Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination

Irrgang P, Gerling J, Kocher K, Lapuente D, Steininger P, Habenicht KM, Wytopil M, Beileke S, Schäfer S, Zhong J, Ssebyatika G, Krey T, Falcone V, Schülein C, Peter AS, Nganou-Makamdop K, Hengel H, Held J, Bogdan C, Überla K, Schober K, Winkler T, Tenbusch M (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Science immunology American Association for the Advancement of Science

DOI: 10.1126/sciimmunol.ade2798

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.

Authors with CRIS profile

Katharina Kocher Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Dennis Lapuente Institute of Clinical and Molecular Virology Philipp Steininger Institute of Clinical and Molecular Virology Katharina Marie Habenicht Professur für Genetik Monika Wytopil Institute of Clinical and Molecular Virology Stephanie Beileke Professur für Oberflächenaktive Proteine Simon Schäfer Lehrstuhl für Genetik Jahn Zhong Lehrstuhl für Genetik Antonia Sophia Peter Professur für Genetik Christiane Krystelle Nganou Makamdop Institute of Clinical and Molecular Virology Jürgen Held Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Christian Bogdan Lehrstuhl für Mikrobiologie und Infektionsimmunologie Klaus Überla Lehrstuhl für Klinische und Molekulare Virologie Kilian Schober Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Thomas Winkler Professur für Genetik Matthias Tenbusch Professur für Genbasierte Immunisierungsverfahren

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung (IZKF)

Related research project(s)

A090: the fate of lung-resident memory T-cells Jan. 1, 2020 - Dec. 31, 2022

Involved external institutions

Universitätsklinikum Freiburg DE Germany (DE) Universität zu Lübeck DE Germany (DE)

How to cite

APA:

Irrgang, P., Gerling, J., Kocher, K., Lapuente, D., Steininger, P., Habenicht, K.M.,... Tenbusch, M. (2022). Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination. Science immunology. https://doi.org/10.1126/sciimmunol.ade2798

MLA:

Irrgang, Pascal, et al. "Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination." Science immunology (2022).

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