Omicron variant Spike-specific antibody binding and Fc activity are preserved in recipients of mRNA or inactivated COVID-19 vaccines

Abstract

The Omicron variant of SARS-CoV-2 has been shown to evade neutralizing antibodies elicited by vaccination or infection. Despite the global spread of the Omicron variant, even among highly vaccinated populations, death rates have not increased concomitantly. These data suggest that immune mechanisms beyond antibody-mediated virus neutralization may protect against severe disease. In addition to neutralizing pathogens, antibodies contribute to control and clearance of infections through Fc effector mechanisms. Here, we probed the ability of vaccine-induced antibodies to drive Fc effector activity against the Omicron variant using samples from individuals receiving one of three SARS-CoV-2 vaccines. Despite a substantial loss of IgM, IgA, and IgG binding to the Omicron variant receptor binding domain (RBD) in samples from individuals receiving BNT162b2, mRNA-1273, and CoronaVac vaccines, stable binding was maintained against the full-length Omicron Spike protein. Compromised RBD binding IgG was accompanied by a loss of RBD-specific antibody Fcγ receptor (FcγR) binding in samples from individuals who received the CoronaVac vaccine, but RBD-specific FcγR2a and FcγR3a binding was preserved in recipients of mRNA vaccines. Conversely, Spike protein-specific antibodies exhibited persistent but reduced binding to FcγRs across all three vaccines, although higher binding was observed in samples from recipients of mRNA vaccines. This was associated with preservation of FcγR2a and FcγR3a binding antibodies and maintenance of Spike protein-specific antibody-dependent natural killer cell activation. Thus, despite the loss of Omicron neutralization, vaccine-induced Spike protein-specific antibodies continue to drive Fc effector functions, suggesting a capacity for extraneutralizing antibodies to contribute to disease control.

Fig. 1.. Vaccine-induced antibody binding to the Spike protein of SARS-CoV-2 is maintained across variants of concern.

Individuals received the full dose regimen of the BNT162b2 mRNA vaccine (n = 11), mRNA-1273 vaccine (n=14), or the aluminum-adjuvanted inactivated particle vaccine CoronaVac (n=13). Samples were obtained from vaccine recipients 13 to 19 days after the second dose. IgM, IgA1, and IgG1 binding titers to D614G, Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529) VOC (A) RBDs or (B) full-length Spike protein were measured by a Luminex assay. The average value of technical replicates is shown. The data was corrected for background and negative values were set to 100 for graphing purposes. A two-sided Kruskal-Wallis test with a Benjamini-Hochberg post-test correcting for multiple comparisons was used to test for statistical differences between D614G and Omicron titers. P-values for significantly different features (p≤0.05) are shown; fold-change reduction of omicron titers compared to D614G are shown below each dataset. MFI, median fluorescence intensity.

Fig. 2.. FcγR binding antibody profiles against SARS-CoV-2 VOCs vary across vaccine type.

Individuals received the full dose regimen of the BNT162b2 mRNA vaccine (n = 11), mRNA-1273 vaccine (n=14), or the aluminum-adjuvanted inactivated particle vaccine CoronaVac (n=13). Samples were profiled 13 to 19 days after the last vaccine dose. Binding to FcγR2a, FcγR2b, FcγR3a, and FcγR3b of antibodies specific to the (A) RBD or (B) full-length spike protein of D614G, Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), or Omicron (B.1.1.529) were determined by a Luminex assay. The average value of technical replicates is shown. The data was corrected for background and negative values were set to 100 for graphing purposes. A two-sided Kruskal-Wallis test with a Benjamini-Hochberg post-test correcting for multiple comparisons was used to test for statistical differences between D614G-specific and Omicron-specific antibody activity. P-values for significant different features (p≤0.05) are shown; fold-change reduction of omicron binding activity compared to D614G is shown below each dataset.

Fig. 3.. Vaccine induced binding titers correlate with FcγR binding across VOCs.

The heatmaps show the Spearman correlation between the D614G or VOC (A) RBD-specific or (B) Spike protein-specific IgG1 titers and antibody binding to the respective FcγRs. The color indicates the correlation coefficient (r) as indicated by the color key. Asterisks indicate statistically significant correlations; *p≤0.05, **p≤0.01, ***p≤0.001, ****p≤0.0001.

Fig. 4.. Spike protein-specific, but not RBD-specific, Fc-mediated effector activity is preserved in samples from vaccinated individuals.

Antibody-dependent NK cell activation (ADNKA) was assessed by CD107a expression, a marker of NK cell degranulation, on CD3^-CD56⁺ NK cells. Samples were incubated with D614G (blue) or Omicron (red) Spike (S) protein (circle) or RBD (square) and samples from recipients of 1 of 3 vaccine platforms: BNT162b2 (n=11), mRNA-1273 (n=13), and CoronaVac (n=13). The assay was performed with three different NK cell donors and the average value of all donors is shown. A two-sided Kruskal-Wallis test with a Benjamini-Hochberg post-test correcting for multiple comparisons was used to test for statistical differences between D614G and omicron. Significance was defined as p≤0.05 and only p-values for significantly different comparisons are shown.