ANTIBODY RESPONSES TO A MULTI-ENVELOPE AIDS VACCINE

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，多包膜疫苗可以引起对多种包膜表位的免疫反应，从而对自然产生的病毒分离物产生广泛的保护。我们的PolyEnve1疫苗的初步临床试验支持了这一假设，该疫苗以重组痘苗病毒的形式呈现23种不同的包膜。开发提高PolyEnv1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多步骤策略的综合评估，其中包膜首先作为DNA，然后作为重组痘苗病毒，最后作为纯化蛋白（即D-V-P方案，包含PolyEnv1, 23个匹配的DNA形式的包膜，以及选定的6个包膜子集作为纯化蛋白）。将对纯化的蛋白质产生单克隆抗体，以促进免疫反应的分型，将评估对单独DNA成分的蛋白质成分的反应的多样性，并评估对完整D-V-P方案的反应的大小和多样性。该项目的第二部分将解决“原始抗原原罪”现象，即用变异分子增强免疫只会增强抗体对与引物抗原共享的表位的反应，而在引发对新表位的反应方面效果较差。将进行实验以验证D-V- P疫苗接种策略将绕过“原始抗原罪”并产生最佳多样化抗体反应的假设。本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。

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.