OBJECTIVES: Repeated COVID-19 mRNA vaccinations increase SARS-CoV-2 IgG4 antibodies, indicating extensive IgG class switching following the first booster dose. This shift in IgG subclasses raises concerns due to the limited ability of IgG4 to mediate Fc-dependent effector functions. METHODS: To assess the impact of IgG4 induction on protective immunity, we analyzed longitudinal SARS-CoV-2 IgG subclasses, C1q and FcγR responses, and neutralizing activity in a well-characterized cohort of healthcare workers in Spain. RESULTS: Elevated IgG4 levels and higher ratios of non-cytophilic to cytophilic antibodies after booster vaccination were significantly associated with an increased risk of breakthrough infections (IgG4 HR[10-fold increase]=1.8, 95% CI=1.2-2.7
non-cytophilic to cytophilic ratio HR[10-fold increase]=1.5, 95% CI=1.1-1.9). Moreover, an increased non-cytophilic to cytophilic antibody ratio correlated with reduced functionality, including neutralization. CONCLUSIONS: These findings suggest a potential association between IgG4 induction by mRNA vaccination and a higher risk of breakthrough infection, warranting further investigation into vaccination strategies to ensure sustained protection.