Japanese encephalitis vaccine-specific envelope protein E138K mutation does not attenuate virulence of West Nile virus.,npj Vaccines

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Japanese encephalitis vaccine-specific envelope protein E138K mutation does not attenuate virulence of West Nile virus.
npj Vaccines ( IF 6.9 ) Pub Date : 2019-12-05 , DOI: 10.1038/s41541-019-0146-0
Jaclyn A Kaiser ₁ , Huanle Luo ₁ , Steven G Widen ₂ , Thomas G Wood ₂ , Claire Y-H Huang ₃ , Tian Wang _{1,

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Affiliation

West Nile (WNV) and Japanese encephalitis viruses (JEV) are closely related, mosquito-borne neurotropic flaviviruses. Although there are no licensed human vaccines for WNV, JEV has multiple human vaccines, including the live, attenuated vaccine SA14-14-2. Investigations into determinants of attenuation of JE SA14-14-2 demonstrated that envelope (E) protein mutation E138K was crucial to the attenuation of mouse virulence. As WNV is closely related to JEV, we investigated whether or not the E-E138K mutation would be beneficial to be included in a candidate live attenuated WNV vaccine. Rather than conferring a mouse attenuated phenotype, the WNV E-E138K mutant reverted and retained a wild-type mouse virulence phenotype. Next-generation sequencing analysis demonstrated that, although the consensus sequence of the mutant had the E-E138K mutation, there was increased variation in the E protein, including a single-nucleotide variant (SNV) revertant to the wild-type glutamic acid residue. Modeling of the E protein and analysis of SNVs showed that reversion was likely due to the inability of critical E-protein residues to be compatible electrostatically. Therefore, this mutation may not be reliable for inclusion in candidate live attenuated vaccines in related flaviviruses, such as WNV, and care must be taken in translation of attenuating mutations from one virus to another virus, even if they are closely related.

中文翻译：

日本脑炎疫苗特有的包膜蛋白E138K突变不会减弱西尼罗河病毒的毒力。

西尼罗河病毒（WNV）和日本脑炎病毒（JEV）是密切相关的蚊媒神经嗜性黄病毒。尽管没有获得许可的WNV人用疫苗，但JEV有多种人用疫苗，包括减毒活疫苗SA14-14-2。对JE SA14-14-2减毒决定因素的研究表明，包膜（E）蛋白突变E138K对于减毒小鼠毒力至关重要。由于WNV与JEV密切相关，因此我们调查了E-E138K突变是否有益于候选减毒WNV活疫苗。WNV E-E138K突变体没有赋予小鼠减毒表型，而是还原并保留了野生型小鼠毒力表型。下一代测序分析表明，尽管该突变体的共有序列具有E-E138K突变，E蛋白的变异增加，包括回复到野生型谷氨酸残基的单核苷酸变异（SNV）。E蛋白的建模和SNV的分析表明，归因于关键E蛋白残基无法静电兼容的可能性很大。因此，该突变可能不可靠，无法包含在相关黄病毒（例如WNV）的候选减毒活疫苗中，即使将减毒突变从一种病毒转换为另一种病毒，也应格外小心，即使它们之间密切相关。E蛋白的建模和SNV的分析表明，归因于关键E蛋白残基无法静电兼容的可能性很大。因此，该突变可能不可靠，无法包含在相关黄病毒（例如WNV）的候选减毒活疫苗中，即使将减毒突变从一种病毒转换为另一种病毒，也应格外小心，即使它们之间密切相关。E蛋白的建模和SNV的分析表明，归因于关键E蛋白残基无法静电兼容的可能性很大。因此，该突变可能不可靠，无法包含在相关黄病毒（例如WNV）的候选减毒活疫苗中，即使将减毒突变从一种病毒转换为另一种病毒，也应格外小心，即使它们之间密切相关。

更新日期：2019-12-05

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