Repeated SARS-CoV-2 mRNA vaccination results in a class switch to noninflammatory spike-specific IgG4 antibodies

The study from German researchers longitudinally monitored the immunoglobulin G (IgG) response in two independent cohorts of health care workers vaccinated with two or three doses of SARS-CoV-2 mRNA vaccines. The results showed that repeated SARS-CoV-2 mRNA vaccination increased levels of noninflammatory spike (S) protein-specific IgG4 antibodies and IgG4-switched memory B cells, 5 to 7 months after the second mRNA immunization.

The previous studies have shown that following the first two doses of mRNA vaccine, the IgG response consists mainly of the proinflammatory subclasses IgG1 and IgG3. Shortly after the administration of two doses of SARS-CoV-2 mRNA vaccine (either Comirnaty or mRNA-1273), subclasses IgG1 and IgG3 were predominant, IgG2 responses were rare, and IgG4 responses were nearly undetectable.

However, 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 have longitudinally monitored the immunoglobulin G (IgG) response in two independent cohorts of healthcare workers vaccinated with two or three doses of SARS-CoV-2 mRNA vaccines.

The results showed that repeated immunization with SARS-CoV-2 mRNA vaccines can increase the level of anti-spike protein IgG4 antibodies and IgG4-switched memory B cells. Noninflammatory IgG4 antibodies were detected in about half of the serum samples collected 5 to 7 months after the second immunization. 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. IgG4 levels increased from 0.04% shortly after the second vaccination to 19.27% late after the third vaccination.

For all other IgG subclasses, a decrease was observed during the same period.

This induction of IgG4 antibodies was not observed following homologous or heterologous SARS-CoV-2 immunization with adenoviral vectors. In addition, antibody-mediated phagocytic activity and complement deposition decreased in sera after the third immunization, in parallel with higher proportions of anti-spike IgG4 antibodies.

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

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

According to the authors, regardless of the underlying mechanism, the induction of antiviral IgG4 antibodies is a phenomenon rarely described. There are important questions about its functional consequences.

Investigations on the role of vaccine-induced IgG4 responses in infectious diseases are very limited. In the area of HIV vaccine development, repeated protein immunization in the trial VAX003 resulted in higher levels of IgG2 and IgG4 specific for HIV gp120. A 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, correlating with partial protection against HIV. The vaccine-induced IgG3 antibodies enhanced effector functions such as antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity, but vaccine-induced IgG4 antibodies inhibited these functions.

The authors concluded that their study demonstrated IgG4 antibody response induced by mRNA vaccine, which occurred late after secondary immunization. Further research is needed to clarify the specific immunological mechanisms driving this response, and to evaluate whether an 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 to new mRNA-based vaccines against other pathogens.

This article was published in the scientific journal Science Immunology.

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