Cross-neutralizing antibodies bind a SARS-CoV-2 cryptic site and resist circulating variants

Tingting Li; Wenhui Xue; Qingbing Zheng; Shuo Song; Chuanlai Yang; Hualong Xiong; Sibo Zhang; Minqing Hong; Yali Zhang; Hai Yu; Yuyun Zhang; Hui Sun; Yang Huang; Tingting Deng; Xin Chi; Jinjin Li; Shaojuan Wang; Lizhi Zhou; Tingting Chen; Yingbin Wang; Tong Cheng; Tianying Zhang; Quan Yuan; Qinjian Zhao; Jun Zhang; Jason S McLellan; Z Hong Zhou; Zheng Zhang; Shaowei Li; Ying Gu; Ningshao Xia

doi:10.1038/s41467-021-25997-3

Cross-neutralizing antibodies bind a SARS-CoV-2 cryptic site and resist circulating variants

Nat Commun. 2021 Sep 27;12(1):5652. doi: 10.1038/s41467-021-25997-3.

Authors

Tingting Li^#^{1

2}, Wenhui Xue^#^{1

2}, Qingbing Zheng^#^{1

2}, Shuo Song^#^{3

4}, Chuanlai Yang^#^{1

2}, Hualong Xiong^#^{1

2}, Sibo Zhang^{1

2}, Minqing Hong^{1

2}, Yali Zhang^{1

2}, Hai Yu^{1

2}, Yuyun Zhang^{1

2}, Hui Sun^{1

2}, Yang Huang^{1

2}, Tingting Deng^{1

2}, Xin Chi^{1

2}, Jinjin Li^{1

2}, Shaojuan Wang^{1

2}, Lizhi Zhou^{1

2}, Tingting Chen^{1

2}, Yingbin Wang^{1

2}, Tong Cheng^{1

2}, Tianying Zhang^{1

2}, Quan Yuan^{1

2}, Qinjian Zhao^{1

2}, Jun Zhang^{1

2}, Jason S McLellan⁵, Z Hong Zhou^{6

7}, Zheng Zhang^{8

9}, Shaowei Li^{10

11}, Ying Gu^{12

13}, Ningshao Xia^{14

15

16}

Affiliations

¹ State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, 361102, Xiamen, Fujian, China.
² National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, 361102, Xiamen, Fujian, China.
³ Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, 518112, Shenzhen, Guangdong, China.
⁴ The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, 518112, Shenzhen, Guangdong, China.
⁵ Department of Molecular Biosciences, The University of Texas at Austin, Austin, 78712, TX, USA.
⁶ California NanoSystems Institute (CNSI), UCLA, Los Angeles, 90095, CA, USA. [email protected].
⁷ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, 90095, CA, USA. [email protected].
⁸ Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, 518112, Shenzhen, Guangdong, China. [email protected].
⁹ The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, 518112, Shenzhen, Guangdong, China. [email protected].
¹⁰ State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, 361102, Xiamen, Fujian, China. [email protected].
¹¹ National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, 361102, Xiamen, Fujian, China. [email protected].
¹² State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, 361102, Xiamen, Fujian, China. [email protected].
¹³ National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, 361102, Xiamen, Fujian, China. [email protected].
¹⁴ State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, 361102, Xiamen, Fujian, China. [email protected].
¹⁵ National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, 361102, Xiamen, Fujian, China. [email protected].
¹⁶ Research Unit of Frontier Technology of Structural Vaccinology, Chinese Academy of Medical Sciences, 518112, Xiamen, Fujian, China. [email protected].

^# Contributed equally.

Abstract

The emergence of numerous variants of SARS-CoV-2, the causative agent of COVID-19, has presented new challenges to the global efforts to control the COVID-19 pandemic. Here, we obtain two cross-neutralizing antibodies (7D6 and 6D6) that target Sarbecoviruses' receptor-binding domain (RBD) with sub-picomolar affinities and potently neutralize authentic SARS-CoV-2. Crystal structures show that both antibodies bind a cryptic site different from that recognized by existing antibodies and highly conserved across Sarbecovirus isolates. Binding of these two antibodies to the RBD clashes with the adjacent N-terminal domain and disrupts the viral spike. Both antibodies confer good resistance to mutations in the currently circulating SARS-CoV-2 variants. Thus, our results have direct relevance to public health as options for passive antibody therapeutics and even active prophylactics. They can also inform the design of pan-sarbecovirus vaccines.

Publication types

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

MeSH terms

Animals
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal / immunology
Antibodies, Monoclonal / isolation & purification
Antibodies, Monoclonal / metabolism
Antibodies, Viral / administration & dosage
Antibodies, Viral / immunology*
Antibodies, Viral / isolation & purification
Antibodies, Viral / metabolism
Binding Sites / genetics
Binding Sites / immunology
Broadly Neutralizing Antibodies / administration & dosage
Broadly Neutralizing Antibodies / immunology*
Broadly Neutralizing Antibodies / isolation & purification
Broadly Neutralizing Antibodies / metabolism
CHO Cells
COVID-19 / epidemiology
COVID-19 / immunology
COVID-19 / therapy*
COVID-19 / virology
Chlorocebus aethiops
Cricetulus
Epitopes / immunology
HEK293 Cells
Humans
Immunization, Passive / methods*
Mice
Middle East Respiratory Syndrome Coronavirus / genetics
Middle East Respiratory Syndrome Coronavirus / immunology
Neutralization Tests
Pandemics / prevention & control
Protein Multimerization
Receptors, Virus / metabolism
SARS-CoV-2 / genetics
SARS-CoV-2 / immunology*
Sf9 Cells
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / immunology
Spike Glycoprotein, Coronavirus / metabolism
Vero Cells

Substances

Antibodies, Monoclonal
Antibodies, Viral
Broadly Neutralizing Antibodies
Epitopes
Receptors, Virus
Spike Glycoprotein, Coronavirus
spike glycoprotein, SARS-CoV
spike protein, SARS-CoV-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding