The study investigates the ability of SARS-CoV-2 to evolve and escape neutralizing antibodies, which are crucial for both therapeutic and prophylactic interventions. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, the researchers found that functional SARS-CoV-2 spike protein variants with mutations in the receptor-binding domain (RBD) and N-terminal domain can be readily selected, conferring resistance to monoclonal antibodies or convalescent plasma. These antibody-resistant variants are already present at low frequencies in circulating SARS-CoV-2 populations. The emergence of such variants can be mitigated by using antibody combinations that target distinct neutralizing epitopes, thereby preventing the rise of viruses resistant to specific antibodies. The findings highlight the need for comprehensive strategies to combat SARS-CoV-2 evolution and ensure the long-term effectiveness of vaccines and therapies.The study investigates the ability of SARS-CoV-2 to evolve and escape neutralizing antibodies, which are crucial for both therapeutic and prophylactic interventions. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, the researchers found that functional SARS-CoV-2 spike protein variants with mutations in the receptor-binding domain (RBD) and N-terminal domain can be readily selected, conferring resistance to monoclonal antibodies or convalescent plasma. These antibody-resistant variants are already present at low frequencies in circulating SARS-CoV-2 populations. The emergence of such variants can be mitigated by using antibody combinations that target distinct neutralizing epitopes, thereby preventing the rise of viruses resistant to specific antibodies. The findings highlight the need for comprehensive strategies to combat SARS-CoV-2 evolution and ensure the long-term effectiveness of vaccines and therapies.