CLINICAL EVALUATION OF A MULTI-ENVELOPE AIDS VACCINE

多包膜艾滋病疫苗的临床评价

• 批准号: 6320777
• 负责人: Karen S Slobod
• 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/6320777
• 关键词: AIDS; AIDS vaccines; HIV envelope protein; cellular immunity; clinical research; clinical trial phase I; cytotoxic T lymphocyte; drug screening /evaluation; human immunodeficiency virus 1; human subject; humoral immunity; immunomodulators; recombinant proteins; recombinant virus; vaccine development; vaccinia virus; vector vaccine

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.

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HIV-1感染。HIV-1对疫苗设计提出了几个挑战：(1)高突变率导致病毒包膜（中和抗体的靶标）的巨大多样性，因此，诱导到一个包膜的抗体可能无法保护具有不同包膜的病毒；(2)直接来自感染者的包膜不同于从t细胞系培养物中获得的包膜，t细胞系培养物通常是疫苗的包膜来源；(3)包膜糖蛋白以寡聚体形式存在于病毒粒子表面，而不是以往疫苗中的单体。为了应对这些挑战，我们提出提供多样化的、低聚的、患者衍生的包膜，以诱导能够识别自然变异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细胞和T细胞，我们提出了一种3层序疫苗策略：(1)DNA疫苗启动->(2)活载体疫苗接种->(3)纯化蛋白增强。这3个替代部分被选择来触发辅助性T细胞、细胞毒性T细胞和B细胞，每一个都被认为是重要的保护相关。本文提出的研究首先集中在多包膜重组痘苗病毒疫苗（PolyEnv1）的I期试验上，这是该方法的核心（目标1-3），然后引入DNA引物和蛋白质增强（目标4）。具体目标是：目标1。确定新型多包膜重组痘苗病毒疫苗PolyEnv1的安全性。目标2。描述PolyEnv1在I期研究中诱导的包膜特异性体液反应。目的3：表征PolyEnv1 I期研究中引起的包膜特异性细胞免疫反应。目标4。确定多包膜DNA疫苗和重组gp140蛋白疫苗的安全性和免疫原性。