Anti-Spike IgG4 and Fc Effector Responses: The Impact of SARS-CoV-2 Vaccine Platform–Specific Priming and Immune Imprinting

Proportional increases in anti-Spike (S) IgG4 associated with decreased Fc effector functions have been reported following repeated mRNA, but not recombinant protein-based (rS) (NVX-CoV2373, Novavax), SARS-CoV-2 vaccination. We demonstrate the first evidence of a negative correlation between anti-S IgG4 and neutralizing antibody (nAb) as well as antibody-dependent Fc effector functions. Priming with two NVX-CoV2373 vaccines followed by a third dose was associated with higher IgG1 and IgG3, lower IgG4, higher nAb titers and Fc effector functions versus mRNA. Immune imprinting of anti-S IgG4 and nAbs, and Fc effector function imprinting after mRNA priming was observed. This effect was partially overcome by updated XBB.1.5 protein subunit vaccination, but not ancestral vaccine strains. We establish correlation of anti-S IgG4 responses to reduced nAbs and Fc effector functions and demonstrate the impact of additional booster vaccination on subsequent immune response and Fc effector functions in the context of ancestral and XBB.1.5 strains.