EFFICACY OF ORAL CMV/SIV VECTORS

口腔 CMV/SIV 载体的功效

• 批准号: 8357864
• 负责人: Louis J. Picker
• 金额: $ 19.49万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357864
• 关键词: CCR5 gene; CD8B1 gene; Cytomegalovirus; Data; Dose-Limiting; Funding; Gene Expression; Generations; Grant; Immunity; Infection; Macaca mulatta; Mediating; Memory; National Center for Research Resources; Oral; Pattern; Phase; Plasma; Primates; Principal Investigator; Property; Research; Research Infrastructure; Resources; Route; SIV; Site; Source; T cell response; T-Lymphocyte; Tissues; United States National Institutes of Health; Vaccinated; Vaccines; Viral; Virus; cost; efficacy trial; mucosal site; nonhuman primate; novel; rectal; subcutaneous; vaccine efficacy; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Two large scale nonhuman primate (NHP) efficacy studies have convincingly demonstrated that CMV/SIV vectors can 1) re-infect CMV-seropositive rhesus macaques (RM), 2) during re-infection, elicit potent and persistent SIV-specific CD4+ and CD8+ T cell responses with a strong "effector memory bias", and 3) protect ~50% of vaccinated RM from progressive SIV infection after limiting dose rectal challenge with the highly pathogenic, CCR5-tropic SIVmac239 virus. The protection manifested in these RM is distinct from previous vaccines in its abruptness and extent, with protected RM manifesting a viral burst in plasma of varying size upon initial infection, followed by immediate control to undetectable levels. Protection correlates with the extent of total SIV-specific CD8+ T cells generation during the vaccine phase, and is stable in the vast majority of protected RM for at least 6 months. These data indicate a novel pattern of protection consistent with very early control, likely taking place in the site of viral entry and/or early sites of viral replication and amplification, and mediated by tissue-resident TEM. To date, our efficacy trials have studied CMV vectors that were systemically administered via subcutaneous inoculation. We have, however, demonstrated that oral inoculation of these vectors can also initiate re-infection of CMV-seropositive RM, and elicit robust SIV-specific T cell immunity. We hypothesize that oral inoculation of CMV vectors, and initial induction of vaccine-generated SIV-specific T cells in a mucosal milieu, might change the character of the resultant SIV-specific TEM, perhaps increasing their representation and function in mucosal sites, and potentially increase the efficacy of these vaccines in protecting against mucosal challenge. In the proposed project we will compare in detail the phenotypic, migratory, functional and gene expression properties of SIV-specific T cells elicited by CMV vectors via systemic vs oral route, and determine whether oral inoculation provides enhanced protection against limiting dose, intra-rectal SIVmac239 challenge.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 两项大规模非人灵长类 (NHP) 功效研究令人信服地证明，CMV/SIV 载体可以 1) 重新感染 CMV 血清阳性恒河猴 (RM)，2) 在再次感染期间，引发有效且持久的 SIV 特异性 CD4+ 和 CD8+ T 细胞反应具有强烈的“效应记忆偏差”，3) 在限制直肠剂量后，可保护约 50% 的接种 RM 免受进行性 SIV 感染高致病性 CCR5 嗜性 SIVmac239 病毒的挑战。 这些 RM 所表现出的保护作用在突然性和程度方面与以前的疫苗不同，受保护的 RM 在初次感染时表现出不同大小的血浆病毒爆发，随后立即控制到不可检测的水平。 保护作用与疫苗阶段 SIV 特异性 CD8+ T 细胞总数的产生程度相关，并且在绝大多数受保护的 RM 中稳定至少 6 个月。这些数据表明一种与非常早期控制一致的新型保护模式，可能发生在病毒进入位点和/或病毒复制和扩增的早期位点，并由组织驻留 TEM 介导。迄今为止，我们的功效试验研究了通过皮下接种全身施用的 CMV 载体。 然而，我们已经证明，口服接种这些载体也可以引发 CMV 血清阳性 RM 的重新感染，并引发强大的 SIV 特异性 T 细胞免疫。 我们假设口服 CMV 载体，并在粘膜环境中初始诱导疫苗产生的 SIV 特异性 T 细胞，可能会改变所得 SIV 特异性 TEM 的特征，或许会增加它们在粘膜位点的代表性和功能，并有可能提高这些疫苗预防粘膜攻击的功效。在拟议的项目中，我们将详细比较 CMV 载体通过全身途径与口服途径诱导的 SIV 特异性 T 细胞的表型、迁移、功能和基因表达特性，并确定口服接种是否能提供针对限制剂量、直肠内接种的增强保护。 SIVmac239 挑战。