IgG4 Neutralization and Sustained Total IgG Fc-Effector Functions Following Repeated SARS-CoV-2 Vaccination with mRNA-1273

INTRODUCTION: Detailed characterization of the antibody profile induced by SARS-CoV-2 mRNA vaccines has shown that repeat dosing boosts all immunoglobulin G (IgG) subclasses, with a notable emergence of antigen-specific IgG4 antibodies. While the IgG4 subclass is traditionally associated with limited Fc-effector functions, its role in SARS-CoV-2 mRNA vaccine-induced immunity remains unclear. METHODS: This study tracked IgG subclass dynamics, IgG Fc-mediated functions, and neutralization following immunization with two or three doses of Moderna SARS-CoV-2 mRNA vaccine (mRNA-1273) in healthy adults. RESULTS: We observed robust spike-specific IgG1 and IgG3 responses after the primary series (two doses) and booster dose, with a significant increase in IgG4 responses after repeated dosing. Despite this rise in spike-specific IgG4 antibodies, strong Fc-effector functions were maintained at the overall IgG level, including antibody-dependent cellular phagocytosis, antibody-dependent neutrophil phagocytosis, and antibody-dependent complement deposition, with no antagonism from IgG4 antibodies. Additionally, IgG4 antibodies exhibited enhanced affinity and potent neutralization, complementing IgG1-driven responses. CONCLUSIONS: These findings suggest that elevated IgG4 responses did not antagonize overall Fc-mediated effector mechanisms, indicating that mRNA-1273 induces a multi-subclass antibody response that preserves antiviral functionality. TRIAL REGISTRATION: NCT04470427.