Antigenic characterization of the SARS-CoV-2 Omicron subvariant BA.2.75

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant BA.2.75 emerged recently and appears to be spreading. It has nine mutations in spike compared with the currently circulating BA.2, raising concerns that it may further evade vaccine-elicited and therapeutic antibodies. We found BA.2.75 to be moderately more neutralization resistant to sera from vaccinated/boosted individuals than BA.2 (1.8-fold), similar to BA.2.12.1 (1.1-fold), but more neutralization sensitive than BA.4/5 (0.6-fold). Relative to BA.2, BA.2.75 showed heightened resistance to class 1 and class 3 monoclonal antibodies targeting the spike-receptor-binding domain while gaining sensitivity to class 2 antibodies. Resistance was largely conferred by G446S and R460K mutations. BA.2.75 was slightly resistant (3.7-fold) to bebtelovimab, a therapeutic antibody with potent activity against all Omicron subvariants. BA.2.75 also exhibited a higher binding affinity to host receptor ACE2 than other Omicron subvariants. BA.2.75 provides further insight into SARS-CoV-2 evolution as it gains transmissibility while incrementally evading antibody neutralization.

Keywords: ACE2 affinity; BA.2.75; COVID-19; Omicron; SARS-CoV-2; antibody evasion; monoclonal antibodies; serum neutralization; vaccine.

Graphical abstract

Figure 1

Serum neutralization profile of BA.2.75 (A) Neutralization of pseudotyped D614G and Omicron subvariants by sera from three different clinical cohorts. Boosted refers to individuals who received three doses of a COVID-19 mRNA vaccine, and breakthrough refers to individuals who were infected and received COVID-19 vaccines. (B) Serum neutralization of pseudotyped BA.2 or BA.2 with point mutations from BA.2.75. For both panels, values above the symbols denote the geometric mean ID₅₀ values and values on the lower left indicate the sample size (n) for each group. The limit of detection (LOD) is 100 (dotted line), and values below the LOD are arbitrarily plotted to allow for visualization of each sample. The p values were determined by using two-tailed Wilcoxon matched-pairs signed-rank tests. In (B), comparisons were made against BA.2. Significance is denoted with asterisks, and the fold change is also denoted. Ns, not significant; ^∗p < 0.05; ^∗∗p < 0.01; ^∗∗∗p < 0.001; and ^∗∗∗∗p < 0.0001. See also Figure S1 and Table S1.

Figure 2

Neutralization of BA.2.75 by monoclonal antibodies and receptor-binding affinity (A) Neutralization of pseudotyped D614G and Omicron subvariants by NTD-SD2-, SD1-, and RBD-directed mAbs. Values above the LOD of 10 μg/mL (dotted line) are arbitrarily plotted to allow for visualization of each sample. (B) Fold change in IC₅₀ values for the neutralization of pseudotyped point mutants, relative to D614G or BA.2, with resistance colored red and sensitization colored green. NA, not applicable. (C) Modeling of the impact of G446S and N460K on antibody neutralization. Clashes are shown as red discs, and hydrogen bonds are shown as dashed lines. (D) Binding affinity of D614G, BA.2, BA.2.75, and BA.4/5 stabilized spike trimers to dimeric human ACE2. See also Figures S1 and S2 and Table S2.