The BNT162b2 mRNA SARS-CoV-2 vaccine induces transient afucosylated IgG1 in naive but not antigen-experienced vaccinees

Abstract

The onset of severe SARS-CoV-2 infection is characterized by the presence of afucosylated IgG1 responses against the viral spike (S) protein, which can trigger exacerbated inflammatory responses. Here, we studied IgG glycosylation after BNT162b2 SARS-CoV-2 mRNA vaccination to explore whether vaccine-induced S protein expression on host cells also generates afucosylated IgG1 responses. SARS-CoV-2 naive individuals initially showed a transient afucosylated anti-S IgG1 response after the first dose, albeit to a lower extent than severely ill COVID-19 patients. In contrast, previously infected, antigen-experienced individuals had low afucosylation levels, which slightly increased after immunization. Afucosylation levels after the first dose correlated with low fucosyltransferase 8 (FUT8) expression levels in a defined plasma cell subset. Remarkably, IgG afucosylation levels after primary vaccination correlated significantly with IgG levels after the second dose. Further studies are needed to assess efficacy, inflammatory potential, and protective capacity of afucosylated IgG responses.One sentence summaryA transient afucosylated IgG response to the BNT162b2 mRNA vaccine was observed in naive but not in antigen-experienced individuals, which predicted antibody titers upon the second dose.

Afucosylated IgG responses in humans – structural clues to the regulation of humoral immunity

“…(D) The potency of afucosylated IgG might be harnessed in vaccine design by mimicking natural antigen display as depicted in (B) and (C). Using mRNA templates or viral shuttles for transcription in host cells, foreign antigens might be expressed in the context of a self-membrane which could induce afucosylated IgG [ 64 ]. Abbreviation: adeno, adenovirus.…”

“…Genome-wide association studies have implied that the transcription regulator IKAROS might account for small differences in IgG fucosylation in B cells, whereas the transcription factor HNF-1α might control the expression of fucosyltransferases in hepatic cells, suggesting that protein fucosylation is likely controlled on the transcriptomic level [ 84 , 85 ]. Furthermore, during HIV-1 infections, peripheral B cells from elite controllers, as well as plasma cells during acute natural and vaccination responses against SARS-CoV-2, have been reported to exhibit decreased expression of α1,6-fucosyltransferase FUT8 [ 16 , 26 , 64 ]. As FUT8 is responsible for core fucosylation in B cells, and because the degree of antigen-specific IgG fucosylation correlates with FUT8 expression, FUT8 is a tempting candidate for studying IgG-Fc fucosylation given that no clear molecular mechanism for this process has been described [ 16 , 26 , 64 ].…”

“…Furthermore, during HIV-1 infections, peripheral B cells from elite controllers, as well as plasma cells during acute natural and vaccination responses against SARS-CoV-2, have been reported to exhibit decreased expression of α1,6-fucosyltransferase FUT8 [ 16 , 26 , 64 ]. As FUT8 is responsible for core fucosylation in B cells, and because the degree of antigen-specific IgG fucosylation correlates with FUT8 expression, FUT8 is a tempting candidate for studying IgG-Fc fucosylation given that no clear molecular mechanism for this process has been described [ 16 , 26 , 64 ].…”

“…This is exemplified by responses to CMV and HIV-1, which are latent viruses that cause low inflammation and a stable low degree of Fc fucosylation [ 86 ]. Moreover, in severe SARS-CoV2 responses, the initial low degree of Fc fucosylation upon seroconversion increases while the plasma concentrations of proinflammatory cytokines are at their highest [ 27 , 64 ]. High antibody titers are insufficient to induce strong cytotoxic responses at low antigen density [ 48 ], and antibodies with strong effector functions are thus probably necessary to clear specific infections.…”

“…Despite the low abundance and relatively stable concentrations of afucosylated IgG in plasma, multiple studies of antigen-specific IgG, all using affinity-purified IgG and mass spectrometry analysis, recently highlighted the clinical importance of some antigen-specific afucosylated IgG responses, which were also verified by FcγRIIIa-dependent serological methods in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responses [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][63][64][65]. These afucosylated IgG responses include those directed towards alloantigens (Table 1), which can contribute to alloimmune-mediated diseases (Box 1), against enveloped viruses, and against P. falciparum proteins expressed on red blood cells (RBCs), all responses in which the degree of afucosylation can influence disease severity [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][63][64][65].…”