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Potently neutralizing and protective human antibodies against SARS-CoV-2.
Metadata
Journalnature42.778Date
2020 Jul 15
a month ago
Publication Type
Journal Article
Volume
2020-Jul-15 / :
Author
Zost SJ 1, Gilchuk P 1, Case JB 2, Binshtein E 1, Chen RE 2, 3, Nkolola JP 4, Schäfer A 5, Reidy JX 1, Trivette A 1, Nargi RS 1, Sutton RE 1, Suryadevara N 1, Martinez DR 5, Williamson LE 6, Chen EC 6, Jones T 1, Day S 1, Myers L 1, Hassan AO 2, Kafai NM 2, 3, Winkler ES 2, 3, Fox JM 2, Shrihari S 2, Mueller BK 7, Meiler J 7, 8, Chandrashekar A 4, Mercado NB 4, Steinhardt JJ 9, Ren K 10, Loo YM 10, Kallewaard NL 10, McCune BT 2, Keeler SP 2, 11, Holtzman MJ 2, 11, Barouch DH 4, Gralinski LE 5, Baric RS 5, Thackray LB 2, Diamond MS 2, 3, 12, 13, Carnahan RH 14, 15, Crowe JE 16, 17, 18
Affiliation
  • 2. Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
  • 3. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
  • 4. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 5. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 6. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 7. Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
  • 8. Leipzig University Medical School, Institute for Drug Discovery, Leipzig, Germany.
  • 9. Antibody Discovery and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • 10. Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • 11. Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
  • 12. Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA.
  • 13. Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA.
  • 14. Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected]
  • 15. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected]
  • 16. Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected]
  • 17. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected]
  • 18. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected]
Doi
PMIDMESH
Abstract
The ongoing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health1 and the medical countermeasures available so far are limited2,3. Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-24. Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein5, and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (SRBD) from interacting with human angiotensin-converting enzyme 2 (ACE2). Using competition-binding, structural and functional studies, we show that the monoclonal antibodies can be clustered into classes that recognize distinct epitopes on the SRBD, as well as distinct conformational states of the S trimer. Two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130 or a combination of both of these antibodies protected mice from weight loss and reduced the viral burden and levels of inflammation in the lungs. In addition, passive transfer of either of two of the most potent ACE2-blocking monoclonal antibodies (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on the SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents.
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