Analyzing Vaccine Trials in Epidemics With Mild and Asymptomatic Infection

Am J Epidemiol. 2019 Feb 1;188(2):467-474. doi: 10.1093/aje/kwy239.


Vaccine 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, because such infections may contribute to onward transmission and long-term sequelae, such as congenital Zika syndrome. However, estimating VES is resource-intensive. We aimed to identify approaches for accurately estimating VES when limited information is available and resources are constrained. We modeled an individually randomized vaccine trial by generating a network of individuals and simulating an epidemic. The disease natural history followed a "susceptible-exposed-infectious/symptomatic (or infectious/asymptomatic)-recovered" model. We then used 7 approaches to estimate VES, and we also estimated vaccine efficacy against progression to symptoms (VEP). A corrected relative risk and an interval-censored Cox model accurately estimate VES and only require serological 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 VES estimates across values of the basic reproduction number (R0) and accurate estimates of VEP for higher R0 values. Identifying resource-preserving methods for accurately estimating VES and VEP is important in designing trials for diseases with a high proportion of asymptomatic infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Asymptomatic Infections / epidemiology*
  • Basic Reproduction Number
  • Data Interpretation, Statistical
  • Epidemics
  • Humans
  • Proportional Hazards Models
  • Randomized Controlled Trials as Topic / methods*
  • Randomized Controlled Trials as Topic / standards
  • Research Design*
  • Risk
  • Seroepidemiologic Studies
  • Vaccines / immunology*
  • Virus Diseases / epidemiology*
  • Virus Diseases / prevention & control*
  • Zika Virus Infection / epidemiology
  • Zika Virus Infection / prevention & control


  • Vaccines