Estimating the seroincidence of scrub typhus using antibody dynamics following infection

Introduction Scrub typhus is an acute febrile illness caused by the bacterium Orientia tsutsugamushi . Characterizing the population-level burden of scrub typhus is challenging due to the lack of accessible and accurate diagnostics. We describe a new approach using information about seroresponse after infection to generate population-level scrub typhus seroincidence estimates. Methods We use data from two clinical studies of scrub typhus patients enrolled in Chiang Rai, Thailand, and Vellore, India, and representative population data from two serosurveys in and around the Kathmandu valley, Nepal, and Vellore, India. The samples were tested for IgM and IgG responses to Orientia tsutsugamushi -derived recombinant 56-kDa antigen using commercial ELISA kits. We used Bayesian hierarchical models to fit two-phase models to the antibody responses from scrub typhus cases and used the joint distributions of the peak antibody titers and decay rates to estimate population-level incidence rates in the cross-sectional serosurveys. We compared this new method to a traditional cut-off-based approach for estimating seroincidence. Results Among 18 to 29-year-olds, the seroincidence of scrub typhus was 886 (95% CI 432-1817) per 100,000 person-years in India and 945 (95% CI: 616-1449) per 100,000 in Nepal. Seroincidence rose with age, reaching a rate of 3231 (95% CI: 2630-3969) per 100,000 among 50 to 89-year-olds in Vellore, India. The seroincidence rates estimated using a cutoff were half the rates we estimated using antibody dynamics. Conclusion The approach described here can be deployed prospectively, coupled with existing serosurveys, or leverage banked samples to rapidly characterize scrub typhus burden and generate scrub typhus seroincidence estimates that are comparable across populations, regions, and time. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Fogarty International Center at National Institutes of Health [K01 TW012177-01A1] ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Boards in India (Christian Medical College, Vellore), Thailand (Chiang Rai Hospital, the Faculty of Tropical Medicine, Mahidol University, and the Thai Ministry of Public Health), The United States (Stanford University Institutional Review Board), and Nepal (Nepal Health Research Council Ethical Review Board)) approved the study forms and protocols. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Not Applicable Before publication we will make all de-identified data available via Open Science Framework.