Combined TNFSF and TLR stimulation of HIV vaccines

HIV 疫苗的 TNFSF 和 TLR 联合刺激

• 批准号: 7039168
• 负责人: Richard Syd Kornbluth
• 金额: $ 21.15万
• 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 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039168
• 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感染疫苗的障碍是导致强烈免疫反应的疫苗接种方法的要求。 DNA疫苗具有潜力，但是除非添加辅助质粒，否则它们通常是较差的免疫原子。描述了实验表明，用于新的可溶性，多聚体的CD40L的质粒DNA是小鼠模型中DNA疫苗的有效佐剂，并且测试TNF超级家族（TNFSF）的其他免疫刺激成员非常重要。 结合Toll样受体（TLR）和CD40刺激是高度协同的，将使用上面CD40L的新形式进行测试。另外，用PLGA/PBAE共聚物对DNA疫苗的微囊化有助于将DNA携带到树突状细胞并上调CD40，表明它可能与CD40L作为佐剂协同。因此，该项目具有以下目的：目标1：测试质粒对OX40L，RANKL，CD27L的各个影响，以及小鼠HIV DNA疫苗接种的光。 目标2：测试CD40L和细菌脂肽（BLP）TLR2激动剂作为DNA疫苗佐剂的组合。目标3：确定具有PLGA/PBAE的DNA微囊化是否与CD40L协同，以增强对HIV DNA疫苗的免疫反应。 AIM 4：准备最佳TNFSF构造的猕猴版本，以促进SIV/猕猴模型。该R21提案的创新方面是：使用有前途的CD40L和其他TNFSF的新型交付平台； CD40L和BLP作为DNA疫苗辅助的研究；并将CD40L与HIV DNA疫苗中的PLGA/PBAE微囊化结合在一起。总而言之，这些研究将优化一个强大的HIV DNA疫苗辅助平台，该平台具有仅DNA疫苗接种或DNA Prime/病毒载体增强方案的巨大潜力。此外，这种DNA疫苗方法通常证明适用于需要有效疫苗的新兴感染和其他疾病。