Stalking influenza by vaccination with pre-fusion headless HA mini-stem
Identifieur interne : 000405 ( Main/Exploration ); précédent : 000404; suivant : 000406Stalking influenza by vaccination with pre-fusion headless HA mini-stem
Auteurs : Sophie A. Valkenburg [Hong Kong] ; V. Vamsee Aditya Mallajosyula [Inde] ; Olive T. W. Li [Hong Kong] ; Alex W. H. Chin [Hong Kong] ; George Carnell [Royaume-Uni] ; Nigel Temperton [Royaume-Uni] ; Raghavan Varadarajan [Inde] ; Leo L. M. Poon [Hong Kong]Source :
- Scientific Reports [ 2045-2322 ] ; 2016.
Abstract
Inaccuracies in prediction of circulating viral strain genotypes and the possibility of novel reassortants causing a pandemic outbreak necessitate the development of an anti-influenza vaccine with increased breadth of protection and potential for rapid production and deployment. The hemagglutinin (HA) stem is a promising target for universal influenza vaccine as stem-specific antibodies have the potential to be broadly cross-reactive towards different HA subtypes. Here, we report the design of a bacterially expressed polypeptide that mimics a H5 HA stem by protein minimization to focus the antibody response towards the HA stem. The HA mini-stem folds as a trimer mimicking the HA prefusion conformation. It is resistant to thermal/chemical stress, and it binds to conformation-specific, HA stem-directed broadly neutralizing antibodies with high affinity. Mice vaccinated with the group 1 HA mini-stems are protected from morbidity and mortality against lethal challenge by both group 1 (H5 and H1) and group 2 (H3) influenza viruses, the first report of cross-group protection. Passive transfer of immune serum demonstrates the protection is mediated by stem-specific antibodies. Furthermore, antibodies indudced by these HA stems have broad HA reactivity, yet they do not have antibody-dependent enhancement activity.
Url:
DOI: 10.1038/srep22666
PubMed: 26947245
PubMed Central: 4780079
Affiliations:
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Le document en format XML
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Valkenburg</name><affiliation wicri:level="3"><nlm:aff id="a1"><institution>HKU-Pasteur Research Pole, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong</institution>, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>, Chicago</wicri:regionArea><placeName><settlement type="city">Chicago</settlement><region type="state">Illinois</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="a2"><institution>Center of Influenza Research and School of Public Health, The University of Hong Kong</institution>, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>, Chicago</wicri:regionArea><placeName><settlement type="city">Chicago</settlement><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Mallajosyula, V Vamsee Aditya" sort="Mallajosyula, V Vamsee Aditya" uniqKey="Mallajosyula V" first="V. Vamsee Aditya" last="Mallajosyula">V. Vamsee Aditya Mallajosyula</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Molecular Biophysics Unit, Indian Institute of Science</institution>, Bangalore,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Li, Olive T W" sort="Li, Olive T W" uniqKey="Li O" first="Olive T. W." last="Li">Olive T. W. Li</name><affiliation wicri:level="3"><nlm:aff id="a2"><institution>Center of Influenza Research and School of Public Health, The University of Hong Kong</institution>, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>, Chicago</wicri:regionArea><placeName><settlement type="city">Chicago</settlement><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Chin, Alex W H" sort="Chin, Alex W H" uniqKey="Chin A" first="Alex W. H." last="Chin">Alex W. H. Chin</name><affiliation wicri:level="3"><nlm:aff id="a2"><institution>Center of Influenza Research and School of Public Health, The University of Hong Kong</institution>, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>, Chicago</wicri:regionArea><placeName><settlement type="city">Chicago</settlement><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Carnell, George" sort="Carnell, George" uniqKey="Carnell G" first="George" last="Carnell">George Carnell</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Viral Pseudotype Unit, School of Pharmacy, University of Kent</institution>, Kent,<country>United Kingdom</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Temperton, Nigel" sort="Temperton, Nigel" uniqKey="Temperton N" first="Nigel" last="Temperton">Nigel Temperton</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Viral Pseudotype Unit, School of Pharmacy, University of Kent</institution>, Kent,<country>United Kingdom</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Varadarajan, Raghavan" sort="Varadarajan, Raghavan" uniqKey="Varadarajan R" first="Raghavan" last="Varadarajan">Raghavan Varadarajan</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Molecular Biophysics Unit, Indian Institute of Science</institution>, Bangalore,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Poon, Leo L M" sort="Poon, Leo L M" uniqKey="Poon L" first="Leo L. M." last="Poon">Leo L. M. Poon</name><affiliation wicri:level="3"><nlm:aff id="a2"><institution>Center of Influenza Research and School of Public Health, The University of Hong Kong</institution>, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>, Chicago</wicri:regionArea><placeName><settlement type="city">Chicago</settlement><region type="state">Illinois</region></placeName></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Inaccuracies in prediction of circulating viral strain genotypes and the possibility of novel reassortants causing a pandemic outbreak necessitate the development of an anti-influenza vaccine with increased breadth of protection and potential for rapid production and deployment. The hemagglutinin (HA) stem is a promising target for universal influenza vaccine as stem-specific antibodies have the potential to be broadly cross-reactive towards different HA subtypes. Here, we report the design of a bacterially expressed polypeptide that mimics a H5 HA stem by protein minimization to focus the antibody response towards the HA stem. The HA mini-stem folds as a trimer mimicking the HA prefusion conformation. It is resistant to thermal/chemical stress, and it binds to conformation-specific, HA stem-directed broadly neutralizing antibodies with high affinity. Mice vaccinated with the group 1 HA mini-stems are protected from morbidity and mortality against lethal challenge by both group 1 (H5 and H1) and group 2 (H3) influenza viruses, the first report of cross-group protection. Passive transfer of immune serum demonstrates the protection is mediated by stem-specific antibodies. Furthermore, antibodies indudced by these HA stems have broad HA reactivity, yet they do not have antibody-dependent enhancement activity.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Gerhard, W" uniqKey="Gerhard W">W. Gerhard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, Y" uniqKey="Wu Y">Y. Wu</name></author><author><name sortKey="Tefsen, B" uniqKey="Tefsen B">B. Tefsen</name></author><author><name sortKey="Shi, Y" uniqKey="Shi Y">Y. Shi</name></author><author><name sortKey="Gao, G F" uniqKey="Gao G">G. F. Gao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Skehel, J J" uniqKey="Skehel J">J. J. Skehel</name></author><author><name sortKey="Wiley, D C" uniqKey="Wiley D">D. C. Wiley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Skehel, J J" uniqKey="Skehel J">J. J. 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Valkenburg</name></country><country name="Inde"><noRegion><name sortKey="Mallajosyula, V Vamsee Aditya" sort="Mallajosyula, V Vamsee Aditya" uniqKey="Mallajosyula V" first="V. Vamsee Aditya" last="Mallajosyula">V. Vamsee Aditya Mallajosyula</name></noRegion><name sortKey="Varadarajan, Raghavan" sort="Varadarajan, Raghavan" uniqKey="Varadarajan R" first="Raghavan" last="Varadarajan">Raghavan Varadarajan</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Carnell, George" sort="Carnell, George" uniqKey="Carnell G" first="George" last="Carnell">George Carnell</name></noRegion><name sortKey="Temperton, Nigel" sort="Temperton, Nigel" uniqKey="Temperton N" first="Nigel" last="Temperton">Nigel Temperton</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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