Preclinical development of candidate Zika virus vaccines using mouse models

摘要 寨卡病毒(Zika Virus，ZIKV)是黄病毒属的成员，由伊蚊传播。蚊子。确实有 ZIKV的三种遗传谱系：东非、西非和亚洲。直到最近，寨卡病毒热通常是 被认为是一种罕见的轻度发烧疾病，但自2012年以来的报告显示，潜在的严重并发症 与寨卡病毒感染有关，包括小头畸形症和格林-巴利综合征，与亚洲人有关 血统病毒。自2015年以来，ZIKV已在美洲流行，据报道，在美国有临床病例 美洲至少有37个国家。显然需要一种疫苗。然而，这种情况很少发生。 到2015年为止，对ZIKV的研究和疫苗开发都是从零开始。迈出的重要一步 疫苗开发流程是临床前开发，对候选疫苗进行安全性评估和 临床评估前动物模型的免疫原性。一些候选的寨卡病毒疫苗正在研发中 在动物模型中评估它们将是至关重要的，以帮助那些将被 在人体上进行了测试。最近，有许多论文描述了老鼠或非人类 ZIKV的灵长类(NHP)模型。NHP模型是非致命性的，表现为病毒血症，但它是一过性的 而且很低。小鼠模型会导致致命性感染，但只会导致干扰素受体αβ的临床疾病 (A129)和αβγ(AG129)基因敲除小鼠。然而，人们对这种鼠标的适用性存在疑问 从模型到疫苗开发。此探索性R21应用程序的目标是评估 A129和/或AG129小鼠模型可用于评估候选ZIKV疫苗并通过基准测试 对一种有执照的黄病毒疫苗，即日本脑炎(乙脑)，因为有商业活疫苗 将小鼠模型的效力作为评估标准的减毒和灭活疫苗 对人类的管理。具体地说，中和抗体滴度为1/10是乙脑保护的相关性 疫苗。具体目标1a将检查乙脑活疫苗和灭活疫苗是否会导致保护性 野生型129、A129和AG129小鼠的免疫和中和抗体。具体目标1b将检查 无论候选重组包膜蛋白、ZIKV灭活疫苗和减毒ZIKV疫苗 诱导野生型129、A129和AG129小鼠产生保护性免疫和中和抗体。具体目标2 将通过被动注射中和抗体来保护小鼠免受ZIKV的挑战。比较 获得许可的乙脑疫苗与候选寨卡病毒疫苗的结果中，将能够对A129和/或 AG129小鼠作为ZIKV疫苗研制的临床前模型。

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.