Molecular basis for attenuation of neurovirulence of a yellow fever virus/Japanese encephalitis virus chimera vaccine (ChimeriVax-JE)
Molecular basis for attenuation of neurovirulence of a yellow fever virus/Japanese encephalitis virus chimera vaccine (ChimeriVax-JE)
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DOI：
10.1128/jvi.75.2.934-942.2001
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发表时间：
2001-01-01
影响因子：
5.4
通讯作者：
Chambers, TJ
中科院分区：
文献类型：
--
作者：
Arroyo, J;Guirakhoo, F;Chambers, TJ
黄热病病毒（YFV）/日本脑炎病毒（JEV）嵌合体（其中YFV 17 D的结构蛋白prM和E被JEV SA 14 -14-2疫苗株的结构蛋白prM和E取代）正在被评价为针对日本脑炎的候选疫苗。在小鼠和非人灵长类动物模型中，嵌合体（YFV/JEV SA 14 -14-2或ChimeriVax-JE）的神经毒性低于YFV 17 D疫苗（F. Guirakhoo等人，Virology 257：363-372，1999; T. P. Monath等人，Vaccine 17：1869-1882，1999）。减毒依赖于JEV SA 14 -14-2 E蛋白的存在，如来源于野生JEV Nakayama株的类似YFV/JEV Nakayama嵌合体的高神经毒力所示（T. J.钱伯斯，A. Nestorowicz，P. W. Mason和C. M. Rice，J，Virol. 73：3095-3101，1999）。ChimeriVax-JE和YFV/JEV Nakayama病毒的E蛋白之间存在10个氨基酸差异，其中4个基于各种序列比较被预测为神经毒力决定因子。为了鉴定参与减毒的残基，对一系列含有单个或多个氨基酸取代的胞内YFV/JEV嵌合体进行工程改造并测试小鼠神经毒力。恢复典型的YFV/JEV中山病毒的神经毒力需要至少三个不同簇的回复。不同组合的簇特异性回复可以赋予神经毒力，然而，残基138的E蛋白（E-138）表现出显性效应。没有单个氨基酸回复产生与ChimeriVax-JE亲本显著不同的表型。加上已知的病毒在长期细胞培养和小鼠脑传代过程中的遗传稳定性，这些发现支持这种实验疫苗作为一种新型乙型脑炎减毒活病毒疫苗的候选资格。
A yellow fever virus (YFV)/Japanese encephalitis virus (JEV) chimera in which the structural proteins prM and E of YFV 17D are replaced with those of the JEV SA14-14-2 vaccine strain is under evaluation as a candidate vaccine against Japanese encephalitis. The chimera (YFV/JEV SA14-14-2, or ChimeriVax-JE) is less neurovirulent than is YFV 17D vaccine in mouse and nonhuman primate models (F. Guirakhoo et al., Virology 257:363-372, 1999; T. P. Monath et al., Vaccine 17:1869-1882, 1999). Attenuation depends on the presence of the JEV SA14-14-2 E protein, as shown by the high neurovirulence of an analogous YFV/JEV Nakayama chimera derived from the wild JEV Nakayama strain (T. J. Chambers, A. Nestorowicz, P. W. Mason, and C. M. Rice, J, Virol. 73:3095-3101, 1999). Ten amino acid differences exist between the E proteins of ChimeriVax-JE and the YFV/JEV Nakayama virus, four of which are predicted to be neurovirulence determinants based on various sequence comparisons. To identify residues that are involved in attenuation, a series of intratypic YFV/JEV chimeras containing either single or multiple amino acid substitutions were engineered and tested for mouse neurovirulence. Reversions in at least three distinct clusters were required to restore the neurovirulence typical of the YFV/JEV Nakayama virus. Different combinations of cluster-specific reversions could confer neurovirulence; however, residue 138 of the E protein (E-138) exhibited a dominant effect. No single amino acid reversion produced a phenotype significantly different from that of the ChimeriVax-JE parent. Together with the known genetic stability of the virus during prolonged cell culture and mouse brain passage, these findings support the candidacy of this experimental vaccine as a novel live-attenuated viral vaccine against Japanese encephalitis.