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

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.由于我们对艾滋病的认识不全面， 在HIV感染期间免疫保护的相关性。很难比较 目前被认为是候选艾滋病疫苗平台的许多载体的临床疗效。 尽管存在这些概念上的限制，但许多临床和临床前免疫原性研究 使用最先进的分析表明，基于人的复制缺陷型腺病毒（Ad）载体， 血清型5（AdHuS）可以稳健地诱导对HIV/SIV抗原的强烈和持久的免疫应答。 不幸的是，预先存在的暴露和/或对人类广告的免疫，特别是对AdHuS，可能会妨碍 基于AdHuS的候选艾滋病疫苗的有效性。IPCAVD提案的首要假设是 基于黑猩猩腺病毒（AdC）的载体代表了有希望的候选艾滋病疫苗 因为它们显示出与AdHuS所观察到的免疫原性一样好（如果不是更好的话）的免疫原性特征， 在先前存在的豁免权方面只存在一些小问题。AdC 6和AdC 7作为疫苗的用途 载体是在Ertl博士实验室进行的一系列关键研究中开创的。在项目#2中， 建议详细研究不同免疫策略产生的细胞免疫应答， 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应答水平 通过测试的载体。HIV/SIV特异性CD 4+和CD 8 + T细胞的表型、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应答， 与接种疫苗和免疫后实验性SIV感染后产生的T细胞应答相比， 未接种疫苗的动物此外，我们将确定恒河猴对SIV攻击的保护水平 用不同的方法接种疫苗的猕猴。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中的功效， 病毒复制，延长无病生存期，减少二次传播。定义 这种有效免疫反应的特征也将促进我们对以下相关因素的理解： 免疫保护是今后艾滋病疫苗研制工作的重点。