ANTIBODY RESPONSES TO A MULTI-ENVELOPE AIDS VACCINE

有大量证据表明，有效的艾滋病毒疫苗，以打击艾滋病的流行必须针对艾滋病毒包膜糖蛋白的巨大多样性。我们的论点是，一个多包膜疫苗，激发免疫反应的多样性包膜表位将产生广泛的保护自然发生的病毒分离株。我们的PolyEnve 1疫苗的初步临床试验为这一假设提供了支持，该疫苗以重组牛痘病毒的形式呈现23种不同的包膜。开发提高PolyEnv 1有效性的方法现在是一个主要目标。我们在小鼠模型中的初步研究强烈支持对多步骤策略的综合评价，其中包膜首先作为DNA施用，然后作为重组牛痘病毒施用，最后作为纯化的蛋白质（即，D-V-P方案掺入PolyEnv 1、23个DNA形式的匹配包膜和6个包膜的选定子集作为纯化蛋白。将针对纯化的蛋白质生成促进免疫应答分型的单克隆抗体，将评价对单独的DNA组分的蛋白质组分的应答的多样性，并将评估对完整D-V-P方案的应答的幅度和多样性。该项目的第二部分将解决“原始抗原罪”现象，即用变体分子加强免疫仅用于增强对与引发抗原共享的表位的抗体应答，并且在引发对新表位的应答方面效果较差。将进行实验以检验D-V- P疫苗接种策略将规避“原始抗原罪恶”并产生最佳多样性抗体应答的假设。该项目中描述的研究是实现多包膜HIV疫苗潜力的重要一步。

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.