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Cell
04 01, 2021;184 (7): 1804-1820.e16.

Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection.

Emma S Winkler, Pavlo Gilchuk, Jinsheng Yu, Adam L Bailey, Rita E Chen, Zhenlu Chong, Seth J Zost, Hyesun Jang, Ying Huang, James D Allen, James Brett Case, Rachel E Sutton, Robert H Carnahan, Tamarand L Darling, Adrianus C M Boon, Matthias Mack, Richard D Head, Ted M Ross, James E Crowe, Michael S Diamond
Author Information
  1. Emma S Winkler: Department of Medicine, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA.
  2. Pavlo Gilchuk: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  3. Jinsheng Yu: Department of Genetics, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA.
  4. Adam L Bailey: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA.
  5. Rita E Chen: Department of Medicine, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA.
  6. Zhenlu Chong: Department of Medicine, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA.
  7. Seth J Zost: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  8. Hyesun Jang: Center for Vaccines and Immunology, University of Georgia, Athens, GA 30605, USA.
  9. Ying Huang: Center for Vaccines and Immunology, University of Georgia, Athens, GA 30605, USA.
  10. James D Allen: Center for Vaccines and Immunology, University of Georgia, Athens, GA 30605, USA.
  11. James Brett Case: Department of Medicine, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA.
  12. Rachel E Sutton: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  13. Robert H Carnahan: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  14. Tamarand L Darling: Department of Medicine, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA.
  15. Adrianus C M Boon: Department of Medicine, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA.
  16. Matthias Mack: Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany.
  17. Richard D Head: Department of Genetics, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA.
  18. Ted M Ross: Center for Vaccines and Immunology, University of Georgia, Athens, GA 30605, USA.
  19. James E Crowe: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: james.crowe@vumc.org.
  20. Michael S Diamond: Department of Medicine, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, USA. Electronic address: diamond@wusm.wustl.edu.
PMID: 33691139 DOI: 10.1016/j.cell.2021.02.026

Abstract

SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes and CD8 T cells for optimal clinical and virological benefit. Thus, potently neutralizing mAbs utilize Fc effector functions during therapy to mitigate lung infection and disease.

Keywords

CD8+ T cells RNA sequencing SARS-CoV-2 antibody effector function lung monocytes mouse model pathogenesis therapy

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Grants

  1. 75N93019C00074/NIAID NIH HHS
  2. 75N93019C00062/NIAID NIH HHS
  3. P30 AR073752/NIAMS NIH HHS
  4. R01 AI157155/NIAID NIH HHS
  5. T32 AI007163/NIAID NIH HHS
  6. F30 AI152327/NIAID NIH HHS

MeSH Term

Animals
Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
CD8-Positive T-Lymphocytes
CHO Cells
COVID-19
Chlorocebus aethiops
Cricetulus
Disease Models, Animal
Female
Humans
Immunoglobulin Fc Fragments
Male
Mice
Mice, Inbred C57BL
SARS-CoV-2
Vero Cells
Viral Load

Chemicals

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Immunoglobulin Fc Fragments
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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