TY  - JOUR
A1  - Krenn, Brigitte M.
A1  - Egorov, Andrej
A1  - Romanovskaya-Romanko, Ekaterina
A1  - Wolschek, Markus
A1  - Nakowitsch, Sabine
A1  - Ruthsatz, Tanja
A1  - Kiefmann, Bettina
A1  - Morokutti, Alexander
A1  - Humer, Johannes
A1  - Geiler, Janina
A1  - Cinatl, Jindrich
A1  - Michaelis, Martin
A1  - Wressnigg, Nina
A1  - Sturlan, Sanda
A1  - Ferko, Boris
A1  - Batishchev, Oleg V.
A1  - Indenbom, Andrey V.
A1  - Zhu, Rong
A1  - Kastner, Markus
A1  - Hinterdorfer, Peter
A1  - Kiselev, Oleg A.
A1  - Muster, Thomas
A1  - Romanova, Julia
T1  - Single HA2 mutation increases the infectivity and immunogenicity of a live attenuated H5N1 intranasal influenza vaccine candidate lacking NS1
T2  - PLoS One
N2  - 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.
Y1  - 2011
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/22589
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30-113164
SN  - 1932-6203
N1  - 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.
VL  - 6
IS  - (4): e18577
ER  -