MULTI-TIER AIDS VACCINE--MANUFACTURE AND TESTING

该项目的长期目标是开发一种疫苗，以保护人类免受自然界中发现的抗原性不同形式的艾滋病毒-1的感染。这种保护需要激发针对多种HIV- 1包膜蛋白的免疫反应。我们认为，必须在疫苗中呈递多个HIV-1包膜蛋白，以诱导针对一系列HIV-1变异的免疫记忆。我们进一步提出，不同反应的大小可以通过使用多个疫苗递送系统来优化。我们的临床前研究评估了三组疫苗递送系统(i)重组DNA疫苗，然后（ii）重组痘苗病毒疫苗，然后（iii）纯化蛋白疫苗（D-V-P），在小鼠中显示出高水平的HIV-1中和抗体。该项目的目标是将这种疫苗策略转化为人类应用。一种多包膜重组痘苗病毒疫苗（PolyEnv1）目前处于临床试验阶段（项目4）。因此，在这个项目中，我们将准备DNA和纯化的蛋白质用于人类。该项目的前两个目标描述了临床级材料的设计和生产。虽然在技术上受到驱动，但这两个目标对于小规模人体试验的实施至关重要（项目4）。第三个目标测试了这样一个假设，即这些目标对于进行小规模人体试验至关重要（项目）。第三个目的是验证我们的三层多包膜疫苗策略可以保护非人类灵长类动物免受异源病毒感染的假设。这一目标的实现对于疫苗方法的临床进展至关重要。本项目制定的具体目标是：目标1：制备一种安全、具有免疫原性并适合于人类使用的多包膜DNA疫苗。目的2：制备一种安全、具有免疫原性且适合人类使用的多包膜蛋白疫苗。目的3：确定三层多包膜疫苗是否能保护非人类灵长类动物免受异源病毒攻击。

The long term objective of this project is to develop a vaccine to protect humans from antigenically different forms of HIV-1 found in nature. Such protection will require elicitation of immune responses against diverse HIV- 1 envelop proteins. We submit that multiple HIV-1 envelope proteins must be presented in a vaccine to induce immunological memory against the range of HIV-1 variants. We further proposed that the magnitude of diverse responses may be optimized by utilization of more than one vaccine delivery system. Our pre-clinical studies evaluation a three-tired vaccine delivery system with (i) recombinant DNA vaccine followed by (ii) recombinant vaccinia virus vaccine followed by (iii) purified protein vaccine (D-V-P) demonstrate high levels of HIV-1 neutralizing antibodies in mice. The goal of this project is to translate this vaccine strategy to human application. A multi-envelope recombinant vaccinia virus vaccine (PolyEnv1) is currently in clinical trial (Project 4). Accordingly, in this project we will prepare DNA and purified proteins fro use in humans. The first two aims of this project describe the design and production of clinical grade material. While technically driven these two aims are critical for the conduct of small scale human trials (Project 4). The third aim tests the hypothesis that these aims are critical for the conduct of small scale human trials (Project). The third aim tests the hypothesis that our 3-tiered, multi- envelope vaccine strategy can protect non-human primates from heterologous virus. The implementation of this aim is critical for clinical advanced of the vaccine approach. Specific aims developed in this project are: Aim 1: To prepare a multi-envelope DNA vaccine that is safe, immunogenic and suitable for use in humans. Aim 2: To prepare a multi-envelope protein vaccine that is safe, immunogenic and suitable for use in humans. Aim 3: To determine whether a three-tiered multi-envelope vaccine protects non-human primates from heterologous virus challenge.