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HIV Envelope Peptide-Based Vaccine in SHIV-Rhesus Model

SHIV-恒河猴模型中的 HIV 包膜肽疫苗

基本信息

批准号：
7008828
负责人：
Jagannadha K Sastry
金额：
$ 61.51万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-12-01 至 2008-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Vaccine development efforts against human immunodeficiency virus type 1 (HIV-1) are hindered by the high mutation rate of the virus, lack of clear understanding of the nature of the protective immunity, and limitations of available animal models for direct testing of HIV antigens for protection. We tested protective efficacy of a highly conserved HIV envelope peptide cocktail vaccine in Indian origin rhesus macaques by taking advantage of the chimeric virus SHIV, that expresses HIV envelope and causes AIDS in this model thereby allowing for direct testing of HIV vaccines based on envelope sequences. The HIV envelope peptides for the vaccine cocktail were selected through a series of studies in multiple animal models and in vitro studies with cells from HIV-infected long-term non-progressors, for broadly cross reactive T cell responses in the context of multiple MHC haplotypes. Since the peptide cocktail vaccine selectively primes cell-mediated immunity (CMI) in the absence of anti-HIV antibody production, it is possible to test protective efficacy of antiviral TH and CTL responses in this model. Three separate vaccine studies were conducted employing a total of 30 macaques for delivering the peptide cocktail vaccine with Freund's adjuvant and/or autologous dendritic cells (DC). Macaques immunized with ex vivo peptide cocktail-pulsed DC exhibited efficient induction of CMI, and upon challenge with pathogenic strains of SHIV (SHIV[ku2] and SHIV[89.6P]) showed significant reduction in viral set point accompanied by undetectable virus in the blood of majority of vaccinated animals. Importantly, no rebounds were observed in the vaccinated monkeys, some followed for over three years. These results strongly support the vaccine potential of the HIV envelope peptide cocktail and the efficiency of DC loaded ex vivo with peptides for priming protective CMI responses. We hypothesize that FIt3-ligand (FL) treatment followed by delivering the vaccine cocktail in the presence of CpG-containing oligodeoxynucleotides (ODN) will be an effective strategy for targeting the vaccine to DC in vivo. Further we propose that this strategy would entail the HIV envelope peptide cocktail to be a viable vaccine approach applicable to humans. We obtained preliminary data supporting FL-mediated mobilization of multiple subsets of DC with immunogenic properties in murine and primate studies. We will test whether FL treatment of macaques followed by vaccination with the HIV envelope peptide cocktail in CpG-ODN would be effective in priming strong CMI and protection against intravenous challenge using SHIV[KU2]. Since the major route of HIV infection is the mucosal epithelium and is predominantly by macrophage-tropic HIV strains, we will also test the effectiveness of the peptide cocktail targeted to DC in vivo using FL-treatment and CpG-ODN followed by mucosal challenge using SHIV[SF162P], (expressing macrophage-tropic HIV envelope). We will also test a mucosal vaccination strategy for delivering the peptide cocktail using a novel mutant cholera toxin (CT2*) that we observed to be a strong adjuvant for priming systemic and mucosal immune responses to several peptide antigens, including the HIV vaccine peptides in mice.

描述（由申请方提供）：针对人类免疫缺陷病毒1型（HIV-1）的疫苗开发工作受到以下因素的阻碍：病毒的高突变率、对保护性免疫的性质缺乏明确认识以及直接检测HIV抗原以获得保护的可用动物模型的局限性。我们测试了高度保守的HIV包膜肽鸡尾酒疫苗在印度起源的恒河猴中的保护效力，通过利用嵌合病毒SHIV，其在该模型中表达HIV包膜并引起AIDS，从而允许基于包膜序列直接测试HIV疫苗。通过在多个动物模型中的一系列研究和使用来自HIV感染的长期非进展者的细胞的体外研究来选择用于疫苗混合物的HIV包膜肽，用于在多种MHC单倍型的背景下的广泛交叉反应性T细胞应答。由于肽鸡尾酒疫苗在不产生抗HIV抗体的情况下选择性地引发细胞介导的免疫（CMI），因此可以在该模型中测试抗病毒TH和CTL应答的保护功效。采用总共30只猕猴进行三项单独的疫苗研究，用于递送具有弗氏佐剂和/或自体树突细胞（DC）的肽混合物疫苗。用离体肽混合物脉冲的DC免疫的猕猴表现出有效的CMI诱导，并且在用SHIV的致病株（SHIV[ku 2]和SHIV[89.6P]）攻击时，显示病毒设定点显著降低，伴随着大多数接种动物血液中不可检测的病毒。重要的是，在接种疫苗的猴子中没有观察到反弹，有些猴子随访了三年多。这些结果强烈支持HIV包膜肽混合物的疫苗潜力和离体负载肽的DC用于引发保护性CMI应答的效率。我们假设，FIt 3-配体（FL）治疗，然后在含CpG的寡脱氧核苷酸（ODN）的存在下提供疫苗鸡尾酒将是一种有效的策略，靶向疫苗在体内DC。此外，我们建议，这种策略将需要HIV包膜肽鸡尾酒是一个可行的疫苗方法适用于人类。我们获得的初步数据支持FL介导的动员多个子集的DC免疫原性在小鼠和灵长类动物的研究。我们将测试FL处理猕猴后接种CpG-ODN中的HIV包膜肽混合物是否能有效引发强CMI并保护其免受SHIV静脉内攻击[KU 2]。由于HIV感染的主要途径是粘膜上皮，并且主要是通过嗜巨噬细胞的HIV毒株，我们还将使用FL处理和CpG-ODN，然后使用SHIV[SF 162 P]（表达嗜巨噬细胞的HIV包膜）进行粘膜攻击，在体内测试靶向DC的肽混合物的有效性。我们还将测试粘膜疫苗接种策略，用于使用新型突变霍乱毒素（CT 2 *）递送肽鸡尾酒，我们观察到所述新型突变霍乱毒素是引发对几种肽抗原（包括小鼠中的HIV疫苗肽）的全身和粘膜免疫应答的强佐剂。