Preclinical development of candidate Zika virus vaccines using mouse models

摘要 寨卡病毒（ZIKV）是黄病毒属的成员，由伊蚊属蚊子传播。有 ZIKV的三个遗传谱系：东非，西非和亚洲。直到最近，寨卡热通常都是 被认为是一种罕见的轻度发热性疾病，但自2012年以来的报告表明可能存在严重并发症 与ZIKV感染相关，包括小头畸形和格林-巴利综合征，与亚洲 谱系病毒自2015年以来，ZIKV已在美洲流行， 美洲至少有37个国家。显然需要一种疫苗。然而，很少有 ZIKV研究将持续到2015年，疫苗开发将从零开始。的重要一步 疫苗开发管道是临床前开发，其中评估候选疫苗的安全性， 在临床评价之前，在动物模型中进行免疫原性研究。一些候选寨卡疫苗在 因此，在动物模型中评估它们以帮助向下选择那些将被 在人类身上测试。最近，有许多论文描述了小鼠或非人类 ZIKV的灵长类动物（NHP）模型。NHP模型是非致死性的，并显示病毒血症，但它是短暂的 而且很低小鼠模型导致致死性感染，但仅引起干扰素受体αβ的临床疾病 （A129）和αβγ（AG 129）敲除小鼠。然而，这种鼠标的适用性存在问题 疫苗开发的模式。本探索性R21应用程序的目的是评估 A129和/或AG 129小鼠模型可用于评估候选ZIKV疫苗，并且通过基准测试， 由于市面上有市面上出售的活疫苗， 使用小鼠模型进行效力评估的减毒和灭活疫苗，作为以下评价标准的一部分： 对人类的管理。特别地，1/10的中和抗体滴度是保护JE的相关性 疫苗。具体目标1a将检查活的和灭活的乙脑疫苗是否会诱导保护性免疫反应， 野生型129、A129和AG 129小鼠的免疫力和中和抗体。具体目标1b将审查 候选重组包膜蛋白、灭活ZIKV和减毒ZIKV疫苗是否 在野生型129、A129和AG 129小鼠中诱导保护性免疫和中和抗体。具体目标2 将通过被动施用中和抗体保护小鼠免受ZIKV攻击。比较 获得许可的JE疫苗与候选ZIKV疫苗的结果的百分比将能够评估A129和/或 AG 129小鼠作为ZIKV疫苗开发的临床前模型。

ABSTRACT Zika virus (ZIKV) is a member of the genus Flavivirus, and transmitted by Aedes sp. mosquitoes. There are three genetic lineages of ZIKV: East Africa, West Africa, and Asia. Until recently Zika fever has normally been considered a rare, mild febrile disease, but reports since 2012 indicate potentially severe complications associated with ZIKV infection, including microcephaly and Guillain-Barré syndrome, associated with Asian lineage viruses. Since 2015, ZIKV has become epidemic in the Americas with reports of clinical cases in at least 37 countries in the Americas. There is a clear need for a vaccine. However, there have been very few studies on ZIKV until 2015 and vaccine development is starting from ground zero. An important step in the vaccine development pipeline is preclinical development where a candidate vaccine is evaluated for safety and immunogenicity in animal models prior to clinical evaluation. A number of candidate Zika vaccines are in development and it will be critical to evaluate them in animal models to aid down-selection for those that will be tested in humans. Very recently, there have been a number of papers describing either mouse or non-human primate (NHP) models for ZIKV. The NHP models are non-lethal and demonstrate viremia but it is transient and low. The mouse models result in a lethal infection but only cause clinical disease in interferon receptor αβ (A129) and αβγ (AG129) knockout mice. However, there are questions about the applicability of such mouse models to vaccine development. The objective of this exploratory R21 application is to evaluate whether or not A129 and/or AG129 mouse models can be used to evaluate candidate ZIKV vaccines and by benchmarking against a licensed flavivirus vaccine, namely Japanese encephalitis (JE), as there are commercial live attenuated and inactivated vaccines that utilize mouse models for potency as part of the evaluation criteria for administration to humans. In particular, a neutralizing antibody titer of 1 in 10 is the correlate of protection of JE vaccines. Specific Aim 1a will examine whether or not live and inactivated JE vaccines will induce protective immunity and neutralizing antibodies in wild-type 129, A129 and AG129 mice. Specific Aim 1b will examine whether or not candidate recombinant envelope protein, inactivated ZIKV and attenuated ZIKV vaccines will induce protective immunity and neutralizing antibodies in wild-type 129, A129 and AG129 mice. Specific Aim 2 will protection of mice against ZIKV challenge by passive administration of neutralizing antibodies. Comparison of the results from licensed JE vaccine with candidate ZIKV vaccines will enable evaluation of A129 and/or AG129 mice as a preclinical model for ZIKV vaccine development.