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Title: Development of a human live attenuated West Nile infectious DNA vaccine: Suitability of attenuating mutations found in SA14-14-2 for WN vaccine design

Abstract

Direct attenuation of West Nile (WN) virus strain NY99 for the purpose of vaccine development is not feasible due to its high virulence and pathogenicity. Instead, we created highly attenuated chimeric virus W1806 with the serological identity of NY99. To further attenuate W1806, we investigated effects of mutations found in Japanese encephalitis virus vaccine SA14-14-2. WN viruses carrying all attenuating mutations lost infectivity in mammalian, but not in mosquito cells. No single reversion restored infectivity in mammalian cells, although increased infectivity in mosquito cells was observed. To identify a subset of mutations suitable for further attenuation of W1806, we analyzed effects of E{sub 138}K and K{sub 279}M changes on virulence, growth properties, and immunogenicity of derivatized W956, from which chimeric W1806 inherited its biological properties and attenuation profile. Despite strong dominant attenuating effect, introduction of only two mutations was not sufficient for attenuating W1806 to the safety level acceptable for human use. - Highlights: • Further attenuation of a WN vaccine precursor is outlined. • Effect of SA14-14-2 attenuating mutations is tested. • Mechanism of attenuation is proposed and illustrated. • The need for additional attenuating mutations is justified.

Authors:
; ;
Publication Date:
OSTI Identifier:
22581663
Resource Type:
Journal Article
Journal Name:
Virology
Additional Journal Information:
Journal Volume: 487; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0042-6822
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ATTENUATION; DERIVATIZATION; DNA; ENCEPHALITIS; INFECTIVITY; MICE; MOSQUITOES; MUTATIONS; VACCINES; VIRULENCE; VIRUSES

Citation Formats

Yamshchikov, Vladimir, Manuvakhova, Marina, and Rodriguez, Efrain. Development of a human live attenuated West Nile infectious DNA vaccine: Suitability of attenuating mutations found in SA14-14-2 for WN vaccine design. United States: N. p., 2016. Web. doi:10.1016/J.VIROL.2015.10.015.
Yamshchikov, Vladimir, Manuvakhova, Marina, & Rodriguez, Efrain. Development of a human live attenuated West Nile infectious DNA vaccine: Suitability of attenuating mutations found in SA14-14-2 for WN vaccine design. United States. doi:10.1016/J.VIROL.2015.10.015.
Yamshchikov, Vladimir, Manuvakhova, Marina, and Rodriguez, Efrain. Fri . "Development of a human live attenuated West Nile infectious DNA vaccine: Suitability of attenuating mutations found in SA14-14-2 for WN vaccine design". United States. doi:10.1016/J.VIROL.2015.10.015.
@article{osti_22581663,
title = {Development of a human live attenuated West Nile infectious DNA vaccine: Suitability of attenuating mutations found in SA14-14-2 for WN vaccine design},
author = {Yamshchikov, Vladimir and Manuvakhova, Marina and Rodriguez, Efrain},
abstractNote = {Direct attenuation of West Nile (WN) virus strain NY99 for the purpose of vaccine development is not feasible due to its high virulence and pathogenicity. Instead, we created highly attenuated chimeric virus W1806 with the serological identity of NY99. To further attenuate W1806, we investigated effects of mutations found in Japanese encephalitis virus vaccine SA14-14-2. WN viruses carrying all attenuating mutations lost infectivity in mammalian, but not in mosquito cells. No single reversion restored infectivity in mammalian cells, although increased infectivity in mosquito cells was observed. To identify a subset of mutations suitable for further attenuation of W1806, we analyzed effects of E{sub 138}K and K{sub 279}M changes on virulence, growth properties, and immunogenicity of derivatized W956, from which chimeric W1806 inherited its biological properties and attenuation profile. Despite strong dominant attenuating effect, introduction of only two mutations was not sufficient for attenuating W1806 to the safety level acceptable for human use. - Highlights: • Further attenuation of a WN vaccine precursor is outlined. • Effect of SA14-14-2 attenuating mutations is tested. • Mechanism of attenuation is proposed and illustrated. • The need for additional attenuating mutations is justified.},
doi = {10.1016/J.VIROL.2015.10.015},
journal = {Virology},
issn = {0042-6822},
number = ,
volume = 487,
place = {United States},
year = {2016},
month = {1}
}