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Here, we report that several months after the second vaccination, SARS-CoV-2\u2013specific 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.<\/jats:p>","DOI":"10.1126\/sciimmunol.ade2798","type":"journal-article","created":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T13:58:09Z","timestamp":1671717489000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":264,"title":["Class switch toward noninflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination"],"prefix":"10.1126","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2829-6096","authenticated-orcid":true,"given":"Pascal","family":"Irrgang","sequence":"first","affiliation":[{"name":"Institut f\u00fcr klinische und molekulare Virologie, Universit\u00e4tsklinikum Erlangen und Friedrich-Alexander-Universit\u00e4t (FAU) 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Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9833-5313","authenticated-orcid":true,"given":"Dennis","family":"Lapuente","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr klinische und molekulare Virologie, Universit\u00e4tsklinikum Erlangen und Friedrich-Alexander-Universit\u00e4t (FAU) Erlangen-N\u00fcrnberg, Schlossgarten 4, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Steininger","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr klinische und molekulare Virologie, Universit\u00e4tsklinikum Erlangen und Friedrich-Alexander-Universit\u00e4t (FAU) Erlangen-N\u00fcrnberg, Schlossgarten 4, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Habenicht","sequence":"additional","affiliation":[{"name":"Department of Biology, Division of Genetics, Nikolaus-Fiebiger-Center for 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