Immunity against conserved and non-conserved Spike epitopes after COVID-19 booster vaccination provides long-term protection against symptomatic Omicron infections

The objective of this study was to investigate the features of immune protection against SARS-CoV-2 infection in a single cohort during the 6–17 months following booster immunization with an mRNA-based vaccine. The results illustrate the influence of humoral and cellular immunity on the efficacy of the vaccine. Notably, neutralizing antibody titers were found to serve as a reasonably reliable correlate of protection prior to booster immunization. However, this predictive power was largely lost after boosting. The loss appears to be due to the critical remodeling of the humoral immune response following booster immunization. Our findings support the hypothesis that immunity to both conserved and non-conserved epitopes of the viral Spike protein's receptor-binding domain (RBD) is crucial for optimal long-term protection against Omicron infection. While immunity to conserved epitopes may provide cross-variant protection, antibodies targeting non-conserved RBD epitopes play a pivotal role in achieving maximum protection. These observations highlight the critical role of repeated immunization in shaping the immune response landscape and reinforce the necessity of considering both humoral and cellular immune components, alongside intended use considerations, when assessing vaccine efficacy and developing future immunization strategies.