Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics
Identifieur interne : 000375 ( Pmc/Corpus ); précédent : 000374; suivant : 000376Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics
Auteurs : Katie L. Winarski ; Juanjie Tang ; Laura Klenow ; Jeehyun Lee ; Elizabeth M. Coyle ; Jody Manischewitz ; Hannah L. Turner ; Kazuyo Takeda ; Andrew B. Ward ; Hana Golding ; Surender KhuranaSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2019.
Abstract
Next-generation influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these do not block virus–receptor interactions and thus are predicted to provide protection via alternative mechanisms at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of respiratory disease (ERD). Our study describes ADE with two different functional MAbs that destabilized HA stem domain, increased influenza virus fusion kinetics, and led to enhanced lung pathology and ERD in a dose-dependent manner in a mice model. This study underlines careful preclinical evaluation of next-generation influenza vaccines or antibody-based therapeutics that do not block influenza virus receptor binding.
Url:
DOI: 10.1073/pnas.1821317116
PubMed: 31296560
PubMed Central: 6660725
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics</title><author><name sortKey="Winarski, Katie L" sort="Winarski, Katie L" uniqKey="Winarski K" first="Katie L." last="Winarski">Katie L. Winarski</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Tang, Juanjie" sort="Tang, Juanjie" uniqKey="Tang J" first="Juanjie" last="Tang">Juanjie Tang</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Klenow, Laura" sort="Klenow, Laura" uniqKey="Klenow L" first="Laura" last="Klenow">Laura Klenow</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Lee, Jeehyun" sort="Lee, Jeehyun" uniqKey="Lee J" first="Jeehyun" last="Lee">Jeehyun Lee</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Coyle, Elizabeth M" sort="Coyle, Elizabeth M" uniqKey="Coyle E" first="Elizabeth M." last="Coyle">Elizabeth M. Coyle</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Manischewitz, Jody" sort="Manischewitz, Jody" uniqKey="Manischewitz J" first="Jody" last="Manischewitz">Jody Manischewitz</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Turner, Hannah L" sort="Turner, Hannah L" uniqKey="Turner H" first="Hannah L." last="Turner">Hannah L. Turner</name><affiliation><nlm:aff id="aff2">Department of Integrative Structural and Computational Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037</nlm:aff></affiliation></author><author><name sortKey="Takeda, Kazuyo" sort="Takeda, Kazuyo" uniqKey="Takeda K" first="Kazuyo" last="Takeda">Kazuyo Takeda</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Ward, Andrew B" sort="Ward, Andrew B" uniqKey="Ward A" first="Andrew B." last="Ward">Andrew B. Ward</name><affiliation><nlm:aff id="aff2">Department of Integrative Structural and Computational Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037</nlm:aff></affiliation></author><author><name sortKey="Golding, Hana" sort="Golding, Hana" uniqKey="Golding H" first="Hana" last="Golding">Hana Golding</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Khurana, Surender" sort="Khurana, Surender" uniqKey="Khurana S" first="Surender" last="Khurana">Surender Khurana</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31296560</idno><idno type="pmc">6660725</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660725</idno><idno type="RBID">PMC:6660725</idno><idno type="doi">10.1073/pnas.1821317116</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000375</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000375</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics</title><author><name sortKey="Winarski, Katie L" sort="Winarski, Katie L" uniqKey="Winarski K" first="Katie L." last="Winarski">Katie L. Winarski</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Tang, Juanjie" sort="Tang, Juanjie" uniqKey="Tang J" first="Juanjie" last="Tang">Juanjie Tang</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Klenow, Laura" sort="Klenow, Laura" uniqKey="Klenow L" first="Laura" last="Klenow">Laura Klenow</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Lee, Jeehyun" sort="Lee, Jeehyun" uniqKey="Lee J" first="Jeehyun" last="Lee">Jeehyun Lee</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Coyle, Elizabeth M" sort="Coyle, Elizabeth M" uniqKey="Coyle E" first="Elizabeth M." last="Coyle">Elizabeth M. Coyle</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Manischewitz, Jody" sort="Manischewitz, Jody" uniqKey="Manischewitz J" first="Jody" last="Manischewitz">Jody Manischewitz</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Turner, Hannah L" sort="Turner, Hannah L" uniqKey="Turner H" first="Hannah L." last="Turner">Hannah L. Turner</name><affiliation><nlm:aff id="aff2">Department of Integrative Structural and Computational Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037</nlm:aff></affiliation></author><author><name sortKey="Takeda, Kazuyo" sort="Takeda, Kazuyo" uniqKey="Takeda K" first="Kazuyo" last="Takeda">Kazuyo Takeda</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Ward, Andrew B" sort="Ward, Andrew B" uniqKey="Ward A" first="Andrew B." last="Ward">Andrew B. Ward</name><affiliation><nlm:aff id="aff2">Department of Integrative Structural and Computational Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037</nlm:aff></affiliation></author><author><name sortKey="Golding, Hana" sort="Golding, Hana" uniqKey="Golding H" first="Hana" last="Golding">Hana Golding</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author><author><name sortKey="Khurana, Surender" sort="Khurana, Surender" uniqKey="Khurana S" first="Surender" last="Khurana">Surender Khurana</name><affiliation><nlm:aff id="aff1">Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>Next-generation influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these do not block virus–receptor interactions and thus are predicted to provide protection via alternative mechanisms at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of respiratory disease (ERD). Our study describes ADE with two different functional MAbs that destabilized HA stem domain, increased influenza virus fusion kinetics, and led to enhanced lung pathology and ERD in a dose-dependent manner in a mice model. This study underlines careful preclinical evaluation of next-generation influenza vaccines or antibody-based therapeutics that do not block influenza virus receptor binding.</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">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31296560</article-id><article-id pub-id-type="pmc">6660725</article-id><article-id pub-id-type="publisher-id">201821317</article-id><article-id pub-id-type="doi">10.1073/pnas.1821317116</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Microbiology</subject></subj-group></subj-group></article-categories><title-group><article-title>Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Winarski</surname><given-names>Katie L.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tang</surname><given-names>Juanjie</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Klenow</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Jeehyun</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Coyle</surname><given-names>Elizabeth M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Manischewitz</surname><given-names>Jody</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Turner</surname><given-names>Hannah L.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Takeda</surname><given-names>Kazuyo</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ward</surname><given-names>Andrew B.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Golding</surname><given-names>Hana</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-0593-7965</contrib-id><name><surname>Khurana</surname><given-names>Surender</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1"><sup>a</sup>Division of Viral Products, Center for Biologics Evaluation and Research,<institution>Food and Drug Administration</institution>, Silver Spring,<addr-line>MD</addr-line> 20993;</aff><aff id="aff2"><sup>b</sup>Department of Integrative Structural and Computational Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037</aff></contrib-group><author-notes><corresp id="cor1"><sup>2</sup>To whom correspondence may be addressed. Email: <email>Surender.Khurana@fda.hhs.gov</email>.</corresp><fn fn-type="edited-by"><p>Edited by Robert G. Webster, St. Jude Children’s Research Hospital, Memphis, TN, and approved June 19, 2019 (received for review December 14, 2018)</p></fn><fn fn-type="con"><p>Author contributions: S.K. designed research; K.L.W., J.T., L.K., J.L., E.M.C., J.M., H.L.T., K.T., A.B.W., and S.K. performed research; K.L.W., J.T., L.K., H.L.T., K.T., A.B.W., and S.K. analyzed data; and A.B.W., H.G., and S.K. wrote the paper.</p></fn><fn fn-type="equal" id="fn1"><p><sup>1</sup>K.L.W., J.T., and L.K. contributed equally to this work.</p></fn><fn fn-type="COI-statement"><p>The authors declare no conflict of interest.</p></fn></author-notes><pub-date pub-type="ppub"><day>23</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>11</day><month>7</month><year>2019</year></pub-date><volume>116</volume><issue>30</issue><fpage>15194</fpage><lpage>15199</lpage><permissions><copyright-year>2019</copyright-year><license><ali:license_ref specific-use="vor">https://www.pnas.org/site/aboutpnas/licenses.xhtml</ali:license_ref><license-p>Published under the <ext-link ext-link-type="uri" xlink:href="https://www.pnas.org/site/aboutpnas/licenses.xhtml">PNAS license</ext-link>.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:href="pnas.201821317.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>Next-generation influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these do not block virus–receptor interactions and thus are predicted to provide protection via alternative mechanisms at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of respiratory disease (ERD). Our study describes ADE with two different functional MAbs that destabilized HA stem domain, increased influenza virus fusion kinetics, and led to enhanced lung pathology and ERD in a dose-dependent manner in a mice model. This study underlines careful preclinical evaluation of next-generation influenza vaccines or antibody-based therapeutics that do not block influenza virus receptor binding.</p></abstract><abstract><p>Several next-generation (universal) influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these mediate inhibitions of virus replication at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of viral infection or disease. In the current study, two monoclonal antibodies (MAbs) 72/8 and 69/1, enhanced respiratory disease (ERD) in mice following H3N2 virus challenge by demonstrating increased lung pathology and changes in lung cytokine/chemokine levels. MAb 78/2 caused changes in the lung viral loads in a dose-dependent manner. Both MAbs increased HA sensitivity to trypsin cleavage at a higher pH range, suggesting MAb-induced conformational changes. pHrodo-labeled virus particles’ entry and residence time in the endocytic compartment were tracked during infection of Madin-Darby canine kidney (MDCK) cells. Both MAbs reduced H3N2 virus residence time in the endocytic pathway, suggesting faster virus fusion kinetics. Structurally, 78/2 and 69/1 Fabs bound the globular head or base of the head domain of influenza hemagglutinin (HA), respectively, and induced destabilization of the HA stem domain. Together, this study describes Mab-induced destabilization of the influenza HA stem domain, faster kinetics of influenza virus fusion, and ERD in vivo. The in vivo animal model and in vitro assays described could augment preclinical safety evaluation of antibodies and next-generation influenza vaccines that generate antibodies which do not block influenza virus–receptor interaction.</p></abstract><kwd-group><kwd>universal</kwd><kwd>stem</kwd><kwd>influenza</kwd><kwd>antibody-dependent enhancement (ADE)</kwd><kwd>vaccine</kwd></kwd-group><funding-group><award-group id="gs1"><funding-source id="sp1">CBER (FDA)</funding-source><award-id rid="sp1">Intramural funding</award-id><principal-award-recipient>Surender Khurana</principal-award-recipient></award-group></funding-group><counts><page-count count="6"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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