Abstract:  

Repeated mRNA vaccination induces IgG4, a subclass with impaired capacity for viral clearance. While neutralizing antibody titres remain key correlates of protection, the clinical impact of an IgG4 class switch warrants further investigation across age groups and multiple mRNA doses, while taking important functional modulators such as Fc glycosylation into account.

Our findings support a saturable anti-spike IgG4 class-switch in both paediatric (MARVELS) and adult (COMMUNITY) cohorts following three to six mRNA vaccine doses, without major skewing in Fc glycosylation. Importantly, high IgG4 proportions – shaped by prior immune history – were associated with susceptibility to breakthrough infections, supporting continued monitoring.