Pre-Clinical Immunogenicity Testing of Chimp Adenovirus Vectors

黑猩猩腺病毒载体的临床前免疫原性测试

• 批准号: 7280615
• 负责人: Hildegund C. J. Ertl
• 金额: $ 78.3万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7280615
• 关键词: AIDS Vaccines; AIDS vaccine development; Acquired Immunodeficiency Syndrome; Adenovirus Vector; Adenoviruses; Africa South of the Sahara; Anatomy; Animals; Antigens; Arts; Asia; Biological Assay; CD8B1 gene; Characteristics; Chimeric Proteins; Clinical; Clinical Trials; Development; Disease Progression; Disease-Free Survival; Dose; Exhibits; Future; Gagging; Generations; Genes; Genetic; Glycoproteins; Goals; Growth; HIV; HIV Infections; HIV-1; HIV/SIV vaccine; Human; Human Adenoviruses; Immune; Immune response; Immune system; Immunity; Immunization; Individual; Infection; Infection Control; Infectious Agent; Knowledge; Laboratories; Light; Macaca mulatta; Mediating; Memory; Methods; Minor; Mus; Numbers; Pan Genus; Pan troglodytes; Pathogenesis; Phase; Phenotype; Production; Property; Protocols documentation; Quality Control; Regulatory Element; SIV; Series; Serotyping; Shuttle Vectors; Study models; T memory cell; T-Lymphocyte; Testing; Treatment Protocols; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccines; Virus; Virus Replication; base; clinical efficacy; cytokine; defective adenoviral vector; design; expression vector; immunogenicity; in vivo; neutralizing antibody; nonhuman primate; pol genes; polypeptide; pre-clinical; preclinical study; prevent; promoter; research clinical testing; research study; response; tool; transmission process; uptake; vaccine-induced immunity; vector; vector vaccine; vector-induced

Project 2. The generation of an effective AIDS vaccine is greatly complicated by our incomplete knowledge of the correlates of immune protection during HIV infection. It has been difficult to compare the potential clinical efficacy of the numerous vectors currently considered as platforms for candidate AIDS vaccines. Notwithstanding these conceptual limitations, a number of clinical and pre-clinical immunogenicity studies using state-of-the-art assays indicate that replication-defective adenovirus (Ad) vectors based on the human serotype 5 (AdHuS) can robustly induce strong and persistent immune responses to HIV/SIV antigens. Unfortunately, pre-existing exposure and/or immunity to human Ads, and particularly to AdHuS, may hamper the efficacy of AdHuS-based candidate AIDS vaccines. The overarching hypothesis of this IPCAVD proposal is that chimpanzee (chimp) Adenovirus (AdC)-based vectors represent promising candidate AIDS vaccines as they show a profile of immunogenicity that is as good, if not better, than that observed for AdHuS while presenting only minor problems in terms of pre-existing immunity. The use of AdC6 and AdC7 as vaccine vectors was pioneered in a series of pivotal studies conducted in the laboratory of Dr. Ertl. In Project #2 we propose to study in detail the cellular immune responses generated by different immunization strategies that include various combinations of AdC-based candidate HIV/SIV vaccines used in prime-boost regimens. We will perform contemporary immunological studies to assess the level of cellular immune responses induced by the tested vectors. The phenotypes, properties, and functions of the HIV/SIV-specific CD4+ and CD8+ T cell-mediated responses induced by different AdC-based vaccination regimens will be defined, and compared to the T cell responses that arise following experimental SIV infections of both vaccinated and unvaccinated animals. In addition, we will determine the level of protection from SIV challenge in rhesus macaques that are vaccinated with different protocols. Ultimately, the proposed studies are aimed at defining the efficacy of AdC-based candidate AIDS vaccines in inducing host responses that can contain virus replication, prolong disease-free survival, and decrease secondary transmission. Definition of the characteristics of such effective immune responses will also advance our understanding of the correlates of immune protection to be pursued in future efforts of AIDS vaccine development.

项目 2. 由于我们的知识不完整，有效的艾滋病疫苗的研制变得非常复杂 HIV感染期间免疫保护的相关性。很难比较潜力 目前被认为是候选艾滋病疫苗平台的众多载体的临床功效。 尽管存在这些概念上的限制，许多临床和临床前免疫原性研究 使用最先进的检测表明，基于人类的复制缺陷型腺病毒（Ad）载体 血清型 5 (AdHuS) 可以强烈诱导针对 HIV/SIV 抗原的强烈且持久的免疫反应。 不幸的是，预先存在的对人类广告（尤其是 AdHuS）的暴露和/或免疫力可能会妨碍 基于 AdHuS 的候选艾滋病疫苗的功效。该 IPCVD 提案的总体假设 基于黑猩猩（chimp）腺病毒（AdC）的载体代表了有希望的候选艾滋病疫苗 因为它们表现出的免疫原性与 AdHuS 观察到的免疫原性一样好，甚至更好。 就预先存在的免疫力而言，仅存在一些小问题。 AdC6和AdC7作为疫苗的用途 载体是 Ertl 博士实验室进行的一系列关键研究的先驱。在项目 #2 中，我们 建议详细研究不同免疫策略产生的细胞免疫反应 包括用于初免-加强方案的基于 AdC 的候选 HIV/SIV 疫苗的各种组合。我们 将进行当代免疫学研究，以评估诱导的细胞免疫反应的水平 由测试的向量。 HIV/SIV 特异性 CD4+ 和 CD8+ T 的表型、特性和功能 将定义由不同的基于 AdC 的疫苗接种方案诱导的细胞介导的反应，并且 与接种疫苗和接种疫苗的实验性 SIV 感染后出现的 T 细胞反应相比 未接种疫苗的动物。此外，我们将确定恒河猴免受 SIV 攻击的保护水平 接受不同方案疫苗接种的猕猴。最终，拟议的研究旨在 确定基于 AdC 的候选艾滋病疫苗在诱导宿主反应方面的功效，这些反应可以包含 病毒复制，延长无病生存期，并减少二次传播。的定义 这种有效免疫反应的特征也将促进我们对相关因素的理解 未来艾滋病疫苗研发的重点是免疫保护。