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 E138K and K279M 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.
authors.affiliation: Southern Research, 2000 9th Avenue South, Birmingham, AL 35205, United States. Electronic address: yaximik@gmail.com.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yamshchikov
authors.affiliation: Southern Research, 2000 9th Avenue South, Birmingham, AL 35205, United States.
authors.forename: Marina
authors.initials: M
authors.lastname: Manuvakhova
authors.affiliation: Southern Research, 2000 9th Avenue South, Birmingham, AL 35205, United States.
authors.forename: Efrain
authors.initials: E
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004664:Encephalitis Virus, Japanese / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D014613:Vaccines, Attenuated / Q000276:immunology*; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D014901:West Nile Fever / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D053060:West Nile Virus Vaccines / Q000276:immunology*; D014902:West Nile virus / Q000145:classification / Q000235:genetics* / Q000276:immunology
chemical_list: D014613:Vaccines, Attenuated; D014759:Viral Envelope Proteins; D053060:West Nile Virus Vaccines
keywords: Attenuation; Envelope; JEV; Mice; SA14-14-2; Vaccine; W1806; W956; WNV; iDNA