Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

Vincent Dussupt; Rajeshwer S Sankhala; Letzibeth Mendez-Rivera; Samantha M Townsley; Fabian Schmidt; Lindsay Wieczorek; Kerri G Lal; Gina C Donofrio; Ursula Tran; Nathaniel D Jackson; Weam I Zaky; Michelle Zemil; Sarah R Tritsch; Wei-Hung Chen; Elizabeth J Martinez; Aslaa Ahmed; Misook Choe; William C Chang; Agnes Hajduczki; Ningbo Jian; Caroline E Peterson; Phyllis A Rees; Magdalena Rutkowska; Bonnie M Slike; Christopher N Selverian; Isabella Swafford; I-Ting Teng; Paul V Thomas; Tongqing Zhou; Clayton J Smith; Jeffrey R Currier; Peter D Kwong; Morgane Rolland; Edgar Davidson; Benjamin J Doranz; Christopher N Mores; Theodora Hatziioannou; William W Reiley; Paul D Bieniasz; Dominic Paquin-Proulx; Gregory D Gromowski; Victoria R Polonis; Nelson L Michael; Kayvon Modjarrad; M Gordon Joyce; Shelly J Krebs

doi:10.1038/s41590-021-01068-z

Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

Nat Immunol. 2021 Dec;22(12):1503-1514. doi: 10.1038/s41590-021-01068-z. Epub 2021 Oct 29.

Authors

Vincent Dussupt^#^{1

2

3}, Rajeshwer S Sankhala^#^{1

3}, Letzibeth Mendez-Rivera^{2

3}, Samantha M Townsley^{2

3}, Fabian Schmidt⁴, Lindsay Wieczorek^{2

3}, Kerri G Lal^{1

2

3}, Gina C Donofrio^{2

3}, Ursula Tran^{2

3}, Nathaniel D Jackson^{1

2

3}, Weam I Zaky^{2

3}, Michelle Zemil^{2

3}, Sarah R Tritsch⁵, Wei-Hung Chen^{1

3}, Elizabeth J Martinez^{1

3}, Aslaa Ahmed⁶, Misook Choe^{1

3}, William C Chang^{1

3}, Agnes Hajduczki^{1

3}, Ningbo Jian^{2

3}, Caroline E Peterson^{1

3}, Phyllis A Rees^{1

3}, Magdalena Rutkowska⁴, Bonnie M Slike^{2

3}, Christopher N Selverian⁷, Isabella Swafford^{2

3}, I-Ting Teng⁸, Paul V Thomas^{1

3}, Tongqing Zhou⁸, Clayton J Smith⁹, Jeffrey R Currier⁶, Peter D Kwong⁸, Morgane Rolland^{2

3}, Edgar Davidson⁷, Benjamin J Doranz⁷, Christopher N Mores⁵, Theodora Hatziioannou⁴, William W Reiley¹⁰, Paul D Bieniasz^{4

11}, Dominic Paquin-Proulx^{2

3}, Gregory D Gromowski⁶, Victoria R Polonis², Nelson L Michael¹², Kayvon Modjarrad¹, M Gordon Joyce^{13

14}, Shelly J Krebs^{15

16

17}

Affiliations

¹ Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
² U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
³ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
⁴ Laboratory of Retrovirology, The Rockefeller University, New York, NY, USA.
⁵ Milken Institute School of Public Health, The George Washington University, Washington, DC, USA.
⁶ Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁷ Integral Molecular, Philadelphia, PA, USA.
⁸ Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA.
⁹ NCI, NIH, Bethesda, MD, USA.
¹⁰ Trudeau Institute, Saranac Lake, NY, USA.
¹¹ Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
¹² Center of Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
¹³ Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA. gjoyce@eidresearch.org.
¹⁴ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA. gjoyce@eidresearch.org.
¹⁵ Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA. skrebs@hivresearch.org.
¹⁶ U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA. skrebs@hivresearch.org.
¹⁷ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA. skrebs@hivresearch.org.

^# Contributed equally.

Abstract

Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

Publication types

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

MeSH terms

Amino Acid Sequence
Animals
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal / immunology*
Antibodies, Monoclonal / metabolism
Antibodies, Neutralizing / chemistry
Antibodies, Neutralizing / immunology*
Antibodies, Neutralizing / metabolism
Antibodies, Viral / immunology
Antibodies, Viral / metabolism
Binding Sites / genetics
COVID-19 / immunology*
COVID-19 / metabolism
COVID-19 / prevention & control
Disease Models, Animal
Dose-Response Relationship, Drug
Epitope Mapping
Epitopes / chemistry
Epitopes / immunology
Epitopes / metabolism
Humans
Mice, Transgenic
Neutralization Tests
Protein Binding
Protein Conformation
SARS-CoV-2 / genetics
SARS-CoV-2 / immunology*
SARS-CoV-2 / metabolism
Sequence Homology, Amino Acid
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / immunology*
Spike Glycoprotein, Coronavirus / metabolism
Survival Analysis

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Epitopes
Spike Glycoprotein, Coronavirus

Supplementary concepts

SARS-CoV-2 variants

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding