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

Detailed characterization of the antibody profile induced by SARS-CoV-2 mRNA vaccines has shown that repeat dosing boosts all 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. This study tracked IgG subclass dynamics, IgG Fc-mediated functions and neutralization following immunization with two or three doses of mRNA-1273. 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 ADCP, ADNP, and ADCD, with no antagonism from IgG4 antibodies. Additionally, IgG4 antibodies exhibited enhanced affinity and potent neutralization, complementing IgG1-driven responses. These findings suggest that the IgG4 response induced by mRNA-1273 vaccination co-evolves with other subclasses to enhance Fab- and Fc-mediated immunity, underscoring the ability of mRNA vaccines to induce a balanced, multi-subclass immune response optimized for durable protection and robust functionality.