ADJUVANT STRATEGIES USING T CELL HELP ENHANCER PEPTIDES

使用 T 细胞帮助增强肽的佐剂策略

• 批准号: 3547529
• 负责人: Kemp Bailey Cease
• 金额: $ 12.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3547529
• 关键词: AIDS; AIDS vaccines; CD4 molecule; antigens; antiviral agents; enzyme linked immunosorbent assay; helper T lymphocyte; human immunodeficiency virus; human immunodeficiency virus 1; immunogenetics; immunological substance; immunomodulators; laboratory mouse; laboratory rabbit; major histocompatibility complex; peptide chemical synthesis; radioimmunoassay; synthetic antigens; virus antigen; virus envelope; virus protein; western blottings

Immunologic protection, the essence of any effective vaccine, is generally obtained by exposure to an agent that simulates disease experience immunologically. In the case of infection with the AIDS virus, it is not clear that disease experience itself results in effective immunity that could confer protection. Though not clear that disease experience itself results in effective immunity that could confer protection. Though one immunologic parameter of specific immunity, the presence of neutralizing antibody, may correlate with a more favorable short term clinical course in some risk groups, overall, the immunologic prerequisites for protection against AIDS remain unknown. The goal of any potential AIDS vaccine must, therefore, be to induce the strongest possible T cell and B cell immunity in an individual prior to exposure to the AIDS virus or infected cells. While a subunit vaccine for AIDS would be attractive with regard to safety, such vaccines typically lack the strong immunogenicity that may be so critical for AIDS vaccine efficacy. The overall goal of this project is to develop general methods for enhancing the immunogenicity of any native or recombinant antigen by the covalent attachment of small synthetic peptides that enhance T cell help. This novel T cell help enhancer peptide (TEP) adjuvant strategy will be pursued by: 1. Synthesizing a panel of appropriately protected peptide derivatives representing peptides with well characterized immunogenicity and major histocopatibility (MHC) restriction, 2. Using these to prepare TEP-modified protein antigen using biochemically and immunologically well characterized model antigens and the pathologically important gp160 envelope protein of Human Immunodeficiency Virus Type 1, 3. Quantitatively comparing the immunogenicity of these TEP-modified antigens and control antigens formulated in currently available adjuvants, and 4. Evaluating the in vitro antiviral activity of antisera raised against TAP-gp160 in quantitative HIV-1 plaguing assays. Repeated cycles of TEP-antigen design, synthesis, and testing should reveal methods for enhancing the immunogenicity of gp 160 which are generally applicable to other HIV antigens or any other antigen of pathologic importance. The TEP-gp160 constructs developed in these studies will themselves be candidates for continuing preclinical and clinical studies. This project thus has the potential to make substantial contributions to the development of a highly immunogenic, safe and effective vaccine for AIDS.

免疫保护，任何有效疫苗的本质都是 通常通过接触一种模拟疾病的试剂而获得 免疫学上的经验。在感染艾滋病的情况下 病毒，目前还不清楚疾病经历本身会导致 可以提供保护的有效豁免权。虽然不是很清楚 疾病经历本身就会产生有效的免疫力，这可能会赋予 保护。虽然特异性免疫的一个免疫学参数， 中和抗体的存在，可能与更有利的 一些风险组的短期临床病程，总体来说，免疫学 预防艾滋病的先决条件尚不清楚。的目标是 因此，任何可能的艾滋病疫苗都必须诱导出最强的 接触艾滋病前个体可能的T细胞和B细胞免疫 艾滋病病毒或受感染的细胞。而针对艾滋病的亚单位疫苗将 在安全性方面很有吸引力，这种疫苗通常缺乏 很强的免疫原性，这可能是艾滋病疫苗效力的关键。 这个项目的总体目标是开发通用的方法来 通过增强任何天然或重组抗原的免疫原性 小分子合成肽的共价连接有助于增强T细胞。 这种新的T细胞帮助增强肽(TEP)佐剂策略将是 追求：1.合成一组适当保护的多肽 具有良好免疫原性的代表多肽的衍生物 和主要组织复制能力(MHC)限制，2.使用这些来准备 TEP修饰的蛋白质抗原在生化和免疫学上的良好应用 特征化的模型抗原和病理上重要的gp160 人类免疫缺陷病毒1型、3型包膜蛋白。 定量比较这些TEP修饰后的免疫原性 目前可用的配制的抗原和对照抗原 佐剂；4.抗血清的体外抗病毒活性评价 在HIV-1感染的定量检测中针对TAP-gp160提高。 TEP-抗原设计、合成和测试的重复周期应该 揭示增强GP 160免疫原性的方法，这些方法包括 一般适用于其他HIV抗原或任何其他HIV抗原 病理学上的重要性。开发的TEP-gp160结构 研究本身将是继续进行临床前和基础研究的候选人 临床研究。因此，这个项目有可能使 为开发一种高度免疫原性、 安全有效的艾滋病疫苗。