A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response upon Challenge▿
Identifieur interne : 000C66 ( Pmc/Corpus ); précédent : 000C65; suivant : 000C67A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response upon Challenge▿
Auteurs : Meagan Bolles ; Damon Deming ; Kristin Long ; Sudhakar Agnihothram ; Alan Whitmore ; Martin Ferris ; William Funkhouser ; Lisa Gralinski ; Allison Totura ; Mark Heise ; Ralph S. BaricSource :
- Journal of Virology [ 0022-538X ] ; 2011.
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) is an important emerging virus that is highly pathogenic in aged populations and is maintained with great diversity in zoonotic reservoirs. While a variety of vaccine platforms have shown efficacy in young-animal models and against homologous viral strains, vaccine efficacy has not been thoroughly evaluated using highly pathogenic variants that replicate the acute end stage lung disease phenotypes seen during the human epidemic. Using an adjuvanted and an unadjuvanted double-inactivated SARS-CoV (DIV) vaccine, we demonstrate an eosinophilic immunopathology in aged mice comparable to that seen in mice immunized with the SARS nucleocapsid protein, and poor protection against a nonlethal heterologous challenge. In young and 1-year-old animals, we demonstrate that adjuvanted DIV vaccine provides protection against lethal disease in young animals following homologous and heterologous challenge, although enhanced immune pathology and eosinophilia are evident following heterologous challenge. In the absence of alum, DIV vaccine performed poorly in young animals challenged with lethal homologous or heterologous strains. In contrast, DIV vaccines (both adjuvanted and unadjuvanted) performed poorly in aged-animal models. Importantly, aged animals displayed increased eosinophilic immune pathology in the lungs and were not protected against significant virus replication. These data raise significant concerns regarding DIV vaccine safety and highlight the need for additional studies of the molecular mechanisms governing DIV-induced eosinophilia and vaccine failure, especially in the more vulnerable aged-animal models of human disease.
Url:
DOI: 10.1128/JVI.06048-11
PubMed: 21937658
PubMed Central: 3209347
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PMC:3209347Le document en format XML
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<author><name sortKey="Bolles, Meagan" sort="Bolles, Meagan" uniqKey="Bolles M" first="Meagan" last="Bolles">Meagan Bolles</name>
<affiliation><nlm:aff id="aff1">Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<author><name sortKey="Deming, Damon" sort="Deming, Damon" uniqKey="Deming D" first="Damon" last="Deming">Damon Deming</name>
<affiliation><nlm:aff id="aff1">Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<author><name sortKey="Long, Kristin" sort="Long, Kristin" uniqKey="Long K" first="Kristin" last="Long">Kristin Long</name>
<affiliation><nlm:aff id="aff2"> Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<author><name sortKey="Agnihothram, Sudhakar" sort="Agnihothram, Sudhakar" uniqKey="Agnihothram S" first="Sudhakar" last="Agnihothram">Sudhakar Agnihothram</name>
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<author><name sortKey="Whitmore, Alan" sort="Whitmore, Alan" uniqKey="Whitmore A" first="Alan" last="Whitmore">Alan Whitmore</name>
<affiliation><nlm:aff id="aff2"> Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<author><name sortKey="Ferris, Martin" sort="Ferris, Martin" uniqKey="Ferris M" first="Martin" last="Ferris">Martin Ferris</name>
<affiliation><nlm:aff id="aff2"> Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<author><name sortKey="Funkhouser, William" sort="Funkhouser, William" uniqKey="Funkhouser W" first="William" last="Funkhouser">William Funkhouser</name>
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<author><name sortKey="Totura, Allison" sort="Totura, Allison" uniqKey="Totura A" first="Allison" last="Totura">Allison Totura</name>
<affiliation><nlm:aff id="aff1">Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<author><name sortKey="Heise, Mark" sort="Heise, Mark" uniqKey="Heise M" first="Mark" last="Heise">Mark Heise</name>
<affiliation><nlm:aff id="aff1">Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff2"> Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5"> Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
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<author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<affiliation><nlm:aff id="aff1">Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<affiliation><nlm:aff id="aff3">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response upon Challenge<xref ref-type="fn" rid="FN2"><sup>▿</sup>
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<author><name sortKey="Bolles, Meagan" sort="Bolles, Meagan" uniqKey="Bolles M" first="Meagan" last="Bolles">Meagan Bolles</name>
<affiliation><nlm:aff id="aff1">Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<author><name sortKey="Deming, Damon" sort="Deming, Damon" uniqKey="Deming D" first="Damon" last="Deming">Damon Deming</name>
<affiliation><nlm:aff id="aff1">Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Long, Kristin" sort="Long, Kristin" uniqKey="Long K" first="Kristin" last="Long">Kristin Long</name>
<affiliation><nlm:aff id="aff2"> Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
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<author><name sortKey="Agnihothram, Sudhakar" sort="Agnihothram, Sudhakar" uniqKey="Agnihothram S" first="Sudhakar" last="Agnihothram">Sudhakar Agnihothram</name>
<affiliation><nlm:aff id="aff3">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<author><name sortKey="Whitmore, Alan" sort="Whitmore, Alan" uniqKey="Whitmore A" first="Alan" last="Whitmore">Alan Whitmore</name>
<affiliation><nlm:aff id="aff2"> Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ferris, Martin" sort="Ferris, Martin" uniqKey="Ferris M" first="Martin" last="Ferris">Martin Ferris</name>
<affiliation><nlm:aff id="aff2"> Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Funkhouser, William" sort="Funkhouser, William" uniqKey="Funkhouser W" first="William" last="Funkhouser">William Funkhouser</name>
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</affiliation>
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<author><name sortKey="Gralinski, Lisa" sort="Gralinski, Lisa" uniqKey="Gralinski L" first="Lisa" last="Gralinski">Lisa Gralinski</name>
<affiliation><nlm:aff id="aff3">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
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<author><name sortKey="Totura, Allison" sort="Totura, Allison" uniqKey="Totura A" first="Allison" last="Totura">Allison Totura</name>
<affiliation><nlm:aff id="aff1">Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
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<author><name sortKey="Heise, Mark" sort="Heise, Mark" uniqKey="Heise M" first="Mark" last="Heise">Mark Heise</name>
<affiliation><nlm:aff id="aff1">Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff2"> Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5"> Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
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<author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<affiliation><nlm:aff id="aff1">Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff3">Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</nlm:aff>
</affiliation>
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<series><title level="j">Journal of Virology</title>
<idno type="ISSN">0022-538X</idno>
<idno type="eISSN">1098-5514</idno>
<imprint><date when="2011">2011</date>
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<front><div type="abstract" xml:lang="en"><p>Severe acute respiratory syndrome coronavirus (SARS-CoV) is an important emerging virus that is highly pathogenic in aged populations and is maintained with great diversity in zoonotic reservoirs. While a variety of vaccine platforms have shown efficacy in young-animal models and against homologous viral strains, vaccine efficacy has not been thoroughly evaluated using highly pathogenic variants that replicate the acute end stage lung disease phenotypes seen during the human epidemic. Using an adjuvanted and an unadjuvanted double-inactivated SARS-CoV (DIV) vaccine, we demonstrate an eosinophilic immunopathology in aged mice comparable to that seen in mice immunized with the SARS nucleocapsid protein, and poor protection against a nonlethal heterologous challenge. In young and 1-year-old animals, we demonstrate that adjuvanted DIV vaccine provides protection against lethal disease in young animals following homologous and heterologous challenge, although enhanced immune pathology and eosinophilia are evident following heterologous challenge. In the absence of alum, DIV vaccine performed poorly in young animals challenged with lethal homologous or heterologous strains. In contrast, DIV vaccines (both adjuvanted and unadjuvanted) performed poorly in aged-animal models. Importantly, aged animals displayed increased eosinophilic immune pathology in the lungs and were not protected against significant virus replication. These data raise significant concerns regarding DIV vaccine safety and highlight the need for additional studies of the molecular mechanisms governing DIV-induced eosinophilia and vaccine failure, especially in the more vulnerable aged-animal models of human disease.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id>
<journal-id journal-id-type="hwp">jvi</journal-id>
<journal-id journal-id-type="pmc">jvi</journal-id>
<journal-id journal-id-type="publisher-id">JVI</journal-id>
<journal-title-group><journal-title>Journal of Virology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0022-538X</issn>
<issn pub-type="epub">1098-5514</issn>
<publisher><publisher-name>American Society for Microbiology</publisher-name>
<publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">21937658</article-id>
<article-id pub-id-type="pmc">3209347</article-id>
<article-id pub-id-type="publisher-id">6048-11</article-id>
<article-id pub-id-type="doi">10.1128/JVI.06048-11</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Pathogenesis and Immunity</subject>
</subj-group>
</article-categories>
<title-group><article-title>A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response upon Challenge<xref ref-type="fn" rid="FN2"><sup>▿</sup>
</xref>
</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Bolles</surname>
<given-names>Meagan</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="FN1">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Deming</surname>
<given-names>Damon</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="FN1">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Long</surname>
<given-names>Kristin</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Agnihothram</surname>
<given-names>Sudhakar</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Whitmore</surname>
<given-names>Alan</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ferris</surname>
<given-names>Martin</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Funkhouser</surname>
<given-names>William</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gralinski</surname>
<given-names>Lisa</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Totura</surname>
<given-names>Allison</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Heise</surname>
<given-names>Mark</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Baric</surname>
<given-names>Ralph S.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
</contrib>
<aff id="aff1"><label>1</label>
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</aff>
<aff id="aff2"><label>2</label>
Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</aff>
<aff id="aff3"><label>3</label>
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</aff>
<aff id="aff4"><label>4</label>
Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, North Carolina</aff>
<aff id="aff5"><label>5</label>
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</aff>
</contrib-group>
<author-notes><corresp id="cor1"><label>*</label>
Corresponding author. Mailing address: <addr-line>University of North Carolina at Chapel Hill, 3304 Michael Hooker Research Center, CB 7435, Chapel Hill, NC 27599-7435</addr-line>
. Phone: <phone>(919) 966-3895</phone>
. Fax: <fax>(919) 966-0584</fax>
. E-mail: <email>rbaric@email.unc.edu</email>
.</corresp>
<fn fn-type="equal" id="FN1"><label>†</label>
<p>These authors contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>12</month>
<year>2011</year>
</pub-date>
<volume>85</volume>
<issue>23</issue>
<fpage>12201</fpage>
<lpage>12215</lpage>
<history><date date-type="received"><day>22</day>
<month>8</month>
<year>2011</year>
</date>
<date date-type="accepted"><day>8</day>
<month>9</month>
<year>2011</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2011, American Society for Microbiology. All Rights Reserved.</copyright-statement>
<copyright-year>2011</copyright-year>
<copyright-holder>American Society for Microbiology</copyright-holder>
</permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zjv02311012201.pdf"></self-uri>
<abstract><p>Severe acute respiratory syndrome coronavirus (SARS-CoV) is an important emerging virus that is highly pathogenic in aged populations and is maintained with great diversity in zoonotic reservoirs. While a variety of vaccine platforms have shown efficacy in young-animal models and against homologous viral strains, vaccine efficacy has not been thoroughly evaluated using highly pathogenic variants that replicate the acute end stage lung disease phenotypes seen during the human epidemic. Using an adjuvanted and an unadjuvanted double-inactivated SARS-CoV (DIV) vaccine, we demonstrate an eosinophilic immunopathology in aged mice comparable to that seen in mice immunized with the SARS nucleocapsid protein, and poor protection against a nonlethal heterologous challenge. In young and 1-year-old animals, we demonstrate that adjuvanted DIV vaccine provides protection against lethal disease in young animals following homologous and heterologous challenge, although enhanced immune pathology and eosinophilia are evident following heterologous challenge. In the absence of alum, DIV vaccine performed poorly in young animals challenged with lethal homologous or heterologous strains. In contrast, DIV vaccines (both adjuvanted and unadjuvanted) performed poorly in aged-animal models. Importantly, aged animals displayed increased eosinophilic immune pathology in the lungs and were not protected against significant virus replication. These data raise significant concerns regarding DIV vaccine safety and highlight the need for additional studies of the molecular mechanisms governing DIV-induced eosinophilia and vaccine failure, especially in the more vulnerable aged-animal models of human disease.</p>
</abstract>
</article-meta>
</front>
</pmc>
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