Epistasis at the SARS-CoV-2 Receptor-Binding Domain Interface and the Propitiously Boring Implications for Vaccine Escape.

At the time of this writing, December 2021, potential emergence of vaccine escape variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a grave global concern. The interface between the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein and the host receptor (ACE2) overlaps the binding site of principal neutralizing antibodies (NAb), limiting the repertoire of viable mutations. Nonetheless, variants with multiple RBD mutations have risen to dominance. Nonadditive, epistatic relationships among RBD mutations are apparent, and assessing the impact of such epistasis on the mutational landscape, particularly the risk of vaccine escape, is crucial. We employed protein structure modeling using Rosetta to compare the effects of all single mutants at the RBD-NAb and RBD-ACE2 interfaces for the wild type and Delta, Gamma, and Omicron variants. Overall, epistasis at the RBD interface appears to be limited, and the effects of most multiple mutations are additive. Epistasis at the Delta variant interface weakly stabilizes NAb interaction relative to ACE2 interaction, whereas in Gamma, epistasis more substantially destabilizes NAb interaction. Despite bearing many more RBD mutations, the epistatic landscape of Omicron closely resembles that of Gamma. Thus, although Omicron poses new risks not observed with Delta, structural constraints on the RBD appear to hamper continued evolution toward more complete vaccine escape. The modest ensemble of mutations relative to the wild type that are currently known to reduce vaccine efficacy is likely to contain the majority of all possible escape mutations for future variants, predicting the continued efficacy of the existing vaccines. IMPORTANCE Emergence of vaccine escape variants of SARS-CoV-2 is arguably the most pressing problem during the COVID-19 pandemic as vaccines are distributed worldwide. We employed a computational approach to assess the risk of antibody escape resulting from mutations in the receptor-binding domain of the spike protein of the wild-type SARS-CoV-2 virus as well as the Delta, Gamma, and Omicron variants. The efficacy of the existing vaccines against Omicron could be substantially reduced relative to the wild type, and the potential for vaccine escape is of grave concern. Our results suggest that although Omicron poses new evolutionary risks not observed for Delta, structural constraints on the RBD make continued evolution toward more complete vaccine escape from either Delta or Omicron unlikely. The modest set of escape-enhancing mutations already identified for the wild type likely include the majority of all possible mutations with this effect.