Venezuelan Equine Encephalitis Immunology and Vaccine Design

描述(由申请人提供)：本提案描述了一项为期5年的计划，旨在支持PI发展成为病毒免疫学和疫苗设计的独立研究人员。在这个项目中，PI将建立在人类免疫学的坚实基础上，作为过渡到翻译病毒学和疫苗学职业的一种手段。为了实现这一目标，这项建议包括从发现和描述委内瑞拉马脑炎(VEE)病毒重要抗原区到设计、建造和临床前试验预防VEE感染的新疫苗的完整进展。为了解决缺乏任何商业上可用的VEE治疗或疫苗的问题，这项建议的研究目的是：1)表征委内瑞拉马脑炎病毒对两个关键抗原靶标：VEE结构蛋白E1和E2的体液免疫反应的良好特异性，2)确定E1和E2的共同抗原靶标引起保护性免疫，并建立单个抗体特异性的相对贡献，3)通过疫苗接种，表征暴露于活的、减毒的TC-83株病毒的个体对VEE的细胞免疫反应，4)在小动物模型中测试AIMS 1-3中确定的B和T细胞靶标作为候选疫苗抗原的能力。除了新方法和新技术的实践培训外，候选人还将参加旨在促进科学独立性发展的综合课程。该课程将包括关于病毒学和疫苗的研讨会和专题讨论会，在国家会议上介绍研究，通过经典课程和国家讲习班进行教学培训，以及与精心挑选的病毒学和疫苗设计和实施的基础和临床研究方面的专家咨询委员会进行密切的个人互动。这项提议旨在充分利用两所紧密合作的大学--杜克大学和北卡罗来纳大学教堂山分校--的众多优势，以最大限度地扩大该计划的曝光率和培训方面。这种环境培养了合作精神，并为开始独立的科学事业提供了理想的环境。相关性(见说明)：委内瑞拉马脑炎是北美和南美洲部分地区的一种主要人类病原体，可导致严重头痛、肌痛、虚弱、脑炎，甚至死亡。它是美国疾病控制与预防中心指定的B类精选毒剂，确定了其作为生物恐怖主义毒剂的潜在用途，事实上，VEE是过去美国和苏联实际上都武器化的少数几种毒剂之一。目前还没有已知的治疗剂或商业上可用的疫苗来预防VEE感染。

DESCRIPTION (provided by applicant): This proposal describes a 5 year program designed to support the development of the PI into an independent investigator in viral immunology and vaccine design. During this program the PI will build upon a strong foundation in human immunology as a means to transition into a career in translational virology and vaccinology. In order to attain this goal, this proposal involves the complete progression from discovery and description of important antigenic regions of the Venezuelan Equine Encephalitis (VEE) virus through the design, construction, and preclinical testing of a new vaccine for prevention of VEE infection. In order to address the lack of any commercially available treatment or vaccine for VEE, the research Aims of this proposal are: 1) To characterize the fine specificity of the Venezuelan Equine Encephalitis virus humoral immune response to two key antigenic targets: VEE structural proteins E1 and E2, 2) To identify which common antigenic targets of E1 and E2 elicit protective immunity and establish the relative contribution of individual antibody specificities, 3) To characterize the cellular immune responses to VEE in individuals exposed to the live, attenuated TC-83 strain of virus through vaccination, and 4) Test the ability of the B and T cell targets identified in Aims 1-3 as candidate vaccine antigens in a small animal model. In addition to practical training in new methodologies and techniques, the candidate will participate in an integrated curriculum designed to foster the development of scientific independence. This curriculum will involve seminars and symposia on virology and vaccines, presentation of research at national meetings, didactic training through classical coursework as well as national workshops, and close personal interactions with a carefully selected Advisory Committee of experts on the basic and clinical research aspects of virology and vaccine design and implementation. This proposal is designed to take full advantage of the myriad strengths of two closely allied and situated Universities - Duke and UNC-Chapel Hill - in order to maximize the exposure and training aspects of the program. This environment fosters a collaborative spirit and provides an ideal setting for launching an independent science career. RELEVANCE (See instructions): Venezuelan Equine Encephalitis is a major human pathogen throughout parts of North and South America which can cause severe headaches, myalgias, prostration, encephalitis, and even death. It is a CDC- designated Category B Select Agent, identifying its potential use as an agent of bioterrorism, and in fact VEE is one of the few agents that has actually been weaponized by both the US and USSR in the past. There are currently no known therapeutic agents or commercially available vaccines for the prevention of VEE infection.