Human Monoclonal Antibody Combination against SARS Coronavirus: Synergy and Coverage of Escape Mutants
Identifieur interne : 003E74 ( Main/Exploration ); précédent : 003E73; suivant : 003E75Human Monoclonal Antibody Combination against SARS Coronavirus: Synergy and Coverage of Escape Mutants
Auteurs : Jan Ter Meulen ; Edward N. Van Den Brink ; Leo L. M. Poon ; Wilfred E. Marissen ; Cynthia S. W. Leung ; Freek Cox ; Chung Y. Cheung ; Arjen Q. Bakker ; Johannes A. Bogaards ; Els Van Deventer ; Wolfgang Preiser ; Hans Wilhelm Doerr ; Vincent T. Chow ; John De Kruif ; Joseph S. M. Peiris ; Jaap GoudsmitSource :
- PLoS Medicine [ 1549-1277 ] ; 2006.
Descripteurs français
- KwdFr :
- Affinité des anticorps, Animaux, Anticorps monoclonaux (administration et posologie), Anticorps monoclonaux (génétique), Anticorps monoclonaux (immunologie), Anticorps monoclonaux (usage thérapeutique), Antigènes viraux (immunologie), Cellules Vero, Cellules cultivées (virologie), Chaines lourdes des immunoglobulines (génétique), Chaines lourdes des immunoglobulines (immunologie), Chaines légères des immunoglobulines (génétique), Chaines légères des immunoglobulines (immunologie), Données de séquences moléculaires, Flambées de maladies, Glycoprotéine de spicule des coronavirus, Glycoprotéines membranaires (génétique), Glycoprotéines membranaires (immunologie), Glycoprotéines membranaires (physiologie), Humains, Immunisation passive, Macrophages (virologie), Mutation faux-sens, Mutation ponctuelle, Nandiniidae (virologie), Protéines de fusion recombinantes (immunologie), Protéines de l'enveloppe virale (génétique), Protéines de l'enveloppe virale (immunologie), Protéines de l'enveloppe virale (physiologie), Relation dose-réponse (immunologie), Réaction antigène-anticorps, Région variable d'immunoglobuline (), Région variable d'immunoglobuline (immunologie), Réplication virale, Résonance plasmonique de surface, Sites de fixation, Spécificité des anticorps, Structure tertiaire des protéines, Substitution d'acide aminé, Syndrome respiratoire aigu sévère (), Syndrome respiratoire aigu sévère (traitement médicamenteux), Syndrome respiratoire aigu sévère (virologie), Syndrome respiratoire aigu sévère (épidémiologie), Synergie des médicaments, Séquence nucléotidique, Sérums immuns, Tests de neutralisation, Variation des antigènes, Virus du SRAS (génétique), Virus du SRAS (immunologie), Épitopes (immunologie).
- MESH :
- administration et posologie : Anticorps monoclonaux.
- génétique : Anticorps monoclonaux, Chaines lourdes des immunoglobulines, Chaines légères des immunoglobulines, Glycoprotéines membranaires, Protéines de l'enveloppe virale, Virus du SRAS.
- immunologie : Anticorps monoclonaux, Antigènes viraux, Chaines lourdes des immunoglobulines, Chaines légères des immunoglobulines, Glycoprotéines membranaires, Protéines de fusion recombinantes, Protéines de l'enveloppe virale, Région variable d'immunoglobuline, Virus du SRAS, Épitopes.
- physiologie : Glycoprotéines membranaires, Protéines de l'enveloppe virale.
- traitement médicamenteux : Syndrome respiratoire aigu sévère.
- usage thérapeutique : Anticorps monoclonaux.
- virologie : Cellules cultivées, Macrophages, Nandiniidae, Syndrome respiratoire aigu sévère.
- épidémiologie : Syndrome respiratoire aigu sévère.
- Affinité des anticorps, Animaux, Cellules Vero, Données de séquences moléculaires, Flambées de maladies, Glycoprotéine de spicule des coronavirus, Humains, Immunisation passive, Mutation faux-sens, Mutation ponctuelle, Relation dose-réponse (immunologie), Réaction antigène-anticorps, Région variable d'immunoglobuline, Réplication virale, Résonance plasmonique de surface, Sites de fixation, Spécificité des anticorps, Structure tertiaire des protéines, Substitution d'acide aminé, Syndrome respiratoire aigu sévère, Synergie des médicaments, Séquence nucléotidique, Sérums immuns, Tests de neutralisation, Variation des antigènes.
English descriptors
- KwdEn :
- Amino Acid Substitution, Animals, Antibodies, Monoclonal (administration & dosage), Antibodies, Monoclonal (genetics), Antibodies, Monoclonal (immunology), Antibodies, Monoclonal (therapeutic use), Antibody Affinity, Antibody Specificity, Antigen-Antibody Reactions, Antigenic Variation, Antigens, Viral (immunology), Base Sequence, Binding Sites, Cells, Cultured (virology), Chlorocebus aethiops, Disease Outbreaks, Dose-Response Relationship, Immunologic, Drug Synergism, Epitopes (immunology), Humans, Immune Sera, Immunization, Passive, Immunoglobulin Heavy Chains (genetics), Immunoglobulin Heavy Chains (immunology), Immunoglobulin Light Chains (genetics), Immunoglobulin Light Chains (immunology), Immunoglobulin Variable Region (chemistry), Immunoglobulin Variable Region (immunology), Macrophages (virology), Membrane Glycoproteins (genetics), Membrane Glycoproteins (immunology), Membrane Glycoproteins (physiology), Molecular Sequence Data, Mutation, Missense, Nandiniidae (virology), Neutralization Tests, Point Mutation, Protein Structure, Tertiary, Recombinant Fusion Proteins (immunology), SARS Virus (genetics), SARS Virus (immunology), Severe Acute Respiratory Syndrome (drug therapy), Severe Acute Respiratory Syndrome (epidemiology), Severe Acute Respiratory Syndrome (prevention & control), Severe Acute Respiratory Syndrome (therapy), Severe Acute Respiratory Syndrome (virology), Spike Glycoprotein, Coronavirus, Surface Plasmon Resonance, Vero Cells, Viral Envelope Proteins (genetics), Viral Envelope Proteins (immunology), Viral Envelope Proteins (physiology), Virus Replication.
- MESH :
- chemical , administration & dosage : Antibodies, Monoclonal.
- chemical , chemistry : Immunoglobulin Variable Region.
- chemical , genetics : Antibodies, Monoclonal, Immunoglobulin Heavy Chains, Immunoglobulin Light Chains, Membrane Glycoproteins, Viral Envelope Proteins.
- chemical , immunology : Antibodies, Monoclonal, Antigens, Viral, Epitopes, Immunoglobulin Heavy Chains, Immunoglobulin Light Chains, Immunoglobulin Variable Region, Membrane Glycoproteins, Recombinant Fusion Proteins, Viral Envelope Proteins.
- chemical , physiology : Membrane Glycoproteins, Viral Envelope Proteins.
- chemical , therapeutic use : Antibodies, Monoclonal.
- drug therapy : Severe Acute Respiratory Syndrome.
- epidemiology : Severe Acute Respiratory Syndrome.
- genetics : SARS Virus.
- immunology : SARS Virus.
- prevention & control : Severe Acute Respiratory Syndrome.
- therapy : Severe Acute Respiratory Syndrome.
- virology : Cells, Cultured, Macrophages, Nandiniidae, Severe Acute Respiratory Syndrome.
- Amino Acid Substitution, Animals, Antibody Affinity, Antibody Specificity, Antigen-Antibody Reactions, Antigenic Variation, Base Sequence, Binding Sites, Chlorocebus aethiops, Disease Outbreaks, Dose-Response Relationship, Immunologic, Drug Synergism, Humans, Immune Sera, Immunization, Passive, Molecular Sequence Data, Mutation, Missense, Neutralization Tests, Point Mutation, Protein Structure, Tertiary, Spike Glycoprotein, Coronavirus, Surface Plasmon Resonance, Vero Cells, Virus Replication.
Abstract
Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties.
Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318–510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one.
The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. At the same time, synergy between CR3014 and CR3022 may allow for a lower total antibody dose to be administered for passive immune prophylaxis of SARS-CoV infection.
Url:
DOI: 10.1371/journal.pmed.0030237
PubMed: 16796401
PubMed Central: 1483912
Affiliations:
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Chow</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="De Kruif, John" sort="De Kruif, John" uniqKey="De Kruif J" first="John" last="De Kruif">John De Kruif</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Peiris, Joseph S M" sort="Peiris, Joseph S M" uniqKey="Peiris J" first="Joseph S. M" last="Peiris">Joseph S. M. Peiris</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Goudsmit, Jaap" sort="Goudsmit, Jaap" uniqKey="Goudsmit J" first="Jaap" last="Goudsmit">Jaap Goudsmit</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS Medicine</title><idno type="ISSN">1549-1277</idno><idno type="eISSN">1549-1676</idno><imprint><date when="2006">2006</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Substitution</term><term>Animals</term><term>Antibodies, Monoclonal (administration & dosage)</term><term>Antibodies, Monoclonal (genetics)</term><term>Antibodies, Monoclonal (immunology)</term><term>Antibodies, Monoclonal (therapeutic use)</term><term>Antibody Affinity</term><term>Antibody Specificity</term><term>Antigen-Antibody Reactions</term><term>Antigenic Variation</term><term>Antigens, Viral (immunology)</term><term>Base Sequence</term><term>Binding Sites</term><term>Cells, Cultured (virology)</term><term>Chlorocebus aethiops</term><term>Disease Outbreaks</term><term>Dose-Response Relationship, Immunologic</term><term>Drug Synergism</term><term>Epitopes (immunology)</term><term>Humans</term><term>Immune Sera</term><term>Immunization, Passive</term><term>Immunoglobulin Heavy Chains (genetics)</term><term>Immunoglobulin Heavy Chains (immunology)</term><term>Immunoglobulin Light Chains (genetics)</term><term>Immunoglobulin Light Chains (immunology)</term><term>Immunoglobulin Variable Region (chemistry)</term><term>Immunoglobulin Variable Region (immunology)</term><term>Macrophages (virology)</term><term>Membrane Glycoproteins (genetics)</term><term>Membrane Glycoproteins (immunology)</term><term>Membrane Glycoproteins (physiology)</term><term>Molecular Sequence Data</term><term>Mutation, Missense</term><term>Nandiniidae (virology)</term><term>Neutralization Tests</term><term>Point Mutation</term><term>Protein Structure, Tertiary</term><term>Recombinant Fusion Proteins (immunology)</term><term>SARS Virus (genetics)</term><term>SARS Virus (immunology)</term><term>Severe Acute Respiratory Syndrome (drug therapy)</term><term>Severe Acute Respiratory Syndrome (epidemiology)</term><term>Severe Acute Respiratory Syndrome (prevention & control)</term><term>Severe Acute Respiratory Syndrome (therapy)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Spike Glycoprotein, Coronavirus</term><term>Surface Plasmon Resonance</term><term>Vero Cells</term><term>Viral Envelope Proteins (genetics)</term><term>Viral Envelope Proteins (immunology)</term><term>Viral Envelope Proteins (physiology)</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Affinité des anticorps</term><term>Animaux</term><term>Anticorps monoclonaux (administration et posologie)</term><term>Anticorps monoclonaux (génétique)</term><term>Anticorps monoclonaux (immunologie)</term><term>Anticorps monoclonaux (usage thérapeutique)</term><term>Antigènes viraux (immunologie)</term><term>Cellules Vero</term><term>Cellules cultivées (virologie)</term><term>Chaines lourdes des immunoglobulines (génétique)</term><term>Chaines lourdes des immunoglobulines (immunologie)</term><term>Chaines légères des immunoglobulines (génétique)</term><term>Chaines légères des immunoglobulines (immunologie)</term><term>Données de séquences moléculaires</term><term>Flambées de maladies</term><term>Glycoprotéine de spicule des coronavirus</term><term>Glycoprotéines membranaires (génétique)</term><term>Glycoprotéines membranaires (immunologie)</term><term>Glycoprotéines membranaires (physiologie)</term><term>Humains</term><term>Immunisation passive</term><term>Macrophages (virologie)</term><term>Mutation faux-sens</term><term>Mutation ponctuelle</term><term>Nandiniidae (virologie)</term><term>Protéines de fusion recombinantes (immunologie)</term><term>Protéines de l'enveloppe virale (génétique)</term><term>Protéines de l'enveloppe virale (immunologie)</term><term>Protéines de l'enveloppe virale (physiologie)</term><term>Relation dose-réponse (immunologie)</term><term>Réaction antigène-anticorps</term><term>Région variable d'immunoglobuline ()</term><term>Région variable d'immunoglobuline (immunologie)</term><term>Réplication virale</term><term>Résonance plasmonique de surface</term><term>Sites de fixation</term><term>Spécificité des anticorps</term><term>Structure tertiaire des protéines</term><term>Substitution d'acide aminé</term><term>Syndrome respiratoire aigu sévère ()</term><term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Syndrome respiratoire aigu sévère (épidémiologie)</term><term>Synergie des médicaments</term><term>Séquence nucléotidique</term><term>Sérums immuns</term><term>Tests de neutralisation</term><term>Variation des antigènes</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (immunologie)</term><term>Épitopes (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Antibodies, Monoclonal</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Immunoglobulin Variable Region</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Antibodies, Monoclonal</term><term>Immunoglobulin Heavy Chains</term><term>Immunoglobulin Light Chains</term><term>Membrane Glycoproteins</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Antibodies, Monoclonal</term><term>Antigens, Viral</term><term>Epitopes</term><term>Immunoglobulin Heavy Chains</term><term>Immunoglobulin Light Chains</term><term>Immunoglobulin Variable Region</term><term>Membrane Glycoproteins</term><term>Recombinant Fusion Proteins</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Membrane Glycoproteins</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antibodies, Monoclonal</term></keywords><keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Anticorps monoclonaux</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="epidemiology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Anticorps monoclonaux</term><term>Chaines lourdes des immunoglobulines</term><term>Chaines légères des immunoglobulines</term><term>Glycoprotéines membranaires</term><term>Protéines de l'enveloppe virale</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Anticorps monoclonaux</term><term>Antigènes viraux</term><term>Chaines lourdes des immunoglobulines</term><term>Chaines légères des immunoglobulines</term><term>Glycoprotéines membranaires</term><term>Protéines de fusion recombinantes</term><term>Protéines de l'enveloppe virale</term><term>Région variable d'immunoglobuline</term><term>Virus du SRAS</term><term>Épitopes</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Glycoprotéines membranaires</term><term>Protéines de l'enveloppe virale</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Anticorps monoclonaux</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Cellules cultivées</term><term>Macrophages</term><term>Nandiniidae</term><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Cells, Cultured</term><term>Macrophages</term><term>Nandiniidae</term><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="épidémiologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Substitution</term><term>Animals</term><term>Antibody Affinity</term><term>Antibody Specificity</term><term>Antigen-Antibody Reactions</term><term>Antigenic Variation</term><term>Base Sequence</term><term>Binding Sites</term><term>Chlorocebus aethiops</term><term>Disease Outbreaks</term><term>Dose-Response Relationship, Immunologic</term><term>Drug Synergism</term><term>Humans</term><term>Immune Sera</term><term>Immunization, Passive</term><term>Molecular Sequence Data</term><term>Mutation, Missense</term><term>Neutralization Tests</term><term>Point Mutation</term><term>Protein Structure, Tertiary</term><term>Spike Glycoprotein, Coronavirus</term><term>Surface Plasmon Resonance</term><term>Vero Cells</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Affinité des anticorps</term><term>Animaux</term><term>Cellules Vero</term><term>Données de séquences moléculaires</term><term>Flambées de maladies</term><term>Glycoprotéine de spicule des coronavirus</term><term>Humains</term><term>Immunisation passive</term><term>Mutation faux-sens</term><term>Mutation ponctuelle</term><term>Relation dose-réponse (immunologie)</term><term>Réaction antigène-anticorps</term><term>Région variable d'immunoglobuline</term><term>Réplication virale</term><term>Résonance plasmonique de surface</term><term>Sites de fixation</term><term>Spécificité des anticorps</term><term>Structure tertiaire des protéines</term><term>Substitution d'acide aminé</term><term>Syndrome respiratoire aigu sévère</term><term>Synergie des médicaments</term><term>Séquence nucléotidique</term><term>Sérums immuns</term><term>Tests de neutralisation</term><term>Variation des antigènes</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="st1"><title>Background</title><p>Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties.</p></sec><sec id="st2"><title>Methods and Findings</title><p>Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318–510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one.</p></sec><sec id="st3"><title>Conclusions</title><p>The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. 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Ruan</name></author><author><name sortKey="Ling, Ae" uniqKey="Ling A">AE Ling</name></author><author><name sortKey="Ng, Lfp" uniqKey="Ng L">LFP Ng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Poon, Llm" uniqKey="Poon L">LLM Poon</name></author><author><name sortKey="Leung, Csw" uniqKey="Leung C">CSW Leung</name></author><author><name sortKey="Yuen, Ky" uniqKey="Yuen K">KY Yuen</name></author><author><name sortKey="Guan, Y" uniqKey="Guan Y">Y Guan</name></author><author><name sortKey="Peiris, Jsm" uniqKey="Peiris J">JSM Peiris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jeffers, Sa" uniqKey="Jeffers S">SA Jeffers</name></author><author><name sortKey="Tusell, Sm" uniqKey="Tusell S">SM Tusell</name></author><author><name sortKey="Gillim Ross, L" uniqKey="Gillim Ross L">L Gillim-Ross</name></author><author><name sortKey="Hemmila, Em" uniqKey="Hemmila E">EM Hemmila</name></author><author><name sortKey="Achebach, Je" uniqKey="Achebach J">JE Achebach</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Klepfer, S" uniqKey="Klepfer S">S Klepfer</name></author><author><name sortKey="Reed, Ap" uniqKey="Reed A">AP Reed</name></author><author><name sortKey="Martinez, M" uniqKey="Martinez M">M Martinez</name></author><author><name sortKey="Bhogal, B" uniqKey="Bhogal B">B Bhogal</name></author><author><name sortKey="Jones, E" uniqKey="Jones E">E Jones</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Takada, A" uniqKey="Takada A">A Takada</name></author><author><name sortKey="Kawaoka, Y" uniqKey="Kawaoka Y">Y Kawaoka</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list></list><tree><noCountry><name sortKey="Bakker, Arjen Q" sort="Bakker, Arjen Q" uniqKey="Bakker A" first="Arjen Q" last="Bakker">Arjen Q. Bakker</name><name sortKey="Bogaards, Johannes A" sort="Bogaards, Johannes A" uniqKey="Bogaards J" first="Johannes A" last="Bogaards">Johannes A. Bogaards</name><name sortKey="Cheung, Chung Y" sort="Cheung, Chung Y" uniqKey="Cheung C" first="Chung Y" last="Cheung">Chung Y. Cheung</name><name sortKey="Chow, Vincent T" sort="Chow, Vincent T" uniqKey="Chow V" first="Vincent T" last="Chow">Vincent T. Chow</name><name sortKey="Cox, Freek" sort="Cox, Freek" uniqKey="Cox F" first="Freek" last="Cox">Freek Cox</name><name sortKey="De Kruif, John" sort="De Kruif, John" uniqKey="De Kruif J" first="John" last="De Kruif">John De Kruif</name><name sortKey="Doerr, Hans Wilhelm" sort="Doerr, Hans Wilhelm" uniqKey="Doerr H" first="Hans Wilhelm" last="Doerr">Hans Wilhelm Doerr</name><name sortKey="Goudsmit, Jaap" sort="Goudsmit, Jaap" uniqKey="Goudsmit J" first="Jaap" last="Goudsmit">Jaap Goudsmit</name><name sortKey="Leung, Cynthia S W" sort="Leung, Cynthia S W" uniqKey="Leung C" first="Cynthia S. W" last="Leung">Cynthia S. W. Leung</name><name sortKey="Marissen, Wilfred E" sort="Marissen, Wilfred E" uniqKey="Marissen W" first="Wilfred E" last="Marissen">Wilfred E. Marissen</name><name sortKey="Peiris, Joseph S M" sort="Peiris, Joseph S M" uniqKey="Peiris J" first="Joseph S. M" last="Peiris">Joseph S. M. Peiris</name><name sortKey="Poon, Leo L M" sort="Poon, Leo L M" uniqKey="Poon L" first="Leo L. M" last="Poon">Leo L. M. Poon</name><name sortKey="Preiser, Wolfgang" sort="Preiser, Wolfgang" uniqKey="Preiser W" first="Wolfgang" last="Preiser">Wolfgang Preiser</name><name sortKey="Ter Meulen, Jan" sort="Ter Meulen, Jan" uniqKey="Ter Meulen J" first="Jan" last="Ter Meulen">Jan Ter Meulen</name><name sortKey="Van Den Brink, Edward N" sort="Van Den Brink, Edward N" uniqKey="Van Den Brink E" first="Edward N" last="Van Den Brink">Edward N. Van Den Brink</name><name sortKey="Van Deventer, Els" sort="Van Deventer, Els" uniqKey="Van Deventer E" first="Els" last="Van Deventer">Els Van Deventer</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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