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（根据申请人的摘要改编）： 该提议是要表征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的混合物组成 HIV抗原蛋白以及编码这些蛋白质的质粒， 和可生物降解的微球，以提供局部持续交付 细胞因子。 HIV-1基因产物的DNA免疫已引起有效的体液，并且 细胞介导的啮齿动物和非人类灵长类动物的免疫反应。 这 质粒通常作为推注或通过基因给药 枪。 申请人开发了基于非病毒基因输送系统 在通过盐诱导的DNA复合物共凝结合成的DNA纳米球上 与明胶或壳聚糖。 该基因输送系统有几个 有用的特征，即：（1）配体可以与纳米圈结合到 刺激受体介导的内吞作用； （2）其他生物活性剂或 可以共同封装多种质粒； （3）DNA的生物利用度可以 得到改善； （4）纳米球可以冻干以存储而没有 生物活性的丧失。 据报道，抗原与珠子相结合，例如聚苯乙烯 颗粒可以靶向吞噬途径以诱导保护性 肿瘤免疫。 与可溶性抗原相比，颗粒抗原具有 也证明MHC的淋巴细胞更有效地表现出来 II类演示。 在拟议的HIV疫苗设计中，重组 HIV-1抗原蛋白可以在DNA纳米球中共封存 上面描述的，有可能增加免疫反应 通过DNA接种引起。 为了增强和指导免疫反应的类型（THL与TH2）， 研究人员已将细胞因子与HIV疫苗构建体共同代码。 但是，可能很难控制通过 瞬态非病毒转染。 如果通过注射推注， 先前关于肿瘤疫苗的研究表明，细胞因子将是 在几个小时内从注射部位清除。 微球对照 释放配方可以维持高水平的细胞因子局部 疫苗部位几天，提供共同刺激的信号 浸润淋巴细胞。 该提议的假设是应用程序的应用 释放技术以输送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。 拟议工作的具体目的是 合成这些颗粒物HIV疫苗并评估其免疫 根据T细胞淋巴细胞增生，细胞毒性T细胞反应的反应， 抗体滴度和THL/TH2轮廓。