Modeling Indirect Protection from Typhoid Conjugate Vaccines in the TyVAC-Bangladesh Trial

In the TyVAC-Bangladesh cluster-randomized trial, a single dose of typhoid conjugate vaccine (TCV) in children aged 9 months to <16 years old conferred strong total protection against typhoid fever. However, indirect protection among unvaccinated cluster residents, including older age groups ineligible for vaccination, was modest and did not reach statistical significance. This result raises questions about the effectiveness of TCV against transmission of Salmonella Typhi and whether TCV introduction in endemic settings will induce herd effects. We hypothesize that the low indirect protection observed in the TyVAC-Bangladesh study could be explained by some combination of transmission across cluster boundaries (contamination), limited direct vaccine protection against infection, and insufficient population-wide vaccine coverage. To evaluate these hypotheses, we simulated the trial using two transmission dynamic models: a primary model fit exclusively to clinical surveillance data from the Bangladesh study site, and an alternative model simultaneously fit to clinical and serological data. Vaccinating 64% of eligible children (the coverage level achieved in the TyVAC-Bangladesh trial) induced 0% to 67% indirect protection in the primary model, and 0% to 54% indirect protection in the alternative model, depending on the transmissibility of chronic carriers and TCV efficacy against S. Typhi infection. The results of the TyVAC-Bangladesh trial were consistent with a TCV efficacy against infection of 15% to 85% in the primary model, and 60% to 90% in the alternative model. If adults had been vaccinated in the trial at the same coverage level as children, we estimate that indirect protection would have increased from 19% to between 40%-57%. These findings suggest that TCV confers protection against transmission from acute S. Typhi infections, and that the low indirect protection observed in the TyVAC-Bangladesh trial can be explained by transmission from unvaccinated adults.