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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 avian influenza viruses (HPAIV) was shown to be more susceptible to acidic pH t...

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Autores principales: Krenn, Brigitte M., Egorov, Andrej, Romanovskaya-Romanko, Ekaterina, Wolschek, Markus, Nakowitsch, Sabine, Ruthsatz, Tanja, Kiefmann, Bettina, Morokutti, Alexander, Humer, Johannes, Geiler, Janina, Cinatl, Jindrich, Michaelis, Martin, Wressnigg, Nina, Sturlan, Sanda, Ferko, Boris, Batishchev, Oleg V., Indenbom, Andrey V., Zhu, Rong, Kastner, Markus, Hinterdorfer, Peter, Kiselev, Oleg, Muster, Thomas, Romanova, Julia
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072404/
https://www.ncbi.nlm.nih.gov/pubmed/21490925
http://dx.doi.org/10.1371/journal.pone.0018577
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author Krenn, Brigitte M.
Egorov, Andrej
Romanovskaya-Romanko, Ekaterina
Wolschek, Markus
Nakowitsch, Sabine
Ruthsatz, Tanja
Kiefmann, Bettina
Morokutti, Alexander
Humer, Johannes
Geiler, Janina
Cinatl, Jindrich
Michaelis, Martin
Wressnigg, Nina
Sturlan, Sanda
Ferko, Boris
Batishchev, Oleg V.
Indenbom, Andrey V.
Zhu, Rong
Kastner, Markus
Hinterdorfer, Peter
Kiselev, Oleg
Muster, Thomas
Romanova, Julia
author_facet Krenn, Brigitte M.
Egorov, Andrej
Romanovskaya-Romanko, Ekaterina
Wolschek, Markus
Nakowitsch, Sabine
Ruthsatz, Tanja
Kiefmann, Bettina
Morokutti, Alexander
Humer, Johannes
Geiler, Janina
Cinatl, Jindrich
Michaelis, Martin
Wressnigg, Nina
Sturlan, Sanda
Ferko, Boris
Batishchev, Oleg V.
Indenbom, Andrey V.
Zhu, Rong
Kastner, Markus
Hinterdorfer, Peter
Kiselev, Oleg
Muster, Thomas
Romanova, Julia
author_sort Krenn, Brigitte M.
collection PubMed
description 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 dose(50). 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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spelling pubmed-30724042011-04-13 Single HA2 Mutation Increases the Infectivity and Immunogenicity of a Live Attenuated H5N1 Intranasal Influenza Vaccine Candidate Lacking NS1 Krenn, Brigitte M. Egorov, Andrej Romanovskaya-Romanko, Ekaterina Wolschek, Markus Nakowitsch, Sabine Ruthsatz, Tanja Kiefmann, Bettina Morokutti, Alexander Humer, Johannes Geiler, Janina Cinatl, Jindrich Michaelis, Martin Wressnigg, Nina Sturlan, Sanda Ferko, Boris Batishchev, Oleg V. Indenbom, Andrey V. Zhu, Rong Kastner, Markus Hinterdorfer, Peter Kiselev, Oleg Muster, Thomas Romanova, Julia PLoS One Research Article 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 dose(50). 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. Public Library of Science 2011-04-07 /pmc/articles/PMC3072404/ /pubmed/21490925 http://dx.doi.org/10.1371/journal.pone.0018577 Text en Krenn et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Krenn, Brigitte M.
Egorov, Andrej
Romanovskaya-Romanko, Ekaterina
Wolschek, Markus
Nakowitsch, Sabine
Ruthsatz, Tanja
Kiefmann, Bettina
Morokutti, Alexander
Humer, Johannes
Geiler, Janina
Cinatl, Jindrich
Michaelis, Martin
Wressnigg, Nina
Sturlan, Sanda
Ferko, Boris
Batishchev, Oleg V.
Indenbom, Andrey V.
Zhu, Rong
Kastner, Markus
Hinterdorfer, Peter
Kiselev, Oleg
Muster, Thomas
Romanova, Julia
Single HA2 Mutation Increases the Infectivity and Immunogenicity of a Live Attenuated H5N1 Intranasal Influenza Vaccine Candidate Lacking NS1
title Single HA2 Mutation Increases the Infectivity and Immunogenicity of a Live Attenuated H5N1 Intranasal Influenza Vaccine Candidate Lacking NS1
title_full Single HA2 Mutation Increases the Infectivity and Immunogenicity of a Live Attenuated H5N1 Intranasal Influenza Vaccine Candidate Lacking NS1
title_fullStr Single HA2 Mutation Increases the Infectivity and Immunogenicity of a Live Attenuated H5N1 Intranasal Influenza Vaccine Candidate Lacking NS1
title_full_unstemmed Single HA2 Mutation Increases the Infectivity and Immunogenicity of a Live Attenuated H5N1 Intranasal Influenza Vaccine Candidate Lacking NS1
title_short Single HA2 Mutation Increases the Infectivity and Immunogenicity of a Live Attenuated H5N1 Intranasal Influenza Vaccine Candidate Lacking NS1
title_sort single ha2 mutation increases the infectivity and immunogenicity of a live attenuated h5n1 intranasal influenza vaccine candidate lacking ns1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072404/
https://www.ncbi.nlm.nih.gov/pubmed/21490925
http://dx.doi.org/10.1371/journal.pone.0018577
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