OmniVira

Literature detail

Broad sarbecovirus neutralization by a human monoclonal antibody.

M Alejandra Tortorici1,2 Nadine Czudnochowski3 Tyler N Starr4 Roberta Marzi5 Alexandra C Walls1 Fabrizia Zatta5 John E Bowen1 Stefano Jaconi5 Julia Di Iulio3 Zhaoqian Wang1 Anna De Marco5 Samantha K Zepeda1 Dora Pinto5 Zhuoming Liu6 Martina Beltramello5 Istvan Bartha5 Michael P Housley3 Florian A Lempp3 Laura E Rosen3 Exequiel Dellota3 Hannah Kaiser3 Martin Montiel-Ruiz3 Jiayi Zhou3 Amin Addetia4 Barbara Guarino3 Katja Culap5 Nicole Sprugasci5 Christian Saliba5 Eneida Vetti5 Isabella Giacchetto-Sasselli5 Chiara Silacci Fregni5 Rana Abdelnabi7 Shi-Yan Caroline Foo7 Colin Havenar-Daughton3 Michael A Schmid5 Fabio Benigni5 Elisabetta Cameroni5 Johan Neyts7 Amalio Telenti3 Herbert W Virgin3 Sean P J Whelan6 Gyorgy Snell3 Jesse D Bloom4,8 Davide Corti9 David Veesler10 Matteo Samuele Pizzuto11
Affiliations 11 institutions
  1. Department of Biochemistry, University of Washington, Seattle, WA, USA.
  2. Institut Pasteur and CNRS UMR 3569, Unité de Virologie Structurale, Paris, France.
  3. Vir Biotechnology, San Francisco, CA, USA.
  4. Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  5. Humabs Biomed SA, a subsidiary of Vir Biotechnology, Bellinzona, Switzerland.
  6. Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA.
  7. Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium.
  8. Howard Hughes Medical Institute, Seattle, WA, USA.
  9. Humabs Biomed SA, a subsidiary of Vir Biotechnology, Bellinzona, Switzerland. [email protected].
  10. Department of Biochemistry, University of Washington, Seattle, WA, USA. [email protected].
  11. Humabs Biomed SA, a subsidiary of Vir Biotechnology, Bellinzona, Switzerland. [email protected].
PMID 34280951 2021 Nature eng ppublish
PubMed DOI Browse context

Article

Publication summary

The recent emergence of SARS-CoV-2 variants of concern<sup>1-10</sup> and the recurrent spillovers of coronaviruses<sup>11,12</sup> into the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here we describe a human monoclonal antibody designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses.

Animals Antibodies, Monoclonal Antibodies, Viral Broadly Neutralizing Antibodies COVID-19 Cross Reactions Disease Models, Animal Female Humans Immune Evasion Mesocricetus Mutation Neutralization Tests SARS-CoV-2 Viral Zoonoses

Structured evidence records

Evidence records

4 total
Host Range Experiment 2 records
Host Range Experiment Extraction confidence 0.90
Key finding

Syrian hamsters were experimentally infected with SARS-CoV-2 and the B.1.351 variant, and administration of the monoclonal antibody S2X259 conferred protection, demonstrating infection and protection in this animal model.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern.

Method
challenge study; experimental infection
Experimental system
in vivo animal experiment
Host Range Experiment Extraction confidence 0.85
Key finding

In vitro assays demonstrated that the monoclonal antibody S2X259 neutralized spike-mediated cell entry across human and zoonotic sarbecoviruses, showing cross-species entry inhibition.

Virus
Sarbecovirus
Location
Not specified
Supporting text

S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern, as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding.

Method
neutralization assay; cell-entry assay
Experimental system
in vitro cell culture
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.85
Key finding

A single spike mutation, G504D, confers escape from the broadly neutralizing antibody S2X259 in SARS-CoV-2, indicating a molecular adaptation affecting immune recognition.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

Deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D.

Genes or proteins
spike; receptor-binding domain
Receptors
ACE2
Mutations
G504D
Mechanism types
immune_escape; receptor_binding
Receptor Usage 1 records
Receptor Usage Extraction confidence 0.95
Key finding

S2X259 inhibits sarbecovirus spike-mediated entry by blocking the interaction between viral receptor-binding domains and the ACE2 receptor.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern, as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain.

Method
neutralization assay; cell-entry assay
Receptors
ACE2