Accounting for local incidence when estimating rotavirus vaccine efficacy among countries: a pooled analysis of monovalent rotavirus vaccine trials

Abstract

Rotavirus vaccine appears to perform suboptimally in countries with higher rotavirus burden. We hypothesized that differences in the magnitude of rotavirus exposures may bias vaccine efficacy (VE) estimates, so true differences in country-specific rotavirus VE would be exaggerated without accommodating differences in exposure. We estimated VE against any-severity and severe rotavirus gastroenteritis (RVGE) using Poisson regression models fit to pooled individual-level data from phase II and III monovalent rotavirus vaccine trials conducted between 2000 and 2012. The standard approach model included terms for vaccination, country, and a vaccination-country interaction. Other models used proxies for exposure magnitude like severe RVGE rate or age at severe RVGE instead of country. Country-specific proxies were calculated from placebo group data or extracted from an external meta-analysis. Analyses included 83 592 infants from 23 countries in the Americas, Europe, Africa, and Asia. Using the standard approach, VE against severe RVGE substantially varied (10%-100%). Using the severe RVGE rate proxy brought VE from all but 2 countries between 80% and 86%. Heterogeneity for VE against any-severity RVGE was similarly attenuated. Adjusting for exposure proxies reduced heterogeneity in country-specific rotavirus VE estimates. This phenomenon may extend to other vaccines against partially immunizing pathogens with global disparities in burden.

Keywords: bias; clinical trials; force of infection; infectious exposures; rotavirus; vaccine efficacy.