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

Abstract

BackgroundThe new types of mRNA-containing lipid nanoparticle vaccines BNT162b2 and mRNA-1273 and the adenovirus-based vaccine AZD1222 were developed against SARS-CoV-2 and code for its spike (S) protein. Several studies have investigated short-term antibody (Ab) responses after vaccination.ObjectiveHowever, the impact of these new vaccine formats with unclear effects on the long-term Ab response – including isotype, subclass, and their type of Fc glycosylation – is less explored.MethodsHere, we analyzed anti-S Ab responses in blood serum and the saliva of SARS-CoV-2 naïve and non-hospitalized pre-infected subjects upon two vaccinations with different mRNA- and adenovirus-based vaccine combinations up to day 270.ResultsWe show that the initially high mRNA vaccine-induced blood and salivary anti-S IgG levels, particularly IgG1, markedly decrease over time and approach the lower levels induced with the adenovirus-based vaccine. All three vaccines induced, contrary to the short-term anti-S IgG1 response with high sialylation and galactosylation levels, a long-term anti-S IgG1 response that was characterized by low sialylation and galactosylation with the latter being even below the corresponding total IgG1 galactosylation level. Instead, the mRNA, but not the adenovirus-based vaccines induced long-term IgG4 responses – the IgG subclass with inhibitory effector functions. Furthermore, salivary anti-S IgA levels were lower and decreased faster in naïve as compared to pre-infected vaccinees. Predictively, age correlated with lower long-term anti-S IgG titers for the mRNA vaccines. Furthermore, higher total IgG1 galactosylation, sialylation, and bisection levels correlated with higher long-term anti-S IgG1 sialylation, galactosylation, and bisection levels, respectively, for all vaccine combinations.ConclusionIn summary, the study suggests a comparable “adjuvant” potential of the newly developed vaccines on the anti-S IgG Fc glycosylation, as reflected in relatively low long-term anti-S IgG1 galactosylation levels generated by the long-lived plasma cell pool, whose induction might be driven by a recently described TH1-driven B cell response for all three vaccines. Instead, repeated immunization of naïve individuals with the mRNA vaccines increased the proportion of the IgG4 subclass over time which might influence the long-term Ab effector functions. Taken together, these data shed light on these novel vaccine formats and might have potential implications for their long-term efficacy.

IgG4 Antibodies Induced by mRNA Vaccines Generate Immune Tolerance to SARS-CoV-2’spike Protein by Suppressing the Immune System

“…It is important to note that this virus causes severe immune suppression at different levels due to an evolved ability to evade our immune system [13]. There is now compelling evidence that only mRNA vaccines induce a remarkable increase in IgG4 levels, and such an increase was detected in COVID-19 uninfected individuals who received mRNA vaccinations before contracting COVID-19 infection, whereas for patients who had a previous COVID-19 infection before vaccination, IgG4 levels did not rise [94]. This is in contrast with findings from another study showing that the highest IgG4 levels were found in those individuals who developed a breakthrough infection after receiving three doses of mRNA vaccination, indicating that SARS-CoV-2 infections can also induce IgG4 production [11].…”

“…It has been proposed that the amount and duration of the spike protein produced are presumably affected by the higher mRNA concentrations in the mRNA-1273 vaccine (100 µg) compared to the BNT162b2 vaccine (30 µg) [94]. Thus, it is probable that the spike protein produced in response to mRNA vaccination is too high and last too much time in the body.…”

“…However, they were unable to detect this rise after two doses of the AZD1222 vaccine in uninfected individuals up to day 270, showing that only mRNA vaccines induce produce detectable and prolonged IgG4 responses until day 270. Importantly, in patients who had a previous COVID-19 infection (before vaccination), IgG4 did not rise, even after mRNA injections, implying that those with higher IgG4 levels are uninfected people who were immunized with mRNA vaccines before having their COVID-19 infection [94].…”

“…Intriguingly, among the mRNA vaccines, the mRNA-1273 vaccine generated increased anti-S1 serum IgG4 concentrations in COVID-19 uninfected individuals with previously unknown repercussions on pathogen defense. Until day 270, uninfected people who received the adenovirus-based vaccine did not exhibit this long-lasting IgG4 response [94].…”

“…A recently published study found that long-term IgG4 responses were produced by the mRNA vaccines but not by the vaccines using adenoviruses [94]. It's interesting to note that two mRNA vaccines, together with one AZD1222 (AstraZeneca) inoculation with an mRNA booster, and especially the mRNA-1273 vaccine, caused prolonged anti-S1 IgG4 responses in uninfected subjects.…”