"Abstract
... 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) response 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 noninflammatory IgG4, which were further boosted by a third mRNA vaccination and/or SARS-CoV-2 variant breakthrough 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 sequencing 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 antibody-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 vaccination regimens using mRNA vaccines, including future booster immunizations against SARS-CoV-2...
Discussion
... Independent of the underlying mechanism, the induction of antiviral IgG4 antibodies is a phenomenon infrequently described and raises important questions about its functional consequences. Neutralizing antibodies preventing the initial binding of the viral particle to its specific cellular receptor are considered to be the most protective measure against SARS-CoV-2 infections. This competitive binding is mediated by the variable antigen-binding site and does not rely on the constant part of the Fc fragment. In the present study, we confirmed previous reports on improved avidity and neutralizing potential of vaccine-induced antibodies after the third vaccination. However, the large number of breakthrough infections caused by the Omicron variant indicates that current vaccination regimens do not confer sterilizing protection."
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