Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses
Identifieur interne : 000511 ( Main/Exploration ); précédent : 000510; suivant : 000512Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses
Auteurs : Peter H. Goff [États-Unis] ; Tomoko Hayashi [États-Unis] ; Luis Martínez-Gil [États-Unis] ; Maripat Corr [États-Unis] ; Brian Crain [États-Unis] ; Shiyin Yao [États-Unis] ; Howard B. Cottam [États-Unis] ; Michael Chan [États-Unis] ; Irene Ramos [États-Unis] ; Dirk Eggink [États-Unis] ; Mitra Heshmati [États-Unis] ; Florian Krammer [États-Unis] ; Karen Messer [États-Unis] ; Minya Pu [États-Unis] ; Ana Fernandez-Sesma [États-Unis] ; Peter Palese [États-Unis] ; Dennis A. Carson [États-Unis]Source :
- Journal of Virology [ 0022-538X ] ; 2015.
Abstract
Current vaccines against influenza virus infection rely on the induction of neutralizing antibodies targeting the globular head of the viral hemagglutinin (HA). Protection against seasonal antigenic drift or sporadic pandemic outbreaks requires further vaccine development to induce cross-protective humoral responses, potentially to the more conserved HA stalk region. Here, we present a novel viral vaccine adjuvant comprised of two synthetic ligands for Toll-like receptor 4 (TLR4) and TLR7. 1Z105 is a substituted pyrimido[5,4-b]indole specific for the TLR4-MD2 complex, and 1V270 is a phospholipid-conjugated TLR7 agonist. Separately, 1Z105 induces rapid Th2-associated IgG1 responses, and 1V270 potently generates Th1 cellular immunity. 1Z105 and 1V270 in combination with recombinant HA from the A/Puerto Rico/8/1934 strain (rPR/8 HA) effectively induces rapid and sustained humoral immunity that is protective against lethal challenge with a homologous virus. More importantly, immunization with the combined adjuvant and rPR/8 HA, a commercially available split vaccine, or chimeric rHA antigens significantly improves protection against both heterologous and heterosubtypic challenge viruses. Heterosubtypic protection is associated with broadly reactive antibodies to HA stalk epitopes. Histological examination and cytokine profiling reveal that intramuscular (i.m.) administration of 1Z105 and 1V270 is less reactogenic than a squalene-based adjuvant, AddaVax. In summary, the combination of 1Z105 and 1V270 with a recombinant HA induces rapid, long-lasting, and balanced Th1- and Th2-type immunity; demonstrates efficacy in a variety of murine influenza virus vaccine models assaying homologous, heterologous, and heterosubtypic challenge viruses; and has an excellent safety profile.
Url:
DOI: 10.1128/JVI.03337-14
PubMed: 25568203
PubMed Central: 4337541
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: 000692
- to stream Pmc, to step Curation: 000692
- to stream Pmc, to step Checkpoint: 000354
- to stream Ncbi, to step Merge: 000B26
- to stream Ncbi, to step Curation: 000B26
- to stream Ncbi, to step Checkpoint: 000B26
- to stream Main, to step Merge: 000512
- to stream Main, to step Curation: 000511
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses</title>
<author><name sortKey="Goff, Peter H" sort="Goff, Peter H" uniqKey="Goff P" first="Peter H." last="Goff">Peter H. Goff</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff2">Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hayashi, Tomoko" sort="Hayashi, Tomoko" uniqKey="Hayashi T" first="Tomoko" last="Hayashi">Tomoko Hayashi</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Martinez Gil, Luis" sort="Martinez Gil, Luis" uniqKey="Martinez Gil L" first="Luis" last="Martínez-Gil">Luis Martínez-Gil</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Corr, Maripat" sort="Corr, Maripat" uniqKey="Corr M" first="Maripat" last="Corr">Maripat Corr</name>
<affiliation wicri:level="2"><nlm:aff id="aff4">Department of Medicine, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Crain, Brian" sort="Crain, Brian" uniqKey="Crain B" first="Brian" last="Crain">Brian Crain</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Yao, Shiyin" sort="Yao, Shiyin" uniqKey="Yao S" first="Shiyin" last="Yao">Shiyin Yao</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cottam, Howard B" sort="Cottam, Howard B" uniqKey="Cottam H" first="Howard B." last="Cottam">Howard B. Cottam</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Chan, Michael" sort="Chan, Michael" uniqKey="Chan M" first="Michael" last="Chan">Michael Chan</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ramos, Irene" sort="Ramos, Irene" uniqKey="Ramos I" first="Irene" last="Ramos">Irene Ramos</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Eggink, Dirk" sort="Eggink, Dirk" uniqKey="Eggink D" first="Dirk" last="Eggink">Dirk Eggink</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Heshmati, Mitra" sort="Heshmati, Mitra" uniqKey="Heshmati M" first="Mitra" last="Heshmati">Mitra Heshmati</name>
<affiliation wicri:level="2"><nlm:aff id="aff2">Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Krammer, Florian" sort="Krammer, Florian" uniqKey="Krammer F" first="Florian" last="Krammer">Florian Krammer</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Messer, Karen" sort="Messer, Karen" uniqKey="Messer K" first="Karen" last="Messer">Karen Messer</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pu, Minya" sort="Pu, Minya" uniqKey="Pu M" first="Minya" last="Pu">Minya Pu</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Fernandez Sesma, Ana" sort="Fernandez Sesma, Ana" uniqKey="Fernandez Sesma A" first="Ana" last="Fernandez-Sesma">Ana Fernandez-Sesma</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff2">Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff5">Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Palese, Peter" sort="Palese, Peter" uniqKey="Palese P" first="Peter" last="Palese">Peter Palese</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff5">Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Carson, Dennis A" sort="Carson, Dennis A" uniqKey="Carson D" first="Dennis A." last="Carson">Dennis A. Carson</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">25568203</idno>
<idno type="pmc">4337541</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337541</idno>
<idno type="RBID">PMC:4337541</idno>
<idno type="doi">10.1128/JVI.03337-14</idno>
<date when="2015">2015</date>
<idno type="wicri:Area/Pmc/Corpus">000692</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000692</idno>
<idno type="wicri:Area/Pmc/Curation">000692</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000692</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000354</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000354</idno>
<idno type="wicri:Area/Ncbi/Merge">000B26</idno>
<idno type="wicri:Area/Ncbi/Curation">000B26</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">000B26</idno>
<idno type="wicri:doubleKey">0022-538X:2015:Goff P:synthetic:toll:like</idno>
<idno type="wicri:Area/Main/Merge">000512</idno>
<idno type="wicri:Area/Main/Curation">000511</idno>
<idno type="wicri:Area/Main/Exploration">000511</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses</title>
<author><name sortKey="Goff, Peter H" sort="Goff, Peter H" uniqKey="Goff P" first="Peter H." last="Goff">Peter H. Goff</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff2">Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hayashi, Tomoko" sort="Hayashi, Tomoko" uniqKey="Hayashi T" first="Tomoko" last="Hayashi">Tomoko Hayashi</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Martinez Gil, Luis" sort="Martinez Gil, Luis" uniqKey="Martinez Gil L" first="Luis" last="Martínez-Gil">Luis Martínez-Gil</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Corr, Maripat" sort="Corr, Maripat" uniqKey="Corr M" first="Maripat" last="Corr">Maripat Corr</name>
<affiliation wicri:level="2"><nlm:aff id="aff4">Department of Medicine, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Crain, Brian" sort="Crain, Brian" uniqKey="Crain B" first="Brian" last="Crain">Brian Crain</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Yao, Shiyin" sort="Yao, Shiyin" uniqKey="Yao S" first="Shiyin" last="Yao">Shiyin Yao</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cottam, Howard B" sort="Cottam, Howard B" uniqKey="Cottam H" first="Howard B." last="Cottam">Howard B. Cottam</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Chan, Michael" sort="Chan, Michael" uniqKey="Chan M" first="Michael" last="Chan">Michael Chan</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ramos, Irene" sort="Ramos, Irene" uniqKey="Ramos I" first="Irene" last="Ramos">Irene Ramos</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Eggink, Dirk" sort="Eggink, Dirk" uniqKey="Eggink D" first="Dirk" last="Eggink">Dirk Eggink</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Heshmati, Mitra" sort="Heshmati, Mitra" uniqKey="Heshmati M" first="Mitra" last="Heshmati">Mitra Heshmati</name>
<affiliation wicri:level="2"><nlm:aff id="aff2">Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Krammer, Florian" sort="Krammer, Florian" uniqKey="Krammer F" first="Florian" last="Krammer">Florian Krammer</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Messer, Karen" sort="Messer, Karen" uniqKey="Messer K" first="Karen" last="Messer">Karen Messer</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pu, Minya" sort="Pu, Minya" uniqKey="Pu M" first="Minya" last="Pu">Minya Pu</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Fernandez Sesma, Ana" sort="Fernandez Sesma, Ana" uniqKey="Fernandez Sesma A" first="Ana" last="Fernandez-Sesma">Ana Fernandez-Sesma</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff2">Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff5">Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Palese, Peter" sort="Palese, Peter" uniqKey="Palese P" first="Peter" last="Palese">Peter Palese</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff5">Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Carson, Dennis A" sort="Carson, Dennis A" uniqKey="Carson D" first="Dennis A." last="Carson">Dennis A. Carson</name>
<affiliation wicri:level="2"><nlm:aff id="aff3">UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California</wicri:regionArea>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of Virology</title>
<idno type="ISSN">0022-538X</idno>
<idno type="eISSN">1098-5514</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>Current vaccines against influenza virus infection rely on the induction of neutralizing antibodies targeting the globular head of the viral hemagglutinin (HA). Protection against seasonal antigenic drift or sporadic pandemic outbreaks requires further vaccine development to induce cross-protective humoral responses, potentially to the more conserved HA stalk region. Here, we present a novel viral vaccine adjuvant comprised of two synthetic ligands for Toll-like receptor 4 (TLR4) and TLR7. 1Z105 is a substituted pyrimido[5,4-b]indole specific for the TLR4-MD2 complex, and 1V270 is a phospholipid-conjugated TLR7 agonist. Separately, 1Z105 induces rapid Th2-associated IgG1 responses, and 1V270 potently generates Th1 cellular immunity. 1Z105 and 1V270 in combination with recombinant HA from the A/Puerto Rico/8/1934 strain (rPR/8 HA) effectively induces rapid and sustained humoral immunity that is protective against lethal challenge with a homologous virus. More importantly, immunization with the combined adjuvant and rPR/8 HA, a commercially available split vaccine, or chimeric rHA antigens significantly improves protection against both heterologous and heterosubtypic challenge viruses. Heterosubtypic protection is associated with broadly reactive antibodies to HA stalk epitopes. Histological examination and cytokine profiling reveal that intramuscular (i.m.) administration of 1Z105 and 1V270 is less reactogenic than a squalene-based adjuvant, AddaVax. In summary, the combination of 1Z105 and 1V270 with a recombinant HA induces rapid, long-lasting, and balanced Th1- and Th2-type immunity; demonstrates efficacy in a variety of murine influenza virus vaccine models assaying homologous, heterologous, and heterosubtypic challenge viruses; and has an excellent safety profile.</p>
<p><bold>IMPORTANCE</bold>
Novel adjuvants are needed to enhance immunogenicity and increase the protective breadth of influenza virus vaccines to reduce the seasonal disease burden and ensure pandemic preparedness. We show here that the combination of synthetic Toll-like receptor 4 (TLR4) and TLR7 ligands is a potent adjuvant for recombinant influenza virus hemagglutinin, inducing rapid and sustained immunity that is protective against influenza viruses in homologous, heterologous, and heterosubtypic challenge models. Combining TLR4 and TLR7 ligands balances Th1- and Th2-type immune responses for long-lived cellular and neutralizing humoral immunity against the viral hemagglutinin. The combined adjuvant has an attractive safety profile and the potential to augment seasonal-vaccine breadth, contribute to a broadly neutralizing universal vaccine formulation, and improve response time in an emerging pandemic.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>État de New York</li>
</region>
</list>
<tree><country name="États-Unis"><region name="État de New York"><name sortKey="Goff, Peter H" sort="Goff, Peter H" uniqKey="Goff P" first="Peter H." last="Goff">Peter H. Goff</name>
</region>
<name sortKey="Carson, Dennis A" sort="Carson, Dennis A" uniqKey="Carson D" first="Dennis A." last="Carson">Dennis A. Carson</name>
<name sortKey="Chan, Michael" sort="Chan, Michael" uniqKey="Chan M" first="Michael" last="Chan">Michael Chan</name>
<name sortKey="Corr, Maripat" sort="Corr, Maripat" uniqKey="Corr M" first="Maripat" last="Corr">Maripat Corr</name>
<name sortKey="Cottam, Howard B" sort="Cottam, Howard B" uniqKey="Cottam H" first="Howard B." last="Cottam">Howard B. Cottam</name>
<name sortKey="Crain, Brian" sort="Crain, Brian" uniqKey="Crain B" first="Brian" last="Crain">Brian Crain</name>
<name sortKey="Eggink, Dirk" sort="Eggink, Dirk" uniqKey="Eggink D" first="Dirk" last="Eggink">Dirk Eggink</name>
<name sortKey="Fernandez Sesma, Ana" sort="Fernandez Sesma, Ana" uniqKey="Fernandez Sesma A" first="Ana" last="Fernandez-Sesma">Ana Fernandez-Sesma</name>
<name sortKey="Fernandez Sesma, Ana" sort="Fernandez Sesma, Ana" uniqKey="Fernandez Sesma A" first="Ana" last="Fernandez-Sesma">Ana Fernandez-Sesma</name>
<name sortKey="Fernandez Sesma, Ana" sort="Fernandez Sesma, Ana" uniqKey="Fernandez Sesma A" first="Ana" last="Fernandez-Sesma">Ana Fernandez-Sesma</name>
<name sortKey="Goff, Peter H" sort="Goff, Peter H" uniqKey="Goff P" first="Peter H." last="Goff">Peter H. Goff</name>
<name sortKey="Hayashi, Tomoko" sort="Hayashi, Tomoko" uniqKey="Hayashi T" first="Tomoko" last="Hayashi">Tomoko Hayashi</name>
<name sortKey="Heshmati, Mitra" sort="Heshmati, Mitra" uniqKey="Heshmati M" first="Mitra" last="Heshmati">Mitra Heshmati</name>
<name sortKey="Krammer, Florian" sort="Krammer, Florian" uniqKey="Krammer F" first="Florian" last="Krammer">Florian Krammer</name>
<name sortKey="Martinez Gil, Luis" sort="Martinez Gil, Luis" uniqKey="Martinez Gil L" first="Luis" last="Martínez-Gil">Luis Martínez-Gil</name>
<name sortKey="Messer, Karen" sort="Messer, Karen" uniqKey="Messer K" first="Karen" last="Messer">Karen Messer</name>
<name sortKey="Palese, Peter" sort="Palese, Peter" uniqKey="Palese P" first="Peter" last="Palese">Peter Palese</name>
<name sortKey="Palese, Peter" sort="Palese, Peter" uniqKey="Palese P" first="Peter" last="Palese">Peter Palese</name>
<name sortKey="Pu, Minya" sort="Pu, Minya" uniqKey="Pu M" first="Minya" last="Pu">Minya Pu</name>
<name sortKey="Ramos, Irene" sort="Ramos, Irene" uniqKey="Ramos I" first="Irene" last="Ramos">Irene Ramos</name>
<name sortKey="Yao, Shiyin" sort="Yao, Shiyin" uniqKey="Yao S" first="Shiyin" last="Yao">Shiyin Yao</name>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/H2N2V1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000511 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000511 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= H2N2V1 |flux= Main |étape= Exploration |type= RBID |clé= PMC:4337541 |texte= Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:25568203" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \ | NlmPubMed2Wicri -a H2N2V1
This area was generated with Dilib version V0.6.33. |