VEE PATHOGENESIS AND VACCINE DEVELOPMENT

VEE 发病机制和疫苗开发

• 批准号: 7038300
• 负责人: Slobodan Paessler
• 金额: $ 11.53万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038300
• 关键词: Sindbis virus; Venezuelan equine encephalitis virus; active immunization; age difference; biotechnology; host organism interaction; laboratory mouse; neutralizing antibody; recombinant virus; vaccine development; viral vaccines; virus infection mechanism; virus protein; virus replication

DESCRIPTION (provided by applicant): The applicant, a D.V.M. with some clinical and laboratory experience, seeks support to become an independent researcher in the field of viral pathogenesis and vaccine development. His long-term goal is to better understand the pathogenesis of human alphaviral encephalitides, including the roles of each viral gene. This information will be used to develop safer and more effective vaccines and therapeutics. The proposed research focuses on Venezuelan equine encephalitis virus (VEEV), an important, naturally emerging human pathogen and a potent biological weapon categorized by the NIAID as a Category B Priority Pathogen. Although VEEV is an important human pathogen and an efficient vaccine expression vector, little is known about the role of the nonstructural proteins (replicative machinery) of this virus in pathogenesis. Furthermore, no licensed human VEEV vaccine is available. The goals are to1l) develop safe and effective VEEV vaccines using chimeric VEEV/Sindbis viruses (SINV) that are efficiently produced at large scale, and; 2) study VEEV pathogenesis using reciprocal SINV/VEEVchimeras to assess the roles of structural vs. nonstructural proteins in tissue tropism and pathogenicity. Two central hypotheses will be addressed: 1) The virulence potential of VEEV strongly depends on the nonstructural proteins and probably their interactions with cellular/organismal factors, and; 2) VEEV tissue tropism depends on the ability of the virus not only to bind and enter target cells, but also to establish productive infection. Better understanding of these VEEV-cell interactions will allow the applicant to generate highly attenuated SINV/VEEV chimeras that induce protective immunity against VEEV. The specific aims are: 1. Characterize the replication in vitro and in vivo, pathogenicity and immunogenicity of chimeric SINV/VEEV vaccine candidates in mice. 2. Determine the tissue tropism and pathogenicity of reciprocal, chimeric SINV/VEEV viruses in mice. Through this project, the applicant will create SINV/VEEV chimeric vaccine candidate viruses that are highly attenuated, immunogenie and replicate efficiently in cell culture. By dissecting the nonstructural proteins of VEEV from the structural proteins, the role of replieative machinery (nonstructural proteins) in the pathogenesis will be elucidated.

描述（由申请人提供）： 申请人，D.V.M.具有一定的临床和实验室经验，寻求支持成为病毒发病机制和疫苗开发领域的独立研究人员。他的长期目标是更好地了解人类甲病毒性脑炎的发病机制，包括每个病毒基因的作用。这些信息将用于开发更安全、更有效的疫苗和疗法。拟议的研究重点是委内瑞拉马脑炎病毒（VEEV），这是一种重要的、自然出现的人类病原体，也是一种强大的生物武器，被 NIAID 归类为 B 类优先病原体。尽管 VEEV 是一种重要的人类病原体和有效的疫苗表达载体，但人们对该病毒的非结构蛋白（复制机制）在发病机制中的作用知之甚少。此外，还没有获得许可的人类 VEEV 疫苗。目标是1l) 使用可大规模高效生产的嵌合 VEEV/Sindbis 病毒 (SINV) 开发安全有效的 VEEV 疫苗； 2) 使用相互的 SINV/VEEV 嵌合体研究 VEEV 发病机制，以评估结构蛋白与非结构蛋白在组织趋向性和致病性中的作用。将讨论两个中心假设：1）VEEV 的毒力潜力强烈依赖于非结构蛋白及其与细胞/有机体因素的相互作用； 2）VEEV的组织向性不仅取决于病毒结合和进入靶细胞的能力，还取决于病毒建立有效感染的能力。更好地了解这些 VEEV-细胞相互作用将使申请人能够产生高度减毒的 SINV/VEEV 嵌合体，从而诱导针对 VEEV 的保护性免疫。具体目标是： 1. 表征嵌合 SINV/VEEV 候选疫苗在小鼠体内的体外和体内复制、致病性和免疫原性。 2. 确定小鼠中相互嵌合的 SINV/VEEV 病毒的组织向性和致病性。通过该项目，申请人将创建SINV/VEEV嵌合疫苗候选病毒，该病毒具有高度减毒、免疫原性并在细胞培养物中高效复制。通过将 VEEV 的非结构蛋白与结构蛋白分开，复制机制（非结构蛋白）在发病机制中的作用将得到阐明。