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）是与生物恐怖主义和新兴病原体的NIH/CDC清单上的优先“ A”病原体，它会感染人类，引起人类，引起各种临床表现，包括登革热，登革热大量，登革热大量发烧和登革热休克综合征。严重的疾病与第二种感染有关，具有不同的血清型或具有母体抗体的婴儿的感染。有效的DEN疫苗开发的挑战之一是面对母体抗体，诱导主动免疫，这也是面临麻疹和其他疾病的疫苗的问题。我们假设基于非传播的委内瑞拉马脑炎病毒载体（VRP）的DEN疫苗也能够在年轻小鼠中诱导内源性免疫反应，即使在存在被动转移的中和中和中和中和抗抗体抗体的情况下。我们将假设基于VEE载体的三个特性，（i）den抗原不会在VRP表面暴露，（ii）VRP将靶向抗原代码基因对淋巴结，促进和增强抗原呈递的抗原呈递，（III）非构造VRP VRP VECTER的较高级别的高度元素。在这项探索性授予中，我们建议以1）为特征，表征由表达den2 PRM和E膜蛋白的原型VRP疫苗引起的基线体液和介导的免疫反应； 2）确定原型疫苗在断奶小鼠中诱导内源性免疫反应的能力，在存在中和通过接种或通过哺乳免疫坝被动转移的中和抗登记抗体的能力； 3）修改VRP表达的DEN2 PRM和E蛋白的细胞内靶向，以改善小鼠的表达水平和免疫原性。这些实验将证明VRP方法对四位价值DEN疫苗的可行性，同时提出了与其他婴儿疫苗（包括麻疹）遇到的母体抗体的类似困难的解决方案。