CORRELATES OF EFFICACY OF VEE-BASED SIV VACCINES

基于 VEE 的 SIV 疫苗功效的相关性

• 批准号: 6352652
• 负责人: Philip R Johnson
• 金额: $ 40.36万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6352652
• 关键词: AIDS vaccines; Macaca; Venezuelan equine encephalitis virus; cellular immunity; cytotoxic T lymphocyte; drug administration routes; drug screening /evaluation; humoral immunity; leukocyte activation /transformation; neutralizing antibody; replicon; simian immunodeficiency virus; vaccine development; vector vaccine; virus antigen; virus replication

The goal of Project 3 is to elucidate the immune correlates of efficacy in macaques immunized with SIV vaccines derived from the elegant Venezuelan Equine Encephalitis (VEE) virus replicon system (SIV-VRP). We previously showed that macaques immunized with an SIV vaccine derived from the Venezuelan Equine Encephalitis (VEE) virus replicon system (SIV-VRP) controlled replication of a virulent SIV intravenous challenge significantly better than mock immunized macaques. Prior to challenge, SIV-specific CD8+ CTL were easily detected in bulk cultures of PBMC, whereas serum neutralizing antibodies against the challenge virus were absent. Thus, it appeared that efficient control of SIV replication after challenge in SIV-VRP vaccinated macaques was due to vaccine elicited virus-specific CTL. To further explore this supposition, we propose to examine immune correlates of efficacy in macaques immunized with first and future generation SIV-VRP vaccines. First, we will determine which viral immunogen(s) in the first generation SIV-VRP vaccine was responsible for post-challenge control of in vivo SIV replication and characterize humoral and cellular immune responses associated with efficacy. Also, we will test SIV-VRP vaccines that contain additional CTL epitopes (in Gag and Pol) on the premise that "more is better." Second, we will assess sera from SIV- VRP immunized macaques for the ability to block or dampen SIV replication using an"in vivo" neutralization assay. Third, we will test an optimized SIV-VRP vaccine in combination with a purified Env subunit boost. The purpose of this experiment is to assess the role of neutralizing antibodies in vaccine efficacy. Two challenge routes (i.v and i.r.) will be used. Finally, we will combine technology and results from all 3 HIV- RAD Projects to generate the optimum SIV-VRP vaccine strategy, and this will be tested in both the SIV and SHIV models.

项目3的目标是阐明用来自优雅的委内瑞拉马脑炎（VEE）病毒复制子系统（SIV-VRP）的SIV疫苗免疫的猕猴中的免疫相关性。我们以前表明，猕猴免疫的SIV疫苗来自委内瑞拉马脑炎（VEE）病毒复制子系统（SIV-VRP）控制复制的毒力SIV静脉内的挑战显着优于模拟免疫猕猴。在攻击前，SIV特异性CD 8 + CTL在PBMC的大量培养物中很容易检测到，而针对攻击病毒的血清中和抗体不存在。因此，似乎在SIV-VRP免疫的猕猴中攻击后对SIV复制的有效控制是由于疫苗引起的病毒特异性CTL。为了进一步探讨这一假设，我们建议检查免疫相关的效力与猕猴免疫的第一代和未来的SIV-VRP疫苗。首先，我们将确定第一代SIV-VRP疫苗中的哪种病毒免疫原负责体内SIV复制的攻毒后控制，并表征与效力相关的体液和细胞免疫应答。此外，我们将测试SIV-VRP疫苗，含有额外的CTL表位（在Gag和Pol）的前提下，“越多越好。其次，我们将使用体内中和试验评估SIV-VRP免疫猕猴的血清阻断或抑制SIV复制的能力。第三，我们将测试优化的SIV-VRP疫苗与纯化的Env亚单位加强的组合。本实验的目的是评估中和抗体在疫苗效力中的作用。两种激发途径（i. v.和i.r.）将用于最后，我们将结合联合收割机技术和所有3个HIV-RAD项目的结果，以产生最佳的SIV-VRP疫苗策略，并将在SIV和SHIV模型中进行测试。