Class switch towards non-inflammatory IgG isotypes after repeated SARS-CoV-2 mRNA vaccination

Abstract

Repeated mRNA vaccinations are an efficient tool 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 first or second mRNA vaccine dose, the IgG response mainly consists of the pro-inflammatory isotypes IgG1 and IgG3 and is driven by T helper (Th) 1 cells. Here, we report that several months after the second vaccination, SARS-CoV-2-specific antibodies were increasingly composed of non-inflammatory IgG2 and particularly IgG4, which were further boosted by a third mRNA vaccination and/or SARS-CoV-2 variant breakthrough infections. While IgG antibodies were affinity matured and of high neutralization capacity, the switch in constant domains caused changes in fragment crystallizable (Fc)-receptor mediated effector functions, including a decreased capacity to facilitate phagocytosis. IgG4 induction was neither induced by Th2 cells nor observed after homologous or heterologous SARS-CoV-2 vaccination with adenoviral vectors. In addition, IgG2- and IgG4-producing memory B cells were phenotypically indistinguishable from IgG1- or IgG3-producing cells. Since Fc-mediated effector functions are critical for antiviral immunity, the described class switch towards non-inflammatory IgG isotypes, which otherwise rarely occurs after vaccination or viral infection, may have consequences for the choice and timing of vaccination regimens using mRNA vaccines.

mRNA vaccines against SARS-CoV-2 induce comparably low long-term IgG Fc galactosylation and sialylation levels but increasing long-term IgG4 responses compared to an adenovirus-based vaccine

“…Supporting evidence stems from another study, where comparable results were observed, additionally with a further increase of IgG4 after the third vaccination with BNT162b2 (74). Similarly to our results, no IgG4 response was detected after two AZD1222 vaccinations.…”

SARS-CoV-2 Vaccine Booster Elicits Robust Prolonged Maternal Antibody Responses and Passive Transfer Via The Placenta And Breastmilk

“…Plasma observations are similar to those reported in recent studies. 42 Since B-cells undergo the class switching pattern of IgM>IgG3>IgG1>IgA>IgG2>IgG4, 48 the IgG4 dominance we observed suggest enhanced maternal B-cell class switching. Our study results align with a study that showed an increase in IgG4 with pregnancy and higher IgG4 response in the pregnant population when compared to non-pregnant individuals.…”

“…24 Our results confirm earlier conclusions that the initial two dose vaccination series during gestation resulted in appreciable RBD-specific IgG response in maternal circulation, UCB, and breastmilk. 20, 27 Importantly, longitudinal analysis of post-partum samples indicates that the booster dose is essential for producing higher and more durable antibody levels in both maternal circulation and breastmilk, 28, 29, 42 and should be strongly encouraged for all pregnant people to increase neonatal passive immune protection against SARS-CoV-2.…”

Specific long-term changes in anti-SARS-CoV-2 IgG modifications and antibody functions in mRNA, adenovector, and protein subunit vaccines

“…The beads were resuspended in 1 mL of FACS buffer for flow cytometry. To measure ADCP, the phagoscore 7 was calculated as a fraction of bead-positive cells multiplied by the mean fluorescence intensity (MFI, Supplementary Figure 1 A, B). For ADCD, the MFI was used (Supplementary Figure 1 C,D).…”

“…The affinity of IgG for Fc-mediated functions is determined by the isotype (subclass) and the conserved n-297 glycosylation site 5,6 . Several studies have investigated the long-term changes in the IgG profile of mRNA vaccines, showing an increased contribution of the IgG4 subclass of anti-S IgG [7][8][9] associated with weaker Fc-mediated functions 7 (7). In Taiwan, a domestically developed protein subunit vaccine against COVID-19 was developed and administered (Medigen MVC-COV1901) 10,11 .…”