期刊
CELL
卷 184, 期 9, 页码 2332-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2021.03.028
关键词
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资金
- National Institute of General Medical Sciences [R01GM120553]
- National Institute of Allergy and Infectious Diseases [DP1AI158186, HHSN272201700059C]
- Pew Biomedical Scholars Award
- Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund
- Fast Grants
- Natural Sciences and Engineering Research Council of Canada
- Pasteur Institute
- University of Washington Arnold and Mabel Beckman cryo-EM center
- Advanced Light Source, a US DOE Office of Science User Facility [DE-AC02-05CH11231]
The study identifies 41 human monoclonal antibodies that recognize the N-terminal domain of the SARS-CoV-2 spike protein and exhibit strong neutralizing activity. These antibodies inhibit cell-to-cell fusion, activate effector functions, and protect animals from virus challenge, highlighting the importance of NTD-specific neutralizing antibodies for protective immunity and vaccine development. Several SARS-CoV-2 variants with mutations in the NTD supersite suggest ongoing selective pressure on the virus.
The SARS-CoV-2 spike (S) glycoprotein contains an immunodominant receptor-binding domain (RBD) targeted by most neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite (designated site i) recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge, albeit selecting escape mutants in some animals. Indeed, several SARSCoV-2 variants, including the B.1.1.7, B.1.351, and P.1 lineages, harbor frequent mutations within the NTD supersite, suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.
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