Impact of Vaccine-Elicited Anti-Spike IgG4 Antibodies on Fc-Effector Functions Against SARS-CoV-2

mRNA vaccines have demonstrated considerable efficacy and safety against SARS-CoV-2, limiting the pandemic burden worldwide. The emergence of new variants of concern and the decline in neutralizing activity observed several weeks post-vaccination reinforced the call for repeated mRNA vaccination. We and others have shown that vaccine efficacy does not exclusively rely on antibody neutralizing activites; Fc-effector functions play an important role as well. However, it is well known that long-term exposure and repeated antigen stimulation elicit the IgG4 subclass of antibodies, which are inefficient at mediating Fc-effector functions. In this regard, recent studies highlighted concerns about IgG4 induction by mRNA vaccines. Here, we explored the impact of repeated mRNA vaccination on IgG4 induction and its impact on Fc-effector functions. We observed anti-Spike IgG4 elicitation after three doses of mRNA vaccine; the antibody levels further increased with additional doses. Vaccine-elicited IgG4 preferentially bound the ancestral D614G Spike. We also observed that Breakthrough Infection (BTI) after several doses of vaccine strongly increased IgG1 levels but had no impact on IgG4 levels, thereby improving Fc-effector functions. Finally, we observed that elderly donors vaccinated with Moderna mRNA vaccines elicited higher IgG4 levels and presented lower Fc-effector functions than donors vaccinated with the Pfizer mRNA vaccine. Altogether, our results highlight the importance of monitoring the IgG subclasses elicited by vaccination.