title: Comparison of the live-attenuated Japanese encephalitis vaccine SA14-14-2 strain with its pre-attenuated virulent parent SA14 strain: similarities and differences in vitro and in vivo.
abstract: Japanese encephalitis virus (JEV) is the main cause of acute viral encephalitis, primarily affecting children and young adults in the Asia-Pacific region. JEV is a vaccine-preventable pathogen, with four types of JE vaccine licensed in different regions of the world. To date, the most common JEV strain used in vaccine development and production is SA14-14-2, an attenuated strain derived from its wild-type parental strain SA14. In this study, we directly compared the phenotypic and genotypic characteristics of SA14 and SA14-14-2 to determine the biological and genetic properties associated with their differential virulence. In susceptible BHK-21 cells, SA14-14-2 grew slightly more slowly and formed smaller plaques than SA14, but unlike SA14, it showed almost no expression of the viral protein NS1', the product of a conserved predicted RNA pseudoknot-mediated ribosomal frameshift. In weanling ICR mice, SA14-14-2 was highly attenuated in terms of both neuroinvasiveness and neurovirulence, with its median lethal doses invariably over five logs higher than those of SA14 when inoculated intramuscularly and intracerebrally. Interestingly, the neurovirulence of SA14-14-2 was dependent on mouse age, with the 1- to 7-day-old mice being highly susceptible and the 14- to 21-day-old mice becoming resistant to intracerebral inoculation. At the genome level, SA14-14-2 differed from SA14 by 57 nucleotides, including one silent G-to-A substitution at position 3599 within the predicted RNA pseudoknot for NS1' synthesis; of the 57 differences, 25 resulted in amino acid substitutions. Our data pave the way for the development of new genetically modified JE vaccines.
authors: Department of Animal, Dairy, and Veterinary Sciences, Utah Science Technology and Research, College of Agriculture and Applied Sciences, Utah State University, 4815 Old Main Hill, Logan, UT 84322, USA.
authors: Sang-Im
authors: SI
authors: Yun
authors: Department of Animal, Dairy, and Veterinary Sciences, Utah Science Technology and Research, College of Agriculture and Applied Sciences, Utah State University, 4815 Old Main Hill, Logan, UT 84322, USA.
authors: Byung-Hak
authors: BH
authors: Song
authors: Department of Animal, Dairy, and Veterinary Sciences, Utah Science Technology and Research, College of Agriculture and Applied Sciences, Utah State University, 4815 Old Main Hill, Logan, UT 84322, USA.
authors: Irina A
authors: IA
authors: Polejaeva
authors: Department of Animal, Dairy, and Veterinary Sciences, Utah Science Technology and Research, College of Agriculture and Applied Sciences, Utah State University, 4815 Old Main Hill, Logan, UT 84322, USA.
authors: Christopher J
authors: CJ
authors: Davies
authors: Department of Animal, Dairy, and Veterinary Sciences, Utah Science Technology and Research, College of Agriculture and Applied Sciences, Utah State University, 4815 Old Main Hill, Logan, UT 84322, USA.
authors: Kenneth L
authors: KL
authors: White
authors: Department of Animal, Dairy, and Veterinary Sciences, Utah Science Technology and Research, College of Agriculture and Applied Sciences, Utah State University, 4815 Old Main Hill, Logan, UT 84322, USA.
authors: Young-Min
authors: YM
authors: Lee
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D004664:Encephalitis Virus, Japanese / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D004672:Encephalitis, Japanese / Q000276:immunology* / Q000821:virology; D005260:Female; D006801:Humans; D022321:Japanese Encephalitis Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014774:Virulence
chemical_list: D022321:Japanese Encephalitis Vaccines; D014613:Vaccines, Attenuated; D014759:Viral Envelope Proteins