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

Pascal Irrgang, Juliane Gerling, Katharina Kocher, Dennis Lapuente, Philipp Steininger, Katharina Habenicht, Monika Wytopil, Stephanie Beileke, Simon Schäfer, Jahn Zhong, George Ssebyatika, Thomas Krey, Valeria Falcone, Christine Schülein, Antonia Sophia Peter, Krystelle Nganou-Makamdop, Hartmut Hengel, Jürgen Held, Christian Bogdan, Klaus ÜberlaKilian Schober*, Thomas H. Winkler*, Matthias Tenbusch*

*Corresponding author for this work
43 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbereade2798
JournalScience Immunology
Volume8
Issue number79
DOIs
Publication statusPublished - 01.2023

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)
  • Centers: Center for Structural and Cell Biology (CSCM/ZMSZ)

DFG Research Classification Scheme

  • 204-04 Virology
  • 204-05 Immunology
  • 201-04 Structural Biology

Coronavirus related work

  • Research on SARS-CoV-2 / COVID-19

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