2. Academic Validation
  3. Potently neutralizing and protective human antibodies against SARS-CoV-2

Potently neutralizing and protective human antibodies against SARS-CoV-2

  • Nature. 2020 Aug;584(7821):443-449. doi: 10.1038/s41586-020-2548-6.
Seth J Zost # 1,  Pavlo Gilchuk # 1,  James Brett Case 2,  Elad Binshtein 1,  Rita E Chen 2 3,  Joseph P Nkolola 4,  Alexandra Schäfer 5,  Joseph X Reidy 1,  Andrew Trivette 1,  Rachel S Nargi 1,  Rachel E Sutton 1,  Naveenchandra Suryadevara 1,  David R Martinez 5,  Lauren E Williamson 6,  Elaine C Chen 6,  Taylor Jones 1,  Samuel Day 1,  Luke Myers 1,  Ahmed O Hassan 2,  Natasha M Kafai 2 3,  Emma S Winkler 2 3,  Julie M Fox 2,  Swathi Shrihari 2,  Benjamin K Mueller 7,  Jens Meiler 7 8,  Abishek Chandrashekar 4,  Noe B Mercado 4,  James J Steinhardt 9,  Kuishu Ren 10,  Yueh-Ming Loo 10,  Nicole L Kallewaard 10,  Broc T McCune 2,  Shamus P Keeler 2 11,  Michael J Holtzman 2 11,  Dan H Barouch 4,  Lisa E Gralinski 5,  Ralph S Baric 5,  Larissa B Thackray 2,  Michael S Diamond 2 3 12 13,  Robert H Carnahan 14 15,  James E Crowe Jr 16 17 18
Affiliations

Affiliations

  • 1 Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 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. Robert.carnahan@vumc.org.
  • 15 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA. Robert.carnahan@vumc.org.
  • 16 Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA. james.crowe@vumc.org.
  • 17 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. james.crowe@vumc.org.
  • 18 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA. james.crowe@vumc.org.
  • # Contributed equally.
PMID: 32668443 DOI: 10.1038/s41586-020-2548-6
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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