Expanding cholera serosurveillance to vaccinated populations

Mass oral cholera vaccination campaigns targeted at subnational areas with high incidence are central to global cholera elimination efforts. Serological surveillance offers a complementary approach to address gaps in clinical surveillance in these regions. However, similar immune responses from vaccination and infection can lead to overestimates of incidence of infection. To address this, we analyzed antibody dynamics in infected and vaccinated individuals to refine seroincidence estimation strategies for partially vaccinated populations. We tested 757 longitudinal serum samples from confirmed Vibrio cholerae O1 cases and uninfected contacts in Bangladesh as well as vaccinees from Bangladesh and Haiti, using a multiplex bead assay to measure IgG, IgM, and IgA binding to five cholera-specific antigens. Infection elicited stronger and broader antibody responses than vaccination, with rises in cholera toxin B-subunit (CTB) and toxin-coregulated pilus A (TcpA) antibodies uniquely associated with infection. Previously proposed random forest models frequently misclassified vaccinated individuals as recently infected (over 20% at some time points) during the first four months post-vaccination. To address this, we developed new random forest models incorporating vaccinee data, which kept false positive rates among vaccinated (1%) and unvaccinated (4%) individuals low without a significant loss in sensitivity. Simulated serosurveys demonstrated that unbiased seroincidence estimates could be achieved within 21 days of vaccination campaigns by ascertaining vaccination status of participants or applying updated models. These approaches to overcome biases in serological surveillance enable reliable seroincidence estimation even in areas with recent vaccination campaigns enhancing the utility of serological surveillance as an epidemiologic tool in moderate-to-high cholera incidence settings.