Combined TNFSF and TLR stimulation of HIV vaccines

HIV 疫苗的 TNFSF 和 TLR 联合刺激

• 批准号: 6947368
• 负责人: Richard Syd Kornbluth
• 金额: $ 21.66万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 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/6947368
• 关键词: AIDS vaccines; CD40 molecule; active immunization; bacterial proteins; biotechnology; combination chemotherapy; dendritic cells; drug interactions; human immunodeficiency virus 1; immune response; immunologic substance development /preparation; immunomodulators; laboratory mouse; microcapsule; plasmids; polymers; simian immunodeficiency virus; toll like receptor; tumor necrosis factor alpha; vaccine development; vaccine evaluation; vector vaccine; virus antigen

DESCRIPTION (provided by applicant): One impediment to developing an effective vaccine for HIV infection is the requirement for a vaccination method that leads to strong immune responses. DNA vaccines have potential, but they are often poor immunogens unless an adjuvant plasmid is added. Experiments are described that show that plasmid DNA for a new soluble, multimeric form of CD40L is an effective adjuvant for DNA vaccines in mouse models, and it will be important to test other immunostimulatory members of the TNF superfamily (TNFSF). Combining Toll-like Receptor (TLR) and CD40 stimulation is highly synergistic, and will be tested using the novel form of CD40L above. Additionally, microencapsulation of DNA vaccines with PLGA/PBAE copolymer helps to carry the DNA to dendritic cells and also upregulates CD40, indicating that it might synergize with CD40L as an adjuvant. Consequently, this project has the following aims: Aim 1: To test the individual effects of plasmids for OX40L, RANKL, CD27L, and LIGHT on HIV DNA vaccination in mice. Aim 2: To test combinations of CD40L and bacterial lipopeptide (BLP) TLR2 agonists as DNA vaccine adjuvants. Aim 3: To determine if DNA microencapsulation with PLGA/PBAE synergizes with CD40L to enhance the immune response to an HIV DNA vaccine. Aim 4: To prepare macaque versions of the best TNFSF constructs for advancement to the SIV/macaque model. The innovative aspects of this R21 proposal are: its use of a promising new delivery platform for CD40L and other TNFSFs; studies of CD40L plus BLPs as DNA vaccine adjuvants; and combining CD40L with PLGA/PBAE microencapsulation in an HIV DNA vaccine. In sum, these studies will optimize a powerful adjuvant platform for HIV DNA vaccines that has great potential for DNA-only vaccination or DNA prime/viral vector boost protocols. In addition, this DNA vaccine approach may prove generally applicable for emerging infections and other diseases for which a potent vaccine is needed.

描述（由申请人提供）：开发有效的 HIV 感染疫苗的一个障碍是需要一种能产生强烈免疫反应的疫苗接种方法。 DNA 疫苗具有潜力，但除非添加佐剂质粒，否则它们通常是较差的免疫原。实验表明，CD40L 的新型可溶性多聚体形式的质粒 DNA 是小鼠模型中 DNA 疫苗的有效佐剂，并且测试 TNF 超家族 (TNFSF) 的其他免疫刺激成员也很重要。 Toll 样受体 (TLR) 和 CD40 刺激的结合具有高度协同作用，将使用上述新型 CD40L 进行测试。此外，用 PLGA/PBAE 共聚物微囊化 DNA 疫苗有助于将 DNA 携带至树突状细胞，并上调 CD40，表明它可能与 CD40L 作为佐剂产生协同作用。因此，该项目有以下目标： 目标 1：测试 OX40L、RANKL、CD27L 和 LIGHT 质粒对小鼠 HIV DNA 疫苗接种的个体影响。 目标 2：测试 CD40L 和细菌脂肽 (BLP) TLR2 激动剂的组合作为 DNA 疫苗佐剂。目标 3：确定 PLGA/PBAE 的 DNA 微胶囊化是否与 CD40L 协同作用，以增强对 HIV DNA 疫苗的免疫反应。目标 4：制备最佳 TNFSF 构建体的猕猴版本，以推进 SIV/猕猴模型。 R21提案的创新之处在于：它使用了一种有前途的CD40L和其他TNFSF新型递送平台； CD40L加BLP作为DNA疫苗佐剂的研究；将 CD40L 与 PLGA/PBAE 微胶囊结合在 HIV DNA 疫苗中。总之，这些研究将优化 HIV DNA 疫苗的强大佐剂平台，该平台对于纯 DNA 疫苗接种或 DNA 初免/病毒载体加强方案具有巨大潜力。此外，这种 DNA 疫苗方法可能普遍适用于新出现的感染和其他需要有效疫苗的疾病。