A structure-function analysis of the SARS-CoV-2 variant B.1.351 using serum samples from convalescent and vaccinated individuals reveals how mutations in the viral spike protein result in tighter binding to the receptor ACE2 and allow escape from monoclonal antibody neutralization. The study shows that the B.1.351 variant has mutations in the receptor-binding domain (RBD) that cause widespread escape from monoclonal antibodies (mAbs), particularly E484K, K417N, and N501Y. These mutations reduce the neutralization titer of sera from both naturally infected and vaccinated individuals by 8- to 9-fold for Pfizer and AstraZeneca vaccinees. The study also shows that the N-terminal domain (NTD) deletion in B.1.351 abrogates neutralization by a potent neutralizing human mAb. The results indicate that convalescent and some vaccine sera offer limited protection against this variant. The study highlights the importance of understanding the structural and functional changes in the spike protein that enable immune escape and the need for new vaccine strategies to target these variants. The findings suggest that the B.1.351 variant is more difficult to neutralize than parental strains, with 14 of 20 mAbs showing significant reduction or complete loss of neutralization activity. The study also shows that the Oxford-AstraZeneca and Pfizer vaccines have reduced efficacy against B.1.351, with neutralization titers reduced by 9-fold and 7.6-fold, respectively. The results emphasize the need for continued surveillance and research to develop effective vaccines and treatments against emerging variants of SARS-CoV-2.A structure-function analysis of the SARS-CoV-2 variant B.1.351 using serum samples from convalescent and vaccinated individuals reveals how mutations in the viral spike protein result in tighter binding to the receptor ACE2 and allow escape from monoclonal antibody neutralization. The study shows that the B.1.351 variant has mutations in the receptor-binding domain (RBD) that cause widespread escape from monoclonal antibodies (mAbs), particularly E484K, K417N, and N501Y. These mutations reduce the neutralization titer of sera from both naturally infected and vaccinated individuals by 8- to 9-fold for Pfizer and AstraZeneca vaccinees. The study also shows that the N-terminal domain (NTD) deletion in B.1.351 abrogates neutralization by a potent neutralizing human mAb. The results indicate that convalescent and some vaccine sera offer limited protection against this variant. The study highlights the importance of understanding the structural and functional changes in the spike protein that enable immune escape and the need for new vaccine strategies to target these variants. The findings suggest that the B.1.351 variant is more difficult to neutralize than parental strains, with 14 of 20 mAbs showing significant reduction or complete loss of neutralization activity. The study also shows that the Oxford-AstraZeneca and Pfizer vaccines have reduced efficacy against B.1.351, with neutralization titers reduced by 9-fold and 7.6-fold, respectively. The results emphasize the need for continued surveillance and research to develop effective vaccines and treatments against emerging variants of SARS-CoV-2.