CLINICAL EVALUATION OF A MULTI-ENVELOPE AIDS VACCINE

多包膜艾滋病疫苗的临床评价

• 批准号: 6167470
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-05-15 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6167470
• 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，以保护人类免受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的巨大多样性，中和抗体的靶点，使得针对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细胞系培养物获得的包膜，T细胞系培养物是疫苗包膜的通常来源;（3）包膜糖蛋白在病毒粒子表面以寡聚体形式存在，而不是在先前的疫苗中以单体形式存在。为了解决这些挑战，我们提出递送多样化的、寡聚的、患者来源的包膜以诱导能够识别天然变体上的天然包膜的多种类型特异性应答。为了募集这些长寿的B和T细胞阵列，我们提出了3层顺序疫苗策略：（）DNA疫苗引发->（2）活载体疫苗接种->（3）纯化蛋白加强。选择这3种替代部分以触发辅助T细胞、细胞毒性T细胞和B细胞，每种细胞被认为是重要的保护相关物。本文提出的研究首先集中在多包膜重组牛痘病毒疫苗（PolyEnv 1）的I期试验，这是该方法的核心（目标1-3），然后引入DNA引发和蛋白加强（目标4）。具体目标是：目标1。测定新型多包膜重组痘苗病毒疫苗PolyEnv 1的安全性。目标二。表征PolyEnv 1 I期研究中诱导的小鼠特异性体液应答。目的3：表征在PolyEnv 1的I期研究中引起的小鼠特异性细胞免疫应答。目标4。确定多囊膜DNA疫苗和重组gp 140蛋白疫苗的安全性和免疫原性。