CLINICAL EVALUATION OF A MULTI-ENVELOPE AIDS VACCINE

这项研究的长期目标是生产一种有效的疫苗来保护人类免受艾滋病毒-1感染。HIV-1给疫苗设计带来了几个挑战：(1)高变异率导致病毒被膜的巨大多样性，病毒被膜是中和抗体的靶标，因此诱导到一个被膜上的抗体可能不能通过不同的被膜来保护病毒；(2)直接来自感染者的被膜不同于从T细胞培养获得的被膜，后者是疫苗通常的被膜来源；(3)被膜糖蛋白以低聚物的形式存在于病毒粒子表面，而不是以前的疫苗中的单体。为了应对这些挑战，我们建议提供多样化的寡聚体患者来源的包膜，以诱导能够识别自然变体上的天然包膜的多种类型特异性反应。为了招募这些长寿的B和T细胞，我们提出了一个三级序贯疫苗策略：()DNA疫苗启动--GT；(2)活载体疫苗-GT；(3)纯化蛋白增强。这3个交替的部分被选择来触发辅助T细胞、细胞毒性T细胞和B细胞，每个细胞都被认为是重要的保护相关因素。这里建议的研究首先集中在多包膜重组痘苗病毒疫苗(PolyEnv1)的第一阶段试验，这是这一方法的核心(目标1-3)，然后引入DNA启动和蛋白质增强(目标4)。具体目的为：目的1.检测新型多囊膜重组痘苗病毒疫苗PolyEnv1的安全性。目的2.表征在PolyEnv1第一阶段研究中诱导的包膜特异性体液反应。目的3：鉴定在PolyEnv1第一阶段研究中诱导的包膜特异性细胞免疫反应。目的4.检测多囊膜DNA疫苗和重组gp140蛋白疫苗的安全性和免疫原性。

The long term objective of this research is to produce an effective vaccine to protect humans from HIV-1 infection. HIV-1 presents several challenges to vaccine design: (1) high mutation rates result in tremendous diversity of virus envelope, the target of neutralizing antibody, such that antibody elicited to one envelope may not protect from virus with a distinct envelope; (2) envelope directly from infected persons differ from envelopes obtained from T-cell line cultures, the usual source of envelope for vaccines; (3) envelope glycoprotein exists as oligomers on the virion surface, not as monomers in previous vaccines. To address these challenges we proposed to deliver diverse, oligomeric, patient-derived envelopes to induce multiple type-specific responses capable of recognizing native envelope on natural variants. To recruit these array of long-lived B and T cells we propose a 3- tiered sequential vaccine strategy: () DNA vaccine priming-> (2) live vector vaccination->(3) purified protein boosting. These 3 alternate moieties are selected to trigger helper T cells, cytotoxic T cells and B cells, each considered important correlates of protection. Studies proposed here focus first on Phase I trials on a multi-envelope recombinant vaccinia virus vaccine (PolyEnv1) which is central to this approach (aims 1-3) followed by introduction of DNA priming and protein boosting (aim 4). Specific aims are: Aim 1. Determine the safety of PolyEnv1, a novel multi-envelope recombinant vaccinia virus vaccine. Aim 2. Characterize the envelope-specific humoral response induced in the Phase I study of PolyEnv1. Aim 3: Characterize the envelope-specific cellular immune responses elicited in the Phase I study of PolyEnv1. Aim 4. Determine the safety and immunogenicity of a multi-envelope DNA vaccine and a recombinant gp140 protein vaccine.