S1 Graphical abstract -

The urgency to develop vaccines during the COVID-19 pandemic has resulted in the acceleration of clinical trials. Specifically, a broad spectrum of efficacy levels has been reported for various vaccines based on phase III cohort studies. Our study demonstrates that conducting large cohort phase III clinical trials during the peak of an epidemic leads to a significant underestimation of vaccine efficacy, even in the absence of confounding factors. Furthermore, we find that this underestimation increases with the proportion of infectious individuals in the population during the experiment and the severity of the epidemic, as measured by its basic reproduction number.