Additional mutations based on Omicron BA.2.75 mediate its further evasion from broadly neutralizing antibodies

Figure 1. Overall display of mutations in the spike protein and prevalence of BA.2.75 subvariant (A) The mutations in the spike protein of BA.2, BA.4/5, BA.2.12.1, and BA.2.75 subvariants as compared to the reference wild-type isolate (NC_045512). The mutations of BA.4/5, BA.2.12.1, and BA.2.75 were also compared with BA.2. The mutations of BA.2.75.2, BA.2.75.4, BA.2.75.5, BA.2.75.6, and BA.2.75.7 were also compared with BA.2.75 and highlighted in red. BA.4 and BA.5 sharing the same spike protein sequence were represented as BA.4/5. (B and C) The number of BA.2.75 sequences collected in the GISAID and cov-spectrum in 2022 were shown for countries (n = 55,933) (B) and for temporal distributions (n = 59,413) (C).

Figure 2. Overall structure of complexes of ACE2 and 59 mAbs with RBD A total of 59 RBD-specific mAbs were categorized into 8 groups (RBS-A, RBS-B, RBS-C, RBS-D, RBS-E, S309-site, EY6A-site, and S2H97-site) based on their binding epitopes and whether competing with ACE2 or not. RBS-related mAbs bind to the regions overlapping with RBS and compete with ACE2. The binding epitopes of S309-site, EY6A-site, and S2H97-site mAbs are far away from RBS, which do not compete with ACE2 directly. The merged figures show an overview of the complexes of RBD with ACE2 and all mAbs in each class. The antibody fragments in each class are drawn as cartoons in different colors. The ACE2 is shown as cartoon in brown. The RBD is shown in gray. All protein data bank (PDB) codes involved in this study are provided in the figure.

Figure 3. The neutralization of 44 RBD-specific mAbs against WT SARS-CoV-2 and Omicron subvariants The neutralization breadth is defined as the percentage of mAbs with effective neutralizing activities against each pseudovirus among all 44 tested mAbs. The neutralization potency is calculated by the geometric mean of neutralizing value of less than 50 μg/mL. The data shown are means of two or three independent experiments. The IC50 values are highlighted in different colors to show distinct neutralizing activities. Red: high, Yellow: moderate, Green: weak, Dark gray: non-neutralization. Symbol “∗” indicates some approved antibody drugs: REGN10933 (casirivimab), CB6 (etesevimab), COV2-2196 (tixagevimab), CT-P59 (regdanvimab), LY-CoV555 (bamlanivimab), LY-CoV1404 (bebtelovimab), COV2-2130 (cilgavimab), REGN10987 (imdevimab), and S309 (sotrovimab). See also Figures S1 and S2.

Figure 4. Structural analysis of bnAbs binding to WT and mutated RBDs SARS-CoV-2 RBD is shown in gray. Fabs of S2K146 (A), S2E12 (B), COV2-2130 (C), and LY-CoV1404 (D) are shown in green, cyan, yellow, and pink, respectively. Mutated S486, T346, and R452 are represented by red sticks. Hydrogen bonds and salt bridges are represented by black dashed lines.