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: 7681728
• 负责人: Michael R Betts
• 金额: $ 46.88万
• 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/7681728
• 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; End Point; 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; Numbers; Pan Genus; Pan troglodytes; 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 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.

由于我们对艾滋病相关因素的不完全了解，有效艾滋病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疗效。 目前被认为是艾滋病候选疫苗的载体。尽管有这些概念 局限性，一些临床和临床前的免疫原性表明复制缺陷型腺病毒 基于人类血清型5型(AdHuS)的(AD)载体可诱导强烈而持久的免疫反应 对HIV/SIV抗原。不幸的是，先前存在的对人类广告的暴露和/或免疫力，特别是对 AdHuS，可能会阻碍基于AdHu5的艾滋病疫苗的效力。其中最重要的假设是 建议黑猩猩(黑猩猩)基于Add的载体代表有希望的候选艾滋病疫苗，因为它们 展示一份免疫原性概况，即使不是更好，也是与演示时观察到的AdHuS一样好 只有先前存在的豁免权方面的小问题。将AdC6和AdC7用作疫苗载体。 在Ertl博士的实验室中率先开发了这种IPCAVD应用程序。在项目3中，我们建议在 详细说明预先存在的Ad-特异性T细胞对黑猩猩Ad疫苗诱导的免疫反应的影响。在……里面 第一个目标，我们将确定自然发生的疾病的患病率、规模、功能和表型 北美和非洲人的AdC6和AdC7特异性T细胞。在目标2中，我们将确定 预先存在的AdHuS特异性T细胞是否影响AdC6和AdC7 SIV疫苗的免疫原性 载体，并改变疫苗诱导的细胞在恒河猴SIV攻击后的保护能力。在……里面 最终目的是，我们将在接种AdC6和AdC7载体的人类中检查这些相同的问题 I期安全性试验和IIA期免疫原性试验。预先存在的AdHuS、AdC6和 将在挑战之前评估AdC7特异性T细胞，以及它们对疫苗免疫原性和 质量将被确定。最终，拟议的研究旨在确定预先存在的影响 腺病毒特异性T细胞应答对CHMP重组腺病毒疫苗诱导宿主应答的影响 这可以遏制病毒复制，延长无病生存，并减少二次传播。 对这种有效免疫反应的特征的定义也将促进我们对 未来艾滋病疫苗开发工作中需要追求的免疫保护的相关性。