Risk of evolutionary escape from neutralizing antibodies targeting SARS-CoV-2 spike protein

Van Egeren, D.; Novokhodko, A.; Stoddard, M.; Tran, U.; Zetter, B.; Rogers, M.; Pentelute, B. L.; Carlson, J. M.; Hixon, M. S.; Joseph-McCarthy, D.; Chakravarty, A.

As many prophylactics targeting SARS-CoV-2 are aimed at the spike protein receptor-binding domain (RBD), we examined the risk of immune evasion from previously published RBD-targeting neutralizing antibodies (nAbs). Epitopes for RBD-targeting nAbs overlap one another substantially and can give rise to escape mutants with ACE2 affinities comparable to wild type that still infect cells in vitro. Based on this demonstrated mutational tolerance of the RBD, we used evolutionary modeling to predict the frequency of immune escape before and after the widespread presence of nAbs raised by vaccines, administered as prophylactics, or produced through natural immunity. Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and likewise resistance to single or double antibody combinations will develop quickly under positive selection.