In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies

Dapeng Li; Robert J Edwards; Kartik Manne; David R Martinez; Alexandra Schäfer; S Munir Alam; Kevin Wiehe; Xiaozhi Lu; Robert Parks; Laura L Sutherland; Thomas H Oguin 3rd; Charlene McDanal; Lautaro G Perez; Katayoun Mansouri; Sophie M C Gobeil; Katarzyna Janowska; Victoria Stalls; Megan Kopp; Fangping Cai; Esther Lee; Andrew Foulger; Giovanna E Hernandez; Aja Sanzone; Kedamawit Tilahun; Chuancang Jiang; Longping V Tse; Kevin W Bock; Mahnaz Minai; Bianca M Nagata; Kenneth Cronin; Victoria Gee-Lai; Margaret Deyton; Maggie Barr; Tarra Von Holle; Andrew N Macintyre; Erica Stover; Jared Feldman; Blake M Hauser; Timothy M Caradonna; Trevor D Scobey; Wes Rountree; Yunfei Wang; M Anthony Moody; Derek W Cain; C Todd DeMarco; Thomas N Denny; Christopher W Woods; Elizabeth W Petzold; Aaron G Schmidt; I-Ting Teng; Tongqing Zhou; Peter D Kwong; John R Mascola; Barney S Graham; Ian N Moore; Robert Seder; Hanne Andersen; Mark G Lewis; David C Montefiori; Gregory D Sempowski; Ralph S Baric; Priyamvada Acharya; Barton F Haynes; Kevin O Saunders

doi:10.1016/j.cell.2021.06.021

In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies

Cell. 2021 Aug 5;184(16):4203-4219.e32. doi: 10.1016/j.cell.2021.06.021. Epub 2021 Jun 18.

Authors

Dapeng Li¹, Robert J Edwards¹, Kartik Manne¹, David R Martinez², Alexandra Schäfer², S Munir Alam¹, Kevin Wiehe¹, Xiaozhi Lu¹, Robert Parks¹, Laura L Sutherland¹, Thomas H Oguin 3rd¹, Charlene McDanal³, Lautaro G Perez³, Katayoun Mansouri¹, Sophie M C Gobeil¹, Katarzyna Janowska¹, Victoria Stalls¹, Megan Kopp¹, Fangping Cai¹, Esther Lee¹, Andrew Foulger¹, Giovanna E Hernandez¹, Aja Sanzone¹, Kedamawit Tilahun¹, Chuancang Jiang¹, Longping V Tse², Kevin W Bock⁴, Mahnaz Minai⁴, Bianca M Nagata⁴, Kenneth Cronin¹, Victoria Gee-Lai¹, Margaret Deyton¹, Maggie Barr¹, Tarra Von Holle¹, Andrew N Macintyre¹, Erica Stover¹, Jared Feldman⁵, Blake M Hauser⁵, Timothy M Caradonna⁵, Trevor D Scobey², Wes Rountree¹, Yunfei Wang¹, M Anthony Moody⁶, Derek W Cain¹, C Todd DeMarco¹, Thomas N Denny¹, Christopher W Woods⁷, Elizabeth W Petzold⁸, Aaron G Schmidt⁹, I-Ting Teng¹⁰, Tongqing Zhou¹⁰, Peter D Kwong¹¹, John R Mascola¹⁰, Barney S Graham¹⁰, Ian N Moore⁴, Robert Seder¹⁰, Hanne Andersen¹², Mark G Lewis¹², David C Montefiori³, Gregory D Sempowski¹, Ralph S Baric², Priyamvada Acharya¹³, Barton F Haynes¹⁴, Kevin O Saunders¹⁵

Affiliations

¹ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
² Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Department of Surgery, Duke University, Durham, NC 27710, USA.
⁴ Infectious Disease Pathogenesis Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
⁶ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
⁷ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Center for Applied Genomics and Precision Medicine, Duke University Medical Center, Durham, NC 27710, USA.
⁸ Center for Applied Genomics and Precision Medicine, Duke University Medical Center, Durham, NC 27710, USA.
⁹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA.
¹¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
¹² BIOQUAL, Rockville, MD 20850, USA.
¹³ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke University, Durham, NC 27710, USA.
¹⁴ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: barton.haynes@duke.edu.
¹⁵ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: kevin.saunders@duke.edu.

Abstract

SARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo, increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques.

Keywords: COVID-19; N-terminal domain; SARS-CoV-2; antibody-dependent enhancement; cross-neutralization; electron micrograph; infection enhancement; in vivo protection; neutralizing antibody; receptor-binding domain.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / immunology*
Antibodies, Viral / immunology
Bronchoalveolar Lavage Fluid / chemistry
COVID-19 / pathology
COVID-19 / virology
Cytokines / metabolism
Female
Haplorhini
Humans
Lung / pathology
Lung / virology
Male
Mice
Mice, Inbred BALB C
Protein Domains
Receptors, IgG / metabolism
SARS-CoV-2 / isolation & purification
SARS-CoV-2 / physiology*
Spike Glycoprotein, Coronavirus / chemistry
Spike Glycoprotein, Coronavirus / immunology*
Viral Load
Virus Replication

Substances

Antibodies, Neutralizing
Antibodies, Viral
Cytokines
Receptors, IgG
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding