Longitudinal changes in the antibody responses and adverse reactions across successive SARS-CoV-2 mRNA vaccinations from the primary series to the JN.1-adapted booster in hospital employees: A 4-year prospective cohort study

BACKGROUND: Longitudinal profiles of immunogenicity and reactogenicity across successive SARS-CoV-2 vaccinations, including the XBB.1.5- and JN.1-adapted boosters, remain incompletely characterized. It also remains unclear whether the previously observed association between post-vaccination fever and antibody responses persists with these newer boosters. METHODS: In this prospective open-cohort study of healthcare workers, participants received a primary series followed by first wild-type (WT) booster, BA.4/5 bivalent booster, and subsequent XBB.1.5 and JN.1 boosters. Serum samples collected pre- and post-vaccination were assayed for anti-receptor binding domain (RBD) IgG. Adverse reactions were recorded using a self-reported diary. RESULTS: A total of 492 participants provided at least one serum sample (2548 samples in total), with data availability varying across vaccination time points and complete follow-up across all time points limited. Peak WT-specific anti-RBD IgG titers plateaued with successive boosters, irrespective of SARS-CoV-2 infection history. However, XBB.1.5 and JN.1 boosters increased target-strain-specific IgG more than WT-specific IgG, resulting in a 1.5-fold increase in the variant-to-WT IgG ratio. This ratio persisted through day 350 after the XBB.1.5 booster. Local reactions showed no significant change, whereas systemic reaction frequencies declined significantly with successive boosters. The proportion of participants with fever ≥38 °C decreased from 26.2% after the first booster to 5.0% after the XBB.1.5 booster and 8.3% after the JN.1 booster, and the overall reaction severity also decreased. In multivariable regression, fever remained positively associated with post-vaccination IgG titers across boosters; for the XBB.1.5 booster, the association was positive but nonsignificant (p = 0.069), likely due to the low fever incidence. CONCLUSIONS: Repeated boosters yielded a plateau in peak WT-specific anti-RBD IgG titers, while variant-adapted boosters elicited stronger responses against their target strains than against WT. Systemic adverse reactions progressively declined, whereas local reactions remained stable across successive boosters. Post-vaccination fever was significantly associated with higher anti-RBD IgG titers across multiple vaccinations.