Analysis of SARS-CoV-2 variant mutations reveals neutralization escape mechanisms and the ability to use ACE2 receptors from additional species

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 7; pp. 1611 - 1621.e5
• Main Authors: Wang, Ruoke, Zhang, Qi, Ge, Jiwan, Ren, Wenlin, Zhang, Rui, Lan, Jun, Ju, Bin, Su, Bin, Yu, Fengting, Chen, Peng, Liao, Huiyu, Feng, Yingmei, Li, Xuemei, Shi, Xuanling, Zhang, Zheng, Zhang, Fujie, Ding, Qiang, Zhang, Tong, Wang, Xinquan, Zhang, Linqi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.07.2021; Elsevier Limited
• Subjects: ACE2; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; antibody; Antigenic Variation - genetics; Antigens; Coronaviruses; COVID-19; COVID-19 - immunology; COVID-19 - virology; COVID-19 vaccines; Crystal structure; Disease transmission; Domains; Host range; Host Specificity; Humans; immune escape; Immune Evasion - genetics; Immunotherapy; Infections; Mice; Mink; Monoclonal antibodies; Mutation; Neutralization; Pandemics; Protein Binding; Proteins; Receptors; RNA polymerase; SARS-CoV-2; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; SARS-CoV-2 - physiology; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; Structural analysis; Vaccines; variant of concern; Viral diseases; Virus Internalization; United Kingdom > UK; England; variant of concern; SARS-CoV-2; immune escape; antibody; neutralization
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2021.06.003

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge during the global pandemic and may facilitate escape from current antibody therapies and vaccine protection. Here we showed that the South African variant B.1.351 was the most resistant to current monoclonal antibodies and convalescent plasma from coronavirus disease 2019 (COVID-19)-infected individuals, followed by the Brazilian variant P.1 and the United Kingdom variant B.1.1.7. This resistance hierarchy corresponded with Y144del and 242–244del mutations in the N-terminal domain and K417N/T, E484K, and N501Y mutations in the receptor-binding domain (RBD) of SARS-CoV-2. Crystal structure analysis of the B.1.351 triple mutant (417N-484K-501Y) RBD complexed with the monoclonal antibody P2C-1F11 revealed the molecular basis for antibody neutralization and escape. B.1.351 and P.1 also acquired the ability to use mouse and mink ACE2 receptors for entry. Our results demonstrate major antigenic shifts and potential broadening of the host range for B.1.351 and P.1 variants, which poses serious challenges to current antibody therapies and vaccine protection. [Display omitted] •SARS-CoV-2 variants of concern are resistant to antibody neutralization•B.1.351 variant is the most resistant, followed by P.1 and B.1.1.7•The resistance hierarchy corresponds to mutations in NTD and RBD•B.1.351 and P.1 acquire the ability to use mouse and mink ACE2 for entry SARS-CoV-2 variants continue to emerge and spread around the world. Wang et al. conduct comprehensive mutational and crystal structure analyses of the variants and show that variants of concern, and the South African variant B.1.351 in particular, are resistant to many monoclonal antibodies and COVID-19 convalescent plasma and acquire the ability to use mouse and mink ACE2 receptors for infection.