Estimating the Optimal COVID-19 Booster Timing Using Surrogate Correlates of Protection: A Longitudinal Antibody Study in Naïve and Previously Infected Individuals

Standardized, one-size-fits-all COVID-19 booster schedules may be suboptimal due to individual variation in immune backgrounds, particularly prior infection, which induces robust hybrid immunity. This study estimated optimal booster timing by modeling antibody decay in relation to surrogate correlates of protection (CoP). In a prospective cohort of 177 Japanese healthcare workers, we longitudinally monitored anti-spike receptor-binding domain (S-RBD) antibody titers following BNT162b2 vaccination. Participants were stratified into SARS-CoV-2-naïve and previously infected groups. Mixed-effects models were developed to predict when antibody titers would decline below predefined CoP thresholds. The model estimated optimal booster timing after a two-dose primary series to be 3-5 months for naïve individuals and approximately one year for those with prior infection. Following a third dose, the estimated interval extended to 8-12 months for the naïve group and 1.5-2 years for the previously infected group. These substantial differences underscore the limitations of uniform booster schedules. Our findings provide a quantitative framework for personalized vaccination strategies based on individual antibody profiles and immune status, thereby optimizing protection.