Optimization of rAAV Vector Strategies for HIV

HIV 病毒 rAAV 载体策略的优化

• 批准号: 6852995
• 负责人: Philip R Johnson
• 金额: $ 70.31万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-29 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6852995
• 关键词: AIDS vaccines; Macaca mulatta; adeno associated virus group; human immunodeficiency virus 1; immune response; immunomodulators; neutralizing antibody; simian immunodeficiency virus; transfection /expression vector; vaccine development; vaccine evaluation; vector vaccine

The overall objective for Project 1 is to enhance the immunogenicity and efficacy ofrAAV/HIV vaccines. We have shown that a single dose of a first generation SIV vaccine based on rAAV serotype 2 (rAAV2) vectors is highly immunogenic in rhesus macaques. These same vaccines significantly reduced viral burden in macaques after challenge with pathogenic SIV. More recently, we have shown that another serotype (rAAV1) is 1 - 2 orders of magnitude better at gene delivery to muscle than rAAV2. These observations suggest that: (i) the current first generation vaccine is probably sub-optimal; (ii) alternate serotype vectors might allow for dramatic increases in transduction (and immunogenicity); and, (iii) alternate serotype vectors offer the possibility of "prime-boost" regimens where the induction of vector cross-neutralizing antibodies is avoided. In Specific Aim 1, we will extend these observations by testing prime-boost regimens using alternate serotypes (rAAV1 and rAAV5) that are more efficient than rAAV2 at gene transfer and are genetically distinct in the capsid gene (no cross-reacting antibodies). We will also examine the effects of pre-existing immunity to AAV on the immunogenicity of rAAWSIV (and HIV) vaccines in macaques, in addition to vector enhancements, we have tested "non-traditional" molecular adjuvants to augment immune responses engendered by rAAV vaccines and have identified promising candidates. In Specific Aim 2, we will advance these candidates into immunogenicity trials in macaques. Building on the data from this Project, we will design and test a second generation vaccine in immunogenicity and challenge experiments in macaques. A final challenge trial will be combined with a trial proposed in Project 4 wherein the second generation rAAV vaccine will be combined with an rAAV vector that directs the expression of antibody genes that neutralize primary isolates of HIV- 1.

项目1的总体目标是增强rAAV/HIV疫苗的免疫原性和功效。 我们已经证明，基于 rAAV 血清型 2 (rAAV2) 载体的第一代 SIV 疫苗的单剂量在恒河猴中具有高度免疫原性。这些相同的疫苗显着降低了猕猴在受到致病性 SIV 攻击后的病毒负荷。最近，我们发现另一种血清型 (rAAV1) 在将基因传递到肌肉方面比 rAAV2 好 1 - 2 个数量级。这些观察结果表明： (i) 目前的第一代疫苗可能不是最理想的； (ii) 替代血清型载体可能会显着增加转导（和免疫原性）； (iii)替代血清型载体提供了“初免-加强”方案的可能性，其中避免了载体交叉中和抗体的诱导。在具体目标 1 中，我们将通过使用替代血清型（rAAV1 和 rAAV5）测试初免-加强方案来扩展这些观察结果，这些血清型在基因转移方面比 rAAV2 更有效，并且在衣壳基因中具有遗传差异（无交叉反应抗体）。我们还将研究猕猴中预先存在的 AAV 免疫力对 rAAWSIV（和 HIV）疫苗免疫原性的影响，除了载体增强之外，我们还测试了“非传统”分子佐剂，以增强 rAAV 疫苗产生的免疫反应并已经确定了有前途的候选人。在具体目标 2 中，我们将把这些候选药物推进到猕猴身上进行免疫原性试验。 基于该项目的数据，我们将设计并测试第二代疫苗的免疫原性和猕猴挑战实验。最终的挑战试验将与项目 4 中提出的试验相结合，其中第二代 rAAV 疫苗将与指导中和 HIV-1 初级分离株的抗体基因表达的 rAAV 载体相结合。