Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Weisblum, Yiska; Schmidt, Fabian; Zhang, Fengwen; DaSilva, Justin; Poston, Daniel; Lorenzi, Julio C C; Muecksch, Frauke; Rutkowska, Magdalena; Hoffmann, Hans-Heinrich; Michailidis, Eleftherios; Gaebler, Christian; Agudelo, Marianna; Cho, Alice; Wang, Zijun; Gazumyan, Anna; Cipolla, Melissa; Luchsinger, Larry; Hillyer, Christopher D; Caskey, Marina; Robbiani, Davide F; Rice, Charles; Nussenzweig, Michel C; Hatziioannou, Theodora; Bieniasz, Paul D

Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.