Structural Basis for Potent Cross-Neutralizing Human Monoclonal Antibody Protection against Lethal Human and Zoonotic Severe Acute Respiratory Syndrome Coronavirus Challenge

Rockx, Barry; Corti, Davide; Donaldson, Eric; Sheahan, Timothy; Stadler, Konrad; Lanzavecchia, Antonio; Baric, Ralph

doi:10.1128/jvi.02377-07

Cited by 135SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections Studiesvaccines and immunoinformatics approaches

Structural Basis for Potent Cross-Neutralizing Human Monoclonal Antibody Protection against Lethal Human and Zoonotic Severe Acute Respiratory Syndrome Coronavirus Challenge

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Rockx, Barry, Corti, Davide, Donaldson, Eric, Sheahan, Timothy, Stadler, Konrad, Lanzavecchia, Antonio, Baric, Ralph·2008·Journal of Virology

DOI 10.1128/jvi.02377-07PMC PMC2268459

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Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002, and detailed phylogenetic and epidemiological analyses have suggested that it originated from animals. The spike (S) glycoprotein has been identified as a major component of protective immunity, and 23 different amino acid changes were noted during the expanding epidemic. Using a panel of SARS-CoV recombinants bearing the S glycoproteins from isolates representing the zoonotic and human early, middle, and late phases of the epidemic, we identified 23 monoclonal antibodies (MAbs) with neutralizing activity against one or multiple SARS-CoV spike variants and determined the presence of at least six distinct neutralizing profiles in the SARS-CoV S glycoprotein. Four of these MAbs showed cross-neutralizing activity against all human and zoonotic S variants in vitro, and at least three of these were mapped in distinct epitopes using escape mutants, structure analyses, and competition assays. These three MAbs (S109.8, S227.14, and S230.15) were tested for use in passive vaccination studies using lethal SARS-CoV challenge models for young and senescent mice with four different homologous and heterologous SARS-CoV S variants. Both S227.14 and S230.15 completely protected young and old mice from weight loss and virus replication in the lungs for all viruses tested, while S109.8 completely protected mice from weight loss and clinical signs in the presence of viral titers. We conclude that a single human MAb can confer broad protection against lethal challenge with multiple zoonotic and human SARS-CoV isolates, and we identify a robust cocktail formulation that targets distinct epitopes and minimizes the likely generation of escape mutants.

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Self-citation

Authors: Rockx, B., Corti, D., Donaldson, E., Sheahan, T., Stadler, K., Lanzavecchia, A., & Baric, R.
Affiliations: Department of Epidemiology
Institute for Research in Biomedicine (CH)
University of North Carolina at Chapel Hill (US)
Novartis (Italy) (IT)
Corresponding author: Baric, Ralph
ORCID: Rockx, Barry
Corti, Davide
Donaldson, Eric
Sheahan, Timothy
Lanzavecchia, Antonio
Baric, Ralph
Venue: Journal of Virology
Publisher: American Society for Microbiology
Published: 2008-04
Volume: 82
Issue: 7
Pages: 3220-3235
ISSN: 0022-538X (ISSN-L)
1098-5514
DOI: 10.1128/jvi.02377-07
PMC: PMC2268459
OpenAlex: W2155387067
Cited by: 134
References: 58
Citations by year: 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 7 · 2021: 18 · 2020: 49 · 2019: 6 · 2017: 3 · 2015: 4 · 2014: 6 · 2013: 1 · 2012: 4
FWCI: 5.36
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Virology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
UNC Libraries
Funders: European Commission
National Institutes of Health
National Institute of Allergy and Infectious Diseases (P01-AI059136, R01AI059136, P01AI059443)
Topics: Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords: SARS-CoV, monoclonal antibodies, cross-neutralization, spike protein, passive immunization, antibody escape mutants, epitope mapping, antibody cocktail
MeSH terms: Animals, Antibodies, Monoclonal, Antibodies, Viral, Body Weight, Cross Reactions, Female, Humans, Immunization, Passive, Lung, Membrane Glycoproteins, Mice, Inbred BALB C, Models, Molecular, Neutralization Tests, Viral Envelope Proteins, Survival Analysis, Epitope Mapping, Severe Acute Respiratory Syndrome, Severe acute respiratory syndrome-related coronavirus, Mice, Spike Glycoprotein, Coronavirus

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Structural Basis for Potent Cross-Neutralizing Human Monoclonal Antibody Protection against Lethal Human and Zoonotic Severe Acute Respiratory Syndrome Coronavirus Challenge

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