SARS-CoV-2 spike protein variants can escape neutralizing antibodies, which are key for future protection against the virus. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, researchers showed that mutations in the receptor-binding domain (RBD) and N-terminal domain of the S protein can confer resistance to monoclonal antibodies or convalescent plasma. These resistant variants are now present at low frequencies in circulating SARS-CoV-2 populations. The emergence of antibody-resistant variants can be mitigated by using combinations of antibodies targeting distinct epitopes. The study found that SARS-CoV-2 can mutate its spike proteins to evade antibodies, and these mutations are already present in some circulating virus mutants. This suggests that vaccines should target multiple regions of the spike protein to ensure effective immunity. Antibody-based therapies using combinations of antibodies can prevent the rise of resistant viruses and maintain the effectiveness of vaccines and therapies. The study used a replication-competent VSV/SARS-CoV-2 chimeric virus to select SARS-CoV-2 S variants that escape neutralization by antibodies. They found that mutations conferring resistance to convalescent plasma or RBD-specific monoclonal antibodies can be readily generated in vitro. These resistance mutations are present at low frequencies in natural populations. Using combinations of monoclonal antibodies targeting distinct epitopes can suppress the emergence of antibody resistance. The study also analyzed the natural occurrence of antibody-resistance mutations in SARS-CoV-2 populations. They found that many mutations that confer resistance to monoclonal and plasma antibodies are present in naturally circulating SARS-CoV-2 populations at low frequencies. These mutations are found in the RBD and N-terminal domain of the spike protein, and their presence is consistent with the findings from the selection experiments. The study also tested the ability of these mutations to confer resistance to monoclonal antibodies. They found that mutations at specific positions in the RBD confer resistance to certain monoclonal antibodies, while others confer resistance to different antibodies. The study also found that mutations in the N-terminal domain can confer resistance to convalescent plasma. The study concluded that the use of combinations of monoclonal antibodies targeting distinct epitopes can suppress the emergence of antibody-resistant variants. This is important for the development of effective vaccines and therapies against SARS-CoV-2. The study also highlights the importance of understanding the neutralizing antibody response to SARS-CoV-2 for the development of effective vaccines and therapies.SARS-CoV-2 spike protein variants can escape neutralizing antibodies, which are key for future protection against the virus. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, researchers showed that mutations in the receptor-binding domain (RBD) and N-terminal domain of the S protein can confer resistance to monoclonal antibodies or convalescent plasma. These resistant variants are now present at low frequencies in circulating SARS-CoV-2 populations. The emergence of antibody-resistant variants can be mitigated by using combinations of antibodies targeting distinct epitopes. The study found that SARS-CoV-2 can mutate its spike proteins to evade antibodies, and these mutations are already present in some circulating virus mutants. This suggests that vaccines should target multiple regions of the spike protein to ensure effective immunity. Antibody-based therapies using combinations of antibodies can prevent the rise of resistant viruses and maintain the effectiveness of vaccines and therapies. The study used a replication-competent VSV/SARS-CoV-2 chimeric virus to select SARS-CoV-2 S variants that escape neutralization by antibodies. They found that mutations conferring resistance to convalescent plasma or RBD-specific monoclonal antibodies can be readily generated in vitro. These resistance mutations are present at low frequencies in natural populations. Using combinations of monoclonal antibodies targeting distinct epitopes can suppress the emergence of antibody resistance. The study also analyzed the natural occurrence of antibody-resistance mutations in SARS-CoV-2 populations. They found that many mutations that confer resistance to monoclonal and plasma antibodies are present in naturally circulating SARS-CoV-2 populations at low frequencies. These mutations are found in the RBD and N-terminal domain of the spike protein, and their presence is consistent with the findings from the selection experiments. The study also tested the ability of these mutations to confer resistance to monoclonal antibodies. They found that mutations at specific positions in the RBD confer resistance to certain monoclonal antibodies, while others confer resistance to different antibodies. The study also found that mutations in the N-terminal domain can confer resistance to convalescent plasma. The study concluded that the use of combinations of monoclonal antibodies targeting distinct epitopes can suppress the emergence of antibody-resistant variants. This is important for the development of effective vaccines and therapies against SARS-CoV-2. The study also highlights the importance of understanding the neutralizing antibody response to SARS-CoV-2 for the development of effective vaccines and therapies.