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Comprehensive mapping of binding hot spots of SARS-CoV-2 RBD-specific neutralizing antibodies for tracking immune escape variants.
Genome Med. 2021 10 14; 13(1):164.GM

Abstract

BACKGROUND

The receptor-binding domain (RBD) variants of SARS-CoV-2 could impair antibody-mediated neutralization of the virus by host immunity; thus, prospective surveillance of antibody escape mutants and understanding the evolution of RBD are urgently needed.

METHODS

Using the single B cell cloning technology, we isolated and characterized 93 RBD-specific antibodies from the memory B cells of four COVID-19 convalescent individuals in the early stage of the pandemic. Then, global RBD alanine scanning with a panel of 19 selected neutralizing antibodies (NAbs), including several broadly reactive NAbs, was performed. Furthermore, we assessed the impact of single natural mutation or co-mutations of concern at key positions of RBD on the neutralization escape and ACE2 binding function by recombinant proteins and pseudoviruses.

RESULTS

Thirty-three amino acid positions within four independent antigenic sites (1 to 4) of RBD were identified as valuable indicators of antigenic changes in the RBD. The comprehensive escape mutation map not only confirms the widely circulating strains carrying important immune escape RBD mutations such as K417N, E484K, and L452R, but also facilitates the discovery of new immune escape-enabling mutations such as F486L, N450K, F490S, and R346S. Of note, these escape mutations could not affect the ACE2 binding affinity of RBD, among which L452R even enhanced binding. Furthermore, we showed that RBD co-mutations K417N, E484K, and N501Y present in B.1.351 appear more resistant to NAbs and human convalescent plasma from the early stage of the pandemic, possibly due to an additive effect. Conversely, double mutations E484Q and L452R present in B.1.617.1 variant show partial antibody evasion with no evidence for an additive effect.

CONCLUSIONS

Our study provides a global view of the determinants for neutralizing antibody recognition, antigenic conservation, and RBD conformation. The in-depth escape maps may have value for prospective surveillance of SARS-CoV-2 immune escape variants. Special attention should be paid to the accumulation of co-mutations at distinct major antigenic sites. Finally, the new broadly reactive NAbs described here represent new potential opportunities for the prevention and treatment of COVID-19.

Authors+Show Affiliations

State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, 201508, China.Key Laboratory of Medical Molecular Virology (MOE/MOH), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, 200032, China.Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, 201508, China.State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. University of Chinese Academy of Sciences, Beijing, 100049, China.State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.Shanghai Institute of Biological Products Co., Ltd, Shanghai, 200052, China.Shanghai Institute of Biological Products Co., Ltd, Shanghai, 200052, China.Shanghai Institute of Biological Products Co., Ltd, Shanghai, 200052, China.Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, 201508, China.State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. Zhiyangling@sibs.ac.cn.Key Laboratory of Medical Molecular Virology (MOE/MOH), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, 200032, China. yhxie@fudan.edu.cn.Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, 201508, China. luhongzhou@fudan.edu.cn.State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. bsun@sibs.ac.cn. University of Chinese Academy of Sciences, Beijing, 100049, China. bsun@sibs.ac.cn. School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210, China. bsun@sibs.ac.cn. Bio-Research Innovation Center Suzhou, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Suzhou, 215121, China. bsun@sibs.ac.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34649620

Citation

Yi, Chunyan, et al. "Comprehensive Mapping of Binding Hot Spots of SARS-CoV-2 RBD-specific Neutralizing Antibodies for Tracking Immune Escape Variants." Genome Medicine, vol. 13, no. 1, 2021, p. 164.
Yi C, Sun X, Lin Y, et al. Comprehensive mapping of binding hot spots of SARS-CoV-2 RBD-specific neutralizing antibodies for tracking immune escape variants. Genome Med. 2021;13(1):164.
Yi, C., Sun, X., Lin, Y., Gu, C., Ding, L., Lu, X., Yang, Z., Zhang, Y., Ma, L., Gu, W., Qu, A., Zhou, X., Li, X., Xu, J., Ling, Z., Xie, Y., Lu, H., & Sun, B. (2021). Comprehensive mapping of binding hot spots of SARS-CoV-2 RBD-specific neutralizing antibodies for tracking immune escape variants. Genome Medicine, 13(1), 164. https://doi.org/10.1186/s13073-021-00985-w
Yi C, et al. Comprehensive Mapping of Binding Hot Spots of SARS-CoV-2 RBD-specific Neutralizing Antibodies for Tracking Immune Escape Variants. Genome Med. 2021 10 14;13(1):164. PubMed PMID: 34649620.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive mapping of binding hot spots of SARS-CoV-2 RBD-specific neutralizing antibodies for tracking immune escape variants. AU - Yi,Chunyan, AU - Sun,Xiaoyu, AU - Lin,Yixiao, AU - Gu,Chenjian, AU - Ding,Longfei, AU - Lu,Xiao, AU - Yang,Zhuo, AU - Zhang,Yaguang, AU - Ma,Liyan, AU - Gu,Wangpeng, AU - Qu,Aidong, AU - Zhou,Xu, AU - Li,Xiuling, AU - Xu,Jianqing, AU - Ling,Zhiyang, AU - Xie,Youhua, AU - Lu,Hongzhou, AU - Sun,Bing, Y1 - 2021/10/14/ PY - 2021/07/08/received PY - 2021/09/30/accepted PY - 2021/10/15/entrez PY - 2021/10/16/pubmed PY - 2021/10/26/medline KW - Escape variants KW - Neutralizing antibodies KW - RBD antigenic sits KW - SARS-CoV-2 SP - 164 EP - 164 JF - Genome medicine JO - Genome Med VL - 13 IS - 1 N2 - BACKGROUND: The receptor-binding domain (RBD) variants of SARS-CoV-2 could impair antibody-mediated neutralization of the virus by host immunity; thus, prospective surveillance of antibody escape mutants and understanding the evolution of RBD are urgently needed. METHODS: Using the single B cell cloning technology, we isolated and characterized 93 RBD-specific antibodies from the memory B cells of four COVID-19 convalescent individuals in the early stage of the pandemic. Then, global RBD alanine scanning with a panel of 19 selected neutralizing antibodies (NAbs), including several broadly reactive NAbs, was performed. Furthermore, we assessed the impact of single natural mutation or co-mutations of concern at key positions of RBD on the neutralization escape and ACE2 binding function by recombinant proteins and pseudoviruses. RESULTS: Thirty-three amino acid positions within four independent antigenic sites (1 to 4) of RBD were identified as valuable indicators of antigenic changes in the RBD. The comprehensive escape mutation map not only confirms the widely circulating strains carrying important immune escape RBD mutations such as K417N, E484K, and L452R, but also facilitates the discovery of new immune escape-enabling mutations such as F486L, N450K, F490S, and R346S. Of note, these escape mutations could not affect the ACE2 binding affinity of RBD, among which L452R even enhanced binding. Furthermore, we showed that RBD co-mutations K417N, E484K, and N501Y present in B.1.351 appear more resistant to NAbs and human convalescent plasma from the early stage of the pandemic, possibly due to an additive effect. Conversely, double mutations E484Q and L452R present in B.1.617.1 variant show partial antibody evasion with no evidence for an additive effect. CONCLUSIONS: Our study provides a global view of the determinants for neutralizing antibody recognition, antigenic conservation, and RBD conformation. The in-depth escape maps may have value for prospective surveillance of SARS-CoV-2 immune escape variants. Special attention should be paid to the accumulation of co-mutations at distinct major antigenic sites. Finally, the new broadly reactive NAbs described here represent new potential opportunities for the prevention and treatment of COVID-19. SN - 1756-994X UR - https://www.unboundmedicine.com/medline/citation/34649620/Comprehensive_mapping_of_binding_hot_spots_of_SARS_CoV_2_RBD_specific_neutralizing_antibodies_for_tracking_immune_escape_variants_ L2 - https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-021-00985-w DB - PRIME DP - Unbound Medicine ER -