Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape

Abstract

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. Epistasis among RBD mutations can increase the risk of vaccine escape. We compare the effects of all single mutants at the RBD-NAb and RBD-ACE2 interfaces for wild type (WT), Gamma and Delta variants using Rosetta. Epistasis at the RBD surface appears to be limited and the effects of most multiple mutations are additive. For Delta variant, epistasis weakly stabilizes NAb interaction relative to ACE2, whereas in Gamma, epistasis more substantially destabilizes NAb interaction. Thus, the repertoire of potential escape mutations for Delta is not substantially different from that of WT, whereas Gamma poses a moderately greater risk of vaccine escape.Funding: Intramural Research Program of the National Institutes of Health of the USA (National Library of Medicine), to E. V. KooninDeclaration of Interests: The declare they have no competing interests.