A VEE Replicon-Based Vaccine for Dengue Virus

基于 VEE 复制子的登革热病毒疫苗

• 批准号: 7035323
• 负责人: LAURA J WHITE
• 金额: $ 28.51万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035323
• 关键词: Venezuelan equine encephalitis virus; active immunization; antiviral antibody; bioterrorism /chemical warfare; cellular immunity; dengue; dengue virus; emerging infectious disease; enzyme linked immunosorbent assay; gene expression; host organism interaction; humoral immunity; immune response; immunogenetics; intracellular transport; laboratory mouse; microorganism immunology; neutralizing antibody; nonhuman therapy evaluation; placental transfer; replicon; vaccine development; vaccine evaluation; vector vaccine; virus protein; weanling animal

DESCRIPTION (provided by applicant): Dengue virus (DEN), a priority "A" pathogen on the NIH/CDC list of bioterrorism related and emerging pathogens, infects humans causing a spectrum of clinical manifestations including dengue fever, dengue hemorrhagic fever and dengue shock syndrome. Severe disease is associated with a second infection with a different serotype or infection of infants harboring maternal antibodies. One of the challenges to development of an effective DEN vaccine is to induce active immunity in the face of maternal antibodies, a problem also facing vaccines for measles and other diseases. We hypothesize that a vaccine for DEN based on non-propagating Venezuelan equine encephalitis virus vectors (VRP) will be able to induce an endogenous immune response in young mice, even in the presence of passively transferred neutralizing anti-DEN antibodies. We base our hypothesis on three properties of the VEE vectors, (i) The DEN antigens will not be exposed on the VRP surface, (ii) VRP will target the antigen-encoding gene to the lymph node, facilitating and enhancing antigen presentation, (iii) Non-propagating VRP vectors immunize by expressing high levels of the heterologous gene only in a single round of infection. In this exploratory grant we propose to 1) Characterize the baseline humoral and cell-mediated immune responses induced by a prototype VRP vaccine expressing DEN2 prM and E membrane proteins in weanling mice; 2) Determine the ability of the prototype vaccine to induce an endogenous immune response in weanling mice in the presence of neutralizing anti-dengue antibodies passively transferred by inoculation or by suckling on immune dams; and 3) Modify the intracellular targeting of the VRP-expressed DEN2 prM and E proteins to improve expression levels and immunogenicity in mice. These experiments will demonstrate the feasibility of a VRP approach to a tetravalent DEN vaccine while suggesting solutions to similar difficulties with maternal antibodies encountered with other infant vaccines including measles.

描述（由申请人提供）： 登革热病毒 (DEN) 是 NIH/CDC 生物恐怖主义相关和新兴病原体清单中的优先“A”级病原体，它感染人类后会引起一系列临床表现，包括登革热、登革出血热和登革休克综合征。严重疾病与不同血清型的二次感染或携带母体抗体的婴儿的感染有关。开发有效的 DEN 疫苗面临的挑战之一是在母体抗体面前诱导主动免疫，麻疹和其他疾病的疫苗也面临这个问题。我们假设基于非繁殖性委内瑞拉马脑炎病毒载体（VRP）的 DEN 疫苗将能够在幼鼠中诱导内源性免疫反应，即使存在被动转移的中和性抗 DEN 抗体。我们的假设基于 VEE 载体的三个特性，(i) DEN 抗原不会暴露在 VRP 表面，(ii) VRP 会将抗原编码基因靶向淋巴结，促进和增强抗原呈递，（ iii)非增殖VRP载体仅在单轮感染中通过表达高水平的异源基因进行免疫。在这项探索性资助中，我们建议 1) 表征断奶小鼠中表达 DEN2 prM 和 E 膜蛋白的原型 VRP 疫苗诱导的基线体液和细胞介导的免疫反应； 2) 确定原型疫苗在存在通过接种或在免疫母体上哺乳被动转移的中和抗登革热抗体的情况下诱导断奶小鼠内源性免疫反应的能力； 3) 修改 VRP 表达的 DEN2 prM 和 E 蛋白的细胞内靶向，以提高小鼠中的表达水平和免疫原性。这些实验将证明四价 DEN 疫苗的 VRP 方法的可行性，同时提出解决方案，以解决其他婴儿疫苗（包括麻疹）遇到的母体抗体的类似困难。