BNT162b2 (Pfizer- BioNTech) and mRNA 1273 (Moderna) vaccines were the first messenger RNA (mRNA)-based vaccines ever approved. In both vaccines, an mRNA sequence determines the structure and assembly of the immunogen, the SARS-CoV-2 spike (S) glycoprotein. According to previous studies, after two doses of the anti-SARS-CoV-2 mRNA vaccines, the immunoglobulin G (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, German researchers emphasize that the longitudinal evolution of the four IgG subclasses (IgG1, IgG2, IgG3, and IgG4) in response to mRNA vaccination—particularly their long-term development after the second and the third dose—has not yet been analyzed. Therefore, in this study, they longitudinally monitored the IgG response in two independent cohorts of healthcare workers vaccinated with two or three mRNA COVID-19 vaccines to investigate whether the mRNA COVID-19 vaccination increases the proportion of SARS-CoV-2-specific IgG4.
The authors also pointed to limited investigations on the role of vaccine-induced IgG4 responses in infectious diseases. In the anti-human immunodeficiency virus vaccine development, 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. The vaccine-induced IgG3 antibodies enhanced effector functions such as antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity, whereas vaccine-induced IgG4 antibodies inhibited the same effector functions. IgG4, as the least abundant IgG subclass in humans, has some unique structural and functional features that lead to it being described as a “blocking” and “anti-inflammatory” antibody that cannot activate antibody-dependent immune effector responses.
About the Study and Results
The researchers longitudinally monitored the IgG response in serum samples from two independent cohorts of healthcare workers vaccinated with two or three mRNA COVID-19 vaccines. The results showed that repeated immunization with the mRNA COVID-19 vaccines increased the IgG4 antibody levels against SARS-CoV-2 S protein and IgG4-switched memory B cells.
Five to seven months after the second immunization with the mRNA COVID-19 vaccines, noninflammatory IgG4 antibodies were detected in about half of the serum samples. Importantly, IgG4 has not been found in any sample at earlier time points.
After the third immunization with the mRNA COVID-19 vaccines, IgG4 levels increased significantly and became detectable in almost all vaccine recipients. Specifically, IgG4 serum levels increased from 0.04% shortly after the second vaccination to 19.27% late after the third vaccination. The levels of all other IgG subclasses decreased during the same period.
Additionally, 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.
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 SARS-CoV-2 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 against the SARS-CoV-2 S protein in the serum at this time and the rapid increase of IgG4 antibodies support the idea of reactivation of already present IgG4 memory B cells by booster immunization.
Conclusion
Irrgang et al were the first to report an increased proportion of SARS-CoV-2 S protein-specific noninflammatory IgG4 antibodies and IgG4-switched memory B cells in adults, starting after the second and increasing further after the third mRNA vaccine dose.
According to the authors, 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. The authors believe that it 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) https://www.science.org/doi/10.1126/sciimmunol.ade2798
