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.