Analyzing Vaccine Trials in Epidemics with Mild and Asymptomatic Infection

Abstract

ABSTRACTVaccine efficacy against susceptibility to infection (VES), regardless of symptoms, is an important endpoint of vaccine trials for pathogens with a high proportion of asymptomatic infection, as such infections may contribute to onward transmission and outcomes such as Congenital Zika Syndrome. However, estimating VESis resource-intensive. We aim to identify methods to accurately estimate VEswhen limited information is available and resources are constrained. We model an individually randomized vaccine trial by generating a network of individuals and simulating an epidemic. The disease natural history follows a Susceptible, Exposed, Infectious and Symptomatic or Infectious and Asymptomatic, Recovered model. We then use seven approaches to estimate VES, and we also estimate vaccine efficacy against progression to symptoms (VEP). A corrected relative risk and an interval censored Cox model accurately estimate VESand only require serologic testing of participants once, while a Cox model using only symptomatic infections returns biased estimates. Only acquiring serological endpoints in a 10% sample and imputing the remaining infection statuses yields unbiased VESestimates across values of R0and accurate estimates of VEPfor higher values. Identifying resource-preserving methods for accurately estimating VESis important in designing trials for diseases with a high proportion of asymptomatic infection.