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 language | English |
|---|---|
| Article number | eade2798 |
| Journal | Science Immunology |
| Volume | 8 |
| Issue number | 79 |
| DOIs | |
| Publication status | Published - 01.2023 |
Funding
Acknowledgments: We thank A. Schneider, N. Donhauser, and K. Fraedrich for excellent technical assistance. Funding: The study was funded by the Bavarian State Ministry for Science and the Arts for the CoVaKo-2021, CoVaKo-Omicron, and For-COVID projects and the German Federal Ministry of Education and Science (BMBF) through the “Netzwerk Universitaetsmedizin,” project “COVIM” (to T.H.W. and H.H.). T.H.W. received funding from the Deutsche Forschungsgemeinschaft (DFG) within the TRR130 (project no. 215346292). Further support was obtained from faculty COVID-19 funds and the German Centre for Infection Research (DZIF). K.S. is supported by the BMBF (project 01KI2013). K.K. is supported by the Deutsche Forschungsgemeinschaft (DFG) through the research training group RTG 2504 (project number 401821119) and the Else Kröner-Fresenius-Stiftung (project 2020_EKEA.127). Further support was received from the Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg (advanced project A90). The funders had no influence on the study design and data interpretation. Author contributions: Conceptualization: P.S., C.B., K.Ü., K.S., T.H.W., and M.T. Methodology: P.I., J.G., K.K., D.L., M.W., S.B., G.S., T.K., V.F., A.S.P., K.N.-M. H.H., and J.H. Investigation: P.I., J.G., K.K., D.L., M.W., S.B., S.S., K.H., J.Z., G.S., V.F., C.S., A.S.P., K.N.-M., J.H., K.S., T.H.W., and M.T. Visualization: J.G., K.K., D.L., K.S., T.H.W., and M.T. Funding acquisition: K.Ü., K.S., T.H.W., and M.T. Project administration: K.S., T.H.W., and M.T. Supervision: P.S., C.B., K.Ü., K.S., T.H.W., and M.T. Writing (original draft): K.S., T.H.W., and M.T. Writing (review and editing): All authors. Competing interests: The authors declare that they have no competing interests. Data and materials availability: The sequencing datasets generated during this study are available at Gene Expression Omnibus (GEO) under the series accession number GSE221320. The B cell scRNA/BCR data are associated with accession number GSE221316, and the CITE-seq data are associated with GSE221319. All other data generated and/or analyzed during the current study are included in the paper or the Supplementary Materials. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/ artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material. The study was funded by the Bavarian State Ministry for Science and the Arts for the CoVaKo-2021, CoVaKo-Omicron, and For-COVID projects and the German Federal Ministry of Education and Science (BMBF) through the “Netzwerk Universitaetsmedizin,” project “COVIM” (to T.H.W. and H.H.). T.H.W. received funding from the Deutsche Forschungsgemeinschaft (DFG) within the TRR130 (project no. 215346292). Further support was obtained from faculty COVID-19 funds and the German Centre for Infection Research (DZIF). K.S. is supported by the BMBF (project 01KI2013). K.K. is supported by the Deutsche Forschungsgemeinschaft (DFG) through the research training group RTG 2504 (project number 401821119) and the Else Kröner-Fresenius-Stiftung (project 2020_EKEA.127). Further support was received from the Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg (advanced project A90). The funders had no influence on the study design and data interpretation.
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
- 2.21-04 Virology
- 2.21-05 Immunology
- 2.11-04 Structural Biology
Coronavirus related work
- Research on SARS-CoV-2 / COVID-19
