewed additional medical records and clinical information as available. CISA investigators assessed the causal relationship between vaccination and the event using modified WHO criteria as defined. RESULTS: 212 VAERS reports of non-fatal serious neurological events were referred for CISA review. Case reports were equally distributed by gender (50.9% female) with an age range of 6 months to 83 years (median 38 years). The most frequent diagnoses reviewed were: Guillain-Barre Syndrome (37.3%), seizures (10.8%), cranial neuropathy (5.7%), and acute disseminated encephalomyelitis (3.8%). Causality assessment resulted in classification of 72 events as ‘possibly’ related (33%), 108 as ‘unlikely’ related (51%), and 20 as ‘unrelated’ (9%) to H1N1 vaccination; none were classified as ‘probable’ or ‘definite’ and 12 were unclassifiable (6%). CONCLUSION: The absence of a specific test to indicate whether a vaccine component contributes to the pathogenesis of an event occurring within a biologically plausible time period makes assessing causality difficult. The development of standardized protocols for providers to use in evaluation of adverse events following immunization, and rapid identification and follow-up of VAERS reports could improve causality assessment.
Authors: Williams SE; Klein NP; Edwards KM; et al.
Vaccine. 2011 Oct 26;29(46):8302-8. Epub 2011 Sep 3.
Monitoring the safety of quadrivalent human papillomavirus vaccine: Findings from the Vaccine Safety Datalink
BACKGROUND: In 7 large managed care organizations (MCOs), we performed a post-licensure safety assessment of quadrivalent human papillomavirus vaccine (HPV4) among 9-26 year-old female vaccine recipients between August 2006 and October 2009. METHODS: Sequential analyses were conducted weekly to detect associations between HPV4 exposure and pre-specified outcomes. The pre-specified outcomes identified by ICD-9 codes using computerized data at the participating MCOs included: Guillan-Barre Syndrome (GBS), stroke, venous thromboembolism (VTE), appendicitis, seizures, syncope, allergic reactions, and anaphylaxis. For rare outcomes, historical background rates were used as the comparison group. For more common outcomes, a concurrent unexposed comparison group was utilized. A standardized review of medical records was conducted for all cases of GBS, VTE, and anaphylaxis. RESULTS: A total of 600,558 HPV4 doses were administered during the study period. We found no statistically significant increased risk for the outcomes studied. However, a non-statistically significant relative risk (RR) for VTE ICD-9 codes following HPV4 vaccination of 1.98 was detected among females age 9-17 years. Medical record review of all 8 vaccinated potential VTE cases in this age group revealed that 5 met the standard case definition for VTE. All 5 confirmed cases had known risk factors for VTE (oral contraceptive use, coagulation disorders, smoking, obesity or prolonged hospitalization). CONCLUSIONS: In a study of over 600,000 HPV4 vaccine doses administered, no statistically significant increased risk for any of the pre-specified adverse events after vaccination was detected. Further study of a possible association with VTE following HPV4 vaccination is warranted.
Authors: Gee J; Fireman B; Klein NP; Weintraub ES; et al.
Vaccine. 2011 Oct 26;29(46):8279-84. Epub 2011 Sep 9.
Risk of rheumatoid arthritis following vaccination with tetanus, influenza and hepatitis B vaccines among persons 15-59 years of age
BACKGROUND: Associations between vaccinations, particularly hepatitis B, and onset of rheumatoid arthritis (RA) have been reported, but examined in few large-scale studies. METHOD: Onset of RA cases and dates of vaccination against hepatitis B, tetanus, and influenza were identified in a retrospective chart review of approximately 1 million Kaiser Permanente Northern California members ages 15-59 years from 1997 through 1999. In a cohort analysis, rates of new-onset RA were compared between vaccinated and unvaccinated within 90, 180, and 365 days. In a case-control analysis, rates of vaccination during exposure intervals (90, 180, 365, and 730 days) were compared between cases and controls using conditional logistic regression. RESULTS: 378 RA cases were included in the cohort analysis; 37 additional cases were included in the case-control analysis. In the cohort analysis the relative risks of RA onset within 90, 180, or 365 days of hepatitis B vaccination were not significant (R.R.=1.44, p=0.53; R.R.=1.67, p=0.22; R.R.=1.23, p=0.59 respectively). We found a possible association between RA and influenza vaccine in the previous 180 and 365 days in the cohort analysis (R.R=1.36, p=0.03; R.R.=1.34, p=0.01 respectively), but in the case-control analysis, cases were no more likely than controls to have received any of the three vaccines. CONCLUSIONS: In this large retrospective study we found no statistically significant association between exposure to hepatitis B vaccine and onset of RA. A possible association between RA and influenza vaccination in the cohort study was not borne out in the larger case-control analysis.
Authors: Ray P; Black S; Shinefield H; Dillon A; Carpenter D; Lewis E; Ross P; Chen RT; Klein NP; Baxter R; Vaccine Safety Datalink Team
Vaccine. 2011 Sep 2;29(38):6592-7. Epub 2011 Jul 16.
Immunogenicity and Safety of an Inactivated Hepatitis A Vaccine When Coadministered With Diphtheria-tetanus-acellular Pertussis and Haemophilus influenzae Type B Vaccines in Children 15 Months of Age
BACKGROUND: This study (NCT00197236) evaluated the safety and immunogenicity of a hepatitis A virus (HAV) vaccine when coadministered with diphtheria-tetanus-acellular pertussis (DTaP) and Haemophilus influenzae type b (Hib) vaccines in children 15 months of age. METHODS: This was an open-labeled, multicenter study with healthy subjects enrolled and randomized (1:1:1) into 3 treatment groups. A total of 394 subjects received the first study vaccinations at 15 months of age. Group HAV (N = 135) received 2 doses of HAV vaccine 6 to 9 months apart. Group HAV+DTaP+Hib (N = 127) received HAV vaccine coadministered with DTaP and Hib vaccines and the second dose of HAV vaccine, 6 to 9 months later. Group DTaP+Hib–>HAV (N = 132) received the DTaP and Hib vaccines at 15 months of age, followed by HAV vaccine 30 days later and the second dose of HAV vaccine 7 to 10 months after the DTaP+Hib vaccines. Immune responses were evaluated before the first study vaccination and 30 days after each vaccine dose. Solicited, unsolicited, and serious adverse events were collected. RESULTS: After 2 doses of the HAV vaccine, all subjects in the 3 groups were seropositive. The geometric mean concentration of anti-HAV antibodies ranged between 1625.1 and 1904.4 mIU/mL. Coadministration of the 3 vaccines did not impact immunogenicity of the HAV, DTaP, or Hib vaccines. Vaccines were well tolerated in all groups. CONCLUSIONS: A 2-dose schedule of HAV vaccine was well tolerated and immunogenic when administered to children starting at 15 months of age. Immune responses to the DTaP or Hib vaccines were similar whether they were administered alone or were coadministered with the HAV vaccine.
Authors: Trofa AF; Klein NP; Paul IM; Michaels MG; Goessler M; Chandrasekaran V; Blatter M
Pediatr Infect Dis J. 2011 Sep;30(9):e164-9.
Safety of trivalent inactivated influenza vaccine in children aged 24 to 59 months in the vaccine safety datalink
OBJECTIVES: To evaluate the safety of trivalent inactivated influenza vaccine (TIV) in children aged 24 to 59 months and to evaluate the risk of medically attended events (MAEs) in a subcohort of children who had multiple annual doses of TIV over their lifetimes. DESIGN: Self-controlled screening study. SETTING: Seven US managed care organizations from October 1, 2002, to March 31, 2006. PARTICIPANTS: Children aged 24 to 59 months who received at least 1 TIV dose (66 283 children and 91 692 TIV doses). EXPOSURE: Vaccination with TIV. MAIN OUTCOME MEASURES: Medically attended events in inpatient and emergency department settings in one of the following risk windows: 0 to 2, 1 to 14, or 1 to 42 days after vaccination. All MAEs that met the screening criteria of incidence rate ratios (IRRs) exceeding 1.0 and P
Authors: Glanz JM; Klein NP; Weintraub ES; et al.
Arch Pediatr Adolesc Med. 2011 Aug;165(8):749-55.
H1N1 and seasonal influenza vaccine safety in the vaccine safety datalink project
BACKGROUND: The emergence of pandemic H1N1 influenza virus in early 2009 prompted the rapid licensure and use of H1N1 monovalent inactivated (MIV) and live, attenuated (LAMV) vaccines separate from seasonal trivalent inactivated (TIV) and live, attenuated (LAIV) influenza vaccines. A robust influenza immunization program in the U.S. requires ongoing monitoring of potential adverse events associated with vaccination. PURPOSE: To prospectively conduct safety monitoring of H1N1 and seasonal influenza vaccines during the 2009-2010 season. METHODS: The Vaccine Safety Datalink (VSD) Project monitors approximately 9.2 million members in eight U.S. medical care organizations. Electronic data on vaccines and pre-specified adverse events were updated and analyzed weekly for signal detection from November 2009 to April 2010 using either a self-controlled design or a current versus historical comparison. Statistical signals were further evaluated using alternative approaches to identify temporal clusters and to control for time-varying confounders. RESULTS: As of May 1, 2010, a total of 1,345,663 MIV, 267,715 LAMV, 2,741,150 TIV, and 157,838 LAIV doses were administered in VSD. No significant associations were noted during sequential analyses for Guillain-Barre syndrome, most other neurologic outcomes, and allergic and cardiac events. For MIV, a statistical signal was observed for Bell’s palsy for adults aged >/=25 years on March 31, 2010, using the self-controlled approach. Subsequent analyses revealed no significant temporal cluster. Case-centered logistic regression adjusting for seasonality demonstrated an OR for Bell’s palsy of 1.26 (95% CI=0.97, 1.63). CONCLUSIONS: No major safety problems following H1N1 or seasonal influenza vaccines were detected in the 2009-2010 season in weekly sequential analyses. Seasonality likely contributed to the Bell’s palsy signal following MIV. Prospective safety monitoring followed by rigorous signal refinement is critical to inform decision-making by regulatory and public health agencies.
Authors: Lee GM; Fireman BH; Vaccine Safety Datalink Project; et al.
Am J Prev Med. 2011 Aug;41(2):121-8.
Attitudes and beliefs of parents concerned about vaccines: impact of timing of immunization information
OBJECTIVES: To determine if giving vaccine-information materials before the 2-month vaccination visit to mothers with concerns about vaccine safety positively changed their attitudes and beliefs about vaccine safety. METHODS: Mothers who indicated concerns about infant vaccinations were recruited from 2 separate sites in Tennessee and California and were given vaccine information at 1 of 3 times: during a prenatal visit; a 1-week postpartum well-child visit; or a 2-month vaccination visit. A separate group of concerned mothers was assigned to be followed longitudinally at all 3 time points and was analyzed separately. The mothers reviewed a new vaccine-information pamphlet and Vaccine Information Statements (VIS) from the Centers for Disease Control and Prevention. Attitudes and beliefs about immunization were assessed both before and after the review of materials with written surveys. RESULTS: A total of 272 mothers with immunization concerns participated in the study. After review of the materials, mothers in all groups were significantly more likely to respond positively to questions and statements supporting the safety and importance of vaccines. Mothers who received this information at earlier visits were not significantly more likely to respond positively than mothers who received the information at the child’s 2-month vaccination visit; however, participating mothers did indicate a preference for receiving vaccine information before the first vaccination visit. CONCLUSIONS: Distribution of the vaccine-information pamphlet and Vaccine Information Statements significantly improved attitudes about vaccination regardless of at what visit they were provided. Allowing adequate time to review vaccine information, even if done at the vaccination visit, may benefit concerned mothers.
Authors: Vannice KS; Salmon DA; Shui I; Omer SB; Kissner J; Edwards KM; Sparks R; Dekker CL; Klein NP; Gust DA
Pediatrics. 2011 May;127 Suppl 1:S120-6. Epub 2011 Apr 18.
The Vaccine Safety Datalink: a model for monitoring immunization safety
The Vaccine Safety Datalink (VSD) project is a collaborative project between the Centers for Disease Control and Prevention and 8 managed care organizations (MCOs) in the United States. Established in 1990 to conduct postmarketing evaluations of vaccine safety, the project has created an infrastructure that allows for high-quality research and surveillance. The 8 participating MCOs comprise a large population of 8.8 million members annually (3% of the US population), which enables researchers to conduct studies that assess adverse events after immunization. Each MCO prepares computerized data files by using a standardized data dictionary containing demographic and medical information on its members, such as age and gender, health plan enrollment, vaccinations, hospitalizations, outpatient clinic visits, emergency department visits, urgent care visits, and mortality data, as well as additional birth information (eg, birth weight) when available. Other information sources, such as medical chart review, member surveys, and pharmacy, laboratory, and radiology data, are often used in VSD studies to validate outcomes and vaccination data. Since 2000, the VSD has undergone significant changes including an increase in the number of participating MCOs and enrolled population, changes in data-collection procedures, the creation of near real-time data files, and the development of near real-time postmarketing surveillance for newly licensed vaccines or changes in vaccine recommendations. Recognized as an important resource in vaccine safety, the VSD is working toward increasing transparency through data-sharing and external input. With its recent enhancements, the VSD provides scientific expertise, continues to develop innovative approaches for vaccine-safety research, and may serve as a model for other patient safety collaborative research projects.
Authors: Baggs J; Klein NP; Weintraub E; et al.
Pediatrics. 2011 May;127 Suppl 1:S45-53. Epub 2011 Apr 18.
Understanding the role of human variation in vaccine adverse events: the Clinical Immunization Safety Assessment Network
The Clinical Immunization Safety Assessment (CISA) Network is a collaboration between the Centers for Disease Control and Prevention (CDC) and 6 academic medical centers to provide support for immunization safety assessment and research. The CISA Network was established by the CDC in 2001 with 4 primary goals: (1) develop research protocols for clinical evaluation, diagnosis, and management of adverse events following immunization (AEFI); (2) improve the understanding of AEFI at the individual level, including determining possible genetic and other risk factors for predisposed people and subpopulations at high risk; (3) develop evidence-based algorithms for vaccination of people at risk of serious AEFI; and (4) serve as subject-matter experts for clinical vaccine-safety inquiries. CISA Network investigators bring in-depth clinical, pathophysiologic, and epidemiologic expertise to assessing causal relationships between vaccines and adverse events and to understanding the pathogenesis of AEFI. CISA Network researchers conduct expert reviews of clinically significant adverse events and determine the validity of the recorded diagnoses on the basis of clinical and laboratory criteria. They also conduct special studies to investigate the possible pathogenesis of adverse events, assess relationships between vaccines and adverse events, and maintain a centralized repository for clinical specimens. The CISA Network provides specific clinical guidance to both health care providers who administer vaccines and those who evaluate and treat patients with possible AEFI. The CISA Network plays an important role in providing critical immunization-safety data and expertise to inform vaccine policy-makers. The CISA Network serves as a unique resource for vaccine-safety monitoring efforts conducted at the CDC.
Authors: Larussa PS; Edwards KM; Dekker CL; Klein NP; Halsey NA; Marchant C; Baxter R; Engler RJ; Kissner J; Slade BA
Pediatrics. 2011 May;127 Suppl 1:S65-73. Epub 2011 Apr 18.
Active surveillance for adverse events: the experience of the Vaccine Safety Datalink project
OBJECTIVE: To describe the Vaccine Safety Datalink (VSD) project’s experience with population-based, active surveillance for vaccine safety and draw lessons that may be useful for similar efforts. PATIENTS AND METHODS: The VSD comprises a population of 9.2 million people annually in 8 geographically diverse US health care organizations. Data on vaccinations and diagnoses are updated and extracted weekly. The safety of 5 vaccines was monitored, each with 5 to 7 prespecified outcomes. With sequential analytic methods, the number of cases of each outcome was compared with the number of cases observed in a comparison group or the number expected on the basis of background rates. If the test statistic exceeded a threshold, it was a signal of a possible vaccine-safety problem. Signals were investigated by using temporal scan statistics and analyses such as logistic regression. RESULTS: Ten signals appeared over 3 years of surveillance: 1 signal was reported to external stakeholders and ultimately led to a change in national vaccination policy, and 9 signals were found to be spurious after rigorous internal investigation. Causes of spurious signals included imprecision in estimated background rates, changes in true incidence or coding over time, other confounding, inappropriate comparison groups, miscoding of outcomes in electronic medical records, and chance. In the absence of signals, estimates of adverse-event rates, relative risks, and attributable risks from up-to-date VSD data have provided rapid assessment of vaccine safety to policy-makers when concerns about a specific vaccine have arisen elsewhere. CONCLUSIONS: Care with data quality, outcome definitions, comparison groups, and length of surveillance are required to enable detection of true safety problems while minimizing false signals. Some causes of false signals in the VSD system were preventable and have been corrected, whereas others will be unavoidable in any active surveillance system. Temporal scan statistics, analyses to control for confounding, and chart review are indispensable tools in signal investigation. The VSD’s experience may inform new systems for active safety surveillance.
Authors: Yih WK; Fireman BH; Klein NP; Lieu TA; et al.
Pediatrics. 2011 May;127 Suppl 1:S54-64. Epub 2011 Apr 18.
Evaluation of immunization rates and safety among children with inborn errors of metabolism
BACKGROUND: Children with inherited metabolic disorders are a potential high-risk group for vaccine-preventable diseases, yet information regarding immunization rates and vaccine safety within this population is limited. METHODS: Using Northern California Kaiser Permanente’s electronic medical record, we identified children with inborn errors of metabolism from 1990 to 2007. We assessed immunization rates among infants with inborn errors of metabolism born at Northern California Kaiser Permanente matched to healthy infants (1 to 20), comparing both vaccines received by 2 years of age and age at vaccination. We assessed postvaccination adverse events among children up to 18 years old with inborn errors of metabolism, separately comparing emergency-department visits and hospitalizations during postvaccine days 0 to 30 (primary) and days 0 to 14 (secondary). RESULTS: Comparing infants with inborn errors of metabolism (n = 77) versus matched control subjects (n = 1540), similar proportions were up to date for vaccines at 2 years of age, and there was no evidence of delay in receipt of recommended vaccines during the first year. Vaccination of children with inborn errors of metabolism (n = 271) was not associated with any significant increase in emergency-department visits or hospitalizations during the 30 days after vaccination. Secondary analyses suggested that there may be increased rates of hospitalizations 2 weeks after vaccination for the sickest 1- to 4-year-old children. CONCLUSIONS: Children with inborn errors of metabolism at Northern California Kaiser Permanente received vaccines on the same immunization schedule as healthy infants. Immunization was not associated with increased risk for serious adverse events during the month after vaccination, providing overall reassurance that routine vaccination of children with inborn errors of metabolism does not result in adverse effects.
Authors: Klein NP; Aukes L; Lee J; Fireman B; Shapira SK; Slade B; Baxter R; Summar M
Pediatrics. 2011 May;127(5):e1139-46. Epub 2011 Apr 11.
Vaccine safety in special populations
Studies evaluating the safety of vaccines routinely administered to a population of healthy infants and children may not provide adequate reassurance for members of special populations such as premature infants and children with chronic conditions. However, evaluating the safety of vaccines administered to special populations presents a host of challenges, including limited numbers of subjects, lack of appropriate comparisons groups and substantial complexity in both collecting and evaluating the data. Improving the available immunization safety data for those in special populations will provide substantial benefit to the clinicians caring for these vulnerable patients.
Authors: Klein NP;
Hum Vaccin. 2011 Feb;7(2):269-71. Epub 2011 Feb 1.
Comparison of the safety and immunogenicity of an investigational and a licensed quadrivalent meningococcal conjugate vaccine in children 2-10 years of age
BACKGROUND: Routine administration of quadrivalent meningococcal conjugate vaccine to adolescents and certain high risk groups is recommended in the United States and Canada. We compared the immunogenicity and safety of an investigational quadrivalent meningococcal vaccine conjugated to CRM-197 (MenACWY-CRM) with a licensed quadrivalent vaccine conjugated to diphtheria toxoid (MCV4) in children aged 2-10 years. METHODS: Eligible 2-5-year-olds were randomized 1:2:2 to receive either 2 doses of MenACWY-CRM, or 1 dose of MenACWY-CRM or MCV4; 6-10-year-olds were randomized 1:1 to receive a single dose of MenACWY-CRM or MCV4. The primary immunogenicity assessment was seroresponse separately for the two age cohorts 28 days following a single dose of MenACWY-CRM or MCV4. Noninferiority and superiority criteria were predefined. Solicited injection-site and systemic reactions were collected for the 7 days postvaccination. RESULTS: A total of 2907 children were randomized to receive study vaccine. MenACWY-CRM met statistical superiority criteria vs. MCV4 for groups W and Y and was noninferior for group C in both age strata. For group A, noninferiority criteria were not met; the group A seroresponse rates for MenACWY-CRM and MCV4, respectively were 72% (95% confidence interval 68-75%) and 77% (73-80%) in 2-5-year-olds and 77% (73-80%) and 83% (79-86%) in 6-10-year-olds. When the two age strata were combined (2-10-year-old children), MenACWY-CRM was noninferior to MCV4 for all four groups, and statistically superior for groups C, W, and Y. Safety parameters were similar across age cohorts and vaccines groups. CONCLUSIONS: MenACWY-CRM and MCV4 were immunogenic and well tolerated in children aged 2-10 years. Seroresponse to MenACWY-CRM was statistically noninferior to MCV4 for all groups, and statistically superior for groups C, W, and Y. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00616421.
Authors: Halperin SA; Gupta A; Jeanfreau R; Klein NP; Reisinger K; Walter E; Bedell L; Gill C; Dull PM
Vaccine. 2010 Nov 23;28(50):7865-72. Epub 2010 Oct 29.
Effect of influenza vaccination on hospitalizations in persons aged 50 years and older
OBJECTIVE: To estimate influenza vaccine effectiveness (VE) in preventing hospitalizations in persons over 50 years of age. DESIGN: We performed a retrospective, population based study, using a ‘difference-in-differences’ approach to determine the association between hospitalization and prior vaccination. We examined this association when influenza was not circulating and compared it to the association found when influenza was circulating. VE was estimated from the difference in the association between hospitalization and prior vaccination, inside vs. outside influenza seasons. SETTING: Kaiser Permanente in Northern California. PATIENTS: Health plan members aged 50 years and older during the September 1997 to August 2008 study period, when there were about 68,000 pneumonia hospitalizations in 10 million person-years. RESULTS: Vaccination was associated with lower risk of hospitalization for pneumonia and influenza, even before flu season, presumably due to unmeasured confounders. When influenza arrived the hospitalization-vaccination association strengthened, yielding an adjusted VE estimate of 12.4% (95% CI: 1.6-22.0) in persons aged 50-64, and 8.5% (95% CI: 3.3-13.5) in those aged 65 years and older. There was no significant effect on hospitalizations for ischemic heart disease (IHD), congestive heart failure (CHF), cerebrovascular disease (CVD), or trauma. CONCLUSIONS: Influenza vaccination has a modest but significant effect on prevention of hospitalization for pneumonia and influenza in persons 50 years of age and older.
Authors: Baxter R; Ray GT; Fireman BH
Vaccine. 2010 Oct 21;28(45):7267-72. Epub 2010 Sep 9.
A Phase III evaluation of immunogenicity and safety of two trivalent inactivated seasonal influenza vaccines in US children
BACKGROUND: This study (NCT00383123) compared the immunogenicity and safety of 2 trivalent inactivated influenza vaccines: Fluarix [GlaxoSmithKline (study vaccine)] and Fluzone [Sanofi Pasteur (control vaccine)] in children 6 months to <18 years. METHODS: Children, stratified by age and randomized, received either study (N = 2115) or control vaccine (N = 1210) at day 0 (and day 28 for previously unvaccinated children younger than 9 years). Children 6 months to <5 years comprised the according-to-protocol (ATP) cohort for immunogenicity, whereas the reactogenicity/safety group included all children 6 months to <18 years. The study aimed to demonstrate immunologic noninferiority of study vaccine versus control vaccine. RESULTS: For children 6 months to <5 years, the predefined noninferiority criteria were not reached, mainly due to the differences in immune response in children 6 months to <3 years with no influenza vaccination history. All reactogenicity/safety endpoints were within the same range in both vaccine groups. CONCLUSIONS: The study vaccine demonstrated a good safety and reactogenicity profile; however, it did not meet the predefined noninferiority criteria in children 6 months to <5 years. The study vaccine was as immunogenic as the control vaccine in children aged 3 to <5 years.
Authors: Baxter R; Jeanfreau R; Block SL; Blatter M; Pichichero M; Jain VK; Dewe W; Innis BL
Pediatr Infect Dis J. 2010 Oct;29(10):924-30.
Vaccine effectiveness against laboratory-confirmed influenza in infants: A matched case control study
Influenza is a common and potentially serious infection in infants. Previous studies of influenza vaccine in this age group have reported widely varying estimates of vaccine effectiveness, and few have used laboratory confirmation of influenza diagnoses. We evaluated the effectiveness of 1 and 2 doses of the trivalent inactivated vaccine against laboratory-confirmed influenza in children aged 6 to 23 months within the Kaiser Permanente Northern California Medical Care Program for the 2003-2004, 2004-2005 and 2005-2006 influenza seasons. 1,648 children were included in the analyses, with an average of 4.5 controls matched to each of the 300 cases (213, 29 and 58 cases identified for each of the influenza seasons, respectively) based on birth month/year and zip code. Vaccination status was determined as of 14 days prior to the case patient’s positive test result. Conditional logistic regression was used to calculate vaccine effectiveness for each season, adjusting for chronic medical conditions and other possible confounders. During the 2005-2006 influenza season, when predominant circulating virus strains and vaccine strains were well matched, vaccination was 76% [95% CI: 37-91%] effective against laboratory-confirmed infection. There was no statistically significant effect of vaccination, however, for the 2003-2004 or 2004-2005 seasons. Our results highlight the need for further study of influenza vaccine effectiveness in this age group.
Authors: Cochran LW; Black S; Klein NP; Dekker CL; Lewis E; Reingold AL
Hum Vaccin. 2010 Sep 23;6(9). Epub 2010-09-23.
Risk of fever and sepsis evaluations after routine immunizations in the neonatal intensive care unit
OBJECTIVE: Premature infants can experience cardiorespiratory events such as apnea after immunization in the neonatal intensive care unit (NICU). These changes in clinical status may precipitate sepsis evaluations. This study evaluated whether sepsis evaluations are increased after immunizations in the NICU. STUDY DESIGN: We conducted a retrospective cohort study of infants older than 53 days who were vaccinated in the NICU at the KPMCP (Kaiser Permanente Medical Care Program). Chart reviews were carried out before and after all immunizations were administered and for all sepsis evaluations after age 53 days. The clinical characteristics of infants on the day before receiving a sepsis evaluation were compared between children undergoing post-immunization sepsis evaluations and children undergoing sepsis evaluation at other times. The incidence rate of sepsis evaluations in the post-immunization period was compared with the rate in a control time period not following immunization using Poisson regression. RESULT: A total of 490 infants met the inclusion criteria. The rate of fever was increased in the 24 h period after vaccination (2.3%, P<0.05). The incidence rate of sepsis evaluations was 40% lower after immunization than during the control period, although this was not statistically significant (P=0.09). Infants undergoing a sepsis evaluation after immunization were more likely to have an apneic, bradycardic or moderate-to-severe cardiorespiratory event in the day before the evaluation than were infants undergoing sepsis evaluations at other times (P<0.05). CONCLUSION: Despite an increase in fever and cardiorespiratory events after immunization in the NICU, routine vaccination was not associated with increased risk of receiving sepsis evaluations. Providers may be deferring immunizations until infants are clinically stable, or may have a higher threshold for initiating sepsis evaluations after immunization than at other times.
Authors: Navar-Boggan AM; Halsey NA; Golden WC; Escobar GJ; Massolo M; Klein NP
J Perinatol. 2010 Sep;30(9):604-9. Epub 2010 Feb 25.
Lack of association between acellular pertussis vaccine and seizures in early childhood
OBJECTIVES: Receipt of diphtheria-tetanus-whole-cell pertussis vaccine (diphtheria-tetanus toxoids-pertussis [DTP]) is associated with seizures. Limited population-based studies have been conducted on the risk for seizures after receipt of diphtheria-tetanus-acellular pertussis vaccine (diphtheria-tetanus-acellular pertussis [DTaP]). METHODS: We conducted a retrospective study from 1997-2006 by using risk-interval cohort and self-controlled case series (SCCS) analyses on automated data at 7 managed care organizations that participate in the Vaccine Safety Datalink (VSD). Eligible children included the 1997-2006 VSD cohort of patients who were aged 6 weeks to 23 months and had not received DTP during the study period. A seizure event (febrile or afebrile) was defined by International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses assigned to an inpatient or emergency department setting. The exposed period was composed of a predefined 4 person-days after each DTaP dose. All of the remaining observation periods outside the exposed periods were categorized as unexposed. The risk-interval cohort method compared the incidence of seizures between the exposed and unexposed cohorts. In the SCCS method, the comparison was performed between the same patient’s exposed and unexposed period. RESULTS: We identified 7191 seizure events among 433,654 children. The adjusted incidence rate ratio of seizures across all doses was 0.87 in cohort analysis and 0.91 in SCCS analysis. CONCLUSIONS: We did not observe an increased risk for seizures after DTaP vaccination among children who were aged 6 weeks to 23 months. These findings provide reassuring evidence on the safety of DTaP with respect to seizures.
Authors: Huang WT; Gargiullo PM; Broder KR; Weintraub ES; Iskander JK; Klein NP; Baggs JM; Vaccine Safety Datalink Team
Pediatrics. 2010 Aug;126(2):263-9. Epub 2010 Jul 19.
Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures
OBJECTIVE: In February 2008, we alerted the Advisory Committee on Immunization Practices to preliminary evidence of a twofold increased risk of febrile seizures after the combination measles-mumps-rubella-varicella (MMRV) vaccine when compared with separate measles-mumps-rubella (MMR) and varicella vaccines. Now with data on twice as many vaccine recipients, our goal was to reexamine seizure risk after MMRV vaccine. METHODS: Using 2000-2008 Vaccine Safety Datalink data, we assessed seizures and fever visits among children aged 12 to 23 months after MMRV and separate MMR + varicella vaccines. We compared seizure risk after MMRV vaccine to that after MMR + varicella vaccines by using Poisson regression as well as with supplementary regressions that incorporated chart-review results and self-controlled analyses. RESULTS: MMRV vaccine recipients (83,107) were compared with recipients of MMR + varicella vaccines (376,354). Seizure and fever significantly clustered 7 to 10 days after vaccination with all measles-containing vaccines but not after varicella vaccination alone. Seizure risk during days 7 to 10 was higher after MMRV than after MMR + varicella vaccination (relative risk: 1.98 [95% confidence interval: 1.43-2.73]). Supplementary analyses yielded similar results. The excess risk for febrile seizures 7 to 10 days after MMRV compared with separate MMR + varicella vaccination was 4.3 per 10,000 doses (95% confidence interval: 2.6-5.6). CONCLUSIONS: Among 12- to 23-month-olds who received their first dose of measles-containing vaccine, fever and seizure were elevated 7 to 10 days after vaccination. Vaccination with MMRV results in 1 additional febrile seizure for every 2300 doses given instead of separate MMR + varicella vaccines. Providers who recommend MMRV should communicate to parents that it increases the risk of fever and seizure over that already associated with measles-containing vaccines.
Authors: Klein NP; Fireman B; Vaccine Safety Datalink; et al.
Pediatrics. 2010 Jul;126(1):e1-8. Epub 2010 Jun 29.
Post-marketing safety evaluation of a tetanus toxoid, reduced diphtheria toxoid and 3-component acellular pertussis vaccine administered to a cohort of adolescents in a United States health maintenance organization
BACKGROUND: Prelicensure clinical studies may not include sufficient numbers of subjects to assess the potential for rare postvaccination adverse events. The aim of this postlicensure study (NCT00297856) was to evaluate uncommon outcomes following vaccination with a tetanus, reduced-antigen-content diphtheria, and acellular pertussis vaccine (Tdap, Boostrix GlaxoSmithKline) in a large adolescent cohort. METHODS: We monitored safety outcomes among 13,427 10 to 18-year-old adolescents enrolled in the Northern California Kaiser Permanente Health Care Plan who received Tdap vaccination as part of their normal health care. Subjects were evaluated using self-control analysis comparing days 0 to 29 to days 30 to 59 postvaccination for neurologic events, hematologic events and allergic reactions. We evaluated new onset chronic illnesses within 6 months of Tdap vaccination by comparing with historical Td controls matched for age at vaccination, season, sex, and geographic area. We also compared the incidence of events of interest between the Tdap and historical cohorts as exploratory analyses. RESULTS: No increased risk for medically attended neurologic (odds ratio [OR], 0.962; 95% confidence interval [CI], 0.533-1.733) or allergic reactions (OR, 1.091; 95% CI, 0.441-2.729) was observed following Tdap vaccination when comparing the first 30 postvaccination days to the second 30 postvaccination days. There was one hematologic event within 30 days of Tdap, compared with 0 events within days 30 to 59 (P = 1.0). When compared with matched historical Td recipients, no increase in new onset chronic illnesses (OR, 0.634; 95% CI, 0.475-0.840) was seen after Tdap. No deaths occurred in the Tdap cohort during the study. CONCLUSIONS: This study provides no evidence for an increased risk for neurologic, hematologic, allergic events, or new onset of chronic illnesses among adolescents vaccinated with Tdap.
Authors: Klein NP; Hansen J; Lewis E; Lyon L; Nguyen B; Black S; Weston WM; Wu S; Li P; Howe B; Friedland LR
Pediatr Infect Dis J. 2010 Jul;29(7):613-7.
Rates of autoimmune diseases in Kaiser Permanente for use in vaccine adverse event safety studies
Safety monitoring following new vaccine introduction includes assessment of potential new onset autoimmune diseases (AID). As knowledge regarding AID background rates is limited, we evaluated the incidence of 11 AID in Northern California Kaiser Permanente. AID cases were identified using electronic records of members aged 10-62 years from 1998 to 2004, excluding those with AID diagnoses from 1996 to 1997. Using prespecified criteria, all identified cases of rare diseases were verified by medical record review, while a sample of cases was reviewed for common diseases; incidence rates were calculated based on the proportion of confirmed cases. Overall, the incidence of AID varied from 0.8/100,000 person-years (PY) for autoimmune hemolytic anemia (AIHA) to 54.1/100,000 PY for thyroiditis. Incidence rates in increasing order were AIHA, juvenile rheumatoid arthritis, Guillain-Barre Syndrome, idiopathic thromobocytopenia purpura, transverse myelitis, systemic lupus erythematosus, uveitis, multiple sclerosis, rheumatoid arthritis, Type 1 diabetes mellitus and thyroiditis; incidence rates also varied according to age and gender. These background incidence rates should prove useful for future observational vaccine safety studies and will help guide evaluation of potential vaccine AID events following introduction of new vaccines.
Authors: Klein NP; Ray P; Carpenter D; Hansen J; Lewis E; Fireman B; Black S; Galindo C; Schmidt J; Baxter R
Vaccine. 2010 Jan 22;28(4):1062-8. Epub 2009 Nov 5.
Near real-time surveillance for influenza vaccine safety: proof-of-concept in the Vaccine Safety Datalink Project
The emergence of pandemic H1N1 influenza in 2009 has prompted public health responses, including production and licensure of new influenza A (H1N1) 2009 monovalent vaccines. Safety monitoring is a critical component of vaccination programs. As proof-of-concept, the authors mimicked near real-time prospective surveillance for prespecified neurologic and allergic adverse events among enrollees in 8 medical care organizations (the Vaccine Safety Datalink Project) who received seasonal trivalent inactivated influenza vaccine during the 2005/06-2007/08 influenza seasons. In self-controlled case series analysis, the risk of adverse events in a prespecified exposure period following vaccination was compared with the risk in 1 control period for the same individual either before or after vaccination. In difference-in-difference analysis, the relative risk in exposed versus control periods each season was compared with the relative risk in previous seasons since 2000/01. The authors used Poisson-based analysis to compare the risk of Guillain-Barre syndrome following vaccination in each season with that in previous seasons. Maximized sequential probability ratio tests were used to adjust for repeated analyses on weekly data. With administration of 1,195,552 doses to children under age 18 years and 4,773,956 doses to adults, no elevated risk of adverse events was identified. Near real-time surveillance for selected adverse events can be implemented prospectively to rapidly assess seasonal and pandemic influenza vaccine safety.
Authors: Greene SK; Fireman BH; Lee GM; et al.
Am J Epidemiol. 2010 Jan 15;171(2):177-88. Epub 2009 Dec 4.
Evidence of bias in studies of influenza vaccine effectiveness in elderly patients
Although studies have shown influenza vaccines to be effective in preventing death in the elderly population, these findings may be the result of selection bias. We examined the relationship between vaccination, age, underlying morbidity, and probability of death in the upcoming year. Vaccination coverage varied in a curvilinear fashion with age, morbidity, and risk of death. Forgoing vaccination predicted death in those who had received vaccinations in the previous 5 years, but it predicted survival in patients who had never before received a vaccination. We conclude that bias is inherent in studies of influenza vaccination and death among elderly patients.
Authors: Baxter R; Lee J; Fireman B
J Infect Dis. 2010 Jan 15;201(2):186-9.
Preterm infants’ T cell responses to inactivated poliovirus vaccine
BACKGROUND: The antigen-specific T cell responses of preterm infants to immunization are not well understood. The aim of the present study was to compare the T cell responses of preterm infants after inactivated poliovirus vaccination with those of term infants. METHODS: We prospectively enrolled 2-month-old preterm (gestational age, 33 weeks) and term (gestational age, 37 weeks) infants to receive 3 doses of diphtheria-tetanus toxoids-acellular pertussis-hepatitis B virus-inactivated poliovirus vaccine. Whole blood and peripheral blood mononuclear cells (PBMCs) were stimulated with poliovirus vaccine, and memory T cell activation was analyzed by flow cytometry and lymphoproliferation, respectively. Levels of poliovirus neutralizing antibodies were measured in serum. RESULTS: We enrolled 33 preterm and 50 term infants. Preterm infants had fewer circulating CD4(+)CD45RO(+) memory (P = .005) and CD4(+)CD69(+)IFN-gamma(+) cells activated by staphylococcus enterotoxin B at 2 (P = .015) and 7 (P = .05) months of age. After immunization, preterm and term infants had comparable frequencies of poliovirus-specific CD4(+)CD45RO(+)CD69(+)IFN-gamma(+) memory T cells (P = .79). PBMCs from preterm infants had diminished poliovirus-specific lymphoproliferation (P<.001). Although all infants developed seroprotective poliovirus antibody titers, serotype 1 titers were lower among preterm infants (P = .03). CONCLUSIONS: Preterm infants develop poliovirus-specific T cell responses that are comparable to those of term infants. However, they demonstrate nonspecific and poliovirus-specific functional T cell limitations, suggesting that investigations into whether T cell differences remain as preterm infants mature are warranted.
Authors: Klein NP; Gans HA; Sung P; Yasukawa LL; Johnson J; Sarafanov A; Chumakov K; Hansen J; Black S; Dekker CL
J Infect Dis. 2010 Jan 15;201(2):214-22.
Immunogenicity and tolerability of a quadrivalent meningococcal glycoconjugate vaccine in children 2-10 years of age
Meningococcal disease incidence is highest in infants, but a significant burden of disease also occurs in children. In this Phase II, single-centre US study, 619 healthy children (2-10 years of age) received one dose of an investigational quadrivalent meningococcal CRM(197)-conjugated vaccine (MenACWY-CRM) or a licensed quadrivalent meningococcal polysaccharide vaccine (MPSV4). Immunogenicity was assessed using the serum bactericidal assay with human complement (hSBA) at 1 and 12 months post-vaccination. Local and systemic reactions were recorded for 7 days, all adverse events (AEs) for 1 month, and medically significant and serious AEs (SAEs) for 12 months post-vaccination. For all four serogroups, more MenACWY-CRM recipients achieved an hSBA titre >or=1:4 at 1 month post-vaccination (A: 82%; C: 83%; W-135: 95%; Y: 91%) compared with the group that received MPSV4 (A: 45%; C: 66%; W-135: 71%; Y: 61%); this difference persisted through to 12 months post-vaccination. Both vaccines were well tolerated. In children 2-10 years of age, MenACWY-CRM induced a higher immune response than that of MPSV4, and was well tolerated.
Authors: Black S; Klein NP; Shah J; Bedell L; Karsten A; Dull PM
Vaccine. 2010 Jan 8;28(3):657-63. Epub 2009 Nov 4.
Real-time surveillance to assess risk of intussusception and other adverse events after pentavalent, bovine-derived rotavirus vaccine
BACKGROUND: A pentavalent, bovine-derived rotavirus vaccine (RotaTeq, Merck) was licensed in 2006 for use in infants. A previously licensed rotavirus vaccine was withdrawn due to elevated risk of intussusception. We prospectively evaluated the risk of intussusception and other pre-specified adverse events among RotaTeq recipients in the Vaccine Safety Datalink. METHODS: The exposed population included children from age 4 to 48 weeks who received RotaTeq between May 2006 and May 2008. Adverse events over the subsequent 30 days were ascertained from inpatient, outpatient, and emergency department files; cases of intussusception were validated by medical record review. An adaptation of sequential probability ratio testing was employed to compare the cumulative number of observed and expected adverse events on a weekly basis, and a ‘signal’ was generated if the log-likelihood ratio reached a predetermined threshold. This allowed near real-time monitoring to detect selected adverse events. The expected number of cases of intussusception was determined from historical rates in the VSD population. RESULTS: There were 207,621 doses of RotaTeq administered to the study population; 42% were first doses. Five children had computerized diagnosis codes for intussusception, and 6.75 cases were expected based on historical rates (relative risk = 0.74). No elevation in risk was identified for intussusception or any other adverse event. Two of five children with suspected intussusception based on diagnosis codes met the case criteria after medical record review. CONCLUSIONS: This study illustrates the feasibility of rapid vaccine safety assessment and provides additional evidence that RotaTeq is not associated with an increased risk of intussusception.
Authors: Belongia EA; Lewis E; Vaccine Safety Datalink Investigation Group; et al.
Pediatr Infect Dis J. 2010 Jan;29(1):1-5.
Differential maternal responses to a newly developed vaccine information pamphlet
We compared the response to a new vaccine information pamphlet with the current CDC Vaccine Information Statements (VIS) among recently delivered mothers who were screened to identify those with concerns about immunization. Eligible mothers (n=226) were randomly assigned to one of three equal groups; those reviewing only the new pamphlet, those receiving only VIS, or those receiving both. Among those mothers reviewing both, 61% preferred the new pamphlet for its visual appeal (P<0.0001) and ease of understanding (P=0.005). Overall, mothers expressed increased confidence and fewer concerns regarding multiple injections after reviewing the pamphlet. However, older, more-highly educated mothers were less likely to report improved vaccine confidence after reviewing either the pamphlet or the VIS. Mothers in all three groups stated a preference for receiving the vaccine information during pregnancy or prior to the actual immunization visit. These data suggest that early provision of tailored immunization material along with the VIS to new mothers may enhance their overall confidence in vaccines and that additional strategies targeted toward certain mothers may be needed.
Authors: Klein NP; Kissner J; Aguirre A; Sparks R; Campbell S; Edwards KM; Dekker CL; Shui I; Gust DA
Vaccine. 2009 Dec 11;28(2):323-8. Epub 2009 Oct 30.
Compliance with multiple-dose vaccine schedules among older children, adolescents, and adults: results from a vaccine safety datalink study
OBJECTIVES: We studied compliance with multiple-dose vaccine schedules, assessed factors associated with noncompliance, and examined timeliness of series completion among older children, adolescents, and adults. METHODS: We conducted a large, multisite, retrospective cohort study of older children, adolescents, and adults in the Vaccine Safety Datalink population from 1996 through 2004. We quantified the rates of completion of all required doses for varicella, hepatitis A, and hepatitis B vaccines according to their recommended schedules. RESULTS: Among those who received a first dose of varicella (n = 16 075), hepatitis A (n = 594 917), and hepatitis B (n = 590 445) vaccine, relatively few completed the series (55%-65% for hepatitis B vaccine and 40%-50% for hepatitis A and varicella vaccines in most age groups). Compliance was lowest among adolescents (35.9%) and Medicaid recipients (29.7%) who received varicella vaccine and among younger adult age groups who received hepatitis A vaccine (25%-35% across those age groups). Even among series completers, there was a relatively long interval of undervaccination between the first and last doses. CONCLUSIONS: Compliance with multiple-dose vaccine series among older children, adolescents, and adults is suboptimal. Further evaluations of strategies to improve compliance in these populations are needed.
Authors: Nelson JC; Klein NP; Jackson LA; et al.
Am J Public Health. 2009 Oct;99 Suppl 2:S389-97.
Influenza vaccination and mortality: differentiating vaccine effects from bias
It is widely believed that influenza (flu) vaccination of the elderly reduces all-cause mortality, yet randomized trials for assessing vaccine effectiveness are not feasible and the observational research has been controversial. Efforts to differentiate vaccine effectiveness from selection bias have been problematic. The authors examined mortality before, during, and after 9 flu seasons in relation to time-varying vaccination status in an elderly California population in which 115,823 deaths occurred from 1996 to 2005, including 20,484 deaths during laboratory-defined flu seasons. Vaccine coverage averaged 63%; excess mortality when the flu virus was circulating averaged 7.8%. In analyses that omitted weeks when flu circulated, the odds ratio measuring the vaccination-mortality association increased monotonically from 0.34 early in November to 0.56 in January, 0.67 in April, and 0.76 in August. This reflects the trajectory of selection effects in the absence of flu. In analyses that included weeks with flu and adjustment for selection effects, flu season multiplied the odds ratio by 0.954. The corresponding vaccine effectiveness estimate was 4.6% (95% confidence interval: 0.7, 8.3). To differentiate vaccine effects from selection bias, the authors used logistic regression with a novel case-centered specification that may be useful in other population-based studies when the exposure-outcome association varies markedly over time.
Authors: Fireman B; Lee J; Lewis N; Bembom O; van der Laan M; Baxter R
Am J Epidemiol. 2009 Sep 1;170(5):650-6. Epub 2009 Jul 22.
Varicella vaccination and ischemic stroke in children: is there an association?
BACKGROUND: Ischemic stroke is a known complication of varicella disease. Although there have been case reports of ischemic stroke after varicella vaccination, the existence and magnitude of any vaccine-associated risk has not been determined. OBJECTIVE. The purpose of this work was to determine whether varicella vaccination is associated with an increased risk of ischemic stroke and encephalitis in children within 12 months after vaccination. PATIENTS AND METHODS: We conducted a retrospective cohort study based on computerized data from children 11 months through 17 years old enrolled for > or =12 months in the Vaccine Safety DataLink from 1991 through 2004. International Classification of Disease codes identified cases of ischemic stroke (433-436, 437.1, 437.4, 437.6, 437.8-437.9) and encephalitis (052.0, 323.5, 323.8-9). Cox regression was used to model the risk in the 12 months after vaccination relative to all other person-time. Covariates included calendar time, gender, and stroke risk factors (eg, sickle cell disease). RESULTS: Varicella vaccine was administered to 35.3% of the 3.2 million children in the cohort. There were 203 new inpatient ischemic stroke diagnoses, including 8 that occurred within 12 months after vaccination; there was no temporal clustering. The adjusted stroke hazard ratio was not elevated during any of the time periods in the 12 months after vaccination. Stroke was strongly associated with known risk factors such as sickle cell disease and cardiac disease. None of the 243 encephalitis cases occurred during the first 30 days after vaccination, and there was no association between encephalitis and varicella vaccination at any time in the 12 months after vaccination. CONCLUSION: Our retrospective cohort study of >3 million children found no association between varicella vaccine and ischemic stroke.
Authors: Donahue JG; Klein NP; Vaccine Safety Datalink Team; et al.
Pediatrics. 2009 Feb;123(2):e228-34.
Recurrent sterile abscesses following aluminium adjuvant-containing vaccines
Abscess formation following immunisation is a previously reported complication, generally associated with microbial contamination of the vaccine. Less commonly, such abscesses have been sterile. Here we describe two children evaluated in the Center for Disease Control and Prevention (CDC)-funded Clinical Immunization Safety Assessment (CISA) network who developed recurrent sterile abscesses after administration of vaccines containing aluminium adjuvant, either individually or in combination. Although the abscesses healed without sequelae, these occurrences support an association between receipt of aluminium adjuvant and sterile abscesses in susceptible patients. For patients with similar symptoms, clinicians may wish to choose a vaccine formulation containing the least amount of aluminium adjuvant.
Authors: Klein NP; Edwards KM; Sparks RC; Dekker CL; Clinical Immunization Safety Assessment (CISA) Network
BMJ Case Rep. 2009;2009. Epub 2009 Mar 17.
Kinrix: a new combination DTaP-IPV vaccine for children aged 4-6 years
Combination vaccines allow the administration of multiple vaccine antigens without the need for multiple injections. Recently, a combined diphtheria toxoid, tetanus toxoid, acellular pertussis and inactivated poliomyelitis vaccine (DTaP-IPV), Kinrix, has been licensed in the USA for use as the fifth DTaP dose and fourth IPV dose in children 4-6 years of age. Clinical trials have shown Kinrix to be immunogenic in 4-6-year-old children, with a safety profile comparable with that of separate DTaP and IPV vaccination. The use of Kinrix reduces by one the number of injections required to provide this age group with all recommended immunizations. Strategies such as the use of combined vaccines can help to maintain high levels of coverage against diphtheria, tetanus, pertussis and poliomyelitis diseases.
Authors: Weston WM; Klein NP
Expert Rev Vaccines. 2008 Nov;7(9):1309-20.
Diphtheria-tetanus-acellular pertussis and inactivated poliovirus vaccines given separately or combined for booster dosing at 4-6 years of age
BACKGROUND: In the United States, diphtheria-tetanus-acellular pertussis (DTaP) and inactivated poliovirus (IPV) booster vaccinations are recommended for children 4-6 years of age. A combined DTaP-IPV vaccine is being developed, which would reduce by one the number of injections in this age group. METHODS: Children 4-6 years of age were randomized (1:1:1:1) to receive booster vaccination with 1 of 3 combined DTaP-IPV lots plus the measles, mumps, and rubella vaccine (N = 3156 for pooled lots) or separate doses of DTaP + IPV + measles, mumps, and rubella vaccine (N = 1053). Immunogenicity was assessed in a subset of children (N = 1331). Safety (solicited and unsolicited symptoms) including detailed assessment of local swelling reactions, was assessed in all children. RESULTS: Increases in antibody geometric mean concentrations/titers 1 month after vaccination were observed for the diphtheria, tetanus, acellular pertussis, and polio antigens. At least 92.2% of combined DTaP-IPV subjects and 92.6% of separate DTaP + IPV subjects had a postvaccination booster response for one or more DTaP antigens. Booster responses to one or more poliovirus antigens were observed in at least 96.6% of combined DTaP-IPV subjects and 92.8% of separate DTaP + IPV subjects. The combined DTaP-IPV vaccine was noninferior to separately administered DTaP and IPV vaccines with respect to DTaP antigen booster response rates and poliovirus antibody geometric mean titers ratios. Reporting of solicited local and systemic events was comparable between both groups. CONCLUSIONS: The combination DTaP-IPV vaccine provided immunogenicity and reactogenicity that is comparable to separately administered DTaP and IPV vaccines, with the advantage of requiring one less injection.
Authors: Black S; Friedland LR; Ensor K; Weston WM; Howe B; Klein NP
Pediatr Infect Dis J. 2008 Apr;27(4):341-6.
Risk factors for developing apnea after immunization in the neonatal intensive care unit
OBJECTIVES: Among hospitalized NICU infants, preimmunization apnea is a well-recognized predictor of postimmunization apnea. However, predictors for postimmunization apnea among NICU infants without preimmunization apnea have not been investigated. METHODS: Using a large NICU database in the Northern California Kaiser Permanente Medical Care Program, we abstracted NICU charts of infants who were hospitalized for > or = 53 days and who were also immunized, capturing preimmunization (24 hours before immunization) and postimmunization (48 hours after immunization) events. We assessed factors associated with postimmunization apnea by using multivariate logistic regression. RESULTS: Of 16,146 infants admitted to the NICU, 557 received > or = 1 vaccine and 497 met the criteria for study entry. All infants with preimmunization apnea (n = 27) and all except 3 infants with postimmunization apnea (n = 65) had gestational ages of < 31 weeks. Multivariate analyses revealed preimmunization apnea as the most important predictor of postimmunization apnea, although higher 12-hour Score for Neonatal Acute Physiology II and age of < 67 days (mean cohort age) were also associated. Multivariate analysis exclusively among infants without preimmunization apnea similarly found elevated Score for Neonatal Acute Physiology II, age of < 67 days, and weight of < 2000 g to be associated with postimmunization apnea. Forty-nine infants without preimmunization apnea and with > or = 1 apnea predictor were discharged within 48 hours after immunization; 2 were subsequently readmitted because of apnea. CONCLUSIONS: For infants in the NICU without apnea during the 24 hours immediately before immunization, younger age, smaller size, and more severe illness at birth are important predictors of postimmunization apnea.
Authors: Klein NP; Massolo ML; Greene J; Dekker CL; Black S; Escobar GJ; Vaccine Safety Datalink
Pediatrics. 2008 Mar;121(3):463-9.
Case-control study of antibiotic use and subsequent Clostridium difficile-associated diarrhea in hospitalized patients
OBJECTIVE: To determine which antibiotics increase or decrease the risk of Clostridium difficile-associated diarrhea (CDAD). DESIGN: Retrospective case-control study. SETTING: Nonprofit, integrated healthcare delivery system in Northern California. PATIENTS: Study participants included patients with cases of hospital-acquired CDAD that occurred during the period from 1999 through 2005 (n=1,142) and control patients (n= 3,351) matched for facility, calendar quarter during which hospitalization occurred, diagnosis related group for the index hospitalization, and length of hospital stay. All case and control patients had received antibiotics in the 60 days before the index date. For each antibiotic, the risk of CDAD was examined in relation to whether the patient received the antibiotic, after adjustment for use of other antibiotics, demographic characteristics, selected health conditions, and use of healthcare services. RESULTS: The following antibiotics were associated with a significantly increased risk of acquiring CDAD: imipenem-cilastin (odds ratio [OR], 2.77), clindamycin (OR, 2.31), cefuroxime (OR, 2.16), moxifloxacin (OR, 1.88), ceftazidime (OR, 1.82), cefpodoxime (OR, 1.58), ceftizoxime (OR, 1.57), and ceftriaxone (OR, 1.49). Metronidazole and doxycycline were associated with a significantly reduced risk of CDAD (OR for metronidazole, 0.67; OR for doxycycline, 0.41). Other factors associated with an increased risk of CDAD were older age, longer hospital stays, use of proton pump inhibitors, prior gastrointestinal disease, and prior infection (not including C. difficile infection.) CONCLUSIONS: Some antibiotics appear to increase the risk of acquiring CDAD, notably clindamycin, third-generation cephalosporins, and carbapenems, whereas metronidazole and doxycycline appear to be protective, compared with other antibiotics.
Authors: Baxter R; Ray GT; Fireman BH
Infect Control Hosp Epidemiol. 2008 Jan;29(1):44-50.
Real-time vaccine safety surveillance for the early detection of adverse events
BACKGROUND: Rare but serious adverse events associated with vaccines or drugs are often nearly impossible to detect in prelicensure studies and require monitoring after introduction of the agent in large populations. Sequential testing procedures are needed to detect vaccine or drug safety problems as soon as possible after introduction. OBJECTIVE: To develop and evaluate a new real-time surveillance system that uses dynamic data files and sequential analysis for early detection of adverse events after the introduction of new vaccines. RESEARCH DESIGN: The Centers for Disease Control and Prevention (CDC)-sponsored Vaccine Safety Datalink Project developed a real-time surveillance system and initiated its use in an ongoing study of a new meningococcal vaccine for adolescents. Dynamic data files from 8 health plans were updated and aggregated for analysis every week. The analysis used maximized sequential probability ratio testing (maxSPRT), a new signal detection method that supports continuous or time-period analysis of data as they are collected. RESULTS: Using the new real-time surveillance system, ongoing analyses of meningococcal conjugate vaccine (MCV) safety are being conducted on a weekly basis. Two forms of maxSPRT were implemented: an analysis using concurrent matched controls, and an analysis based on expected counts of the outcomes of interest, which were estimated based on historical data. The analysis highlights both theoretical and operational issues, including how to (1) choose appropriate outcomes and stopping rules, (2) select control groups, and (3) accommodate variation in exposed:unexposed ratios between time periods and study sites. CONCLUSIONS: Real-time surveillance combining dynamic data files, aggregation of data, and sequential analysis methods offers a useful and highly adaptable approach to early detection of adverse events after the introduction of new vaccines.
Authors: Lieu TA; Kulldorff M; Davis RL; Lewis EM; Weintraub E; Yih K; Yin R; Brown JS; Platt R; for the Vaccine Safety Datalink Rapid Cycle Analysis Team
Med Care. 2007 Oct;45(10 Supl 2):S89-95.
Surveillance for invasive pneumococcal disease during 2000-2005 in a population of children who received 7-valent pneumococcal conjugate vaccine
OBJECTIVES: To assess the incidence of invasive pneumococcal disease (IPD) in all children younger than 5 years of age in the Northern California Kaiser Permanente (NCKP) health care system during a 5-year surveillance period (2000-2005) after the introduction in April 2000 of routine use of 7-valent pneumococcal conjugate vaccine (PCV7). METHODS: This was a laboratory-based surveillance study of all children younger than 5 years of age in the NCKP health care system from April 2000 to March 2005. The comparison group was all children younger than 5 years of age in the NCKP health care system from April 1996 to March 2000. Data obtained from clinical databases included microbiologic identification and susceptibility testing; serotyping of isolates; immunization records; and IPD diagnoses for inpatients and outpatients. IPD was defined as a positive culture of Streptococcus pneumoniae from a normally sterile body site. RESULTS: For all serotypes, the mean annual incidence of IPD during the postlicensure surveillance period was 15.3 cases/100,000 person-years (10(5) p-y) compared with 62.5 cases/10(5) p-y in the prelicensure years of 1996-2000. The average incidence of IPD caused by vaccine serotypes was reduced from 50.1 cases/10(5) p-y during the prelicensure years to 4.9 cases/10(5) p-y during the postlicensure period. The average incidences of IPD caused by cross-reactive and by nonvaccine serotypes were 5.8 and 5.3 cases/10(5) p-y, respectively, during the prelicensure years and 2.5 and 6.2 cases/10(5) p-y, respectively, during the postlicensure period. Of the 131 IPD cases observed during the postlicensure surveillance period, bacteremia (50.4%) and pneumonia (31.3%) were the most common diagnoses. During the 5-year postlicensure surveillance period, only 3 subjects who were identified to be fully vaccinated for age with PCV7 (3 doses by 7 months of age or 4 doses by 18 months of age) developed vaccine-serotype IPD. CONCLUSION: The incidence of IPD has significantly decreased in a large population of children after the introduction of PCV7. Vaccine-type IPD was rare in patients who received full 4-dose immunization with PCV7. There is no clear evidence of a significant increase in nonvaccine-serotype IPD. Introduction of a 4-dose infant schedule of PCV7 into this population has resulted in a marked and sustained reduction of IPD in children.
Authors: Black S; France EK; Isaacman D; Bracken L; Lewis E; Hansen J; Fireman B; Austrian R; Graepel J; Gray S; Klein NP
Pediatr Infect Dis J. 2007 Sep;26(9):771-7.
A role for genetics in the immune response to the varicella vaccine
BACKGROUND: A wide range in antibody titers has been found after immunization with the varicella vaccine, although the basis for these differences has not been described. METHODS: To evaluate the contribution of a genetic component in the immune response to the varicella vaccine, concordance for six-week postimmunization antibody titers was evaluated among 248 biologic siblings who participated in varicella vaccine clinical trials by comparing all pairs of siblings (151 pairs) to all possible unrelated, nonsibling pairs created from within this same cohort (30,477 pairs). RESULTS: Postimmunization antibody titers after 1 varicella vaccine dose were within the range observed historically among healthy vaccinees, with 85.4% of subjects having antibody responses greater than the approximate correlate of protection of 5 gpELISA units. Postimmunization antibody titers within sibling pairs clustered together more than or less than 10 gpELISA units when compared with within nonsibling pairs (P < 0.0001). Postimmunization titers within sibling pairs were also quantitatively closer together than were those within unrelated, nonsibling pairs (P = 0.022). The age-adjusted intraclass correlation coefficient indicated that the heritability of the varicella vaccine immune response is 45% (95% confidence interval of 15-75%). CONCLUSIONS: Similarities in siblings' response to varicella vaccine are supportive of the hypothesis that genetic factors play a role in the antibody response to the varicella vaccine.
Authors: Klein NP; Fireman B; Enright A; Ray P; Black S; Dekker CL; Clinical Immunization Safety Assessment Network
Pediatr Infect Dis J. 2007 Apr;26(4):300-5.
Respiratory distress and transient tachypnea of the newborn
Authors: Klein N
In: Zaoutis LB, Chiang VW, editors. Comprehensive pediatric hospital medicine. Philadelphia: Mosby/Elsevier, 2007.
Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than 5 years of age for prevention of pneumonia: updated analysis using World Health Organization standardized interpretation of chest radiographs
BACKGROUND: A World Health Organization (WHO) working group in 2001 developed a method for standardizing interpretation of chest radiographs in children for epidemiologic purposes. We reevaluated radiographs from the Kaiser Permanente Pneumococcal Efficacy trial using this method. METHODS: Seven-valent pneumococcal conjugate vaccine was evaluated in a randomized, controlled study including 37,868 infants. Effectiveness against pneumonia was previously evaluated using the original treating radiologist reading. There were 2841 sets of radiographs from this trial and all available radiographs were scanned and read blindly by 2 WHO crosstrained readers (A and B); discordance between the 2 primary readers was resolved through a consensus reading by an adjudicating panel of 2 radiologists. RESULTS: Of the 2841 radiographs, 2446 were available for scanning and were reviewed using WHO-defined descriptive categories. Two hundred fifty of the 2446 radiographs were read as positive by both readers. An additional 129 were read as positive by reader A only and 142 by reader B only for a total of 521 radiographs that were read as positive by one or both of the reviewers. The concordance rate between the 2 reviewers was 250 of 521 (48%). Of the 271 discordant radiographs, 45 of 129 (34.9%) of reader A and 66 of 142 (46.5%) for reader B were finalized as positive by the adjudicating panel. Overall, 361 radiographs were finalized as positive (12.7%). With these 361 images as the standard, the sensitivity and specificity of reader A were 82% and 97%, respectively, and for reader B, 88% and 97%, respectively. Kappa between the 2 readers was 0.58. Of 25 control radiographs read as positive by both A and B, 80% were also read as positive by the panel and all 25 control negative radiographs were read as negative by the panel. Using original readings by point-of-care radiologists, efficacy against first episode of radiograph confirmed pneumonia was 17.7% (95% confidence interval [CI] = 4.8-28.9%) in intent-to-treat and 20.5% (95% CI = 4.4-34%) in per protocol. Using the WHO method, the efficacy against first episode of radiograph confirmed pneumonia adjusting for age, gender and year of vaccination of 25.5% (95% CI = 6.5-40.7%, P = 0.011) for intent-to-treat and 30.3% (95% CI = 10.7-45.7%, P = 0.0043) for per protocol. CONCLUSION: Using WHO criteria for reading of radiographs increased point estimates of vaccine efficacy presumably as a result of improved specificity.
Authors: Hansen J; Black S; Shinefield H; Cherian T; Benson J; Fireman B; Lewis E; Ray P; Lee J
Pediatr Infect Dis J. 2006 Sep;25(9):779-81.
Cost-effectiveness of pneumococcal conjugate vaccine: evidence from the first 5 years of use in the United States incorporating herd effects
BACKGROUND: Pneumococcal conjugate vaccine (PCV) has been in routine use in the United States for 5 years. Prior U.S. cost-effectiveness analyses have not taken into account the effect of the vaccine on nonvaccinated persons. METHODS: We revised a previously published model to simulate the effects of PCV on children vaccinated between 2000 and 2004, and to incorporate the effect of the vaccine in reducing invasive pneumococcal disease (IPD) in nonvaccinated persons during those years. Data from the Active Bacterial Core Surveillance of the Centers for Disease Control and Prevention (2000-2004) were used to estimate changes in the burden of IPD in nonvaccinated adults since the introduction of PCV (compared with the baseline years 1997-1999). Results combined the simulated effects of the vaccine on the vaccinated and nonvaccinated populations. RESULTS: Before incorporating herd effects in the model, the PCV was estimated to have averted 38,000 cases of IPD during its first 5 years of use at a cost of dollar 112,000 per life-year saved. After incorporating the reductions in IPD for nonvaccinated individuals, the vaccine averted 109,000 cases of IPD at a cost of dollar 7500 per life-year saved. When the herd effect was assumed to be half that of the base case, the cost per life-year saved was dollar 18,000. CONCLUSIONS: IPD herd effects in the nonvaccinated population substantially reduce the cost, and substantially improve the cost-effectiveness, of PCV. The cost-effectiveness of PCV in actual use has been more favorable than predicted by estimates created before the vaccine was licensed.
Authors: Ray GT; Whitney CG; Fireman BH; Ciuryla V; Black SB
Pediatr Infect Dis J. 2006 Jun;25(6):494-501.
Impact of the use of heptavalent pneumococcal conjugate vaccine on disease epidemiology in children and adults
Pneumococcal conjugate vaccine was introduced for routine use in infants and toddlers in the United States in March 2000. We report on the impact of the introduction of this vaccine on disease epidemiology in young children as well as secondary effects due to herd immunity in unvaccinated children and adults. As of March 2003, 157,471 children had received one or more doses of PNCV7, but only 24% of those less than two years of age received all four doses as a result of shortages of vaccine. During the last year of observation, no cases of vaccine serotype disease were seen in children less than one year of age compared with an incidence ranging between 51.5 and 98.2 cases/100,000 person years (16-34 cases per year) in the years before vaccine introduction. Similar reductions were seen in children less than five years of age. There was no evidence of any concomittant increase in pneumococcal disease caused by non-vaccine serotypes. High-level resistance of pneumococci to penicillin fell from a peak of 15% in year 2000 to 5% in the first half of 2003.
Authors: Black S; Shinefield H; Baxter R; Austrian R; Elvin L; Hansen J; Lewis E; Fireman B
Vaccine. 2006 Apr 12;24 Suppl 2:S2-79-80.
Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants
The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention recommends influenza vaccination for women who will be in the second or third trimester of pregnancy during the influenza season. We analyzed hospital admissions with principal diagnoses of influenza or pneumonia and influenza-like illness (ILI) outpatient visits to study the effectiveness of influenza vaccine during pregnancy in protecting women and infants from influenza-related morbidity. Estimates of influenza vaccine effectiveness across five flu seasons (Fall 1997 to Spring 2002) were calculated using Cox proportional hazards models for women and infant study populations in Kaiser Permanente Northern California. Outpatient utilization outcomes included physician visits with a diagnosis of upper respiratory infection, pharyngitis, otitis media, asthma, bronchial asthma, viral infection, pneumonia, fever, cough, or wheezing associated with respiratory illness. Inpatient outcomes included hospitalizations with principal diagnoses of influenza or pneumonia. Women who received influenza vaccine during pregnancy had the same risk for ILI visits compared with unvaccinated women, adjusting for women’s age and week of delivery. When asthma visits were excluded from the outcome measure, we also found no difference in the risk of outpatient visits for vaccinated and unvaccinated women. Hospital admissions for influenza or pneumonia for women in the study population were quite rare and no women died of respiratory illness during pregnancy. Infants born to women who received influenza vaccination had the same risks for influenza or pneumonia admissions compared with infants born to unvaccinated women, adjusting for infant’s gender, gestational age, week of birth, and birth facility. Maternal influenza vaccination was also not a significant determinant of risk of ILI (excluding otitis media) outpatient visits for infants, nor did it significantly affect the risk of otitis media visits. Influenza vaccination during pregnancy did not significantly affect the risk of cesarean section, adjusting for the woman’s age. It also did not affect the risk of preterm delivery. Although the immunogenicity of influenza vaccination in pregnancy in mother and infant has been well documented, in this study, we were unable to demonstrate the effectiveness of influenza vaccination with data for hospital admissions and physician visits. One possible interpretation of these findings is that typical influenza surveillance measures based on utilization data are not reliable in distinguishing influenza from other respiratory illness. Hospitalizations for respiratory illness were uncommon in both vaccinees and nonvaccinees.
Authors: Black SB; Shinefield HR; France EK; Fireman BH; Platt ST; Shay D; Vaccine Safety DW
Am J Perinatol. 2004 Aug;21(6):333-9.
Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente
OBJECTIVE: To assess the direct and indirect effects of the introduction of routine use of pneumococcal conjugate vaccine in infants and toddlers at risk for invasive disease caused by vaccine serotypes and nonvaccine serotypes in vaccinated children and unvaccinated children of the same age. Secondary objectives included determination of the risk of pneumococcal infections in unvaccinated older children and adults in the same population and the impact of vaccine introduction on patterns of antimicrobial resistance. METHODS: Northern California Kaiser Permanente provides integrated comprehensive care to 3.1 million people and has an annual birth cohort of 38,000 infants. Microbiology services use a regional laboratory. Automated laboratory results, immunization records as well as diagnoses for inpatient and outpatient utilization are available from clinical data bases. Beginning in April 2000, the heptavalent pneumococcal conjugate (PNCV7) vaccine was introduced into routine use in the Northern California Kaiser Permanente population. Cases of invasive pneumococcal disease were identified from the automated hospital diagnosis as well as laboratory databases for all individuals, vaccinees and nonvaccinees, inpatient and outpatient. For the purpose of these analyses, pneumococcal invasive disease was defined as a positive culture from a normally sterile site. RESULTS: As of March 2003, 157,471 children had received 1 dose or more of PNCV7, but only 24% of those <2 years of age received all 4 doses as a result of shortages of vaccine. During the last year of observation, no cases of vaccine serotype disease were seen in children <1 year of age compared with an incidence ranging between 51.5 and 98.2 cases per 100,000 person-years (16-34 cases per year) in the years before vaccine introduction. Similar reductions were seen in children <5 years of age. There was no evidence of any concomitant increase in pneumococcal disease caused by nonvaccine serotypes. High level resistance of pneumococci to penicillin fell from a peak of 15% in 2000 to 5% in the first half of 2003. Similar trends were seen for other antibiotics. CONCLUSION: The PNCV7 vaccine is highly effective in reducing the burden of pneumococcal disease in children <5 years of age, and there is evidence of a herd effect as well as a decrease in the antibiotic resistant in strains causing disease. For invasive disease, there is no current evidence of serotype replacement.
Authors: Black S; Shinefield H; Baxter R; Austrian R; Bracken L; Hansen J; Lewis E; Fireman B
Pediatr Infect Dis J. 2004 Jun;23(6):485-9.
Pneumococcal conjugate vaccine in children
Authors: Davis RL; Fireman B; Shinefield HR
N Engl J Med. 2004 Jan 1;350(1):84-5; author reply 84-5.
Impact of the pneumococcal conjugate vaccine on otitis media
CONTEXT: The heptavalent pneumococcal conjugate vaccine (PCV) is recommended for infants to protect against invasive disease, but its impact on otitis might also have public health importance. OBJECTIVE: To examine the impact of PCV on the incidence of otitis media, frequent otitis media and tympanostomy tube procedures and to assess whether the effectiveness of the vaccine wanes after age 24 months and varies by race, sex or season. DESIGN, SETTING AND PATIENTS: From 1995 to 1998, 37 868 children at Kaiser Permanente in Northern California were randomized to receive PCV or a control vaccine in a double blind trial and were followed through April 1999. INTERVENTIONS: Children received a primary series at 2, 4 and 6 months of age and a booster at 12 to 15 months. MAIN OUTCOME MEASURES: Visits for otitis, frequent visits for otitis and tympanostomy tube procedures. Otitis was ascertained from diagnosis checklists routinely marked by physicians. RESULTS: Control children averaged 1.8 otitis visits per year. Children given PCV had fewer otitis visits than control children in every age group, sex, race and season examined. Intention-to-treat analysis permitted rejection of the null hypothesis that PCV is ineffective against otitis media (P < 0.0001). In children who completed the primary series per protocol, PCV reduced otitis visits by 7.8% [95% confidence interval (CI), 5.4 to 10.2%] and antibiotic prescriptions by 5.7% (CI 4.2 to 7.2%). Frequent otitis was reduced by amounts that increased with otitis frequency, from a 10% reduction in the risk of 3 visits to a 26% reduction in the risk of 10 visits within a 6-month period. Tube placements were reduced by 24% (CI 12 to 35%). CONCLUSION: In children followed up to 3.5 years, PCV provided a moderate amount of protection against ear infections while reducing frequent otitis media and tube procedures by greater amounts.
Authors: Fireman B; Black SB; Shinefield HR; Lee J; Lewis E; Ray P
Pediatr Infect Dis J. 2003 Jan;22(1):10-6.
Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia
OBJECTIVE: To determine the effectiveness of the Wyeth heptavalent pneumococcal conjugate vaccine against clinical and radiograph-confirmed pneumonia in children. METHODS: The heptavalent CRM(197) pneumococcal conjugate vaccine (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a randomized, double blind trial. Children were randomized to receive either the CRM(197) PCV (vaccine group) or the meningococcal type C CRM(197) conjugate vaccine (control group). The primary outcome of this trial was invasive pneumococcal disease. In addition children with the clinical diagnosis of pneumonia in the study population were identified through review of automated inpatient, emergency and outpatient databases. The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified, and the original reading of their radiographs by the radiologist was obtained from automated databases. Rates of clinically diagnosed pneumonia, of pneumonia with a radiograph obtained regardless of result, of pneumonia with positive radiograph (consolidation, empyema or parenchymal infiltrate) and of pneumonia with only perihilar infiltrates were compared between vaccinated and nonvaccinated groups. In addition risk of disease pneumonia was evaluated by race and ethnicity. RESULTS: The incidence of a first pneumonia episode in the control group was 55.9 per 1000 person-years. A radiograph was obtained in 61% of episodes, a positive radiograph in 21% and perihilar findings in an additional 5%. In per protocol follow-up of children given PCV, first episodes of all clinically diagnosed pneumonia were reduced by 4.3% [95% confidence interval (CI), -3.5, 11.5%, = 0.27], episodes with a radiograph were reduced by 9.8% (CI 0.1, 18.5%, < 0.05) and episodes with a positive radiograph were reduced by 20.5% (CI 4.4, 34.0, = 0.02). In the intent to treat analysis including all episodes after randomization, episodes with a positive radiograph were reduced by 17.7%, =.01). The greatest impact was in the first year of life with a 32.2% reduction and a 23.4% reduction in the first 2 years, but only a 9.1% reduction in children >2 years of age. Asians, blacks and Hispanics were at higher risk of pneumonia than were whites, but there was no evidence of ethnic variation in PCV effectiveness. Ten of the 11 cases of pneumococcal pneumonia with a positive blood culture were in the control group. CONCLUSION: The pneumococcal conjugate vaccine tested was effective in reducing the risk of pneumonia in young children.
Authors: Black SB; Shinefield HR; Ling S; Hansen J; Fireman B; Spring D; Noyes J; Lewis E; Ray P; Lee J; Hackell J
Pediatr Infect Dis J. 2002 Sep;21(9):810-5.
Lack of association between receipt of conjugate haemophilus influenzae type B vaccine (HbOC) in infancy and risk of type 1 (juvenile onset) diabetes: long term follow-up of the HbOC efficacy trial cohort
We evaluated the effect of infant vaccination with HbOC Haemophilus influenzae type b (Hib) conjugate vaccine on the risk of onset of type 1 juvenile diabetes later in life by examining data from a large controlled prospective Phase III clinical efficacy trial conducted within Northern California Kaiser Permanente between 1988 and 1990. The overall study population included children who were offered the Hib conjugate vaccine (acceptors and refusers) as well as a cohort of children who were systemically excluded from the trial on the basis of their birth date. These children are now 10 to 12 years of age. We found no evidence that vaccination with Hib conjugate vaccine in infancy is associated with risk of diabetes later in life.
Authors: Black SB; Lewis E; Shinefield HR; Fireman B; Ray P; DeStefano F; Chen R
Pediatr Infect Dis J. 2002 Jun;21(6):568-9.
Observed costs and health care use of children in a randomized controlled trial of pneumococcal conjugate vaccine
BACKGROUND: Pneumococcal conjugate vaccine for infants has recently been found to be effective for prevention of meningitis, bacteremia, pneumonia and otitis media, but it is more costly than previously introduced vaccines. AIM: We sought to determine the savings in medical costs through 36 months of life attributable to the use of the vaccine in healthy infants in a large randomized trial. METHODS: We analyzed the actual medical costs of 36 471 children involved in a randomized trial of heptavalent pneumococcal conjugate vaccine conducted in the Northern California Kaiser Permanente Medical Care Program. The costs of the vaccine and vaccine administration were excluded. RESULTS: Compared with the control group, the vaccinated group experienced a 2% reduction in clinic related costs [$48; 95% confidence interval (CI), $10 to $83] and a nearly significant 14% reduction in outpatient hospitalization costs ($32; CI -$1 to $66). The savings in total medical costs were 1.2%, but this difference was not significant ($41; CI -$204 to $270). Inpatient hospital costs were highly variable and were responsible for the lack of precision in the difference in total cost. In a post hoc analysis that excluded hospital costs not believed to be potentially pneumococcal related, savings in medical costs were $78 and significant (CI $5 to $158). CONCLUSIONS: The pneumococcal conjugate vaccine reduced ambulatory care costs in children in the first 36 months of life, but without a larger trial, the magnitude of the savings in total medical costs is uncertain. These results indicate, however, that any medical cost savings that are associated with the vaccine are unlikely to be high enough to offset the cost of the vaccine at its current price.
Authors: Ray GT; Butler JC; Black SB; Shinefield HR; Fireman BH; Lieu TA
Pediatr Infect Dis J. 2002 May;21(5):361-5.
Efficacy, immunogenicity and safety of heptavalent pneumococcal conjugate vaccine in low birth weight and preterm infants
OBJECTIVE: To determine the efficacy, immunogenicity and safety of the heptavalent CRM197 pneumococcal conjugate vaccine (PCV) in low birth weight (LBW) and preterm (PT) infants against invasive pneumococcal disease caused by vaccine types. METHODS: In a randomized double blind trial of 37,868 infants given either PCV or meningococcal type C conjugate vaccine (MCV), 1756 infants <750 g <2500 g (LBW) and 4340 infants from 32 to <38 weeks old (PT) were identified. Risk of invasive pneumococcal disease in LBW and PT infants was compared with risk in normal birth weight (NBW) and full term (FT) infants. Local and systemic events observed within 48 h of recent vaccine were assessed by telephone interviews and similar comparisons made. Premature infant Emergency Department visits and hospitalization were also identified and compared with FT and NBW infants. RESULTS: Initiation of immunization and intervals between doses were similar for all groups. The risk ratio for invasive pneumococcal diseases for LBW infants compared with NBW infants was 2.6 (P = 0.03), and for PT compared with FT infants the risk ratio was 1.6 (P = 0.06). Vaccine efficacy for both groups was 100%. PCV was as immunogenic in LBW and PT as in NBW and FT infants. Fever and local events after PCV vaccination were similar when adjusted for clustering among multiple doses per child. When stratified for individual doses there was more redness and swelling for LBW infants and more swelling for PT infants after Dose 3. Isolated local and systemic reactions were more commonly seen with PCV than with MCV, a pattern similar to that in NBW and FT infants. Hospitalization rates were similar for PCV and MCV recipients. CONCLUSION: These data support the use of PCV in LBW infants and PT infants.
Authors: Shinefield H; Black S; Ray P; Fireman B; Schwalbe J; Lewis E
Pediatr Infect Dis J. 2002 Mar;21(3):182-6.
Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis
BACKGROUND: In patients with decreased resistance to infection, Staphylococcus aureus is a major cause of bacteremia and its complications. The capsular polysaccharides are essential for the pathogenesis of and immunity to S. aureus infection and are targets for vaccines. METHODS: In a double-blind trial involving patients with end-stage renal disease who were receiving hemodialysis, we evaluated the safety, immunogenicity, and efficacy of a vaccine with S. aureus type 5 and 8 capsular polysaccharides conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A. Between April 1998 and August 1999, 1804 adult patients at 73 hemodialysis centers were randomly assigned to receive a single intramuscular injection of either vaccine or saline. IgG antibodies to S. aureus type 5 and 8 capsular polysaccharides were measured for up to two years, and episodes of S. aureus bacteremia were recorded. Efficacy was estimated by comparing the incidence of S. aureus bacteremia in the patients who received the vaccine with the incidence in the control patients. RESULTS: Reactions to the vaccine were generally mild to moderate, and most resolved within two days. The capsular polysaccharides elicited an antibody response of at least 80 microg per milliliter (the estimated minimal level conferring protection) in 80 percent of patients for type 5 and in 75 percent of patients for type 8. The efficacy during weeks 3 to 54 was only 26 percent (P=0.23). However, between weeks 3 and 40 after vaccination, S. aureus bacteremia developed in 11 of 892 patients in the vaccine group who could be evaluated for bacteremia, as compared with 26 of 906 patients in the control group (estimate of efficacy, 57 percent; 95 percent confidence interval, 10 to 81 percent; nominal P=0.02). CONCLUSIONS: In patients receiving hemodialysis, a conjugate vaccine can confer partial immunity against S. aureus bacteremia for approximately 40 weeks, after which protection wanes as antibody levels decrease.
Authors: Shinefield H; Fireman B; Naso R; et al.
N Engl J Med. 2002 Feb 14;346(7):491-6.
Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers
OBJECTIVES: The objectives of this study were (1) to determine the safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate (PNCRM7) vaccine in infants and (2) to determine the effect of concurrent hepatitis B immunization during the primary series and the effect of concurrent diphtheria and tetanus toxoid and acellular pertussis [DTaP (ACEL-IMUNE)] and conjugate CRM197 Haemophilus influenzae type b [HbOC (HibTITER) immunization at time of the booster dose on the safety and immunogenicity of PNCRM7and these other concurrently administered vaccines. METHODS: This was a randomized double-blinded study in 302 healthy infants in the Northern California Kaiser Permanente (NCKP) Health Plan. Infants received either PNCRM7 vaccine or meningococcal group C conjugate vaccine as a control at 2, 4 and 6 months of age and a booster at 12 to 15 months of age. Study design permitted the evaluation of immunology and safety of concurrent administration of routine vaccines. Antibody titers were determined on blood samples drawn before and 1 month after the primary series and the booster dose. RESULTS: After the third dose of PNCRM7 geometric mean concentrations (GMCs) ranged from 1.01 for serotype 9V to 3.72 microg/ml for serotype 14. More than 90% of all subjects had a post-third dose titer of > or =0.15 microg/ml for all serotypes, and the percentage of infants with a post-third dose titer of > or =1.0 microg/ml ranged from 51% for type 9V to 89% for type 14. After the PNCRM7 booster dose, the GMCs of all seven serotypes increased significantly over both post-Dose 3 and pre-Dose 4 antibody levels. In the primary series there were no significant differences in GMCs of pneumococcal antibodies between the subjects given PN-CRM7 alone or concurrently with hepatitis B vaccine. At the toddler dose concurrent administration of PNCRM7 and DTaP and HbOC resulted in a near conventional threshold for statistical significance of a post-Dose 4 GMC for serotype 23F [alone 6.75 mirog/ml vs. concurrent 4.11 microg/ml (P = 0.057)] as well as significantly lower antibody GMCs for H. influenza polyribosylribitol phosphate, diphtheria toxoid, pertussis toxin and filamentous hemagglutinin. For all antigens there were no differences between study groups in defined antibody titers that are considered protective. CONCLUSION: We conclude that PNCRM7 vaccine was safe and immunogenic. When this vaccine was administered concurrently at the booster dose with DTaP and HbOC vaccines, lower antibody titers were noted for some of the antigens when compared with the antibody response when PNCRM7 was given separately. Because the GMCs of the booster responses were all generally high and all subjects achieved similar percentages above predefined antibody titers, these differences are probably not clinically significant.
Authors: Shinefield HR; Fireman B; Hansen J; et al.
Pediatr Infect Dis J. 1999 Sep;18(9):757-63.
Safety and immunogenicity of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in infancy. The Northern California Kaiser Permanente Vaccine Study Center Pediatrics Group
The safety and immunogenicity of the HbOC conjugate vaccine have been evaluated in a study population of 61,080 children in the Kaiser Permanente Medical Care Program of Northern California. Half of the population served as controls. The vaccine was given as part of a three-dose regimen in the first year of life with the first dose given between 6 weeks and 6 months of age, a minimum interval of 1 month between doses and with the third dose given by 1 year of age. The vaccine was highly immunogenic with 97% of infants developing 1 microgram/ml or more of anti-polyribosyl phosphate antibody as measured by Farr assay 1 month after completion of the three-dose series and with 71% maintaining this concentration until a booster dose was given at approximately 18 months of age. There were three cases of Haemophilus influenzae type b disease after the first dose of vaccine and two of these children died. However, there was no statistically significant difference between either the incidence of H. influenzae type b disease or the mortality rate in infants after one dose of HbOC vaccine when compared with H. influenzae type b disease incidence and mortality in unvaccinated children of the same age. The rate of sudden infant death syndrome following HbOC vaccine was lower than that observed within the Kaiser Permanente Medical Care Program as a whole or in the three counties in which sudden infant death syndrome surveillance was tabulated. Immediate local and systemic reactions were evaluated by telephone interviews of 6887 infants within 72 hours of vaccine.(ABSTRACT TRUNCATED AT 250 WORDS).
Authors: Black SB; Shinefield HR; Lampert D; Fireman B; Hiatt RA; Polen M; Vittinghoff E
Pediatr Infect Dis J. 1991 Feb;10(2):92-6.
Efficacy in infancy of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in a United States population of 61,080 children. The Northern California Kaiser Permanente Vaccine Study Center Pediatrics Group
The efficacy of the HbOC conjugate Haemophilus influenzae type b vaccine was evaluated in a study population of 61,080 infants in the Northern California Kaiser Permanente Medical Care Program. Between February, 1988, and June, 1990, the HbOC vaccine was given as part of a three-dose series at 2, 4, and 6 months of age to 20,800 infants. The study population included children with a well-care visit at a study center during the first 6 months of life. There were 25 cases of Haemophilus influenzae type b disease in the study population: 22 in unvaccinated children and 3 in children who received only one dose of HbOC vaccine. The efficacy of the full three-dose series was evaluated by several methods: a primary analysis comparing fully vaccinated children with unvaccinated children from 7 to 18 months of age; a stratified exact analysis adjusted for age and seasonality; and a case-control analysis which further adjusted for known risk factors. The efficacy of three doses of vaccine was 100% with the lower bound of the 95% confidence interval for the three analyses at 68, 71, and 64%, respectively. There were no cases of disease resulting from two doses of HbOC vaccine yielding an estimate of 100% efficacy (95% confidence interval, 47 to 100) for two doses of HbOC vaccine. However, for children who had received only one dose of HbOC vaccine, vaccine efficacy was estimated to be 26% and the possibility that one dose of HbOC vaccine had no efficacy could not be excluded.(ABSTRACT TRUNCATED AT 250 WORDS).
Authors: Black SB; Shinefield HR; Fireman B; Hiatt R; Polen M; Vittinghoff E
Pediatr Infect Dis J. 1991 Feb;10(2):97-104.
Efficacy of Haemophilus influenzae type b capsular polysaccharide vaccine
The efficacy of the Haemophilus influenzae type b (Hib) polyribose phosphate vaccine was evaluated in a population of 120,000 children from 23 through 71 months of age in the Kaiser Permanente Medical Care Program (KPMCP) in Northern California over the 2-year period from June 1, 1985, through May 31, 1987. Approximately 37% of the population were vaccinated by the end of the first year and 60% were vaccinated by the end of the second year. There were 35 cases of Hib disease, 4 of whom were vaccine failures. Cases of Hib disease were identified by multiple modality case ascertainment, consisting of: (1) active surveillance in KPMCP microbiology laboratories; (2) active surveillance on KPMCP pediatric wards by a study physician; (3) retrospective review of computer-stored hospital discharge diagnoses; and (4) a review of all hospitalizations outside the health plan. The medical records of cases, matched controls and a random sample of the population were reviewed to obtain information on vaccination and related variables. Efficacy was evaluated using two complementary methods. In a retrospective surveillance approach, efficacy was estimated to be 68% (95% confidence limits of 4, 89%). In a matched case-control analysis, efficacy was estimated to be 69% (95% confidence limits of -13, 91%). Adjustment for day care attendance and parental occupation slightly reduced the efficacy estimate. Other possible confounders including race, parental education and number of siblings were considered. Four cases of Hib disease were observed within 1 week following receipt of vaccine and before the time when immunity could have developed. There are several plausible explanations for the occurrence of these early cases including the possibility of chance alone.(ABSTRACT TRUNCATED AT 250 WORDS).
Authors: Black SB; Shinefield HR; Hiatt RA; Fireman BH; Kaiser Permanente Pediatric Vaccine Study Group
Pediatr Infect Dis J. 1988 Mar;7(3):149-56.
