An updated atlas of antibody evasion by SARS-CoV-2 Omicron sub-variants including BQ.1.1 and XBB

Abstract

Emerging Omicron sub-variants are causing global concerns, and their immune evasion should be monitored continuously. We previously evaluated the escape of Omicron BA.1, BA.1.1, BA.2, and BA.3 from an atlas of 50 monoclonal antibodies (mAbs), covering seven epitope classes of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD). Here, we update the atlas of totally 77 mAbs against emerging sub-variants including BQ.1.1 and XBB and find that BA.4/5, BQ.1.1, and XBB display further evasion. Besides, investigation into the correlation of binding and neutralization of mAbs reveals the important role of antigenic conformation in mAb functioning. Moreover, the complex structures of BA.2 RBD/BD-604/S304 and BA.4/5 RBD/BD-604/S304/S309 further elucidate the molecular mechanism of antibody evasion by these sub-variants. By focusing on the identified broadly potent mAbs, we find a general hotspot epitope on the RBD, which could guide the design of vaccines and calls for new broad-spectrum countermeasures against COVID-19.

Keywords: BA.2.13; BA.2.75; BA.4; BA.5; BQ.1.1; Omicron BA.2.12.1; SARS-CoV-2; XBB; human neutralizing antibodies; immune escape.

Graphical abstract

Figure 1

Binding and neutralizing abilities of the antibodies to the Omicron BA.2.12.1, BA.2.13, BA.2.75, BA.4, BA.5, BQ.1.1, and XBB sub-variants The binding affinity (K_D) of each pair of interactions is shown as the mean of three independent experiments. The neutralizing ability (IC₅₀) of each antibody against the Omicron BA.2, BA.2.12.1, BA.2.13, BA.2.75, BA.4/5, BQ.1.1, and XBB pseudoviruses is one representative result of two independent experiments. The experiments were performed with two technical replicates (n = 2) at each time. Data with a gray background present historical binding and neutralization results from previous research. See also Figures S1–S4.

Figure 2

Correlation of binding and neutralization of antibodies belonging to 8 classes Reciprocal of K_D and IC₅₀ for antibodies belonging to corresponding class against all the sub-variants are set as horizontal and vertical axes, and the red line is result of linear fit of the data points. R² is indicated alongside. See also Figures S1–S4.

Figure 3

Overall structure and structural alignment of the BA.2 RBD/BD-604/S304 complex and BA.4/5 RBD/BD-604/S304/S309 complex (A and B) Overall structures of the BA.2 RBD/BD-604/S304 complex (A) and BA.4/5 RBD/BD-604/S304/S309 complex (B). (C–E) Structural alignment of BD-604 in complex with BA.1/BA.2 RBD (C), BA.1/BA.4/5 RBD (D), and BA.2/BA.4/5 RBD (E). RMSD indicates the divergence of the two complexes. (F) Structural alignment of BD-604 in complex with the PT/BA.4/5 RBD, with only the RBDs superimposed. See also Figure S5.

Figure 4

Structural details of BD-604 binding to the BA.2 RBD and BA.4/5 RBD (A) The footprint of BD-604 on the Omicron BA.2 RBD colored in green. Sixteen mutations in the BA.2 RBD are colored in yellow and those involved in the interaction with BD-604 in blue. (B and C) Structural details of the BA.2 RBD (purple) binding to the heavy (H) chain (yellow) (B) and light (L) chain (blue) (C) of BD-604. The structure is shown as a cartoon and residues involved in the interaction as sticks. Polar interactions (H-bonds and salt bridges) are presented as red dotted lines. (D) The footprint of BD-604 on the Omicron BA.4/5 RBD colored in green. Seventeen mutations in the BA.4/5 RBD are colored in yellow and those involved in the interaction with BD-604 in blue. (E and F) Structure details of the BA.4/5 RBD (cyan) binding to the H chain (E) and L chain (F) of BD-604. The structure is shown as a cartoon and residues involved in the interaction as sticks. Polar interactions (H-bonds and salt bridges) are presented as red dotted lines. (G) Structural comparison of BD-604 binding to the BA.1 RBD and BA.2 RBD on site 405. Involved residues are presented as sticks. (H and I) Structural comparison of BD-604 binding to sites 486 and 493 of the BA.2 RBD and BA.4/5 RBD (H), as well as the PT RBD and BA.4/5 RBD (I). Involved residues are presented as sticks. (J) Structural comparison of N460 and the involved residues of the BA.2 RBD (purple) in complex with BD-604 (yellow) and the modeled N460K substitution. Modeled residues are colored in gray. (K and L) The structural analysis of interactions around the critical mutations of the BA.4/5 RBD (cyan) and PT RBD (wheat) binding to S2E12 (K) and CV07-270 (L). The L chain of S2E12 is colored in yellow and the H chain in purple. The H chain of CV07-270 is colored in dark blue. (M and N) Structural comparison of L452 and the involved residues of the PT RBD (cyan) in complex with CV07-270 (dark blue) and modeled L452Q (L) and L452M (M) substitutions. Modeled residues are colored in gray.

Figure 5

Binding characteristics of the Omicron BA.2 RBD with L452R, F486V, or R493Q mutation The indicated antibodies were captured by a Protein A chip. Then, serially diluted mutated proteins were flowed over the chip surface to assess binding, with the BA.2 RBD and BA.4/5 RBD used for comparison. The raw and fitted curves are shown as dotted and solid lines, respectively. The K_D of each pair of interactions is shown as the mean ± SD of three independent experiments.

Figure 6

Epitope mapping of broadly potent antibodies and structural analysis of the emerging sub-variants XBB and BQ.1.1 (A–G) Epitope mapping of broadly potent mAbs. The epitopes of each mAb are circled with dashed lines in corresponding colors. Residues shared by four and three mAbs are colored in red and green, respectively. (H and I) Structural details of the BA.1 RBD in complex with the XGv289 H and L chain. Residues involved in interaction are presented as sticks, and H-bonds are presented as red dashed lines. (J–L) Structural comparison of R346 (J) and V445 (K) and the involved residues in the PT RBD/LY-CoV1404 complex and V445-involved residues in the PT RBD/Beta-54 complex (L). The modeled T346 and P445 are colored in gray. Red sticks indicate steric hindrance. See also Figure S6.