The appearance of anti-spike receptor binding domain immunoglobulin G4 responses after repetitive immunization with messenger RNA-based COVID-19 vaccines.

OBJECTIVES:It is crucial to analyze the consequences of repeated messenger RNA (mRNA)-based COVID-19 vaccinations on SARS-CoV-2 spike receptor binding domain (RBD)-specific immunoglobulin (Ig)G subclass and the possible causal relationship with breakthrough infection. METHODS:We examined the longitudinal kinetics of RBD-specific IgG subclass antibodies in sera after receiving the second, third, and fourth doses of mRNA-based COVID-19 vaccines in Japanese healthcare workers. Anti-RBD IgG subclass in sera of patients with COVID-19-infected who had not received the COVID-19 vaccine were also examined. We compared anti-RBD IgG subclass antibody titers in the serum of pre-breakthrough-infected vaccinees and non-infected vaccinees. RESULTS:The seropositivity of anti-RBD IgG4 after the vaccination was 6.76% at 1 month after the second dose, gradually increased to 50.5% at 6 months after the second dose, and reached 97.2% at 1 month after the third dose. The seropositivity and titers of anti-RBD IgG1/IgG3 quickly reached the maximum at 1 month after the second dose and declined afterward. The elevated anti-RBD IgG4 Ab levels observed after repeated vaccinations were unlikely to increase the risk of breakthrough infection. CONCLUSIONS:Repeated vaccinations induce delayed but drastic increases in anti-RBD IgG4 responses. Further functional investigations are needed to reveal the magnitude of the high contribution of spike-specific IgG4 subclasses after repeated mRNA-based COVID-19 vaccinations.