Clinical Evaluation of Novel Adenovirus Prime-Boost HIV-1 Vaccine

新型腺病毒 Prime-Boost HIV-1 疫苗的临床评价

• 批准号: 7509711
• 负责人: Raphael Dolin
• 金额: $ 44.98万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7509711
• 关键词: Adenoviruses; Africa South of the Sahara; Antigens; Clinical Research; Clinical Trials; Collaborations; Consensus; DNA; Data; Development; Dose; Funding; Genetic; Gerda brand of difluprednate; Goals; HIV vaccine; HIV-1; HIV-1 vaccine; High Prevalence; Human; Immune response; Immunity; Immunization; Immunologics; Injection of therapeutic agent; International; Laboratory Research; Letters; Logistics; Macaca mulatta; Phase; Phase I Clinical Trials; Principal Investigator; Recombinants; SIV; Safety; Series; Serotyping; Shivering; South Africa; T-Lymphocyte Epitopes; Technology; Testing; Treatment Protocols; United States; United States National Institutes of Health; Vaccines; Virus; base; design; immunogenic; immunogenicity; novel; preclinical study; programs; prototype; research clinical testing; vector

Current HIV-1 vaccine candidates based on recombinant adenovirus serotype 5 (rAd5) vectors are promising but may prove limited by the high prevalence of pre-existing anti-Ad5 immunity in the developing world. To overcome this problem, we have constructed a series of novel serotype and novel chimeric rAd vectors that effectively circumvent anti-Ad5 immunity. We have also demonstrated that heterologous rAd prime-boost regimens utilizing two serologically distinct rAd vectors elicit remarkably potent immune responses, particularly regimens involving rAd26 priming and rAd5 or rAd5HVR48 boosting. In addition, we have generated rAd vectors expressing optimal C clade, M consensus, and M mosaic HIV-1 antigens designed to minimize genetic distance and to optimize T cell epitope coverage among global HIV-1 sequences. We therefore propose to develop a practical, two-injection, heterologous rAd26 prime, rAd5HVR48 boost regimen expressing antigens optimized for global coverage as a novel candidate HIV-1 vaccine. The goals of Project 2 are to define the optimal rAd vector combination in phase 1 studies and to advance this novel HIV-1 vaccine candidate into expanded international phase 2a studies in collaboration with the HIV Vaccine Trials Network (HVTN). The clinical studies in Project 2 will build on the preclinical studies in Project 1 and the manufacturing program in Project 3. In Project 2, we hypothesize that the heterologous rAd26 prime, rAd5HVR48 boost regimen will prove safe and highly immunogenic in humans in both the United States and sub-Saharan Africa. We further hypothesize that this HIV-1 vaccine candidate will not be suppressed by pre-existing antivector immunity and will be a promising candidate for further development into advanced phase clinical trials by the end of this project period. To explore these hypotheses, we propose the following three Specific Aims: 1. To perform a phase 1 study assessing the safety and immunogenicity of rAd26 and rAd5HVR48 HIV-1 vaccine regimens in the United States; 2. To perform a phase 1 study assessing the safety and immunogenicity of rAd26 and rAd5HVR48 HIV-1 vaccine regimens in South Africa; and 3. To perform an international phase 2a study evaluating expanded safety and immunogenicity of the heterologous rAd26 prime, rAd5HVR48 boost HIV-1 vaccine regimen.

基于重组腺病毒血清型5（RAD5）载体的当前HIV-1疫苗候选物是 有希望，但可能受到发育中预先存在的抗AD5免疫的高度限制 世界。为了克服这个问题，我们构建了一系列新颖的血清型和新颖的嵌合Rad 有效规避抗AD5免疫力的载体。我们还证明了异源RAD 利用两个血清学上不同的RAD载体的原始促进方案引起了明显有效的免疫 响应，特别是涉及RAD26启动的方案，以及RAD5或RAD5HVR48提升。另外，我们 已经产生了表达最佳C进枝，M共识和M镶嵌HIV-1抗原的Rad载体 旨在最大程度地减少遗传距离并优化全局HIV-1之间的T细胞表位覆盖率 序列。 因此，我们建议开发一个实用的，两种注射的异源Rad26 Prime， RAD5HVR48增强方案表达了针对全球覆盖范围作为新候选人的全球覆盖范围优化的抗原 HIV-1疫苗。项目2的目标是在第1阶段研究中定义最佳RAD矢量组合 并将这种新颖的HIV-1疫苗候选者推向扩展的国际2A研究 与HIV疫苗试验网络（HVTN）合作。项目2中的临床研究将基于 项目1和项目3中的制造计划中的临床前研究。 在项目2中，我们假设异源RAD26 Prime，Rad5HVR48增强方案 在美国和撒哈拉以南非洲，人类将被证明是安全和高度免疫原性的。 我们进一步假设，这种HIV-1疫苗候选者不会被预先存在的抗体抑制 免疫力，将成为进一步发展为高级阶段的有前途的候选人 临床试验到本项目期末。为了探讨这些假设，我们提出以下内容 三个具体目标： 1。进行1阶段研究，以评估RAD26和RAD5HVR48的安全性和免疫原性 美国HIV-1疫苗方案； 2。进行1阶段研究，以评估RAD26和RAD5HVR48的安全性和免疫原性 南非的HIV-1疫苗疗法；和 3。进行一项国际2A研究，以评估扩大的安全性和免疫原性 异源RAD26 PRIME，RAD5HVR48增强HIV-1疫苗方案。