Antibody and B cell development after vaccination against COVID-19

Abstract

During the COVID-19 pandemic, new mRNA- and adenovirus-based vaccine formats encoding the viral spike protein (S) were developed. These newly developed vaccine formats have helped to successfully combat the pandemic. However, there is a high rate of breakthrough infections, which is why the vaccine induced immune responses should be investigated in detail. Both vaccine formats induce antibodies that have neutralizing functions via their Fab-part. The effect of IgG antibodies also depends on Fc-mediated effector functions, which are influenced by the IgG subclass and its Fc N-glycosylation pattern. At the beginning of this work, it was known that both vaccines induce IgG1 and IgG3 antibodies initially and especially after two vaccinations, but information on long-term antibody responses was lacking. The aim of this work was therefore to longitudinally describe and characterize the vaccine-induced IgG subclasses, their Fc N-glycosylation and their Fc-mediated effector functions. It was shown that the mRNA vaccines produced significantly higher IgG1 and IgG3 antibody levels in the short term compared to adenovirus-based vaccination, but that these levels equalized in the long term. In contrast to this equalization, late emerging IgG4 antibodies were only observed in people who received two mRNA vaccinations. It is generally assumed that IgG4, in contrast to IgG1 and IgG3, has a more inhibitory function. In functional assays, anti-S IgG1 was confirmed as a strongly activating subclass. In contrast, IgG4 antibodies, which increased with every vaccination, showed activating but also inhibitory immunomodulatory effects. These need to be further investigated in the future in order to better assess their role in the long-term vaccination response. In addition, a dynamic development of glycosylation was observed: Highly galactosylated and sialylated IgG antibodies appeared shortly after each vaccination, while significantly lower galactosylated and sialylated IgG antibodies were found in the long term. This wave pattern was described for all IgG subclasses and indicates that differently glycosylated antibodies exert different effector functions, which could mean a new general understanding of early and late antibody responses after vaccination. In contrast to this dynamic, the new vaccines were only able to induce afucosylated antibodies temporarily and only after the first vaccination. By investigating a cohort of patients with inflammatory diseases who received tumor necrosis factor (TNF) inhibitors during vaccination, the influence of TNF on the longitudinal antibody response and thus also on B-cell differentiation could be described. The patients showed lower IgG levels, altered antibody glycosylation patterns and reduced Fc-mediated effector functions both in the short and long term after repeated vaccination. Anti-TNF therapy not only reduced the long-lived IgG response, but also the short-lived IgG response resulting from the re-activation of memory cells. Accordingly, an increased risk of breakthrough infection was observed in patients treated with anti-TNF. These results suggest that patients receiving anti-TNF therapy may benefit little from a booster vaccination.