Phase I therapeutic testing of viral-vectored vaccines that shift CD8+ T cell immunodominance to conserved regions of HIV-1

将 CD8 T 细胞免疫优势转移至 HIV-1 保守区域的病毒载体疫苗的 I 期治疗测试

• 批准号: 9322698
• 负责人: Nilu Goonetilleke
• 金额: $ 101.26万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322698
• 关键词: American; Antigens; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Count; Cell physiology; Cells; Clinical Trials; Combined Modality Therapy; Consensus; Development; Drug usage; Economics; Epidemic; Epitopes; Frequencies; Generations; Genetic Transcription; Goals; Grant; HIV; HIV Infections; HIV Seronegativity; HIV vaccine; HIV-1; Health Care Costs; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunology; Immunotherapy; In Vitro; Income; Individual; Interphase Cell; Interruption; Length; Life; Measures; Modified Vaccinia Virus Ankara; Mosaicism; National Institute of Allergy and Infectious Disease; One-Step dentin bonding system; Participant; Pharmaceutical Preparations; Phase; Proteins; Protocols documentation; Regimen; Reporting; Research Personnel; Safety; Standardization; Stigmatization; T cell response; T-Lymphocyte; Testing; Therapeutic; Translations; Universities; Ursidae Family; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Viral Vector; Virus; aging population; antiretroviral therapy; arm; base; cytotoxic; design; experience; immunogenic; improved; innovation; killings; lymph nodes; novel; novel vaccines; response; success; therapeutic evaluation; vaccine evaluation; vaccine trial; vector; vector vaccine; virology

1.2 million Americans are currently infected with human immunodeficiency virus-1 (HIV). The advent of combination antiretroviral therapy (cART) successfully contains viral proliferation, preserving CD4+ T cell counts and prolonging life. However, HIV infection is still associated with significant stigmatization, and life-long cART treatment, in an ageing population, bears significant societal health costs. ‘HIV cure’ is defined as therapies to take HIV infected individuals off life-long cART. Cure would not only have societal and economic benefits but would also be a critical advance in ending the global HIV epidemic. The challenge for HIV curative strategies is that long-lived resting cells, principally CD4+ T cells, harbor replication-competent virus which can stochastically reactivate. The result is that, for most people, interruption of cART results in HIV rebound within weeks. Curative strategies for HIV largely involve combination therapies, drugs to drive reactivation of HIV and immune-based therapies to detect and clear the reactivated cells. In this study, we propose a first-in-human trial of a novel vaccine regimen which aims to elicit an arm of our immune response, called CD8+ T cells. CD8+ T cells are very effective at detecting virus infected cells. The vaccine regimen called, ChAdOx1.tHIVconsv5–MVA.tHIVconsv3 was developed by our collaborator at the University of Oxford. A previous iteration of this vaccine induced very high CD8+ T cells against HIV. The key features of this vaccine is that it shifts the T cell response to conserved HIV regions that limit the ability of HIV to evade the immune response. In this study, HIV infected durably suppressed participants will be sequentially vaccinated with ChAdOx1.tHIVconsv5 and MVA.tHIVconsv3. We will thoroughly characterize the safety profile of these vaccines. We will also use standardized assays to measure the level of T cells induced by vaccination and investigate whether vaccination has any impact on very low levels of HIV in our participants. Exploratory studies will examine whether we can detect vaccine-induced T cells that target HIV in lymph nodes and also whether checkpoint inhibitor molecules can be used in concert with vaccination to maximize T cell function. The first vaccine study will be followed by a second related study. The second study builds on the first, by examining whether mosaic vaccines (vaccines designed to increase coverage of HIV) can further improve on the conserved immunogen design of ChAdOx1.tHIVconsv5–MVA.tHIVconsv3.

目前，有120万美国人感染了人类免疫缺陷病毒-1（HIV）。冒险 抗逆转录病毒疗法（CART）成功含有病毒增殖，保留CD4+ T细胞 计数和延长寿命。但是，艾滋病毒感染仍然与重大的污名化和终身有关 在老龄化的人口中，购物车治疗承担着巨大的社会健康成本。 “艾滋病毒治愈”定义为 将艾滋病毒感染的人脱离终身购物车的疗法。治愈不仅具有社会和经济 好处，但在结束全球艾滋病毒流行方面也将是一个至关重要的进步。艾滋病毒治愈的挑战 策略是长寿的休息细胞，主要是CD4+ T细胞，具有复制能力的病毒，可以 随机激活。结果是，对于大多数人来说，手推车的中断导致艾滋病毒反弹 几周。 HIV的治疗策略在很大程度上涉及组合疗法，驱动HIV重新激活的药物和 基于免疫的疗法检测并清除重新激活的细胞。在这项研究中，我们提出了一个人类的第一 一种新型疫苗方案的试验，旨在引起我们的免疫响应的手臂，称为CD8+ T 细胞。 CD8+ T细胞非常有效地检测病毒感染的细胞。疫苗方案称为 chadox1.thivconsv5 – mva.thivconsv3是由我们的牛津大学合作者开发的。一个 这种疫苗的先前迭代诱导了非常高的CD8+ T细胞针对HIV。该疫苗的关键特征 是将T细胞反应转移到构成HIV区域，限制了HIV逃避免疫的能力 回复。在这项研究中，将被彻底抑制的参与者感染的HIV接种疫苗 chadox1.thivconsv5和mva.thivconsv3。我们将彻底描述这些的安全性 疫苗。我们还将使用标准化评估来衡量疫苗诱导的T细胞水平和 调查疫苗接种是否会对我们的参与者中的艾滋病毒水平非常低。探索性 研究将检查我们是否可以检测靶向淋巴结中HIV的疫苗诱导的T细胞以及 检查点抑制剂分子是否可以与疫苗接种一起使用以最大化T细胞功能。 首次疫苗研究将进行第二项相关研究。第二项研究是基于第一个研究的 检查马赛克疫苗（旨在增加艾滋病毒覆盖范围的疫苗）是否可以进一步改善 chadox1.thivconsv5 – mva.thivconsv3的保守免疫原设计。