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

Pascal IrrgangJuliane GerlingKatharina KocherDennis LapuentePhilipp SteiningerKatharina HabenichtMonika WytopilStephanie BeilekeSimon SchäferJahn ZhongGeorge Liam SsebyatikaThomas KreyValeria FalconeChristine SchüleinAntonia Sophia PeterKrystelle Nganou-MakamdopHartmut HengelJürgen HeldChristian BogdanKlaus ÜberlaKilian SchoberThomas H WinklerMatthias Tenbusch
Published in: Science immunology (2023)
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) 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.
Keyphrases
  • sars cov
  • respiratory syndrome coronavirus
  • single cell
  • coronavirus disease
  • binding protein
  • flow cytometry
  • dna damage
  • oxidative stress
  • regulatory t cells
  • zika virus
  • immune response
  • current status
  • stress induced