Preexisting IgG forms immune complexes and links local thermal reactogenicity with immunogenicity in influenza vaccination.

Pre-existing pathogen-specific antibodies shape vaccine outcomes, yet their impact on local reactogenicity and qualitative features of the immune response are not fully defined. In this prospective human cohort receiving seasonal influenza vaccination, high baseline hemagglutinin-specific IgG1 levels were associated with more pronounced local thermal responses at the vaccinated arm and greater vaccine-induced antibody levels. These IgG antibodies formed immune complexes with hemagglutinin, activated complement and enhanced Fc-receptor-dependent monocyte activation and phagocytosis in vitro, connecting pre-existing immunity to innate activation and local reactogenicity. Despite higher antibody levels and early plasmablast responses in subjects with strong thermal reactogenicity after vaccination, we observed lower avidity and hemagglutinin-inhibition capacity, suggesting extrafollicular responses. T cell responses were unaltered. These findings support a model in which pre-existing hemagglutinin-specific IgG may contribute to local thermal reactogenicity and qualitative features of the vaccine response through immune complex-mediated pathways, providing a framework for how prior immunity may shape human vaccine responsiveness.