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.

Zika病毒（Zikv）是一种节肢动物传播的黄病毒，在整个美洲迅速传播了35 在过去一年中报告主动病毒传播的国家和地区；这种流行病 促使世卫组织宣布Zikv是全球公共卫生紧急情况。有效的疫苗 ZIKV将是一种具有成本效益的干预措施，限制了临床疾病并控制 由于没有可用的抗病毒治疗，因此感染。该提议的目的是设计小说 ZIKV疫苗候选物并在新生成的小鼠中进行初始临床前测试 感染和疾病的模型。在这方面，基于向量的疫苗系统提供了关键优势 包括它们通过模仿感染来引起体液和细胞免疫的强大效率 从头产生Zikv Antigens de。腺病毒（AD）载体已成为最有前途的媒介之一 刺激先天和适应性免疫反应并已评估的疫苗平台 在癌症疫苗和传染病领域的临床试验中广泛进行。使用猿猴广告 与黑猩猩和大猩猩隔离的物种具有独特的能力，可以绕开预先存在的免疫力 人类广告。在这里，我们将测试基于大猩猩的AD（GAD）向量是否表达可溶性信封（E） 蛋白质或完整的亚病毒颗粒（SVP）可以引起中和体液和细胞免疫反应 并防止ZIKV感染和疾病。此外，我们假设针对GAD 专门针对树突状细胞（DC）的向量将有助于直接呈现ZIKV结构 与常规的AD疫苗相比，抗原和改善疫苗接种结果。测试 我们的假设我们开发了通过遗传修饰的方法来消除天然AD的最偏向主义的方法 病毒式衣壳，同时允许识别靶细胞受体，并且可能具有细胞特异性的可能性 在体内交付。我们展示了将单域抗体（SDAB）物种掺入病毒的实用性 广告靶向癌细胞类型和未成熟的髓样鼠DC的颗粒。我们建议使用 GAD由我们的商业合作伙伴Genvec，Inc。开发，因为该向量平台具有更大的潜力 用于临床翻译。为了支持这项研究，我们生成了一组SDAB候选者 DC特异性受体CLEC9A，可以利用可诱导强大的T和B细胞免疫反应 疫苗接种后。钻石实验室开发了ZIKV的新鼠模型 发病机理，包括母体传播模型。这些模型将使我们能够评估 我们不同候选疫苗的功效迅速。总而言之，我们的协作小组有 必要的试剂，技术和专业知识，以开发和评估新颖的GAD矢量ZIKV 使用相关动物模型的疫苗候选物。我们相信这些结果的翻译可以 对减少ZIKV疾病和扩散有重大影响，这对人类健康有益影响。