PROTECTIVE EFFICACY OF MERCK AD5 PRIME/BOOST AGAINST MUCOSAL CHALLENGE

MERCK AD5 PRIME/Boost 针对粘膜挑战的保护功效

• 批准号: 8358247
• 负责人: David I Watkins
• 金额: $ 17.87万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 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/8358247
• 关键词: Address; Animals; Antigens; Antiviral Agents; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cryopreserved Cell; Dose-Limiting; Epitopes; Failure; Funding; Gagging; Grant; HIV vaccine; Human; Immune; Immune response; Immunization; Interferons; Macaca; Macaca mulatta; National Center for Research Resources; Open Reading Frames; Peripheral Blood Mononuclear Cell; Primates; Principal Investigator; Protocols documentation; Regimen; Research; Research Infrastructure; Resources; Source; Spottings; T cell response; Time; United States National Institutes of Health; Vaccinated; Vaccines; Virus; Virus Replication; Wisconsin; cost; enzyme linked immunospot assay; immunogenicity; protective efficacy; response; 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. Objective: To address some of the lingering questions surrounding the failed STEP HIV vaccine study in humans by assessing the antiviral immune responses and the efficacy of the vaccine regimen in rhesus macaques. PROGRESS: In the wake of the STEP trial, questions remain as to why the vaccine regimen failed to protect against or control virus replication. The limited breadth of vaccine-induced T-cell responses has been suggested as a possible reason for the failure. To address this, we vaccinated eight Indian Rhesus macaques using the STEP trial protocol. Macaques were immunized intramuscularly with a 1:1:1 ratio of three separate Ad5 vectors expressing gag, pol or nef derived from SIVmac239 and administered on weeks 0, 4 and 26 of the study. Using cryopreserved cells collected at four weeks post-immunization, we detected very few vaccine-induced T cell responses (1-2 epitopes/open reading frame) consistent with the STEP trial results. However, one week after the third immunization, we detected vaccine-induced CD8+ and CD4+ T-cell responses against an average of 11 epitopes in IFN-¿ ELISPOT assays (1-5 epitopes/open reading frame). Impressively, the magnitude of these CD8+ and CD4+ T-cell responses ranged up to 3,600 spot forming cells (SFC)/million PBMC and 955 SFC/million PBMC depleted of CD8+ cells. Our results suggest that the time points chosen to perform immune assays may influence the breadth of responses and the perceived immunogenicity of vaccine regimens. We are now challenging the vaccinated animals, along with eight na¿ve controls, with repeated limiting-doses of SIVsmE660, a virus heterologous to the vaccine immunogens. PUBLICATIONS: None.

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。 目的：通过评估恒河猴的抗病毒免疫反应和疫苗方案的功效，解决有关人类 STEP HIV 疫苗研究失败的一些挥之不去的问题。 进步： STEP 试验之后，关于为什么疫苗方案未能预防或控制病毒复制的问题仍然存在。疫苗诱导的 T 细胞反应范围有限被认为是失败的一个可能原因。为了解决这个问题，我们使用 STEP 试验方案为 8 只印度恒河猴接种了疫苗。以 1:1:1 的比例对猕猴进行肌内免疫，并在研究的第 0、4 和 26 周施用表达来自 SIVmac239 的 gag、pol 或 nef 的三种独立 Ad5 载体。使用免疫后 4 周收集的冷冻保存细胞，我们检测到很少的疫苗诱导 T 细胞反应（1-2 个表位/开放阅读框），与 STEP 试验结果一致。然而，第三次免疫后一周，我们在 IFN-¿ ELISPOT 测定中检测到疫苗诱导的 CD8+ 和 CD4+ T 细胞针对平均 11 个表位的反应（1-5 个表位/开放阅读框）。令人印象深刻的是，这些 CD8+ 和 CD4+ T 细胞反应的幅度高达 3,600 个斑点形成细胞 (SFC)/百万个 PBMC 和 955 个 SFC/百万个耗尽 CD8+ 细胞的 PBMC。我们的结果表明，选择进行免疫测定的时间点可能会影响反应的广度和疫苗方案的免疫原性。我们现在正在用重复限制剂量的 SIVsmE660（一种与疫苗免疫原异源的病毒）对接种疫苗的动物以及八只未实验的对照动物进行挑战。 出版物： 没有任何。