PARTICULATE HIV VACCINE DESIGN

详细的 HIV 疫苗设计

• 批准号: 2673210
• 负责人: KAM W LEONG
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1999-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2673210
• 关键词: AIDS vaccines; antibody titering; biomaterial evaluation; cell mediated lymphocytolysis test; cellular immunity; cytokine; cytotoxic T lymphocyte; dosage forms; drug design /synthesis /production; immunoconjugates; interleukin 12; laboratory mouse; lymphocyte proliferation; microcapsule; outcomes research; plasmids; recombinant proteins; simian immunodeficiency virus; vaccine development; vector vaccine

DESCRIPTION (adapted from applicant's abstract): The overall objective of this proposal is to characterize the immune response against a new HIV vaccine design composed of a mixture of biodegradable nanospheres to deliver the HIV antigen proteins as well as the plasmids that encode these proteins, and biodegradable microspheres to provide a local sustained delivery of cytokines. DNA immunization of HIV-1 gene products have induced potent humoral and cell-mediated immune responses in rodents and non-human primates. The plasmids are typically administered as bolus injections or through a gene gun. The applicants have developed a non-viral gene delivery system based on DNA nanospheres synthesized by salt-induced complex coacervation of DNA with either gelatin or chitosan. This gene delivery system has several useful features, namely: (1) ligands can be conjugated to the nanosphere to stimulate receptor-mediated endocytosis; (2) other bioactive agents or multiple plasmids can be co-encapsulated; (3) bioavailability of the DNA can be improved; and (4) the nanosphere can be lyophilized for storage without loss of bioactivity. It has been reported that antigens conjugated to beads, such as polystyrene particles can be targeted into the phagocytic pathway to induce protective tumor immunity. Particulate antigens, compared to soluble antigens, have also been shown to be more effectively presented by lymphocytes for MHC class II presentation. In the proposed HIV vaccine design, the recombinant HIV-1 antigen proteins can be co-encapsulated in the DNA nanospheres described above, with the potential of augmenting the immune response elicited by the DNA inoculation. To enhance and to steer the type of immune response (Thl versus Th2), the researchers have codelivered cytokines with HIV vaccine constructs. However, it may be difficult to control the cytokine delivery achieved by transient non-viral transfection. If administered by bolus injection, previous studies on tumor vaccines have shown that the cytokines would be cleared from the site of injection within hours. A microsphere-controlled release formulation can maintain a high level of cytokines local to the vaccine site for days, providing the co-stimulating signals for the infiltrating lymphocytes. The hypothesis of this proposal is that application of the controlled release technology to deliver the HIV-1 genes, recombinant HIV-1 antigen proteins, and cytokines by nanospheres and microspheres will be an effective HIV vaccine design. The specific aims of the proposed work are to synthesize these particulate HIV vaccines and to evaluate their immune response in terms of T cell lymphoproliferation, cytotoxic T cell response, antibody titers, and Thl/Th2 profiles.

描述（改编自申请人的摘要）：总体目标 该提案旨在描述针对新艾滋病毒的免疫反应 疫苗设计由可生物降解的纳米球混合物组成，以提供 HIV抗原蛋白以及编码这些蛋白的质粒， 和可生物降解的微球提供局部持续递送 细胞因子。 HIV-1基因产物的DNA免疫诱导了有效的体液和 啮齿动物和非人类灵长类动物中细胞介导的免疫反应。 这 质粒通常作为推注或通过基因施用 枪。 申请人开发了一种基于非病毒基因传递系统 盐诱导DNA复合凝聚合成DNA纳米球的研究 与明胶或壳聚糖。 该基因传递系统有几个 有用的特征，即：（1）配体可以缀合到纳米球上 刺激受体介导的内吞作用； (2)其他生物活性剂或 可共封装多个质粒； (3)DNA的生物利用度 得到改善； (4)纳米球可以冻干保存，无需 生物活性丧失。 据报道，抗原与珠子缀合，例如聚苯乙烯 颗粒可以靶向进入吞噬途径以诱导保护性 肿瘤免疫。 与可溶性抗原相比，颗粒性抗原具有 也被证明由淋巴细胞更有效地呈递 MHC II 类演示。 在拟议的 HIV 疫苗设计中，重组 HIV-1 抗原蛋白可以共同封装在 DNA 纳米球中 如上所述，具有增强免疫反应的潜力 由DNA接种引起。 为了增强和引导免疫反应类型（Thl 与 Th2）， 研究人员已经将细胞因子与艾滋病毒疫苗结构一起传递。 然而，控制细胞因子的传递可能很困难。 瞬时非病毒转染。 如果通过推注给药， 之前对肿瘤疫苗的研究表明，细胞因子可以 数小时内从注射部位清除。 微球控制 释放制剂可以维持局部细胞因子的高水平 疫苗位点数天，为疫苗提供共刺激信号 浸润淋巴细胞。 该提案的假设是应用受控 释放技术传递 HIV-1 基因、重组 HIV-1 抗原 纳米球和微球的蛋白质和细胞因子将是一种有效的 HIV 疫苗设计。 拟议工作的具体目标是 合成这些颗粒 HIV 疫苗并评估其免疫能力 T 细胞淋巴增殖反应、细胞毒性 T 细胞反应、 抗体滴度和 Th1/Th2 谱。