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

Reports of unexplained discrepancies in the efficacy of vaccines, as estimated from randomised controlled trials in different parts of the world, are commonplace in the literature [1], [2], [3], [4]. Moreover, there is a consistent trend for lower vaccine efficacy when measured in settings where the disease of interest has a higher incidence, leading to questions about the appropriateness of pooled estimates. Here, we examine the mathematical basis for such trends and propose a measure of efficacy that is valid across settings. The approach relies on fitting mechanistic models, which specify pathogen exposures and host responses, to global vaccine trial data stratified by local disease incidence. Such models enable the estimation of vaccine protection per exposure to the pathogen. A strategy to estimate per-exposure vaccine efficacy will enable more accurate estimates of vaccine efficacy across a range of disease incidence [5].