Preclinical development of candidate Zika virus vaccines using mouse models

使用小鼠模型进行候选寨卡病毒疫苗的临床前开发

• 批准号: 9277118
• 负责人: Alan D.T. Barrett
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277118
• 关键词: Aedes; Africa; African; Americas; Animal Model; Animals; Antibodies; Antibody titer measurement; Asia; Asians; Attenuated; Attenuated Live Virus Vaccine; Benchmarking; Cambodian; Clinical; Country; Culicidae; Data; Development; Disease; Dose; E protein; Epidemic; Evaluation; Family member; Fever; Flavivirus; Genetic; Guillain-Barré Syndrome; Human; Immunity; Immunization; Immunize; Immunocompetent; Inactivated Vaccines; Infection; Interferon Receptor; Interferons; Japanese Encephalitis; Japanese Encephalitis Vaccines; Knockout Mice; Microcephaly; Modeling; Monoclonal Antibodies; Mouse Strains; Mus; N-terminal; Paper; Pre-Clinical Model; Public Health; Recombinants; Reporting; Route; Safety; Testing; Vaccines; Viremia; Virus; Virus Diseases; Work; Zika Virus; Zika virus vaccine; candidate selection; env Gene Products; immunogenicity; intraperitoneal; member; mouse model; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; preclinical development; preclinical evaluation; receptor; research clinical testing; tool; vaccine candidate; vaccine development; vaccine safety

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.

抽象的 Zika病毒（ZIKV）是Flavivirus属的成员，并由Aedes sp。蚊子。有 ZIKV的三个遗传谱系：东非，西非和亚洲。直到最近寨卡发烧通常一直是 被认为是一种罕见的轻度发热疾病，但自2012年以来的报道表明潜在的严重并发症 与ZIKV感染相关，包括小头畸形和与亚洲有关的Guillain-Barré综合征 谱系病毒。自2015年以来，ZIKV在美洲的流行病已成为临床病例的报道 美洲至少有37个国家。显然需要疫苗。但是，很少 直到2015年的ZIKV和疫苗开发的研究从地面零开始。在 疫苗开发管道是临床前开发，其中评估候选疫苗的安全性和 在临床评估之前，动物模型中的免疫原性。许多候选Zika疫苗已在 开发，在动物模型中评估它们，以帮助那些将是那些将是 在人类中测试。最近，有许多论文描述了鼠标或非人类 ZIKV的灵长类动物（NHP）模型。 NHP模型是非致命的，并且证明了病毒血症，但它是短暂的 和低。小鼠模型导致致命感染，但仅引起干扰素受体αβ的临床疾病 （A129）和αβγ（AG129）敲除小鼠。但是，关于这种鼠标的适用性存在疑问 疫苗开发的模型。此探索性R21应用的目的是评估是否是否 A129和/或AG129鼠标模型可用于评估候选ZIKV疫苗并通过基准测试 针对有执照的黄病毒疫苗，即日本脑炎（JE），因为有商业直播 利用小鼠模型作为评估标准的一部分，衰减和灭活的疫苗 管理人类。特别是，中和抗体滴度为10中的1个是JE保护的相关性 疫苗。具体目标1a将检查生命和灭活的JE疫苗是否会诱导受保护 野生型129，A129和AG129小鼠的免疫和中和抗体。特定目标1B将检查 候选重组包络蛋白，灭活的ZIKV和减弱ZIKV疫苗是否会 在野生型129，A129和AG129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来保护小鼠免受ZIKV挑战。比较 在带有候选ZIKV疫苗的JE疫苗的结果中，将评估A129和/或 AG129小鼠作为ZIKV疫苗开发的临床前模型。