Single HA2 mutation increases the infectivity and immunogenicity of a live attenuated H5N1 intranasal influenza vaccine candidate lacking NS1

Background: H5N1 influenza vaccines, including live intranasal, appear to be relatively less immunogenic compared to seasonal analogs. The main influenza virus surface glycoprotein hemagglutinin (HA) of highly pathogenic
Background: H5N1 influenza vaccines, including live intranasal, appear to be relatively less immunogenic compared to seasonal analogs. The main influenza virus surface glycoprotein hemagglutinin (HA) of highly pathogenic avian influenza viruses (HPAIV) was shown to be more susceptible to acidic pH treatment than that of human or low pathogenic avian influenza viruses. The acidification machinery of the human nasal passageway in response to different irritation factors starts to release protons acidifying the mucosal surface (down to pH of 5.2). We hypothesized that the sensitivity of H5 HA to the acidic environment might be the reason for the low infectivity and immunogenicity of intranasal H5N1 vaccines for mammals. Methodology/Principal Findings: We demonstrate that original human influenza viruses infect primary human nasal epithelial cells at acidic pH (down to 5.4), whereas H5N1 HPAIVs lose infectivity at pH <= 5.6. The HA of A/Vietnam/1203/04 was modified by introducing the single substitution HA2 58K -> I, decreasing the pH of the HA conformational change. The H5N1 reassortants containing the indicated mutation displayed an increased resistance to acidic pH and high temperature treatment compared to those lacking modification. The mutation ensured a higher viral uptake as shown by immunohistochemistry in the respiratory tract of mice and 25 times lower mouse infectious dose50. Moreover, the reassortants keeping 58K -> I mutation designed as a live attenuated vaccine candidate lacking an NS1 gene induced superior systemic and local antibody response after the intranasal immunization of mice. Conclusion/Significance: Our finding suggests that an efficient intranasal vaccination with a live attenuated H5N1 virus may require a certain level of pH and temperature stability of HA in order to achieve an optimal virus uptake by the nasal epithelial cells and induce a sufficient immune response. The pH of the activation of the H5 HA protein may play a substantial role in the infectivity of HPAIVs for mammals.
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Author:Brigitte M. Krenn, Andrej Egorov, Ekaterina Romanovskaya-Romanko, Markus Wolschek, Sabine Nakowitsch, Tanja Ruthsatz, Bettina Kiefmann, Alexander Morokutti, Johannes Humer, Janina Geiler, Jindrich Cinatl, Martin Michaelis, Nina Wressnigg, Sanda Sturlan, Boris Ferko, Oleg V. Batishchev, Andrey V. Indenbom, Rong Zhu, Markus Kastner, Peter Hinterdorfer, Oleg Kiselev, Thomas Muster, Julia Romanova
URN:urn:nbn:de:hebis:30-113164
DOI:http://dx.doi.org/10.1371/journal.pone.0018577
ISSN:1932-6203
Parent Title (English):PLoS one
Document Type:Article
Language:English
Date of Publication (online):2011/09/05
Year of first Publication:2011
Publishing Institution:Univ.-Bibliothek Frankfurt am Main
Release Date:2011/09/05
Note:
Copyright: © 2011 Krenn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source:PLoS ONE 6(4): e18577. doi: 10.1371/journal.pone.0018577
HeBIS PPN:274757257
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0

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