NOVEL TECHNOLOGIES APPLIED TO A DENQUE DNA VACCINE

DENQUE DNA 疫苗应用新技术

• 批准号: 6286101
• 负责人: J. Thomas August
• 金额: $ 2.6万
• 依托单位: AARMEDIS, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-03 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6286101
• 关键词: Primates; dengue; dengue virus; vaccine development; vector vaccine; viral vaccines

Dengue viruses cause a significant public health burden in tropical regions of the world and now threaten to proliferate in more temperate climates. There is currently no acceptable vaccine to prevent dengue. This project seeks to develop a DNA vaccine that will prevent dengue fever. Existing dengue DNA vaccine constructs will be improved by the addition of the intracellular trafficking sequences of the lysosome associated membrane protein (LAMP) to dengue genes on the vaccine plasmid. These sequences target the antigen to MHC class II associated intracellular compartments and enhance the immune response of vaccinated animals. The vaccines will be further improved by delivering plasmids in sustained release microspheres made from poly(phosphoester) and other polymers under development. These preparations are expected to increase the efficiency of DNA immunization and reduce the number of doses required. The microspheres will also be used to co-deliver granulocyte- macrophage colony stimulating factor (GMCSF) and other cytokines selected to enhance the appropriate immune response. Formulations that are effective in inducing neutralizing antibodies in mice will be tested in non-human primate studies. Selection of the candidates most likely to succeed in humans will be made based on the ability of vaccines to induce immunity that prevents viremia in non-human primates after challenge with live dengue virus. The results of this project will be directed to a vaccine formulation chosen to enter GMP production for human trials.

登革热病毒在世界热带地区造成严重的公共卫生负担，现在有可能在更温和的气候中扩散。目前没有可接受的疫苗来预防登革热。该项目旨在开发一种预防登革热的DNA疫苗。通过将溶酶体相关膜蛋白（LAMP）的细胞内转运序列添加到疫苗质粒上的登革热基因上，现有的登革热DNA疫苗结构将得到改进。这些序列将抗原靶向MHC II类相关的细胞内区室，并增强接种疫苗动物的免疫应答。通过将质粒放入由聚（磷酸酯）和其他正在开发的聚合物制成的缓释微球中，疫苗将得到进一步改进。这些制剂有望提高DNA免疫的效率并减少所需的剂量。微球还将用于共同递送粒细胞-巨噬细胞集落刺激因子（GMCSF）和其他选定的细胞因子，以增强适当的免疫反应。在小鼠体内有效诱导中和抗体的配方将在非人类灵长类动物研究中进行测试。将根据疫苗诱导免疫的能力来选择最有可能在人类中成功的候选疫苗，这种免疫可以在受到登革热活病毒攻击后防止非人类灵长类动物的病毒血症。该项目的结果将直接用于选择进入GMP生产进行人体试验的疫苗配方。