Stalking influenza by vaccination with pre-fusion headless HA mini-stem
Identifieur interne : 000C65 ( Ncbi/Checkpoint ); précédent : 000C64; suivant : 000C66Stalking 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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PMC:4780079Le document en format XML
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<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>
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<biblStruct><analytic><author><name sortKey="Temperton, N J" uniqKey="Temperton N">N. J. Temperton</name>
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<biblStruct><analytic><author><name sortKey="Valkenburg, S A" uniqKey="Valkenburg S">S. A. Valkenburg</name>
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<affiliations><list><country><li>Hong Kong</li>
<li>Inde</li>
<li>Royaume-Uni</li>
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<region><li>Illinois</li>
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<settlement><li>Chicago</li>
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<tree><country name="Hong Kong"><region name="Illinois"><name sortKey="Valkenburg, Sophie A" sort="Valkenburg, Sophie A" uniqKey="Valkenburg S" first="Sophie A." last="Valkenburg">Sophie A. Valkenburg</name>
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<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>
<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>
<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>
<name sortKey="Valkenburg, Sophie A" sort="Valkenburg, Sophie A" uniqKey="Valkenburg S" first="Sophie A." last="Valkenburg">Sophie A. Valkenburg</name>
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<name sortKey="Varadarajan, Raghavan" sort="Varadarajan, Raghavan" uniqKey="Varadarajan R" first="Raghavan" last="Varadarajan">Raghavan Varadarajan</name>
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<name sortKey="Temperton, Nigel" sort="Temperton, Nigel" uniqKey="Temperton N" first="Nigel" last="Temperton">Nigel Temperton</name>
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