Vaccination-first immune priming shapes a sustained mRNA vaccine-induced IgG4 class switch that associates with SARS-CoV-2 breakthrough infection risk.

Repeated administration of mRNA vaccines against SARS-CoV-2 has been associated with qualitative changes in antibody responses, including the emergence of non-inflammatory IgG4 subclasses and changes in Fc glycosylation. While neutralizing antibody titers remain key correlates of protection, potential functional implications of these structural antibody features warrant further investigation across age groups and multiple mRNA vaccine boosters. We characterized spike-specific IgG responses-including subclasses and Fc glycosylation patterns-using a liquid chromatography-mass spectrometry-based approach across six mRNA vaccine doses in a Swedish healthcare worker cohort (n = 104) and across three mRNA doses in a Singaporean pediatric cohort (n = 18). Repeated mRNA vaccination induced an IgG4 class switch which was sustained across at least six doses. This response associated with an increased risk of breakthrough infection (HR = 1.83, p = 0.028) in infection-naïve individuals (n = 41) lacking mucosal IgA responses that would potentially confound the interpretation of systemic IgG4‑related infection outcomes. Moreover, the IgG4 class switch was preceded with high early IgG1 Fc fucosylation signatures. Notably, these IgG structural changes were observed primarily in individuals who were naïve to SARS-CoV-2 at the time of first vaccination. Similar IgG structural features were observed across three mRNA doses in the small infection-naive pediatric cohort. Our results illustrate an IgG4-dominated immunological signature in both adults and children and highlight that immune priming by prior infection may shape subsequent mRNA vaccine-induced antibody responses. While these findings do not call into question the efficacy or safety of the widely adapted mRNA vaccine platform, they may have implications that merit further investigation.