Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination, 2022, Irrgang et al

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Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination
Pascal Irrgang, Juliane Gerling, Katharina Kocher, Dennis Lapuente, Philipp Steininger, Katharina Habenicht, Monika Wytopil, Stephanie Beileke, Simon Schäfer, Jahn Zhong, George Ssebyatika, Thomas Krey, Valeria Falcone, Christine Schülein, Antonia Sophia Peter, Krystelle Nganou-Makamdop, Hartmut Hengel, Jürgen Held, Christian Bogdan, Klaus Überla, Kilian Schober, Thomas H. Winkler, Matthias Tenbusch

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.

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(IgG1 and 3 are "good", IgG2 and 4 are "less good".)

Most notably, distal IgG variants, in particular IgG2 and IgG4, were reported to mediate mostly non-inflammatory or even anti-inflammatory functions due to decreased Fc-mediated antibody effector functions including antibody-dependent cellular phagocytosis (ADCP), cellular cytotoxicity (ADCC) and complement deposition (ADCD).

Shortly after the administration of two doses of SARS-CoV-2- mRNA vaccine (either Comirnaty or mRNA-1273), IgG1 and IgG3 were found to be the predominant IgG subclasses, whereas IgG2 responses were rare and IgG4 responses almost undetectable. However, the longitudinal evolution of all four IgG subclasses (IgG1, 2, 3 and 4) in response to mRNA vaccination – and particularly their long-term development after the second and the third dose – has not yet been analyzed.

Here, we report on the analysis of two independent cohorts of vaccinated health-care workers, who developed an increase in anti-spike IgG4 antibodies and IgG4-switched memory B cells five to seven months after the second mRNA immunization with Comirnaty. This response was further boosted by a third mRNA vaccination and/or by breakthrough infections with SARS-CoV-2 VOC. While we confirmed an increased antibody avidity and higher neutralization capacity against the recently emerged Omicron VOC after the third vaccine dose, the switch towards distal IgG subclasses was accompanied by reduced fragment crystallizable (Fc) gamma receptor (FcγR)-mediated effector functions such as [antibody-dependent cellular phagocytosis] and [antibody-dependent complement deposition].

Independent of the underlying mechanism, the induction of antiviral IgG4 antibodies is a phenomenon infrequently described and raises important questions about its functional consequences.

In our study, antibody-mediated phagocytic activity and complement deposition were reduced in sera after the third immunization, in parallel to higher proportions of anti-spike IgG4 antibodies. However, how these changes affect subsequent virus infections remains unclear. Since Fc-mediated effector function could be critical for viral clearance, an increase in IgG4 subclasses might result in longer viral persistence in case of infection.

 

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See also Determination of IgG1 and IgG3 SARS-CoV-2 Spike Protein and Nucleocapsid Binding-Who Is Binding Who and Why?

 

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Findings replicated in —

Class switch towards spike protein-specific IgG4 antibodies after SARS-CoV-2 mRNA vaccination depends on prior infection history
Kiszel, Petra; Sík, Pál; Miklós, János; Kajdácsi, Erika; Sinkovits, György; Cervenak, László; Prohászka, Zoltán

Vaccinations against SARS-CoV-2 reduce the risk of developing serious COVID-19 disease. Monitoring spike-specific IgG subclass levels after vaccinations may provide additional information on SARS-CoV-2 specific humoral immune response.

Here, we examined the presence and levels of spike-specific IgG antibody subclasses in health-care coworkers vaccinated with vector(Sputnik, AstraZeneca) or mRNA-based (Pfizer-BioNTech, Moderna) vaccines against SARS-CoV-2 and in unvaccinated COVID-19 patients.

We found that vector-based vaccines elicited lower total spike-specific IgG levels than mRNA vaccines. The pattern of spike-specific IgG subclasses in individuals infected before mRNA vaccinations resembled that of vector-vaccinated subjects or unvaccinated COVID-19 patients. However, the pattern of mRNA-vaccinated individuals without SARS-CoV-2 preinfection showed a markedly different pattern. In addition to IgG1 and IgG3 subclasses presented in all groups, a switch towards distal IgG subclasses (spike-specific IgG4 and IgG2) appeared almost exclusively in individuals who received only mRNA vaccines or were infected after mRNA vaccinations. In these subjects, the magnitude of the spike-specific IgG4 response was comparable to that of the spike-specific IgG1 response.

These data suggest that the priming of the immune system either by natural SARS-CoV-2 infection or by vector or mRNA-based vaccinations has an important impact on the characteristics of the developed specific humoral immunity.

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