title: Genotype-specific neutralization determinants in envelope protein: implications for the improvement of Japanese encephalitis vaccine.
abstract: Japanese encephalitis remains the leading cause of viral encephalitis in children in Asia and is expanding its geographical range to larger areas in Asia and Australasia. Five genotypes of Japanese encephalitis virus (JEV) co-circulate in the geographically affected areas. In particular, the emergence of genotype I (GI) JEV has displaced genotype III (GIII) as the dominant circulating genotype in many Asian regions. However, all approved vaccine products are derived from GIII strains. In the present study, bioinformatic analysis revealed that GI and GIII JEV strains shared two distinct amino acid residues within the envelope (E) protein (E222 and E327). By using reverse genetics approaches, A222S and S327T mutations were demonstrated to decrease live-attenuated vaccine (LAV) SA14-14-2-induced neutralizing antibodies in humans, without altering viral replication. A222S or S327T mutations were then rationally engineered into the infectious clone of SA14-14-2, and the resulting mutant strains retained the same genetic stability and attenuation characteristics as the parent strain. More importantly, immunization of mice with LAV-A222S or LAV-S327T elicited increased neutralizing antibodies against GI strains. Together, these results demonstrated that E222 and E327 are potential genotype-related neutralization determinants and are critical in determining the protective efficacy of live Japanese encephalitis vaccine SA14-14-2 against circulating GI strains. Our findings will aid in the rational design of the next generation of Japanese encephalitis LAVs capable of providing broad protection against all JEV strains belonging to different genotypes.
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.
authors.forename: Yan-Peng
authors.initials: YP
authors.lastname: Xu
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.|State Key Laboratory of Pathogen and Biosecurity, Beijing 100071, PR China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Li
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.
authors.forename: Hong-Jiang
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.
authors.forename: Zhong-Yu
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Li
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.|Graduate School, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Long
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.|State Key Laboratory of Pathogen and Biosecurity, Beijing 100071, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.
authors.forename: Qing-Gong
authors.initials: QG
authors.lastname: Nian
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.
authors.forename: Yong-Qiang
authors.initials: YQ
authors.lastname: Deng
authors.affiliation: Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.
authors.forename: E-De
authors.initials: ED
authors.lastname: Qin
authors.affiliation: Graduate School, Anhui Medical University, Hefei 230032, PR China.|Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, PR China.|State Key Laboratory of Pathogen and Biosecurity, Beijing 100071, PR China.
authors.forename: Cheng-Feng
authors.initials: CF
authors.lastname: Qin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D004664:Encephalitis Virus, Japanese / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000276:immunology; D004672:Encephalitis, Japanese / Q000276:immunology / Q000821:virology*; D005260:Female; D005838:Genotype; D006801:Humans; D022321:Japanese Encephalitis Vaccines / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D022321:Japanese Encephalitis Vaccines; D014759:Viral Envelope Proteins