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Repeated mRNA COVID-19 vaccination results in a class switch to noninflammatory spike protein-specific IgG4 antibodies

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In both messenger RNA anti-SARS-CoV-2 vaccines (mRNA-1273 and BNT162b2), a mRNA sequence determines the structure and assembly of the immunogen, the SARS-CoV-2 spike (S) glycoprotein. The German researchers conducted this study to longitudinally monitor the immunoglobulin G (IgG) response in two independent cohorts of healthcare workers who had been vaccinated with two or three mRNA COVID-19 vaccines. The results showed that repeated mRNA COVID-19 vaccination increased the level of noninflammatory S protein-specific IgG4 antibodies and IgG4-switched memory B cells five to seven months after the second mRNA immunization.

The researchers pointed to limited investigations on the role of vaccine-induced IgG4 responses in infectious diseases. In the development of the anti-human immunodeficiency virus (HIV) vaccine, repeated protein immunization in the VAX003 trial resulted in higher levels of IgG2 and IgG4 specific for HIV gp120. Prime-boost immunization with a canarypox vector (ALVAC-HIV) and the same protein vaccine in the RV144 trial resulted in higher HIV-specific IgG3 responses, that correlated with partial protection against HIV. Importantly, vaccine-induced IgG3 antibodies enhanced effector functions such as antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity, whereas vaccine-induced IgG4 antibodies inhibited these functions.

According to previous studies, after the first two doses of the anti-SARS-CoV-2 mRNA vaccine, the IgG response consists mainly of the proinflammatory subclasses IgG1 and IgG3. Results have shown that subclasses IgG1 and IgG3 were predominant, IgG2 responses were rare, and IgG4 responses were nearly undetectable shortly after two doses of mRNA vaccine (either Comirnaty or mRNA-1273). However, the authors emphasized that the longitudinal evolution of the four IgG subclasses (IgG1, IgG2, IgG3, and IgG4) in response to mRNA vaccinationparticularly their long-term development after the second and the third dosehas not yet been analyzed.

About the study

The researchers longitudinally monitored the IgG response in serum samples from two independent cohorts of healthcare workers who had been vaccinated with two or three mRNA COVID-19 vaccines. The results showed that repeated immunization with mRNA anti-SARS-CoV-2 vaccines increased the levels of anti-S protein IgG4 antibodies and IgG4-switched memory B cells.

Five to seven months after the second immunization, noninflammatory IgG4 antibodies were detected in about half of the serum samples. IgG4 has not been found in any sample at earlier time points.

After the third immunization, IgG4 levels increased significantly and became detectable in almost all vaccine recipients. Importantly, IgG4 levels increased from 0.04% shortly after the second vaccination to 19.27% late after the third vaccination. In addition, antibody-mediated phagocytic activity and complement deposition decreased in sera after the third immunization, in parallel with higher proportions of anti-S protein IgG4 antibodies.

The induction of IgG4 antibodies was not observed after the homologous or heterologous SARS-CoV-2 immunization with adenoviral vectors. In addition, the levels of all other IgG subclasses decreased during the same period.

Flow cytometry and single-cell sequencing of memory B cells specific for the SARS-CoV-2 S protein, isolated after the second and third vaccination, confirmed the presence of a substantial number of S protein-reactive, IgG4-switched B cells. In contrast, IgG3-positive clones were hardly detectable.

The authors emphasized that they could not formally rule out de novo class switching to IgG4 immediately after the booster vaccination. However, the presence of IgG4 antibodies in the serum at this time and the rapid increase of anti-S protein IgG antibodies support the idea of reactivation of already present IgG4 memory B cells by booster immunization.

The researchers concluded that their study demonstrated that repeated mRNA COVID-19 vaccination increased the levels of non-inflammatory S protein-specific IgG4 antibodies that appeared late after the second immunization. The induction of antiviral IgG4 antibodies is a rarely described phenomenon, regardless of the underlying mechanism. Also, there are important questions about its functional consequences.

Further research is needed to clarify the specific immunological mechanisms driving this response and to evaluate whether IgG4-driven antibody response affects subsequent viral infections and booster vaccinations. This is relevant not only for potential future immunization campaigns against SARSCoV-2 but also for new mRNA-based vaccines against other pathogens.

This article was published in Science Immunology.

Journal Reference

Irrgang et al. Sci. Immunol 8, eade2798 (2023) 27 January 2023. (Open Access)



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