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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

References

  1. Virol Sin. 2018 Apr;33(2):201-204 [PMID: 29541941]
  2. J Virol. 2011 Dec;85(23):12201-15 [PMID: 21937658]
  3. Nature. 1992 Jul 23;358(6384):337-41 [PMID: 1386408]
  4. JAMA. 2020 Jul 14;324(2):131-132 [PMID: 32539093]
  5. Virology. 2016 Oct;497:33-40 [PMID: 27420797]
  6. J Am Coll Cardiol. 2020 Oct 27;76(17):1982-1994 [PMID: 33092734]
  7. Nucleic Acids Res. 2015 Sep 3;43(15):e97 [PMID: 25925576]
  8. Science. 2020 Aug 21;369(6506):1010-1014 [PMID: 32540901]
  9. Nature. 2020 Aug;584(7821):437-442 [PMID: 32555388]
  10. J Immunol. 2020 Aug 15;205(4):915-922 [PMID: 32591393]
  11. Immunol Rev. 2015 Nov;268(1):340-64 [PMID: 26497532]
  12. Cell. 2014 Sep 11;158(6):1243-1253 [PMID: 25215485]
  13. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14556-61 [PMID: 22908282]
  14. Nature. 2020 Aug;584(7819):120-124 [PMID: 32454512]
  15. Bioinformatics. 2014 Apr 1;30(7):923-30 [PMID: 24227677]
  16. Cell. 2020 Nov 12;183(4):1070-1085.e12 [PMID: 33031744]
  17. Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):20054-20062 [PMID: 31484758]
  18. Nat Med. 2020 Sep;26(9):1422-1427 [PMID: 32651581]
  19. Cell. 2020 Jul 9;182(1):73-84.e16 [PMID: 32425270]
  20. Prog Mol Biol Transl Sci. 2015;129:141-66 [PMID: 25595803]
  21. Cell Host Microbe. 2020 May 13;27(5):699-703 [PMID: 32407708]
  22. Nature. 2020 Jul;583(7815):290-295 [PMID: 32422645]
  23. Small GTPases. 2015;6(1):1-7 [PMID: 25862160]
  24. Nat Microbiol. 2020 Oct;5(10):1185-1191 [PMID: 32908214]
  25. N Engl J Med. 2021 Jan 21;384(3):229-237 [PMID: 33113295]
  26. J Clin Invest. 2020 Dec 1;130(12):6290-6300 [PMID: 32784290]
  27. Nature. 2020 Aug;584(7821):450-456 [PMID: 32698192]
  28. Cell. 2020 Dec 10;183(6):1508-1519.e12 [PMID: 33207184]
  29. Sci Rep. 2017 Mar 30;7:45552 [PMID: 28358050]
  30. Cell. 2020 Aug 6;182(3):744-753.e4 [PMID: 32553273]
  31. Emerg Microbes Infect. 2020 Dec;9(1):2673-2684 [PMID: 33251966]
  32. Cell. 2020 Nov 12;183(4):1058-1069.e19 [PMID: 33058755]
  33. Nucleic Acids Res. 2015 Apr 20;43(7):e47 [PMID: 25605792]
  34. Nat Med. 2014 Feb;20(2):143-51 [PMID: 24412922]
  35. Immunity. 2005 Nov;23(5):503-14 [PMID: 16286018]
  36. Nat Rev Immunol. 2020 Jul;20(7):401-403 [PMID: 32533109]
  37. Science. 2020 May 8;368(6491):630-633 [PMID: 32245784]
  38. Immunity. 2020 Oct 13;53(4):724-732.e7 [PMID: 32783919]
  39. Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4005-10 [PMID: 16537476]
  40. Nature. 2020 Jul;583(7818):834-838 [PMID: 32408338]
  41. Nature. 2020 Aug;584(7819):115-119 [PMID: 32454513]
  42. Virology. 2020 Sep;548:39-48 [PMID: 32838945]
  43. J Exp Med. 1999 Jan 4;189(1):179-85 [PMID: 9874574]
  44. Sci Immunol. 2019 Feb 22;4(32): [PMID: 30796092]
  45. J Immunol. 1981 Mar;126(3):1042-6 [PMID: 7462625]
  46. MAbs. 2015;7(2):403-12 [PMID: 25621616]
  47. Science. 2020 Aug 21;369(6506):956-963 [PMID: 32540903]
  48. Science. 2020 Nov 27;370(6520):1110-1115 [PMID: 33037066]
  49. Curr Top Microbiol Immunol. 2014;382:237-48 [PMID: 25116103]
  50. J Biol Chem. 2017 Mar 3;292(9):3900-3908 [PMID: 28077575]
  51. Science. 2016 May 20;352(6288):1001-4 [PMID: 27199430]
  52. Nat Rev Immunol. 2020 Jun;20(6):355-362 [PMID: 32376901]
  53. Lancet Infect Dis. 2020 May;20(5):533-534 [PMID: 32087114]
  54. Bioinformatics. 2010 Jan 1;26(1):139-40 [PMID: 19910308]
  55. J Virol. 2004 Apr;78(7):3572-7 [PMID: 15016880]
  56. J Exp Med. 2007 Jun 11;204(6):1359-69 [PMID: 17502666]
  57. Nature. 2020 Dec;588(7838):485-490 [PMID: 33032297]
  58. J Virol. 2011 Nov;85(22):11567-80 [PMID: 21917960]
  59. J Immunol. 2008 Nov 1;181(9):6664-9 [PMID: 18941257]
  60. J Virol. 2007 Jan;81(2):813-21 [PMID: 17079315]
  61. Nature. 2007 Sep 6;449(7158):101-4 [PMID: 17805298]
  62. Science. 2019 Jul 12;365(6449): [PMID: 31296738]
  63. J Clin Invest. 2016 Feb;126(2):605-10 [PMID: 26731473]
  64. Nature. 2020 Aug;584(7821):443-449 [PMID: 32668443]
  65. J Exp Med. 2021 Mar 1;218(3): [PMID: 33211088]
  66. Adv Immunol. 2006;89:39-86 [PMID: 16682272]
  67. PLoS Pathog. 2013 Mar;9(3):e1003207 [PMID: 23516357]
  68. Bioinformatics. 2013 Jan 1;29(1):15-21 [PMID: 23104886]
  69. Nat Commun. 2020 Aug 27;11(1):4303 [PMID: 32855401]
  70. JCI Insight. 2020 Oct 2;5(19): [PMID: 32841215]
  71. J Immunol. 2001 Apr 1;166(7):4697-704 [PMID: 11254730]
  72. Elife. 2017 Sep 26;6: [PMID: 28949917]
  73. Nat Med. 2020 Nov;26(11):1694-1700 [PMID: 32884153]
  74. Front Immunol. 2019 Jun 07;10:1296 [PMID: 31231397]
  75. Science. 2015 Jul 3;349(6243):88-91 [PMID: 26138979]
  76. Vaccine. 2006 Feb 13;24(7):1028-34 [PMID: 16388880]
  77. Cell. 2020 Sep 17;182(6):1419-1440.e23 [PMID: 32810438]
  78. Front Immunol. 2020 Dec 18;11:614256 [PMID: 33391285]
  79. Nat Rev Immunol. 2017 Jun;17(6):349-362 [PMID: 28436425]
  80. Nat Commun. 2017 Oct 10;8(1):846 [PMID: 29018261]
  81. Immunity. 2019 Sep 17;51(3):429-442 [PMID: 31533056]
  82. J Vis Exp. 2013 May 15;(75):e50172 [PMID: 23711876]
  83. Cell Host Microbe. 2020 Jun 10;27(6):992-1000.e3 [PMID: 32320677]
  84. Cell. 2021 Jan 7;184(1):149-168.e17 [PMID: 33278357]
  85. Nat Rev Immunol. 2018 Jan;18(1):46-61 [PMID: 29063907]
  86. Nat Med. 2020 Feb;26(2):222-227 [PMID: 32015556]
  87. Nat Rev Immunol. 2020 Jun;20(6):363-374 [PMID: 32346093]
  88. Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6181-6 [PMID: 22474370]
  89. Immunity. 2003 Jul;19(1):59-70 [PMID: 12871639]
  90. J Infect Dis. 2020 Nov 13;222(12):1946-1950 [PMID: 32785649]
  91. Nat Immunol. 2020 Nov;21(11):1327-1335 [PMID: 32839612]

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

Links to CNCB-NGDC Resources

GEN: GEND000450 (Neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic activity)

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