Structural changes in the SARS-CoV-2 spike E406W mutant escaping a clinical monoclonal antibody cocktail

The SARS-CoV-2 receptor-binding domain (RBD) E406W mutation abrogates neutralization mediated by the REGEN-CoV therapeutic monoclonal antibody (mAb) COVID-19 cocktail and the cilgavimab (AZD1061) mAb. Here, we show that this residue substitution remodels the ACE2-binding site allosterically, thereby dampening receptor recognition severely and altering the epitopes recognized by these three mAbs. Although vaccine-elicited neutralizing antibody titers are decreased similarly against the E406 mutant and the Delta or Epsilon variants, broadly neutralizing sarbecovirus mAbs, including a clinical mAb, inhibit the E406W spike mutant. ### Competing Interest Statement The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. J.D.B. consults for Moderna and Flagship Labs 77 on topics related to viral evolution, and is an inventor on Fred Hutch licensed patents related to viral deep mutational scanning. DC is an employee of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc.