Development of a human live attenuated West Nile infectious DNA vaccine: Identification of a minimal mutation set conferring the attenuation level acceptable for a human vaccine

ABSTRACT For the development of a human West Nile (WN) infectious DNA (iDNA) vaccine, we created highly attenuated chimeric virus W1806 with the serological identity of highly virulent WN-NY99. Earlier, we attempted to utilize mutations found in the E protein of the SA14-14-2 vaccine to bring safety...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2017-01, Vol.500, p.122-129
Main Authors: Yamshchikov, Vladimir, Manuvakhova, Marina, Rodriguez, Efrain, Hébert, Charles
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Amino Acid Sequence
Animals
ATTENUATION
BIOLOGICAL RECOVERY
Cell Line
DNA
Envelope
Female
GENETICS
Humans
iDNA
Infectious Disease
JEV
MICE
Mice, Inbred ICR
Molecular Sequence Data
Mutation, Missense
MUTATIONS
PHENOTYPE
PLANT GROWTH
PROTEINS
RESOLUTION
SA14-14-2
SAFETY
STABILITY
TUNGSTEN NITRIDES
Vaccine
VACCINES
Vaccines, DNA - administration & dosage
Vaccines, DNA - genetics
Vaccines, DNA - immunology
Viral Envelope Proteins - administration & dosage
Viral Envelope Proteins - genetics
Viral Envelope Proteins - immunology
Viral Vaccines - administration & dosage
Viral Vaccines - genetics
Viral Vaccines - immunology
VIRUSES
W1806
W956
West Nile Fever - immunology
West Nile Fever - prevention & control
West Nile Fever - virology
West Nile virus - chemistry
West Nile virus - genetics
West Nile virus - immunology
WNV
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Summary:ABSTRACT For the development of a human West Nile (WN) infectious DNA (iDNA) vaccine, we created highly attenuated chimeric virus W1806 with the serological identity of highly virulent WN-NY99. Earlier, we attempted to utilize mutations found in the E protein of the SA14-14-2 vaccine to bring safety of W1806 to the level acceptable for human use ( Yamshchikov et al., 2016 ). Here, we analyzed effects of the SA14-14-2 changes on growth properties and neurovirulence of W1806. A set including the E138K, K279M, K439R and G447D changes was identified as the perspective subset for satisfying the target safety profile without compromising immunogenicity of the vaccine candidate. The genetic stability of the attenuated phenotype was found to be unsatisfactory being dependent on a subset of attenuating changes incorporated in W1806. Elucidation of underlying mechanisms influencing selection of pathways for restoration of the envelope protein functionality will facilitate resolution of the emerged genetic stability issue.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2016.10.012