Structural Basis for Potent Cross-Neutralizing Human Monoclonal Antibody Protection against Lethal Human and Zoonotic Severe Acute Respiratory Syndrome Coronavirus Challenge
Identifieur interne : 003468 ( Main/Exploration ); précédent : 003467; suivant : 003469Structural Basis for Potent Cross-Neutralizing Human Monoclonal Antibody Protection against Lethal Human and Zoonotic Severe Acute Respiratory Syndrome Coronavirus Challenge
Auteurs : Barry Rockx [États-Unis] ; Davide Corti [Suisse] ; Eric Donaldson [États-Unis] ; Timothy Sheahan [États-Unis] ; Konrad Stadler [Italie] ; Antonio Lanzavecchia [Suisse] ; Ralph Baric [États-Unis]Source :
- Journal of virology [ 0022-538X ] ; 2008.
Descripteurs français
- KwdFr :
- Analyse de survie, Animaux, Anticorps antiviraux (immunologie), Anticorps monoclonaux (immunologie), Cartographie épitopique, Femelle, Glycoprotéine de spicule des coronavirus, Glycoprotéines membranaires (immunologie), Humains, Immunisation passive, Modèles moléculaires, Poids du corps, Poumon (anatomopathologie), Poumon (virologie), Protéines de l'enveloppe virale (immunologie), Réactions croisées, Souris, Souris de lignée BALB C, Syndrome respiratoire aigu sévère (), Syndrome respiratoire aigu sévère (immunologie), Tests de neutralisation, Virus du SRAS (immunologie).
- MESH :
- anatomopathologie : Poumon.
- immunologie : Anticorps antiviraux, Anticorps monoclonaux, Glycoprotéines membranaires, Protéines de l'enveloppe virale, Syndrome respiratoire aigu sévère, Virus du SRAS.
- virologie : Poumon.
- Pascal (Inist)
- Analyse de survie, Animaux, Cartographie épitopique, Femelle, Glycoprotéine de spicule des coronavirus, Homme, Coronavirus, Humains, Immunisation passive, Modèles moléculaires, Poids du corps, Protection croisée, Anticorps neutralisant, Anticorps monoclonal, Aigu, Réactions croisées, Souris, Souris de lignée BALB C, Syndrome respiratoire aigu sévère, Tests de neutralisation, Virologie.
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
- Acute, Animals, Antibodies, Monoclonal (immunology), Antibodies, Viral (immunology), Body Weight, Coronavirus, Cross Reactions, Cross protection, Epitope Mapping, Female, Human, Humans, Immunization, Passive, Lung (pathology), Lung (virology), Membrane Glycoproteins (immunology), Mice, Mice, Inbred BALB C, Models, Molecular, Monoclonal antibody, Neutralization Tests, Neutralizing antibody, SARS Virus (immunology), Severe Acute Respiratory Syndrome (immunology), Severe Acute Respiratory Syndrome (prevention & control), Spike Glycoprotein, Coronavirus, Survival Analysis, Viral Envelope Proteins (immunology), Virology.
- MESH :
- chemical , immunology : Antibodies, Monoclonal, Antibodies, Viral, Membrane Glycoproteins, Viral Envelope Proteins.
- immunology : SARS Virus, Severe Acute Respiratory Syndrome.
- pathology : Lung.
- prevention & control : Severe Acute Respiratory Syndrome.
- virology : Lung.
- Animals, Body Weight, Cross Reactions, Epitope Mapping, Female, Humans, Immunization, Passive, Mice, Mice, Inbred BALB C, Models, Molecular, Neutralization Tests, Spike Glycoprotein, Coronavirus, Survival Analysis.
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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xml:lang="en" level="a">Structural Basis for Potent Cross-Neutralizing Human Monoclonal Antibody Protection against Lethal Human and Zoonotic Severe Acute Respiratory Syndrome Coronavirus Challenge</title><author><name sortKey="Rockx, Barry" sort="Rockx, Barry" uniqKey="Rockx B" first="Barry" last="Rockx">Barry Rockx</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Epidemiology, University of North Carolina</s1><s2>Chapel Hill, North Carolina</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Corti, Davide" sort="Corti, Davide" uniqKey="Corti D" first="Davide" last="Corti">Davide Corti</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute for Research in Biomedicine</s1><s2>Bellinzona</s2><s3>CHE</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>Institute for Research in Biomedicine</wicri:noRegion></affiliation></author><author><name sortKey="Donaldson, Eric" sort="Donaldson, Eric" uniqKey="Donaldson E" first="Eric" last="Donaldson">Eric Donaldson</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, University of North Carolina</s1><s2>Chapel Hill, North Carolina</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Sheahan, Timothy" sort="Sheahan, Timothy" uniqKey="Sheahan T" first="Timothy" last="Sheahan">Timothy Sheahan</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, University of North Carolina</s1><s2>Chapel Hill, North Carolina</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Stadler, Konrad" sort="Stadler, Konrad" uniqKey="Stadler K" first="Konrad" last="Stadler">Konrad Stadler</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Novartis Vaccines, Via Fiorentina 1</s1><s2>53100 Siena</s2><s3>ITA</s3><sZ>5 aut.</sZ></inist:fA14><country>Italie</country><wicri:noRegion>53100 Siena</wicri:noRegion></affiliation></author><author><name sortKey="Lanzavecchia, Antonio" sort="Lanzavecchia, Antonio" uniqKey="Lanzavecchia A" first="Antonio" last="Lanzavecchia">Antonio Lanzavecchia</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute for Research in Biomedicine</s1><s2>Bellinzona</s2><s3>CHE</s3><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>Institute for Research in Biomedicine</wicri:noRegion></affiliation></author><author><name sortKey="Baric, Ralph" sort="Baric, Ralph" uniqKey="Baric R" first="Ralph" last="Baric">Ralph Baric</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Epidemiology, University of North Carolina</s1><s2>Chapel Hill, North Carolina</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, University of North Carolina</s1><s2>Chapel Hill, North Carolina</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Journal of virology</title><title level="j" type="abbreviated">J. virol.</title><idno type="ISSN">0022-538X</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of virology</title><title level="j" type="abbreviated">J. virol.</title><idno type="ISSN">0022-538X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acute</term><term>Animals</term><term>Antibodies, Monoclonal (immunology)</term><term>Antibodies, Viral (immunology)</term><term>Body Weight</term><term>Coronavirus</term><term>Cross Reactions</term><term>Cross protection</term><term>Epitope Mapping</term><term>Female</term><term>Human</term><term>Humans</term><term>Immunization, Passive</term><term>Lung (pathology)</term><term>Lung (virology)</term><term>Membrane Glycoproteins (immunology)</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Models, Molecular</term><term>Monoclonal antibody</term><term>Neutralization Tests</term><term>Neutralizing antibody</term><term>SARS Virus (immunology)</term><term>Severe Acute Respiratory Syndrome (immunology)</term><term>Severe Acute Respiratory Syndrome (prevention & control)</term><term>Spike Glycoprotein, Coronavirus</term><term>Survival Analysis</term><term>Viral Envelope Proteins (immunology)</term><term>Virology</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Analyse de survie</term><term>Animaux</term><term>Anticorps antiviraux (immunologie)</term><term>Anticorps monoclonaux (immunologie)</term><term>Cartographie épitopique</term><term>Femelle</term><term>Glycoprotéine de spicule des coronavirus</term><term>Glycoprotéines membranaires (immunologie)</term><term>Humains</term><term>Immunisation passive</term><term>Modèles moléculaires</term><term>Poids du corps</term><term>Poumon (anatomopathologie)</term><term>Poumon (virologie)</term><term>Protéines de l'enveloppe virale (immunologie)</term><term>Réactions croisées</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Syndrome respiratoire aigu sévère ()</term><term>Syndrome respiratoire aigu sévère (immunologie)</term><term>Tests de neutralisation</term><term>Virus du SRAS (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Antibodies, Monoclonal</term><term>Antibodies, Viral</term><term>Membrane Glycoproteins</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Poumon</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Anticorps antiviraux</term><term>Anticorps monoclonaux</term><term>Glycoprotéines membranaires</term><term>Protéines de l'enveloppe virale</term><term>Syndrome respiratoire aigu sévère</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>SARS Virus</term><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Lung</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Poumon</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Lung</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Body Weight</term><term>Cross Reactions</term><term>Epitope Mapping</term><term>Female</term><term>Humans</term><term>Immunization, Passive</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Models, Molecular</term><term>Neutralization Tests</term><term>Spike Glycoprotein, Coronavirus</term><term>Survival Analysis</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Analyse de survie</term><term>Animaux</term><term>Cartographie épitopique</term><term>Femelle</term><term>Glycoprotéine de spicule des coronavirus</term><term>Homme</term><term>Coronavirus</term><term>Humains</term><term>Immunisation passive</term><term>Modèles moléculaires</term><term>Poids du corps</term><term>Protection croisée</term><term>Anticorps neutralisant</term><term>Anticorps monoclonal</term><term>Aigu</term><term>Réactions croisées</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Syndrome respiratoire aigu sévère</term><term>Tests de neutralisation</term><term>Virologie</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Italie</li><li>Suisse</li><li>États-Unis</li></country><region><li>Caroline du Nord</li></region></list><tree><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Rockx, Barry" sort="Rockx, Barry" uniqKey="Rockx B" first="Barry" last="Rockx">Barry Rockx</name></region><name sortKey="Baric, Ralph" sort="Baric, Ralph" uniqKey="Baric R" first="Ralph" last="Baric">Ralph Baric</name><name sortKey="Baric, Ralph" sort="Baric, Ralph" uniqKey="Baric R" first="Ralph" last="Baric">Ralph Baric</name><name sortKey="Donaldson, Eric" sort="Donaldson, Eric" uniqKey="Donaldson E" first="Eric" last="Donaldson">Eric Donaldson</name><name sortKey="Sheahan, Timothy" sort="Sheahan, Timothy" uniqKey="Sheahan T" first="Timothy" last="Sheahan">Timothy Sheahan</name></country><country name="Suisse"><noRegion><name sortKey="Corti, Davide" sort="Corti, Davide" uniqKey="Corti D" first="Davide" last="Corti">Davide Corti</name></noRegion><name sortKey="Lanzavecchia, Antonio" sort="Lanzavecchia, Antonio" uniqKey="Lanzavecchia A" first="Antonio" last="Lanzavecchia">Antonio Lanzavecchia</name></country><country name="Italie"><noRegion><name sortKey="Stadler, Konrad" sort="Stadler, Konrad" uniqKey="Stadler K" first="Konrad" last="Stadler">Konrad Stadler</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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