Satisfactorily attenuated and protective mutants derived from a partially attenuated cold-passaged respiratory syncytial virus mutant by introduction of additional attenuating mutations during chemical mutagenesis
Identifieur interne : 001332 ( Istex/Corpus ); précédent : 001331; suivant : 001333Satisfactorily attenuated and protective mutants derived from a partially attenuated cold-passaged respiratory syncytial virus mutant by introduction of additional attenuating mutations during chemical mutagenesis
Auteurs : James E. Crowe Jr ; Phuong T. Bui ; William T. London ; Alan R. Davis ; Paul P. Hung ; Robert M. Chanock ; Brian R. MurphySource :
- Vaccine [ 0264-410X ] ; 1994.
English descriptors
- Teeft :
- Attenuated, Attenuating, Attenuation, Chanock, Chemical mutagenesis, Chimpanzee, Chimpanzees numbers, Complete resistance, Cotton rats, Crowe, Genetic stability, Glycoprotein, Inoculated, Inoculum, Monolayer, Monolayer cultures, More attenuated, Mutant, Mutant virus, Mutation, Nasal turbinates, Nasopharynx, Neutralizing, Nude mice, Other attenuating mutations, Partial loss, Phenotype, Plaque, Plaque formation, Plaque progeny, Plaque size, Plaque titration, Previous studies, Progeny, Protective efficacy, Pulmonary histopathology, Replication, Respiratory syncytial virus, Respiratory tract, Rhinorrhoea, Seronegative, Seronegative chimpanzees, Seronegative infants, Seropositive adults, Supernatant, Syncytial, Syncytial virus, Temperaturesensitive mutants, Tracheal lavage specimens, Turbinate, Vaccine, Vaccinia virus recombinants, Vero cells, Virol, Virus, Virus replication, Wild type, Young children.
Abstract
Abstract: A cold-passaged RSV mutant, designated cp-RSV, which acquired host range mutations during 52 passages at low temperature in bovine tissue culture, was completely attenuated for seropositive adults and children but retained the capacity to cause upper respiratory disease in seronegative infants. We sought to introduce additional attenuating mutations, such as temperature-sensitive (ts) and small-plaque (sp) mutations, into the cp-RSV mutant, which is a ts + virus, in order to generate a mutant which would be satisfactorily attenuated in seronegative infants and young children. Nine mutants of cp-RSV, which had acquired either the ts or small-plaque sp phenotype, were generated by chemical mutagenesis with 5-fluorouracil. The two ts mutants with the lowest in vitro shut-off temperature, namely the cpts-248 (38°C) and cpts-530 (39°C) mutants, were the most restricted of the nine cp-RSV mutant progeny tested for efficiency of replication in Balb/c mice. In seronegative chimpanzees, the cpts-248 mutant replicated fourfold less efficiently in the nasopharynx and caused significantly less rhinorrhoea than its cp-RSV parent. The cpts-248 mutant virus, like its cp-RSV parent, was 1000-fold restricted in replication in the trachea compared with wild-type RSV. Previously, another candidate RSV live attenuated vaccine strain, a mutant designated ts-1, exhibited some instability of its ts phenotype following replication in susceptible humans or chimpanzees. Hence, we sought cp-RSV ts progeny that exhibited a greater degree of stability of the ts phenotype than the prototype ts-1 mutant. The cpts-248 and cpts-530 progeny viruses exhibited a greater degree of stability of the ts phenotype in nude mice than the ts-1 virus, and in chimpanzees, the former mutant also exhibited a greater stability of its ts phenotype than ts-1. The cpts-248 mutant was immunogenic and induced a high level of resistance in chimpanzees to subsequent challenge with wild-type RSV. The cpts-248 mutant therefore exhibits a set of properties that make it a promising vaccine candidate. These desirable properties of cpts-248 suggest that the mutant should be tested in humans for its suitability in immunoprophylaxis.
Url:
DOI: 10.1016/0264-410X(94)90218-6
Links to Exploration step
ISTEX:FA462D4E3388C2E1CCC589873A8984211D50FFE4Le document en format XML
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Crowe Jr</name><affiliation><mods:affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>To whom correspondence should be addressed.</mods:affiliation></affiliation></author><author><name sortKey="Bui, Phuong T" sort="Bui, Phuong T" uniqKey="Bui P" first="Phuong T." last="Bui">Phuong T. Bui</name><affiliation><mods:affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</mods:affiliation></affiliation></author><author><name sortKey="London, William T" sort="London, William T" uniqKey="London W" first="William T." last="London">William T. 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Chanock</name><affiliation><mods:affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</mods:affiliation></affiliation></author><author><name sortKey="Murphy, Brian R" sort="Murphy, Brian R" uniqKey="Murphy B" first="Brian R." last="Murphy">Brian R. Murphy</name><affiliation><mods:affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Vaccine</title><title level="j" type="abbrev">JVAC</title><idno type="ISSN">0264-410X</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1994">1994</date><biblScope unit="volume">12</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="691">691</biblScope><biblScope unit="page" to="699">699</biblScope></imprint><idno type="ISSN">0264-410X</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0264-410X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Attenuated</term><term>Attenuating</term><term>Attenuation</term><term>Chanock</term><term>Chemical mutagenesis</term><term>Chimpanzee</term><term>Chimpanzees numbers</term><term>Complete resistance</term><term>Cotton rats</term><term>Crowe</term><term>Genetic stability</term><term>Glycoprotein</term><term>Inoculated</term><term>Inoculum</term><term>Monolayer</term><term>Monolayer cultures</term><term>More attenuated</term><term>Mutant</term><term>Mutant virus</term><term>Mutation</term><term>Nasal turbinates</term><term>Nasopharynx</term><term>Neutralizing</term><term>Nude mice</term><term>Other attenuating mutations</term><term>Partial loss</term><term>Phenotype</term><term>Plaque</term><term>Plaque formation</term><term>Plaque progeny</term><term>Plaque size</term><term>Plaque titration</term><term>Previous studies</term><term>Progeny</term><term>Protective efficacy</term><term>Pulmonary histopathology</term><term>Replication</term><term>Respiratory syncytial virus</term><term>Respiratory tract</term><term>Rhinorrhoea</term><term>Seronegative</term><term>Seronegative chimpanzees</term><term>Seronegative infants</term><term>Seropositive adults</term><term>Supernatant</term><term>Syncytial</term><term>Syncytial virus</term><term>Temperaturesensitive mutants</term><term>Tracheal lavage specimens</term><term>Turbinate</term><term>Vaccine</term><term>Vaccinia virus recombinants</term><term>Vero cells</term><term>Virol</term><term>Virus</term><term>Virus replication</term><term>Wild type</term><term>Young children</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: A cold-passaged RSV mutant, designated cp-RSV, which acquired host range mutations during 52 passages at low temperature in bovine tissue culture, was completely attenuated for seropositive adults and children but retained the capacity to cause upper respiratory disease in seronegative infants. We sought to introduce additional attenuating mutations, such as temperature-sensitive (ts) and small-plaque (sp) mutations, into the cp-RSV mutant, which is a ts + virus, in order to generate a mutant which would be satisfactorily attenuated in seronegative infants and young children. Nine mutants of cp-RSV, which had acquired either the ts or small-plaque sp phenotype, were generated by chemical mutagenesis with 5-fluorouracil. The two ts mutants with the lowest in vitro shut-off temperature, namely the cpts-248 (38°C) and cpts-530 (39°C) mutants, were the most restricted of the nine cp-RSV mutant progeny tested for efficiency of replication in Balb/c mice. In seronegative chimpanzees, the cpts-248 mutant replicated fourfold less efficiently in the nasopharynx and caused significantly less rhinorrhoea than its cp-RSV parent. The cpts-248 mutant virus, like its cp-RSV parent, was 1000-fold restricted in replication in the trachea compared with wild-type RSV. Previously, another candidate RSV live attenuated vaccine strain, a mutant designated ts-1, exhibited some instability of its ts phenotype following replication in susceptible humans or chimpanzees. Hence, we sought cp-RSV ts progeny that exhibited a greater degree of stability of the ts phenotype than the prototype ts-1 mutant. The cpts-248 and cpts-530 progeny viruses exhibited a greater degree of stability of the ts phenotype in nude mice than the ts-1 virus, and in chimpanzees, the former mutant also exhibited a greater stability of its ts phenotype than ts-1. The cpts-248 mutant was immunogenic and induced a high level of resistance in chimpanzees to subsequent challenge with wild-type RSV. The cpts-248 mutant therefore exhibits a set of properties that make it a promising vaccine candidate. These desirable properties of cpts-248 suggest that the mutant should be tested in humans for its suitability in immunoprophylaxis.</div></front></TEI><istex><corpusName>elsevier</corpusName><keywords><teeft><json:string>mutant</json:string><json:string>chimpanzee</json:string><json:string>phenotype</json:string><json:string>attenuated</json:string><json:string>syncytial</json:string><json:string>seronegative</json:string><json:string>chanock</json:string><json:string>replication</json:string><json:string>vaccine</json:string><json:string>mutation</json:string><json:string>rhinorrhoea</json:string><json:string>respiratory syncytial virus</json:string><json:string>neutralizing</json:string><json:string>glycoprotein</json:string><json:string>attenuation</json:string><json:string>monolayer</json:string><json:string>plaque</json:string><json:string>inoculum</json:string><json:string>crowe</json:string><json:string>seronegative chimpanzees</json:string><json:string>seronegative infants</json:string><json:string>virol</json:string><json:string>turbinate</json:string><json:string>nasopharynx</json:string><json:string>inoculated</json:string><json:string>attenuating</json:string><json:string>virus</json:string><json:string>pulmonary histopathology</json:string><json:string>cotton rats</json:string><json:string>plaque size</json:string><json:string>nasal turbinates</json:string><json:string>syncytial virus</json:string><json:string>wild type</json:string><json:string>monolayer cultures</json:string><json:string>virus replication</json:string><json:string>genetic stability</json:string><json:string>chemical mutagenesis</json:string><json:string>previous studies</json:string><json:string>plaque titration</json:string><json:string>young children</json:string><json:string>nude mice</json:string><json:string>tracheal lavage specimens</json:string><json:string>vero cells</json:string><json:string>supernatant</json:string><json:string>progeny</json:string><json:string>protective efficacy</json:string><json:string>chimpanzees numbers</json:string><json:string>plaque progeny</json:string><json:string>respiratory tract</json:string><json:string>vaccinia virus recombinants</json:string><json:string>plaque formation</json:string><json:string>complete resistance</json:string><json:string>other attenuating mutations</json:string><json:string>partial loss</json:string><json:string>seropositive adults</json:string><json:string>temperaturesensitive mutants</json:string><json:string>mutant virus</json:string><json:string>more attenuated</json:string></teeft></keywords><author><json:item><name>James E. Crowe, Jr</name><affiliations><json:string>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</json:string><json:string>To whom correspondence should be addressed.</json:string></affiliations></json:item><json:item><name>Phuong T. Bui</name><affiliations><json:string>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</json:string></affiliations></json:item><json:item><name>William T. London</name><affiliations><json:string>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</json:string></affiliations></json:item><json:item><name>Alan R. Davis</name><affiliations><json:string>Molecular Biology Division, Wyeth-Ayerst Research, Radnor, PA, USA</json:string></affiliations></json:item><json:item><name>Paul P. Hung</name><affiliations><json:string>Molecular Biology Division, Wyeth-Ayerst Research, Radnor, PA, USA</json:string></affiliations></json:item><json:item><name>Robert M. Chanock</name><affiliations><json:string>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</json:string></affiliations></json:item><json:item><name>Brian R. Murphy</name><affiliations><json:string>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Respiratory syncytial virus</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>cold-passaged mutant</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>attenuating mutants</value></json:item></subject><arkIstex>ark:/67375/6H6-00648L12-8</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>Short communication</json:string></originalGenre><abstract>Abstract: A cold-passaged RSV mutant, designated cp-RSV, which acquired host range mutations during 52 passages at low temperature in bovine tissue culture, was completely attenuated for seropositive adults and children but retained the capacity to cause upper respiratory disease in seronegative infants. We sought to introduce additional attenuating mutations, such as temperature-sensitive (ts) and small-plaque (sp) mutations, into the cp-RSV mutant, which is a ts + virus, in order to generate a mutant which would be satisfactorily attenuated in seronegative infants and young children. Nine mutants of cp-RSV, which had acquired either the ts or small-plaque sp phenotype, were generated by chemical mutagenesis with 5-fluorouracil. The two ts mutants with the lowest in vitro shut-off temperature, namely the cpts-248 (38°C) and cpts-530 (39°C) mutants, were the most restricted of the nine cp-RSV mutant progeny tested for efficiency of replication in Balb/c mice. In seronegative chimpanzees, the cpts-248 mutant replicated fourfold less efficiently in the nasopharynx and caused significantly less rhinorrhoea than its cp-RSV parent. The cpts-248 mutant virus, like its cp-RSV parent, was 1000-fold restricted in replication in the trachea compared with wild-type RSV. Previously, another candidate RSV live attenuated vaccine strain, a mutant designated ts-1, exhibited some instability of its ts phenotype following replication in susceptible humans or chimpanzees. Hence, we sought cp-RSV ts progeny that exhibited a greater degree of stability of the ts phenotype than the prototype ts-1 mutant. The cpts-248 and cpts-530 progeny viruses exhibited a greater degree of stability of the ts phenotype in nude mice than the ts-1 virus, and in chimpanzees, the former mutant also exhibited a greater stability of its ts phenotype than ts-1. The cpts-248 mutant was immunogenic and induced a high level of resistance in chimpanzees to subsequent challenge with wild-type RSV. The cpts-248 mutant therefore exhibits a set of properties that make it a promising vaccine candidate. These desirable properties of cpts-248 suggest that the mutant should be tested in humans for its suitability in immunoprophylaxis.</abstract><qualityIndicators><score>10</score><pdfWordCount>6475</pdfWordCount><pdfCharCount>41839</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>9</pdfPageCount><pdfPageSize>612 x 843 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>327</abstractWordCount><abstractCharCount>2219</abstractCharCount><keywordCount>3</keywordCount></qualityIndicators><title>Satisfactorily attenuated and protective mutants derived from a partially attenuated cold-passaged respiratory syncytial virus mutant by introduction of additional attenuating mutations during chemical mutagenesis</title><pmid><json:string>8091846</json:string></pmid><pii><json:string>0264-410X(94)90218-6</json:string></pii><genre><json:string>brief-communication</json:string></genre><host><title>Vaccine</title><language><json:string>unknown</json:string></language><publicationDate>1994</publicationDate><issn><json:string>0264-410X</json:string></issn><pii><json:string>S0264-410X(00)X0240-X</json:string></pii><volume>12</volume><issue>8</issue><pages><first>691</first><last>699</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>1000</json:string><json:string>1994</json:string><json:string>1961</json:string><json:string>30s</json:string></date><geogName></geogName><orgName><json:string>WHO</json:string><json:string>Heat Systems</json:string><json:string>US Government</json:string><json:string>Primate Research Laboratory, Holloman Air Force Base, NM</json:string><json:string>National Cancer Institute, Frederick, MD</json:string><json:string>Southwest Foundation, San Antonio, TX</json:string><json:string>ATCC</json:string><json:string>Wyeth-Ayerst Research, Radnor, PA, USA</json:string><json:string>New Mexico Regio</json:string><json:string>National Institutes of Health, Bethesda, MD</json:string><json:string>River</json:string><json:string>World Health Organization</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>C. Isolates</json:string><json:string>Robert M. Chanock</json:string><json:string>C. Virus</json:string><json:string>C. Level</json:string><json:string>Brian R. Murphy</json:string><json:string>William T. London</json:string><json:string>C. Specimens</json:string><json:string>Phuong T. Bui</json:string><json:string>Louis Potash</json:string></persName><placeName><json:string>Wilmington</json:string><json:string>Immunogenicity</json:string><json:string>MA</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>J.E. Crowe Jr et al.</json:string><json:string>Collins et al.</json:string><json:string>Jr et al.</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/6H6-00648L12-8</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - medicine, research & experimental</json:string><json:string>2 - immunology</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - virology</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Infectious Diseases</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Public Health, Environmental and Occupational Health</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Veterinary</json:string><json:string>3 - General 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mutagenesis</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://scientific-publisher.data.istex.fr">ELSEVIER</publisher><availability><licence><p>elsevier</p></licence></availability><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M"></p><date>1994</date></publicationStmt><notesStmt><note type="brief-communication" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-S9SX2MFS-0">brief-communication</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note type="content">Section title: Paper</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Satisfactorily attenuated and protective mutants derived from a partially attenuated cold-passaged respiratory syncytial virus mutant by introduction of additional attenuating mutations during chemical mutagenesis</title><author xml:id="author-0000"><persName><forename type="first">James E.</forename><surname>Crowe, Jr</surname></persName><affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</affiliation><affiliation>To whom correspondence should be addressed.</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Phuong T.</forename><surname>Bui</surname></persName><affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</affiliation></author><author xml:id="author-0002"><persName><forename type="first">William T.</forename><surname>London</surname></persName><affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Alan R.</forename><surname>Davis</surname></persName><affiliation>Molecular Biology Division, Wyeth-Ayerst Research, Radnor, PA, USA</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Paul P.</forename><surname>Hung</surname></persName><affiliation>Molecular Biology Division, Wyeth-Ayerst Research, Radnor, PA, USA</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Robert M.</forename><surname>Chanock</surname></persName><affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Brian R.</forename><surname>Murphy</surname></persName><affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</affiliation></author><idno type="istex">FA462D4E3388C2E1CCC589873A8984211D50FFE4</idno><idno type="ark">ark:/67375/6H6-00648L12-8</idno><idno type="DOI">10.1016/0264-410X(94)90218-6</idno><idno type="PII">0264-410X(94)90218-6</idno></analytic><monogr><title level="j">Vaccine</title><title level="j" type="abbrev">JVAC</title><idno type="pISSN">0264-410X</idno><idno type="PII">S0264-410X(00)X0240-X</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1994"></date><biblScope unit="volume">12</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="691">691</biblScope><biblScope unit="page" to="699">699</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1994</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: A cold-passaged RSV mutant, designated cp-RSV, which acquired host range mutations during 52 passages at low temperature in bovine tissue culture, was completely attenuated for seropositive adults and children but retained the capacity to cause upper respiratory disease in seronegative infants. We sought to introduce additional attenuating mutations, such as temperature-sensitive (ts) and small-plaque (sp) mutations, into the cp-RSV mutant, which is a ts + virus, in order to generate a mutant which would be satisfactorily attenuated in seronegative infants and young children. Nine mutants of cp-RSV, which had acquired either the ts or small-plaque sp phenotype, were generated by chemical mutagenesis with 5-fluorouracil. The two ts mutants with the lowest in vitro shut-off temperature, namely the cpts-248 (38°C) and cpts-530 (39°C) mutants, were the most restricted of the nine cp-RSV mutant progeny tested for efficiency of replication in Balb/c mice. In seronegative chimpanzees, the cpts-248 mutant replicated fourfold less efficiently in the nasopharynx and caused significantly less rhinorrhoea than its cp-RSV parent. The cpts-248 mutant virus, like its cp-RSV parent, was 1000-fold restricted in replication in the trachea compared with wild-type RSV. Previously, another candidate RSV live attenuated vaccine strain, a mutant designated ts-1, exhibited some instability of its ts phenotype following replication in susceptible humans or chimpanzees. Hence, we sought cp-RSV ts progeny that exhibited a greater degree of stability of the ts phenotype than the prototype ts-1 mutant. The cpts-248 and cpts-530 progeny viruses exhibited a greater degree of stability of the ts phenotype in nude mice than the ts-1 virus, and in chimpanzees, the former mutant also exhibited a greater stability of its ts phenotype than ts-1. The cpts-248 mutant was immunogenic and induced a high level of resistance in chimpanzees to subsequent challenge with wild-type RSV. The cpts-248 mutant therefore exhibits a set of properties that make it a promising vaccine candidate. These desirable properties of cpts-248 suggest that the mutant should be tested in humans for its suitability in immunoprophylaxis.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>Respiratory syncytial virus</term></item><item><term>cold-passaged mutant</term></item><item><term>attenuating mutants</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1993-09-02">Modified</change><change when="1994">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-00648L12-8/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="sco"><item-info><jid>JVAC</jid><aid>94902186</aid><ce:pii>0264-410X(94)90218-6</ce:pii><ce:doi>10.1016/0264-410X(94)90218-6</ce:doi><ce:copyright type="unknown" year="1994"></ce:copyright></item-info><head><ce:dochead><ce:textfn>Paper</ce:textfn></ce:dochead><ce:title>Satisfactorily attenuated and protective mutants derived from a partially attenuated cold-passaged respiratory syncytial virus mutant by introduction of additional attenuating mutations during chemical mutagenesis</ce:title><ce:author-group><ce:author><ce:given-name>James E.</ce:given-name><ce:surname>Crowe</ce:surname><ce:suffix>Jr</ce:suffix><ce:cross-ref refid="AFF1"><ce:sup>∗</ce:sup></ce:cross-ref><ce:cross-ref refid="COR1"><ce:sup>‡</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Phuong T.</ce:given-name><ce:surname>Bui</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>∗</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>William T.</ce:given-name><ce:surname>London</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>∗</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Alan R.</ce:given-name><ce:surname>Davis</ce:surname><ce:cross-ref refid="AFF2"><ce:sup>†</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Paul P.</ce:given-name><ce:surname>Hung</ce:surname><ce:cross-ref refid="AFF2"><ce:sup>†</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Robert M.</ce:given-name><ce:surname>Chanock</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>∗</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Brian R.</ce:given-name><ce:surname>Murphy</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>∗</ce:sup></ce:cross-ref></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>b</ce:label><ce:textfn>Molecular Biology Division, Wyeth-Ayerst Research, Radnor, PA, USA</ce:textfn></ce:affiliation><ce:correspondence id="COR1"><ce:label>Dagger;</ce:label><ce:text>To whom correspondence should be addressed.</ce:text></ce:correspondence></ce:author-group><ce:date-received day="26" month="4" year="1993"></ce:date-received><ce:date-revised day="2" month="9" year="1993"></ce:date-revised><ce:date-accepted day="2" month="9" year="1993"></ce:date-accepted><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>A cold-passaged RSV mutant, designated <ce:italic>cp</ce:italic>-RSV, which acquired host range mutations during 52 passages at low temperature in bovine tissue culture, was completely attenuated for seropositive adults and children but retained the capacity to cause upper respiratory disease in seronegative infants. We sought to introduce additional attenuating mutations, such as temperature-sensitive (<ce:italic>ts</ce:italic>) and small-plaque (<ce:italic>sp</ce:italic>) mutations, into the <ce:italic>cp</ce:italic>-RSV mutant, which is a <ce:italic>ts</ce:italic> + virus, in order to generate a mutant which would be satisfactorily attenuated in seronegative infants and young children. Nine mutants of <ce:italic>cp</ce:italic>-RSV, which had acquired either the <ce:italic>ts</ce:italic> or small-plaque <ce:italic>sp</ce:italic> phenotype, were generated by chemical mutagenesis with 5-fluorouracil. The two <ce:italic>ts</ce:italic> mutants with the lowest <ce:italic>in vitro</ce:italic> shut-off temperature, namely the <ce:italic>cpts</ce:italic>-248 (38°C) and <ce:italic>cpts</ce:italic>-530 (39°C) mutants, were the most restricted of the nine <ce:italic>cp</ce:italic>-RSV mutant progeny tested for efficiency of replication in Balb/c mice. In seronegative chimpanzees, the <ce:italic>cpts</ce:italic>-248 mutant replicated fourfold less efficiently in the nasopharynx and caused significantly less rhinorrhoea than its <ce:italic>cp</ce:italic>-RSV parent. The <ce:italic>cpts</ce:italic>-248 mutant virus, like its <ce:italic>cp</ce:italic>-RSV parent, was 1000-fold restricted in replication in the trachea compared with wild-type RSV. Previously, another candidate RSV live attenuated vaccine strain, a mutant designated <ce:italic>ts</ce:italic>-1, exhibited some instability of its <ce:italic>ts</ce:italic> phenotype following replication in susceptible humans or chimpanzees. Hence, we sought <ce:italic>cp</ce:italic>-RSV <ce:italic>ts</ce:italic> progeny that exhibited a greater degree of stability of the <ce:italic>ts</ce:italic> phenotype than the prototype <ce:italic>ts</ce:italic>-1 mutant. The <ce:italic>cpts</ce:italic>-248 and <ce:italic>cpts</ce:italic>-530 progeny viruses exhibited a greater degree of stability of the <ce:italic>ts</ce:italic> phenotype in nude mice than the <ce:italic>ts</ce:italic>-1 virus, and in chimpanzees, the former mutant also exhibited a greater stability of its <ce:italic>ts</ce:italic> phenotype than <ce:italic>ts</ce:italic>-1. The <ce:italic>cpts</ce:italic>-248 mutant was immunogenic and induced a high level of resistance in chimpanzees to subsequent challenge with wild-type RSV. The <ce:italic>cpts</ce:italic>-248 mutant therefore exhibits a set of properties that make it a promising vaccine candidate. These desirable properties of <ce:italic>cpts</ce:italic>-248 suggest that the mutant should be tested in humans for its suitability in immunoprophylaxis.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>Respiratory syncytial virus</ce:text></ce:keyword><ce:keyword><ce:text>cold-passaged mutant</ce:text></ce:keyword><ce:keyword><ce:text>attenuating mutants</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Satisfactorily attenuated and protective mutants derived from a partially attenuated cold-passaged respiratory syncytial virus mutant by introduction of additional attenuating mutations during chemical mutagenesis</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Satisfactorily attenuated and protective mutants derived from a partially attenuated cold-passaged respiratory syncytial virus mutant by introduction of additional attenuating mutations during chemical mutagenesis</title></titleInfo><name type="personal"><namePart type="given">James E.</namePart><namePart type="family">Crowe, Jr</namePart><affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</affiliation><affiliation>To whom correspondence should be addressed.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Phuong T.</namePart><namePart type="family">Bui</namePart><affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William T.</namePart><namePart type="family">London</namePart><affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alan R.</namePart><namePart type="family">Davis</namePart><affiliation>Molecular Biology Division, Wyeth-Ayerst Research, Radnor, PA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paul P.</namePart><namePart type="family">Hung</namePart><affiliation>Molecular Biology Division, Wyeth-Ayerst Research, Radnor, PA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robert M.</namePart><namePart type="family">Chanock</namePart><affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Brian R.</namePart><namePart type="family">Murphy</namePart><affiliation>Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="brief-communication" displayLabel="Short communication" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-S9SX2MFS-0">brief-communication</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1994</dateIssued><dateModified encoding="w3cdtf">1993-09-02</dateModified><copyrightDate encoding="w3cdtf">1994</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">Abstract: A cold-passaged RSV mutant, designated cp-RSV, which acquired host range mutations during 52 passages at low temperature in bovine tissue culture, was completely attenuated for seropositive adults and children but retained the capacity to cause upper respiratory disease in seronegative infants. We sought to introduce additional attenuating mutations, such as temperature-sensitive (ts) and small-plaque (sp) mutations, into the cp-RSV mutant, which is a ts + virus, in order to generate a mutant which would be satisfactorily attenuated in seronegative infants and young children. Nine mutants of cp-RSV, which had acquired either the ts or small-plaque sp phenotype, were generated by chemical mutagenesis with 5-fluorouracil. The two ts mutants with the lowest in vitro shut-off temperature, namely the cpts-248 (38°C) and cpts-530 (39°C) mutants, were the most restricted of the nine cp-RSV mutant progeny tested for efficiency of replication in Balb/c mice. In seronegative chimpanzees, the cpts-248 mutant replicated fourfold less efficiently in the nasopharynx and caused significantly less rhinorrhoea than its cp-RSV parent. The cpts-248 mutant virus, like its cp-RSV parent, was 1000-fold restricted in replication in the trachea compared with wild-type RSV. Previously, another candidate RSV live attenuated vaccine strain, a mutant designated ts-1, exhibited some instability of its ts phenotype following replication in susceptible humans or chimpanzees. Hence, we sought cp-RSV ts progeny that exhibited a greater degree of stability of the ts phenotype than the prototype ts-1 mutant. The cpts-248 and cpts-530 progeny viruses exhibited a greater degree of stability of the ts phenotype in nude mice than the ts-1 virus, and in chimpanzees, the former mutant also exhibited a greater stability of its ts phenotype than ts-1. The cpts-248 mutant was immunogenic and induced a high level of resistance in chimpanzees to subsequent challenge with wild-type RSV. The cpts-248 mutant therefore exhibits a set of properties that make it a promising vaccine candidate. These desirable properties of cpts-248 suggest that the mutant should be tested in humans for its suitability in immunoprophylaxis.</abstract><note type="content">Section title: Paper</note><subject><genre>Keywords</genre><topic>Respiratory syncytial virus</topic><topic>cold-passaged mutant</topic><topic>attenuating mutants</topic></subject><relatedItem type="host"><titleInfo><title>Vaccine</title></titleInfo><titleInfo type="abbreviated"><title>JVAC</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1994</dateIssued></originInfo><identifier type="ISSN">0264-410X</identifier><identifier type="PII">S0264-410X(00)X0240-X</identifier><part><date>1994</date><detail type="volume"><number>12</number><caption>vol.</caption></detail><detail type="issue"><number>8</number><caption>no.</caption></detail><extent unit="issue-pages"><start>675</start><end>768</end></extent><extent unit="pages"><start>691</start><end>699</end></extent></part></relatedItem><identifier type="istex">FA462D4E3388C2E1CCC589873A8984211D50FFE4</identifier><identifier type="ark">ark:/67375/6H6-00648L12-8</identifier><identifier type="DOI">10.1016/0264-410X(94)90218-6</identifier><identifier type="PII">0264-410X(94)90218-6</identifier><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</recordContentSource></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-00648L12-8/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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