Class switch toward noninflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination

RNA vaccines are efficient preventive measures to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. High levels of neutralizing SARS-CoV-2 antibodies are an important component of vaccine-induced immunity. Shortly after the initial two mRNA vaccine doses, the immunoglobulin G (IgG) re-sponse mainly consists of the proinflammatory subclasses IgG1 and IgG3. Here, we report that several months after the second vaccination, SARS-CoV-2-specific antibodies were increasingly composed of nonin-flammatory IgG4, which were further boosted by a third mRNA vaccination and/or SARS-CoV-2 variant break-through infections. IgG4 antibodies among all spike-specific IgG antibodies rose, on average, from 0.04% shortly after the second vaccination to 19.27% late after the third vaccination. This induction of IgG4 antibodies was not observed after homologous or heterologous SARS-CoV-2 vaccination with adenoviral vectors. Single-cell se-quencing and flow cytometry revealed substantial frequencies of IgG4-switched B cells within the spike -binding memory B cell population [median of 14.4%; interquartile range (IQR) of 6.7 to 18.1%] compared with the overall memory B cell repertoire (median of 1.3%; IQR of 0.9 to 2.2%) after three immunizations. This class switch was associated with a reduced capacity of the spike-specific antibodies to mediate anti-body-dependent cellular phagocytosis and complement deposition. Because Fc-mediated effector functions are critical for antiviral immunity, these findings may have consequences for the choice and timing of vaccina-tion regimens using mRNA vaccines, including future booster immunizations against SARS-CoV-2.

Automated summary

RNA vaccines are effective in preventing SARS-CoV-2 infection, and high levels of neutralizing antibodies are crucial for vaccine-induced immunity. After the second mRNA vaccination, SARS-CoV-2-specific antibodies were increasingly composed of noninflammatory IgG4, which was further boosted by a third vaccination or breakthrough infections. This induction of IgG4 antibodies was not observed with adenoviral vectors. These findings have implications for the choice and timing of mRNA vaccine regimens, including booster shots.