Natural Boosting and the Immunogenicity of the XBB.1.5 Monovalent Vaccine in the Coronavirus Disease 2019 Endemic Era: A Longitudinal Observational Study

Background With the transition from the coronavirus disease 2019 (COVID-19) pandemic into endemicity, changes in group immunity and the effect of updated XBB.1.5 monovalent vaccine (MonoV) need to be investigated. Methods A multicenter vaccine cohort was followed for 3 years, and the investigation period was classified into the pre-Omicron, Omicron, and endemic eras. Thirteen sampling points were assessed, including pre- and post-MonoV administration. Specimens were classified as vaccinated, molecularly or serologically diagnosed breakthrough infection (BI), natural boosting (NB), or waned. Results A total of 327 healthcare workers contributed 2645 blood samples from March 2021 to December 2023. The log10 anti-spike protein antibody (SAb) levels, elevated by vaccination, declined linearly in the pre-Omicron era, were maintained during the Omicron era due to BIs, and increased in the endemic era (slope = 0.02, P = .02) without additional vaccination. NB cases increased significantly across the epidemiologic eras. The incidence rate ratios were 2.72 (P < .001) for Omicron/pre-Omicron and 3.39 (P < .001) for endemic/Omicron. Plaque reduction neutralization test (PRNT) titers against circulating strains (XBB.1.5 and XBB.1.9.1) in the NB group maintained previous levels, but ratios to wild-type PRNT and fold changes exhibited significantly enhanced activity. The XBB.1.5 MonoV increased PRNT by 5.8-fold against XBB.1.5 and 6.6-fold against JN.1, showing stronger enhancement against subsequent epidemic strains than the bivalent vaccine. Conclusions Group immunity in the COVID-19 endemic era exhibited maintained SAb levels and adjusted neutralizing activities through BI and NB. The XBB.1.5 MonoV significantly enhanced neutralizing activity against the vaccine strain and robust immunity against the subsequent epidemic JN.1 strain.