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首页> 外文期刊>Vaccine >Assurance of neuroattenuation of a live vaccine against West Nile virus: A comprehensive study of neuropathogenesis after infection with chimeric WN/DEN4 Delta 30 vaccine in comparison to two parental viruses and a surrogate flavivirus reference vaccine
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Assurance of neuroattenuation of a live vaccine against West Nile virus: A comprehensive study of neuropathogenesis after infection with chimeric WN/DEN4 Delta 30 vaccine in comparison to two parental viruses and a surrogate flavivirus reference vaccine

机译：确保针对西尼罗河病毒的活疫苗的神经减毒：与两种亲本病毒和替代黄病毒参考疫苗相比，嵌合WN / DEN4 Delta 30疫苗感染后神经病变的全面研究

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The upsurge of West Nile virus (WNV) human infections in 2012 suggests that the US can expect periodic WNV outbreaks in the future. Availability of safe and effective vaccines against WNV in endemic areas, particularly for aging populations that are at high risk of West Nile neuroinvasive disease (WNND), could be beneficial. WN/DEN4 Delta 30 is a live, attenuated chimeric vaccine against WNV produced by replacement of the genes encoding the pre-membrane and envelope protein genes of the vaccine virus against dengue virus type 4 (DEN4 Delta 30) with corresponding sequences derived from a wild type WNV. Following intrathalamic inoculation of nonhuman primates (NHPs), a comprehensive neuropathogenesis study was performed and neurovirulence of WN/DEN4 Delta 30 vaccine candidate was compared to that of two parental viruses (i.e., WNV and DEN4 Delta 30), as well as to that of an attenuated flavivirus surrogate reference (i.e., yellow fever YF 17D). Clinical and virological data, as well as results of a semi-quantitative histopathological analysis, demonstrated that WN/DEN4 Delta 30 vaccine is highly attenuated for the central nervous system (CNS) of NHPs in comparison to a wild type WNV. Importantly, based on the virus replicative ability in the CNS of NHPs and the degree of induced histopathological changes, the level of neuroattenuation of WN/DEN4 Delta 30 vaccine was similar to that of YF 17D, and therefore within an acceptable range. In addition, we show that the DEN4 Delta 30 vaccine tested in this study also has a low neurovirulence profile. In summary, our results demonstrate a high level of neuroattenuation of two vaccine candidates, WN/DEN4 Delta 30 and DEN4 Delta 30. We also show here a remarkable sensitivity of our WNV-NY99 NHP model, as well as striking resemblance of the observed neuropathology to that seen in human WNND. These results support the use of this NHP model for translational studies of WNV neuropathogenesis and/or testing the effectiveness of vaccines and therapeutic approaches
机译：2012年，西尼罗河病毒（WNV）人类感染的高涨表明，美国有望在未来出现定期的WNV爆发。在流行地区提供安全有效的抗WNV疫苗可能是有益的，特别是对于高风险的西尼罗河神经浸润性疾病（WNND）的老龄化人群。 WN / DEN4 Delta 30是一种针对WNV的减毒活疫苗，通过将编码4型登革热病毒的疫苗病毒（DEN4 Delta 30）的前膜和包膜蛋白基因编码的基因替换为野生来源而制得输入WNV。在丘脑内接种非人类灵长类动物（NHP）后，进行了全面的神经发病研究，并将WN / DEN4 Delta 30候选疫苗的神经毒力与两种亲本病毒（即WNV和DEN4 Delta 30）的毒力进行了比较。减毒的黄病毒替代参照物（即黄热病YF 17D）。临床和病毒学数据以及半定量组织病理学分析的结果表明，与野生型WNV相比，WN / DEN4 Delta 30疫苗对NHP的中枢神经系统（CNS）具有高度减毒作用。重要的是，根据NHP中枢神经系统中的病毒复制能力和诱导的组织病理学改变程度，WN / DEN4 Delta 30疫苗的神经减毒水平与YF 17D相似，因此处于可接受的范围内。此外，我们显示，在这项研究中测试的DEN4 Delta 30疫苗还具有较低的神经毒性。总而言之，我们的结果证明了两种候选疫苗（WN / DEN4 Delta 30和DEN4 Delta 30）的神经减毒水平很高。在这里，我们还显示了我们的WNV-NY99 NHP模型具有显着的敏感性，并且与观察到的神经病理学非常相似与人类WNND中看到的一样。这些结果支持使用该NHP模型进行WNV神经发病机制的转化研究和/或测试疫苗和治疗方法的有效性

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