Seroresponse to repeated infections with Salmonella enterica Typhi and Paratyphi A.

Enteric fever, a systematic bacterial infection caused by Salmonella Typhi and Paratyphi, continues to impose a significant public health burden in low and middle-income countries, yet our understanding of the serum antibody dynamics following infection remains incomplete. Although previous work has characterized the longitudinal seroresponses following acute typhoid infection, gaps persist in deciphering how repeated exposures influence antibody decay and protection. In our longitudinal cohort study of blood culture-confirmed enteric fever cases enrolled in Bangladesh, Nepal, and Pakistan, we identified several instances of suspected re-infection defined by an initial decline followed by a subsequent rise in antibody levels. The presence of re-infection events interferes with the estimation of antibody decay dynamics and influences the interpretation of seroepidemiological data at the population level. To study the seroresponses to subsequent infections we employed a synthetic within-host model that accounts for elevated baseline antibody levels at time of infection. Compared to the first seroresponse, second or later responses appear to have similar decay rates. As peak levels depend on the time between infections, a new model-derived metric is proposed that does not depend on time since the most recent infection: the minimum baseline antibody level at infection resulting in a small jump (protective) seroconversion. After infection the time to reach the minimum baseline level increases about tenfold. Finally, we show how ignoring variation in subsequent seroresponses into seroincidence estimates leads to bias in population-level infection rates. These findings underscore the importance of accounting for re-infection in seroepidemiological studies and provide refined metrics for interpreting antibody responses, with critical implications for assessing disease burden and guiding public health strategies in endemic regions.