ANTIBODY RESPONSES TO A MULTI-ENVELOPE AIDS VACCINE

多包膜艾滋病疫苗的抗体反应

• 批准号: 6320774
• 负责人: ROBERT G. WEBSTER
• 金额: $ 20.79万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6320774
• 关键词: AIDS; AIDS vaccines; HIV envelope protein; enzyme linked immunosorbent assay; human immunodeficiency virus 1; humoral immunity; immunomodulators; laboratory mouse; recombinant virus; tissue /cell culture; vaccine development; vaccinia virus; vector vaccine; virus DNA

There is substantial evidence that an effective HIV vaccine to combat the AIDS epidemic must target the tremendous diversity of the HIV envelope glycoprotein. Our contention is that a multiple-envelope vaccine that elicits immune responses to a diversity of envelope epitopes will generate broad protection against naturally occurring viral isolates. Support for this hypothesis is provided by preliminary clinical trials of our PolyEnve1 vaccine, which presents 23 different envelopes in the form of recombinant vaccinia viruses. The development of approaches to enhancing the effectiveness of PolyEnv1 is now a primary goal. Our preliminary studies in a mouse model strongly supports the comprehensive evaluation of a multi- step strategy in which envelopes are first administered as DNA, than as recombinant vaccinia viruses, and finally as purified protein (i.e., a D-V-P regimen incorporating PolyEnv1, 23 matching envelopes in the form of DNA, and a selected subset of 6 envelopes as purified protein. Monoclonal antibodies to facilitate the typing of immune responses will be generated to the purified proteins, the diversity of responses to the protein component of the DNA component alone will be evaluated, and the magnitude and diversity of the response to the complete D-V-P regimen will be assessed. The second part of this project will address the phenomenon of "original antigenic sin", whereby boosting immunizations with variant molecules serve only to enhance antibody responses to epitopes that are shared with the priming antigen, and are less effective in eliciting responses to novel epitopes. Experiments will be conducted to test the hypothesis that the D-V- P vaccination strategy will circumvent "original antigen sin" and generate an optimally diverse antibody response. The studies described in this project are an important step towards realizing the potential of multiple-envelope HIV vaccines.

有大量证据表明，对抗艾滋病流行的有效艾滋病毒疫苗必须针对艾滋病毒包膜糖蛋白的巨大多样性。我们的观点是，引发对多种包膜表位的免疫反应的多包膜疫苗将产生针对自然发生的病毒分离株的广泛保护。我们的 PolyEnve1 疫苗的初步临床试验为这一假设提供了支持，该疫苗以重组痘苗病毒的形式呈现 23 种不同的包膜。开发增强 PolyEnv1 有效性的方法是现在的首要目标。我们在小鼠模型中的初步研究强烈支持对多步策略的综合评估，其中包膜首先作为 DNA 施用，然后作为重组痘苗病毒，最后作为纯化蛋白施用（即，包含 PolyEnv1 的 D-V-P 方案、23 个匹配的 DNA 形式的包膜和选定的 6 个包膜子集作为纯化蛋白。 将促进对纯化的蛋白质产生免疫反应的分型，将评估对单独的DNA成分的蛋白质成分的反应的多样性，并且将评估对完整D-V-P方案的反应的幅度和多样性。该项目的第二部分将解决“原始抗原原罪”现象，即用变异分子加强免疫只能增强 抗体对与引发抗原共有的表位产生反应，并且在引发对新表位的反应方面效果较差。将进行实验来检验 D-V-P 疫苗接种策略将规避“原始抗原罪恶”并产生最佳多样化抗体反应的假设。该项目中描述的研究是实现多包膜艾滋病毒疫苗潜力的重要一步。