Genotype-specific neutralization determinants in envelope protein: implications for the improvement of Japanese encephalitis vaccine.
Genotype-specific neutralization determinants in envelope protein: implications for the improvement of Japanese encephalitis vaccine.
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DOI：
10.1099/vir.0.000160
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发表时间：
2015-08
期刊：
影响因子：
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通讯作者：
Qing Ye;Yan-Peng Xu;Yu Zhang-;Xiao-Feng Li;Hongjiang Wang;Zhong-Yu Liu;Shihua Li;Long Liu;Hui Zhao;Qinggong Nian;Yongqiang Deng;E. Qin;C. Qin
中科院分区：
文献类型：
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作者：
Qing Ye;Yan-Peng Xu;Yu Zhang-;Xiao-Feng Li;Hongjiang Wang;Zhong-Yu Liu;Shihua Li;Long Liu;Hui Zhao;Qinggong Nian;Yongqiang Deng;E. Qin;C. Qin
日本脑炎仍然是亚洲儿童病毒性脑炎的主要原因，其地理范围正在扩大到亚洲和澳大拉西亚的更大地区。流行性乙型脑炎病毒（JEV）的五种基因型在地理上受影响的地区共同传播。特别是，基因型I（GI）JEV的出现已经取代基因型III（GIII）成为许多亚洲地区的主要流行基因型。然而，所有获批的疫苗产品均来源于GIII毒株。在本研究中，生物信息学分析显示，GI和GIII株JEV在包膜（E）蛋白（E222和E327）内共享两个不同的氨基酸残基。通过使用反向遗传学方法，A222 S和S327 T突变被证明可以减少减毒活疫苗（LAV）SA 14 -14-2诱导的人体中和抗体，而不改变病毒复制。然后将A222 S或S327 T突变合理地工程化到SA 14 -14-2的感染性克隆中，并且所得突变菌株保留与亲本菌株相同的遗传稳定性和减毒特征。更重要的是，用LAV-A222 S或LAV-S327 T免疫小鼠引起针对GI株的中和抗体增加。总之，这些结果表明，E222和E327是潜在的基因型相关中和决定因素，在确定乙型脑炎活疫苗SA 14 -14-2对流行GI菌株的保护效力方面至关重要。我们的研究结果将有助于下一代日本脑炎LAV的合理设计，能够提供广泛的保护，对所有属于不同基因型的JEV菌株。
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.