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

 PASCAL IRRGANG HTTPS://ORCID.ORG/0000-0003-2829-6096, JULIANE GERLING HTTPS://ORCID.ORG/0000-0003-3528-7251, KATHARINA KOCHER HTTPS://ORCID.ORG/0000-0003-2331-3838, DENNIS LAPUENTE HTTPS://ORCID.ORG/0000-0002-9833-5313, PHILIPP STEININGER, KATHARINA HABENICHT, MONIKA WYTOPIL HTTPS://ORCID.ORG/0000-0002-4919-9773, STEPHANIE BEILEKE, SIMON SCHÄFER, [...], AND MATTHIAS TENBUSCH 

DOI: 10.1126/sciimmunol.ade2798

Abstract

RNA vaccines are efficient preventive measures to combat the 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 IgG response mainly consists of the pro-inflammatory subclasses IgG1 and IgG3. Here, we report that several months after the second vaccination, SARS-CoV-2-specific antibodies were increasingly composed of non-inflammatory 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 14.4%; interquartile range (IQR) 6.7–18.1%) compared to the overall memory B-cell repertoire (median 1.3%; IQR 0.9–2.2%) after three immunizations. Importantly, this class switch was associated with a reduced capacity of the spike-specific antibodies to mediate antibody-dependent cellular phagocytosis and complement deposition. Since 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.

https://www.science.org/doi/10.1126/sciimmunol.ade2798