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: 7681727
• 负责人: Hildegund C. J. Ertl
• 金额: $ 73.69万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681727
• 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; 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。有效的艾滋病疫苗的产生非常复杂，因为我们的知识不完整 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向量的临床功效。 尽管有这些概念上的局限性，但许多临床和临床前免疫原性研究 使用最先进的测定法表明，基于人类的复制缺陷腺病毒（AD）向量 血清型5（ADHUS）可以牢固地诱导对HIV/SIV抗原的强烈和持续的免疫反应。 不幸的是，预先存在的接触和/或对人类广告，尤其是对Adhus的免疫力可能会妨碍 基于ADHUS的候选疗效AIDS疫苗的功效。该IPCAVD提案的总体假设 是黑猩猩（黑猩猩）腺病毒（ADC）的载体代表有希望的候选艾滋病疫苗 因为它们显示出一种免疫原性的特征，即与Adhus观察到的那样好，即使不是更好 就预先存在免疫力而言，仅提出一个小问题。使用ADC6和ADC7作为疫苗 在ERTL博士实验室进行的一系列关键研究中，向量开创了。在项目＃2中 建议详细研究由不同的免疫策略产生的细胞免疫反应 包括基于ADC的候选HIV/SIV疫苗的各种组合，用于促进方案。我们 将进行现代免疫研究以评估诱导的细胞免疫反应水平 通过测试的向量。 HIV/SIV特异性CD4+和CD8+ T的表型，特性和功能 将定义由不同基于ADC的疫苗接种方案诱导的细胞介导的反应，并 与经过疫苗接种和实验性SIV感染后出现的T细胞反应相比 未接种的动物。此外，我们将确定恒河所中SIV挑战的保护水平 用不同方案接种疫苗的猕猴。最终，拟议的研究针对 定义基于ADC的候选艾滋病疫苗在诱导宿主反应中的功效 病毒复制，延长无疾病的生存率和降低二次传播。定义 这种有效免疫反应的特征也将提高我们对相关性的理解 在艾滋病疫苗开发的未来努力中，将寻求免疫保护。