Venezuelan Equine Encephalitis Immunology and Vaccine Design

描述（由申请人提供）：该提案描述了一个为期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者。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的职业生涯的手段。为了实现这一目标，本建议涉及从发现和描述委内瑞拉马脑炎（VEE）病毒的重要抗原区域，到设计、构建和临床前试验预防VEE感染的新疫苗的完整进展。为了解决缺乏任何市售的VEE治疗或疫苗的问题，本提案的研究目的是：1)表征委内瑞拉马脑炎病毒对两个关键抗原靶点的体液免疫反应的精细特异性；VEE结构蛋白E1和E2, 2)确定E1和E2的共同抗原靶点可引起保护性免疫，并确定个体抗体特异性的相对贡献，3)通过疫苗接种暴露于TC-83减毒活病毒株的个体，表征细胞对VEE的免疫反应，4)在小动物模型中测试目的1-3中鉴定的B细胞和T细胞靶点作为候选疫苗抗原的能力。除了新方法和技术方面的实践培训外，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成果，通过经典课程和国家讲习班进行教学培训，并与精心挑选的专家咨询委员会就病毒学和疫苗设计和实施的基础和临床研究方面进行密切的个人互动。该方案旨在充分利用杜克大学和北卡罗来纳大学教堂山分校这两所紧密联合的大学的众多优势，以最大限度地提高该项目的曝光率和培训水平。这种环境培养了合作精神，并为开展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部分地区的一种主要人类病原体，可导致严重头痛、肌痛、萎靡不振、脑炎，甚至死亡。它是疾病控制与预防中心指定的B类特工，确定其作为生物恐怖主义特工的潜在用途，事实上，VEE是美国和苏联在过去都被武器化的少数特工之一。目前还没有已知的治疗药物或市售疫苗来预防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.