GORILLA ADENOVIRUS ZIKA VACCINE FOR HUMANS

人类大猩猩腺病毒寨卡疫苗

• 批准号: 9316943
• 负责人: David Terry Curiel
• 金额: $ 19.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-20 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316943
• 关键词: Adenovirus Vector; Adenoviruses; Adult; Americas; Animal Model; Antibodies; Antigens; Antiviral Agents; Applications Grants; Arboviruses; Arthropods; Attenuated; B-Lymphocytes; Binding; Bypass; Cancer Vaccines; Capsid; Cells; Cellular Immunity; Clinical; Clinical Trials; Communicable Diseases; Congenital Abnormality; Country; Dendritic Cells; Dengue; Diamond; Disease; Disease Outbreaks; Engineering; Epidemic; Epidemiology; Evaluation; Family; Female; Fiber; Flavivirus; Generations; Genetic; Goals; Gorilla gorilla; Guillain-Barré Syndrome; Health; Human; Humoral Immunities; Immune; Immune Targeting; Immune response; Immunity; Infection; Laboratories; Ligand Binding; Maternal-Fetal Transmission; Measures; Methodology; Methods; Microcephaly; Modeling; Modification; Mus; Myelogenous; Neurologic; Outcome; Pan Genus; Preclinical Testing; Preventive vaccine; Public Health; Reagent; Receptor Cell; Reporting; Simian Adenoviruses; Spontaneous abortion; System; Technology; Teratogens; Testing; Translations; Tropism; Vaccination; Vaccines; Viral; Viral Antigens; Viral Proteins; Virus; Virus Diseases; World Health Organization; Yellow fever virus; Zika Virus; Zika virus vaccine; adaptive immune response; base; cancer cell; cell envelope; cell type; chikungunya; clinical translation; cost effective; design; disorder control; effective intervention; env Gene Products; fetal; immunogenicity; improved; in vivo; mouse model; novel; particle; protective efficacy; public health emergency; receptor; transmission process; vaccine candidate; vaccine development; vaccine response; vector; vector vaccine; vector-based vaccine; viral transmission; virus envelope; virus pathogenesis

Zika virus (ZIKV) is an arthropod-borne flavivirus that has spread rapidly across the Americas with 35 countries and territories reporting active viral transmission over the past year; this epidemic has prompted the WHO to declare ZIKV a worldwide public health emergency. An effective vaccine for ZIKV would be a cost-effective intervention that limits clinical disease and controls the spread of the infection since there is no antiviral treatment available. The goal of this proposal is to design novel ZIKV vaccine candidates and conduct initial preclinical testing in newly-generated mouse models of infection and disease. In this regard, vector-based vaccine systems offer key advantages including their robust efficiency to elicit humoral and cellular immunity by mimicking infection while producing ZIKV antigens de novo. Adenovirus (Ad) vectors have emerged as one of the most promising vaccine platforms that stimulate both innate and adaptive immune responses, and have been evaluated extensively in clinical trials in the cancer vaccine and infectious disease fields. The use of simian Ad species isolated from chimpanzee and gorilla offers a unique ability to bypass pre-existing immunity to human Ad. Here, we will test whether gorilla-based Ad (GAd) vectors expressing soluble envelope (E) protein or intact subviral particles (SVPs) can elicit neutralizing humoral and cellular immune responses and protect against ZIKV infection and disease. Furthermore, we hypothesize that targeting GAd vectors specifically to dendritic cells (DCs) will facilitate direct presentation of ZIKV structural antigens and improve vaccination outcome compared to conventional Ad-based vaccine. To test our hypothesis we have developed methods to ablate native Ad tropism via genetic modifications of the viral capsid while allowing recognition of the target cell receptor and the possibility of cell-specific delivery in vivo. We showed the utility of incorporating single domain antibody (sdAb) species into viral particles for Ad targeting to cancer cell types and immature myeloid murine DCs. We propose to use GAd developed by our commercial partner GenVec, Inc., as this vector platform has greater potential for clinical translation. In support of this study, we generated a panel of sdAb candidates that bind to the DC-specific receptor Clec9A that can be exploited to induce robust T- and B-cell immune responses following vaccination. The Diamond laboratory has developed new murine models of ZIKV pathogenesis including a model of maternal-fetal transmission. These models will allow us to assess rapidly the efficacy of our different candidate vaccines. In summary, our collaborative group has the necessary reagents, technology, and expertise to develop and evaluate novel GAd-vectored ZIKV vaccine candidates using relevant animal models. We believe the translation of these results could have a significant impact on reducing ZIKV disease and spread, a beneficial effect on human health.

寨卡病毒(ZIKV)是一种节肢动物传播的黄病毒，已在美洲迅速传播，有35 在过去一年中，报告病毒传播活跃的国家和地区；这种流行病 促使世卫组织宣布寨卡病毒为全球公共卫生紧急状态。一种有效的疫苗 ZIKV将是一种成本效益高的干预措施，可以限制临床疾病并控制病毒的传播 由于目前还没有抗病毒治疗，因此感染的风险很大。这项提议的目标是设计小说 ZIKV候选疫苗并在新生小鼠身上进行初步临床前测试 感染和疾病的模型。在这方面，以媒介为基础的疫苗系统提供了关键的优势。 包括它们通过模仿感染而诱导体液和细胞免疫的强大效率 产生新的寨卡病毒抗原。腺病毒(Ad)载体已经成为最有前途的载体之一 同时刺激先天和获得性免疫反应的疫苗平台，已经过评估 广泛应用于癌症疫苗和传染病领域的临床试验。猿猴广告的运用 从黑猩猩和大猩猩身上分离出来的物种提供了一种独特的能力，可以绕过先前存在的免疫系统 人性化广告。在这里，我们将测试基于大猩猩的Ad(Gad)载体是否表达可溶性包膜(E)。 蛋白质或完整的亚病毒颗粒(SVP)可诱导中和体液和细胞免疫反应 并预防寨卡病毒感染和疾病。此外，我们假设以Gad为目标 树突状细胞(DC)的特异性载体将促进ZIKV结构蛋白的直接呈递 与传统的以Ad为基础的疫苗相比，该疫苗具有更好的抗原性和更好的免疫效果。为了测试 我们的假设是，我们已经开发出通过对基因的修改来消除原生广告趋向性的方法 病毒衣壳，同时允许识别靶细胞受体和细胞特异性的可能性 体内给药。我们展示了将单域抗体(SdAb)物种整合到病毒中的效用。 靶向肿瘤细胞和未成熟髓系小鼠树突状细胞的颗粒。我们建议使用 GAD由我们的商业合作伙伴GenVec，Inc.开发，因为该矢量平台具有更大的潜力 用于临床翻译。为了支持这项研究，我们生成了一个sdAb候选小组，这些小组与 DC特异性受体Clec9A可用于诱导强大的T和B细胞免疫反应 在接种疫苗后。钻石实验室已经开发出新的ZIKV小鼠模型 发病机制包括母婴传播模型。这些模型将使我们能够评估 迅速提高我们不同候选疫苗的效力。总而言之，我们的协作小组拥有 开发和评估新型Gad载体ZIKV所需的试剂、技术和专业知识 使用相关动物模型的候选疫苗。我们相信，这些结果的翻译可以 对减少寨卡病毒疾病和传播有重大影响，对人类健康有有益的影响。