Pre-existing Adenovirus-Specific T Cells & their Effect on Chimp Adenovirus

预先存在的腺病毒特异性 T 细胞

• 批准号: 7925780
• 负责人: Michael R Betts
• 金额: $ 77.64万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7925780
• 关键词: AIDS Vaccines; AIDS vaccine development; Address; Adenovirus Vector; Adenoviruses; Affect; Africa; Africa South of the Sahara; Antigen-Presenting Cells; Antigens; Botswana; CD8B1 gene; Cells; Characteristics; Clinical; Clinical Trials; Data; Databases; Development; Disease-Free Survival; Effectiveness; Exposure to; Flow Cytometry; Frequencies; Future; Gagging; Generations; Genes; HIV; HIV Infections; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Human Adenoviruses; Immune; Immune response; Immunity; Infection; Knowledge; Laboratories; Macaca mulatta; Measures; Minor; Modeling; Mus; North America; Pan Genus; Participant; Peptide Library; Peptide Mapping; Phase; Phenotype; Population; Prevalence; Property; Proteins; Recombinants; Role; SIV; SIV Vaccines; Safety; Serotyping; Serum; South Africa; T-Lymphocyte; Testing; Treatment Protocols; Uganda; Vaccinated; Vaccination; Vaccines; Virus Diseases; Virus Replication; abstracting; base; clinical efficacy; cohort; cross reactivity; defective adenoviral vector; immunogenicity; neutralizing antibody; nonhuman primate; pre-clinical; response; simian human immunodeficiency virus; transmission process; vaccine candidate; vaccine effectiveness; vaccine efficacy; vector; vector vaccine

The generation of an effective AIDS vaccine is complicated by our incomplete knowledge of the correlates of immune protection during HIV infection. As such, it has been difficult to compare the potential clinical efficacy of the vectors that are currently considered as candidate AIDS vaccines. Notwithstanding these conceptual limitations, a number of clinical and pre-clinical immunogenicity indicate that replication-defective adenovirus (Ad) vectors based on the human serotype 5 (AdHuS) can 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 AdHu5-based AIDS vaccines. The overarching hypothesis of this proposal is that chimpanzee (chimp) Ad-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 the laboratory of Dr. Ertl, P.I. of this IPCAVD application. In Project #3 we propose to study in detail the impact of pre-existing Ad-specific T cells upon chimp Ad vaccine induced immune responses. In the first Aim, we will determine the prevalence, magnitude, functionality, and phenotype of naturally occurring AdC6 and AdC7-specific T cells in humans from North America and Africa. In Aim 2 we will determine whether pre-existing AdHuS-specific T cells affect the immunogenicity of AdC6 and AdC7 SIV vaccine vectors, and alter the protective capacity of vaccine-induced cells after SIV challenge in rhesus macaques. In the final Aim, we will examine these same issues in humans vaccinated with the AdC6 and AdC7 vectors in phase I safety trials and a phase IIA immunogenicity trial. The levels of pre-existing AdHuS, AdC6, and AdC7-specific T cells will be assessed prior to challenge, and their impact upon vaccine immunogenicity and quality will be determined. Ultimately, the proposed studies are aimed at defining the impact of pre-existing Ad-specific T cell responses upon the efficacy of chmp Ad-based 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.

由于我们对相关性的不完整知识，有效辅助疫苗的产生变得复杂 艾滋病毒感染期间的免疫保护。因此，很难比较潜在的临床功效 目前被视为候选艾滋病疫苗的媒介。尽管有这些概念 局限性，许多临床和临床前免疫原性表明复制缺陷腺病毒病毒 （AD）基于人血清型5（ADHU）的向量可以诱导强烈而持续的免疫反应 致HIV/SIV抗原。不幸的是，预先存在的接触和/或对人类广告的免疫力，尤其是对 Adhus，可能会妨碍基于ADHU5的艾滋病疫苗的功效。总体假设 建议是黑猩猩（Chimp）基于广告的媒介代表有前途的候选艾滋病疫苗 显示出比出现时观察到的免疫原性的特征 仅在预先存在的免疫力方面只有较小的问题。将ADC6和ADC7用作疫苗向量的使用是 P.I. Ertl博士的实验室开创此IPCAVD应用程序。在项目＃3中，我们建议研究 详细介绍了先前存在的AD特异性T细胞对黑猩猩AD疫苗诱导免疫反应的影响。在 第一个目的，我们将确定自然发生的患病率，大小，功能和表型 来自北美和非洲人类的ADC6和ADC7特异性T细胞。在AIM 2中，我们将确定 先前存在的ADHUS特异性T细胞是否影响ADC6和ADC7 SIV疫苗的免疫原性 向量，并改变恒河猕猴SIV挑战后疫苗诱导的细胞的保护能力。在 最终目的是，我们将研究以ADC6和ADC7载体接种的人类中的这些相同问题 I期安全试验和IIA期免疫原性试验。先前存在的ADHU，ADC6和 ADC7特异性T细胞将在挑战之前进行评估，以及它们对疫苗免疫原性和 质量将被确定。最终，拟议的研究旨在定义先前存在的影响 基于CHMP AD的AIDS疫苗在诱导宿主反应中的功效的AD特异性T细胞反应 这可以包含病毒复制，延长无疾病的生存率并减少二次传播。 这种有效免疫反应的特征的定义也将提高我们对 在艾滋病疫苗开发的未来努力中，应追求免疫保护的相关性。