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Rapid development and testing of Zika virus vaccine candidates

寨卡病毒候选疫苗的快速开发和测试

基本信息

批准号：
9330079
负责人：
PAULO H VERARDI
金额：
$ 19.23万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330079
关键词：
Address Aedes Americas Animal Model Animals Antibiotics Antibody Formation Antibody titer measurement Antigens Biological Assay Brazil Cell Culture Techniques Cells Chikungunya virus Clinical Trials Country Culicidae Data Dengue Dengue Virus Development Disease Disease Outbreaks Electron Microscopy Flavivirus French Polynesia Genes Genome Goals Gold Growth Hemagglutination Heterophile Antigens Human Immunity Immunocompetent Immunocompromised Host In Vitro Interferon Receptor International Knockout Mice Link Membrane Membrane Proteins Methods Mexico Microcephaly Micronesia Modeling Modified Vaccinia Virus Ankara Mothers Mus Philippines Poxviridae Process Reporting Resistance SCID Mice Safety Serum Smallpox Smallpox Viruses Structure Testing Tetracyclines Vaccinated Vaccines Vaccinia virus Virus Diseases Virus-like particle Western Blotting Zika Virus Zika virus vaccine base cell mediated immune response design efficacy testing env Gene Products immunogenicity mouse model neutralizing antibody novel preclinical study protein expression public health emergency vaccine candidate vaccine development vaccine efficacy vaccinia virus vector vector viral vector development virus envelope

项目摘要

PROJECT SUMMARY Zika virus (ZIKV) is an enveloped flavivirus transmitted by Aedes mosquitos which leads to an asymptomatic or mild dengue-like disease. A large ZIKV outbreak started in Brazil in early 2015, recently spreading to more than 25 countries in the Americas. Alarmingly, the ZIKV Brazilian outbreak has been linked to thousands of microcephaly cases in babies born to infected mothers, leading the WHO to recently declare a Public Health Emergency of International Concern. Thus, control efforts are desperately needed to contain the outbreaks and avoid further spread to other countries. No ZIKV vaccines have been developed, although vaccines for the related dengue virus (DENV) based on the Membrane (M) and Envelope (E) proteins, which induce protective immunity, are in advanced clinical trials, and one (Dengvaxia) was just approved in Mexico, Brazil, and the Philippines. Vaccinia virus (VACV) was used to eradicate smallpox, a disease caused by variola virus, a related poxvirus. VACV has also been successfully used as a replication-competent or -defective viral vector for the development of effective human and animal vaccines, as it elicits strong and long-lasting humoral and cell-mediated immune (CMI) responses to heterologous antigens expressed in its genome. We recently generated VACV vectors with a built-in safety mechanism that replicate only in the presence of tetracycline antibiotics. When administered as a vaccine (in the absence of antibiotics), the vector does not replicate but retains its immunogenicity, and therefore is safer for human use. Conveniently, the vector can be propagated in cell culture at high titers in the presence of tetracyclines, unlike other replication-defective VACV-based vectors such as modified vaccinia Ankara (MVA). More recently, we developed a novel method to generate and purify recombinant VACV vaccines without the use of selection markers in as little as one week, a process that normally takes months. Our goal is to use this method to rapidly generate recombinant VACV vaccines expressing the ZIKV E and M proteins and to test their immunogenicity, safety, and efficacy in mice. In Aim 1 we will rapidly generate and characterize replication-defective VACV vaccine candidates expressing the ZIKV E protein (VACV-ZIKVs). A number of ZIKV E and M-E gene constructs were designed for expression of E alone or as virus-like particles (VLPs) to maximize induction of serum neutralizing (SN) antibodies. In Aim 2 we will test the immunogenicity (SN titers and CMI responses) and safety of VACV-ZIKV vaccine candidates in mice. Concurrently, in Aim 3 we will develop a ZIKV mouse challenge model based on current models for the related DENV to test the efficacy of our VACV-ZIKV vaccine candidates. Our goal is to use our accelerated VACV platform to rapidly select the best antigen strategy that leads to high levels of SN antibody production, CMI responses, and protection in mice.

项目总结寨卡病毒(ZIKV)是一种由伊蚊传播的包膜黄病毒，可导致无症状或轻微的登革热样疾病。巴西于2015年初爆发了一场大规模的寨卡病毒疫情，最近传播到美洲超过25个国家。令人震惊的是，巴西ZIKV疫情一直在与感染病毒母亲所生婴儿的数千例小头畸形症有关，导致世卫组织最近宣布进入国际关注的突发公共卫生事件。因此，控制努力是迫切需要控制疫情，避免进一步蔓延到其他国家。没有ZIKV 尽管相关登革热病毒(DENV)的疫苗是基于膜蛋白(M)和包膜蛋白(E)可诱导保护性免疫，已进入晚期临床一种(登革热)药物刚刚在墨西哥、巴西和菲律宾获得批准。牛痘病毒 (VACV)被用来根除天花，天花是一种由天花病毒引起的疾病，天花病毒是一种相关的痘病毒。VACV有也被成功地用作复制能力或缺陷病毒载体用于开发有效的人和动物疫苗，因为它能产生强大而持久的体液和细胞介导性疫苗对其基因组中表达的异源抗原的免疫(CMI)反应。我们最近生成了 VACV载体具有内置的安全机制，仅在四环素存在时复制抗生素。当作为疫苗接种时(在没有抗生素的情况下)，载体不会复制。但保留了其免疫原性，因此对人类使用更安全。方便的是，向量可以在四环素存在的情况下在细胞培养中以高滴度繁殖，与其他复制缺陷不同以VACV为基础的载体，如改良的安卡拉牛痘(MVA)。最近，我们开发了一部小说一种在AS中不使用选择标记的重组VACV疫苗的制备和纯化方法短短一周，这个过程通常需要几个月的时间。我们的目标是使用这种方法快速构建表达ZIKV E和M蛋白的重组VACV疫苗对小鼠的免疫原性、安全性和有效性。在目标1中，我们将快速生成和描述表达ZIKV E蛋白的复制缺陷VACV候选疫苗(VACV-ZIKV)。一个数字 ZIKV E和M-E基因构建体被设计为单独表达E或作为病毒样颗粒表达 (VLP)以最大限度地诱导血清中和(SN)抗体。在目标2中，我们将测试 VACV-ZIKV候选疫苗在小鼠中的免疫原性(SN滴度和CMI反应)和安全性。同时，在目标3中，我们将在现有模型的基础上开发ZIKV小鼠挑战模型相关DENV来测试我们的VACV-ZIKV候选疫苗的效力。我们的目标是用我们的加速VACV平台，快速选择导致高水平SN的最佳抗原策略小鼠的抗体产生、CMI反应和保护。