Protective effectiveness of SARS-CoV-2 infection risk among hybrid, vaccine, and infection-induced immunity against the omicron variant, K-SEROSMART

Abstract Background Estimating infection risk from SARS-CoV-2 Omicron and post-Omicron subvariants is challenging due to the high number of unconfirmed infections. We compared breakthrough infection risks among individuals with hybrid, vaccine-only, and infection-only immunity in South Korea, incorporating laboratory-confirmed and serology-inferred infections. Methods Using nationwide surveillance data (August–December 2022), immunity was classified by vaccination history and spike (S) and nucleocapsid (N) antibody profiles. Outcomes were assessed using two definitions: conservative (laboratory-confirmed cases) and inclusive (serology-inferred infections identified by changes in N-antibody titers). Infection dates for unconfirmed events were imputed via predictive mean matching, enabling Kaplan–Meier analyses. Time-varying Cox models estimated log hazard ratios (log-HRs). Results Including serology markedly increased four-month cumulative infection risk estimates: hybrid immunity rose from 2% to 20%, infection-only from 4% to 24%, and vaccine-only from 30% to 40%. With these additional infections, the relative advantage of hybrid immunity narrowed. Under the conservative definition, log-HRs declined for vaccine-only vs hybrid (4.10 to 2.34) and infection-only vs hybrid (1.56 to 0.31). Under the inclusive definition, the vaccine-only log-HR fell from 3.44 to 0.13, and the infection-only log-HR shifted from 3.31 to −0.56, indicating greater protection for infection-only immunity by month four. Conclusions Because confirmed cases largely capture symptomatic disease, vaccination appears to provide added protection against severe outcomes, though this benefit wanes within months. The rapid decline of hybrid immunity and the large burden of unconfirmed infections highlight the need for routine serological surveillance to detect silent transmission and timely booster campaigns to mitigate severe disease during Omicron-driven waves.