Selective SARS-CoV2 BA.2 escape of antibody Fc/Fc-receptor interactions

Abstract

The number of mutations in the omicron (B.1.1.529) BA.1 variant of concern led to an unprecedented evasion of vaccine induced immunity. However, despite rise in global infections, severe disease did not increase proportionally and is likely linked to persistent recognition of BA.1 by T cells and non-neutralizing opsonophagocytic antibodies. Yet, the emergence of new sublineage BA.2, which is more transmissible than BA.1 despite relatively preserved neutralizing antibody responses, has raised the possibility that BA.2 may evade other vaccine-induced responses. Here, we comprehensively profiled the BNT162b2 vaccine-induced response to several VOCs, including omicron BA.1 and BA.2. While vaccine-induced immune responses were compromised against both omicron sublineages, vaccine-induced antibody isotype titers, and non-neutralizing Fc effector functions were attenuated to the omicron BA.2 spike compared to BA.1. Conversely, FcγR2a and FcγR2b binding was elevated to BA.2, albeit lower than BA.1 responses, potentially contributing to persistent protection against severity of disease.

Keywords: Immunology; Virology.

Graphical abstract

Figure 1

BNT162b2-induced antibody binding titer to different SARS-CoV-2 spike variants of concern Individuals received a three-dose regimen of the BNT162b2 vaccine. Samples were taken approx. 2 weeks after the second dose (post second, n = 18), before the third dose approx. 8 months after the second dose (pre third, n = 14) and approx. 2 weeks after the third dose (post third, n = 22). IgM (A), IgA1 (B), IgG1 (C) and IgG3 (D) binding titers to D614G (WT), alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2) variants of concern, and omicron (B.1.1.529) BA.1 and BA.2 subvariants spike were measured by Luminex. The average value of technical replicates is shown. The data were corrected for background and negative values were set to 100 for graphing purposes. A two-sided paired Wilcoxon test with a Benjamini-Hochberg post-test correcting for multiple comparisons was used to test for statistical differences between BA1 and BA2 titers, respectively. P-values are shown above each dataset. Horizontal lines indicate median and error bars the 95% confidence interval. See also Figure S2.

Figure 2

Fc-receptor binding antibody profiles across SARS-CoV-2 variants of concern Individuals received a three-dose regimen of the BNT162b2 vaccine. Samples were taken approx. 2 weeks after the second dose (post second, n = 18), before the third dose approx. 8 months after the second dose (pre third, n = 14) and approx. 2 weeks after the third dose (post third, n = 22). Binding to FcγR2a (A), FcγR2b (B), FcγR3a (C), FcγR3b (D), and FcαR (E) of D614G (WT), alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2) variants of concern, and omicron (B.1.1.529) BA.1 and BA.2 subvariants spike specific antibodies were measured by Luminex. The average value of technical replicates is shown. The data were corrected for background and negative values were set to 100 for graphing purposes. A two-sided paired Wilcoxon test with a Benjamini-Hochberg post-test correcting for multiple comparisons was used to test for statistical differences between BA1 and BA2 titers, respectively. P-values are shown above each dataset. Horizontal lines indicate median and error bars the 95% confidence interval. See also Figures S3 and S4.

Figure 3

Fc functionality of BNT162b2-induced antibodies is superior to BA.1 compared to BA.2 antigen Antibody-dependent complement deposition (ADCD) (A), Neutrophil phagocytosis (ADNP) (B), Cellular monocyte phagocytosis (ADCP) (C), or NK cell activation (marked by CD107a expression) (D) of D614G, omicron (B.1.1.529) BA.1 or BA.2 specific antibodies was analyzed in BNT162b2 recipients at approx. 2 weeks after the second dose (post second, n = 18), before the third dose approx. 8 months after the second dose (pre third, n = 14) and approx. 2 weeks after the third dose (post third, n = 22). The average value of two donors is shown for ADNP and ADNKA or of two technical replicates for ADCD and ADCP. The data were corrected for background and negative values were set to 1 for graphing purposes. A two-sided paired Wilcoxon test with a Benjamini-Hochberg post-test correcting for multiple comparisons was used to test for statistical differences between BA1 and BA2 titers, respectively. P-values are shown above each dataset. Horizontal lines indicate median and error bars the 95% confidence interval. See also Figures S5–S8.

Figure 4

BNT162b2 induces distinct BA.1 and BA.2 specific responses A machine learning model was built using BA.1 and BA.2 spike specific features in BNT162b2 vaccinated individuals post third dose (n = 22). (A) A minimal set of LASSO selected features was used to discriminate between humoral responses in a PLS-DA analysis. Each point represents an individual’s humoral response for BA.1 (purple) and BA.2 (red). (B) Selected features were ordered according to their variable importance in projection (VIP) score (purple = enriched for BA.1 antigen).