Novel Adenovirus Vaccine Vectors for HIV/SIV

HIV/SIV 新型腺病毒疫苗载体

• 批准号: 7061430
• 负责人: Dan H. Barouch
• 金额: $ 61.07万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061430
• 关键词: AIDS vaccines; Adenoviridae; Macaca mulatta; biotechnology; capsid; cellular immunity; chimeric proteins; human immunodeficiency virus 1; humoral immunity; laboratory mouse; mucosal immunity; serotyping; simian immunodeficiency virus; vaccine development; vector vaccine; virus replication

DESCRIPTION (provided by applicant): A critical roadblock in the development of an HIV-1 vaccine is our current inability to deliver HIV-1 antigens efficiently to the immune system and to prime predictable, high frequency immune responses in humans. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for HIV-1 have elicited potent immune responses in preclinical studies. However, the high frequency of anti-Ad5 immunity in the developing world will likely limit the immunogenicity and clinical utility of rAd5 vaccines. We therefore propose the development of novel rAd vector-based vaccines for HIV-1. We hypothesize that rAd vector-based vaccines derived from rare Ad serotypes and engineered for improved immunogenicity will prove significantly more immunogenic than rAd5 vaccines in rhesus monkeys with anti-Ad5 immunity. We further hypothesize that the optimal rAd vaccine regimen will be a heterologous prime-boost regimen involving two different serotype vectors that are both rare in human populations, engineered for optimal immunogenicity, derived from different Ad subfamilies, and distinct from Ad5. To investigate these hypotheses, we propose the following four Specific Aims: 1. To compare the immunogenicity of rAd5, rAd35, and capsid chimeric rAd5/rAd35 vectors in rhesus monkeys with anti-Ad5 immunity; 2. To assess the immunogenicity of heterologous rAd prime-boost regimens involving vectors derived from two different Ad subfamilies in mice; 3. To assess the immunogenicity and protective efficacy of the optimal heterologous rAd prime-boost regimen against an SIVmac251 challenge in rhesus monkeys with and without anti-Ad5 immunity; and 4. To determine the immunogenicity and protective efficacy of the optimal heterologous rAd prime- boost regimen delivered by either systemic or mucosal routes against repetitive, low-dose, mucosal SIVmac251 challenges in rhesus monkeys with anti-Ad5 immunity. The overall goal of these studies is to develop a novel heterologous rAd prime-boost regimen for HIV-1 that is highly immunogenic in the presence of anti-Ad5 immunity and that can be advanced rapidly into clinical vaccine trials in the developing world.

描述（由申请人提供）：开发HIV-1疫苗的关键障碍是我们目前无法将HIV-1抗原有效地传递给免疫系统，并在人类中促进了可预测的高频免疫反应。重组，复制不足的腺病毒血清型5（RAD5）基于载体的HIV-1疫苗在临床前研究中引起了有效的免疫反应。但是，发展中国家的抗AD5免疫力的高频可能会限制RAD5疫苗的免疫原性和临床实用性。因此，我们提出了用于HIV-1的新型基于RAD载体的疫苗的开发。 我们假设基于稀有的AD血清型并为改善免疫原性而设计的基于RAD载体的疫苗比具有抗AD5免疫力的恒河猴中的Rad5疫苗要比Rad5疫苗更明显更高的免疫原性。我们进一步假设，最佳的RAD疫苗方案将是一种异源的原始促进疗法，涉及两个不同的血清型载体，它们在人类种群中都很少见，该载体均为最佳免疫原性，源自不同的AD亚富度，与AD5不同。 为了调查这些假设，我们提出以下四个特定目标： 1。比较具有抗AD5免疫力的恒河猴中Rad5，Rad35和Capsid Chimeric rad5/rad35载体的免疫原性； 2。评估涉及源自小鼠两种不同AD亚家族的载体的异源rad质子增强方案的免疫原性； 3。评估最佳异源RAD Prime促进方案的免疫原性和保护性疗效，以抗抗AD5免疫的恒河猴中的SIVMAC251挑战；和4。确定由全身性或粘膜途径与抗AD5免疫力的恒河猴在恒河猴面临的重复性，低剂量的粘膜SIVMAC251挑战所提供的最佳异源异源质原质增强方案的免疫原性和保护效果。 这些研究的总体目的是开发一种新型的HIV-1异源RAD Prime-bumost方案，该方案在存在抗AD5免疫力的情况下具有高度免疫原性，并且可以迅速将其迅速发展为发展中国家的临床疫苗试验。