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: 7899533
• 负责人: Michael R Betts
• 金额: $ 20万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899533
• 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.

有效的艾滋病疫苗的产生是复杂的，因为我们对艾滋病相关因素的不完全了解， HIV感染期间的免疫保护。因此，很难比较潜在的临床疗效 目前被认为是候选艾滋病疫苗的载体。尽管这些概念 由于其局限性，许多临床和临床前免疫原性表明，复制缺陷型腺病毒 (Ad)基于人血清型5（AdHuS）的载体可以诱导强烈和持久的免疫应答 HIV/SIV抗原。不幸的是，预先存在的暴露和/或对人类广告的免疫力，特别是对 AdHuS可能会妨碍基于AdHu 5的艾滋病疫苗的效力。这个最重要的假设是 一种建议是，黑猩猩（黑猩猩）的广告为基础的载体代表有前途的候选艾滋病疫苗，因为他们 显示出与AdHuS所观察到免疫原性一样好（如果不是更好的话）的免疫原性特征，同时呈现 只是在先前存在的豁免权方面存在一些小问题。使用AdC 6和AdC 7作为疫苗载体， 由PI Ertel博士的实验室开创这个IPCAVD应用程序。在项目#3中，我们建议在 详细描述了预先存在的Ad特异性T细胞对黑猩猩Ad疫苗诱导的免疫应答的影响。在 第一个目标，我们将确定自然发生的疾病的患病率、程度、功能和表型。 AdC 6和AdC 7特异性T细胞来自北美和非洲的人类。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AdC 6和AdC 7 SIV疫苗的免疫原性 载体，并改变恒河猴SIV攻击后疫苗诱导的细胞的保护能力。在 最后，我们将在用AdC 6和AdC 7载体接种的人类中研究这些相同的问题。 I期安全性试验和IIA期免疫原性试验。预先存在的AdHuS、AdC 6和 将在攻击前评估AdC 7特异性T细胞，并评估其对疫苗免疫原性和免疫原性的影响。 质量将被确定。最终，拟议的研究旨在确定预先存在的 基于chmp Ad的AIDS疫苗诱导宿主应答的Ad特异性T细胞应答 可以抑制病毒复制，延长无病生存期，减少二次传播。 对这种有效免疫应答的特征的定义也将促进我们对免疫应答的理解。 在今后的艾滋病疫苗开发工作中，免疫保护的相关因素将被继续研究。