Insights on the mutational landscape of the SARS-CoV-2 Omicron variant

Abstract

The SARS-COV2 Omicron variant has sparked global concern due to the possibility of enhanced transmissibility and escape from vaccines and therapeutics. In this study, we describe the mutational landscape of the Omicron variant using amino acid interaction (AAI) networks. AAI network analysis is particularly well suited for interrogating the impact of constellations of mutations as occur on Omicron that may function in an epistatic manner. Our analyses suggest that as compared to previous variants of concern, the Omicron variant has increased antibody escape breadth due to mutations in class 3 and 4 antibody epitopes as well as increased escape depth due to accumulated mutations in class 1 antibody epitopes. We note certain RBD mutations that might further enhance Omicron's escape, and in particular advise careful surveillance of two subclades bearing R346S/K mutations with relevance for certain therapeutic antibodies. Further, AAI network analysis suggests that the function of certain therapeutic monoclonal antibodies may be disrupted by Omicron mutations as a result of the cumulative indirect perturbations to the epitope surface properties, despite point-mutation analyses suggesting these antibodies are tolerant of the set of Omicron mutations in isolation. Finally, for several Omicron mutations that do not appear to contribute meaningfully to antibody escape, we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBD-RBD interface.

Keywords: Antibody Escape; Antigenic Drift; Epistasis; Mutation; Network Analysis; Omicron; RBD Interface Stability; SARS-CoV-2; Variant of Concern.

Figure 1:. RBD epitopes and variant mutational constellations.

AAI networking between a panel of antibodies and nanobodies covering all anti-RBD antibody classes (x-axis) and RBD sites (y-axis) is shown, with networking strength annotated as heat map intensity. RBD sites mutated on the Omicron, Beta, Delta, and PMS20 RBDs are highlighted by red, blue, purple, and green arrows, respectively. The Beta and Delta variant mutations primarily reside at sites corresponding to class 1 and 2 antibodies, the PMS20 mutations occur at sites residing within class 1–3 epitopes, and the Omicron mutations cover the epitopes of all four antibody classes. Further, Omicron and PMS20 feature several class 1 and 3 antibody mutations suggestive of escape depth in these classes. The four Omicron mutations affecting class 4 epitopes do so via indirect networking, though may still cumulatively affect antibody binding at this epitope region.

Figure 2:. The Omicron, Beta, Delta and PMS20 RBDs versus therapeutic mAbs.

The data in Figure 1 is refined to highlight the cumulative direct and indirect networking between the sites of Omicron mutations and the currently authorized therapeutic mAbs. The cumulative networking between these antibodies and the Beta, Delta, and PMS20 RBDs is shown for comparison. AAI network diagrams describing connections between specific sites are provided in the supplement.

Figure 3.

The effects of Omicron mutations on the RBD-RBD interface. Top, an Omicron RBD-RBD homology model overlayed with the wild-type RBD-RBD interface in the furin-cleaved state. Omicron mutations S373P and Y505H reduce the energetic favorability of the RBD-RBD complex at these sites, though enable a more energetically favorable conformation for the unmutated R403. Bottom, the energetic contribution of all RBD-interface sites mutated on Omicron to RBD-RBD complexation.