Clinical trials: The mathematics of falling vaccine efficacy with rising disease incidence

Reports of unexplained discrepancies in the efficacy of vaccines, s estimated from randomised controlled trials in different parts of he world, are commonplace in the literature [1–4]. Moreover, there s a consistent trend for lower vaccine efficacy when measured in ettings where the disease of interest has a higher incidence, leadng to questions about the appropriateness of pooled estimates. ere, we examine the mathematical basis for such trends and proose a measure of efficacy that is valid across settings. The approach elies on fitting mechanistic models, which specify pathogen expoures and host responses, to global vaccine trial data stratified by ocal disease incidence. Such models enable the estimation of vacine protection per exposure to the pathogen. A strategy to estimate er-exposure vaccine efficacy will enable more accurate estimates f vaccine efficacy across a range of disease incidence [5].