GORILLA ADENOVIRUS ZIKA VACCINE FOR HUMANS

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， 过去一年报告病毒传播活跃的国家和地区;这一流行病 促使世界卫生组织宣布ZIKV为全球公共卫生紧急事件。一种有效的疫苗 ZIKV将是一种具有成本效益的干预措施，可以限制临床疾病并控制病毒的传播。 感染，因为没有抗病毒治疗。本提案的目标是设计新颖的 ZIKV候选疫苗并在新产生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，基于载体的疫苗系统具有关键优势 包括它们通过模拟感染引发体液和细胞免疫的强大效率， 从头产生ZIKV抗原。腺病毒载体已成为最有前途的 疫苗平台，刺激先天性和适应性免疫反应，并已评估 广泛应用于癌症疫苗和传染病领域的临床试验。Simian Ad的使用 从黑猩猩和大猩猩中分离出来的物种提供了一种独特的能力，可以绕过预先存在的免疫力， 人类广告在这里，我们将测试表达可溶性包膜（E）的基于大猩猩的Ad（GAd）载体是否 蛋白质或完整的亚病毒颗粒（SVP）可以引发中和性体液和细胞免疫应答 并防止ZIKV感染和疾病。此外，我们假设靶向GAd 特异性针对树突状细胞（DC）的载体将促进ZIKV结构的直接呈递。 与传统的基于Ad的疫苗相比，测试 我们的假设是，我们已经开发出通过基因修饰来消除天然向异性的方法。 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， 体内递送。我们展示了将单结构域抗体（sdAb）种类并入病毒中的效用， 用于Ad靶向癌细胞类型和未成熟髓样鼠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，因为这个载体平台有更大的潜力 临床翻译。为了支持这项研究，我们生成了一组sdAb候选物，它们结合到 DC特异性受体Clec 9A可用于诱导强大的T细胞和B细胞免疫应答 接种疫苗后。Diamond实验室开发了新的ZIKV小鼠模型 发病机制包括母胎传播模型。这些模型将使我们能够评估 快速验证不同候选疫苗的有效性。总之，我们的合作小组有 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疾病和传播有显著影响，对人类健康有有益影响。

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.