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)。 联合抗逆转录病毒疗法 (cART) 成功遏制病毒增殖，保留 CD4+ T 细胞 然而，艾滋病毒感染仍然与严重的耻辱和终身相关。 在人口老龄化中，cART 治疗承担着巨大的社会健康成本。 使艾滋病毒感染者摆脱终身 cART 的疗法不仅具有社会和经济意义。 艾滋病毒治疗的挑战。 策略是长寿命的静息细胞，主要是 CD4+ T 细胞，含有具有复制能力的病毒，可以 结果是，对于大多数人来说，cART 的中断会导致 HIV 反弹。 HIV 的治疗策略主要涉及联合疗法、驱动 HIV 重新激活的药物和 在这项研究中，我们提出了一种基于免疫的疗法来检测和清除重新激活的细胞。 试验一种新型疫苗方案，旨在引发我们的免疫反应，称为 CD8+ T CD8+ T 细胞对于检测病毒感染的细胞非常有效。 ChAdOx1.tHIVconsv5–MVA.tHIVconsv3 由我们在牛津大学的合作者开发。 该疫苗的上一次迭代诱导了非常高的抗 HIV 的 CD8+ T 细胞 该疫苗的主要特征。 是它将 T 细胞反应转移到保守的 HIV 区域，从而限制了 HIV 逃避免疫的能力 在这项研究中，感染艾滋病毒并受到长期抑制的参与者将依次接种疫苗。 我们将彻底描述 ChAdOx1.tHIVconsv5 和 MVA.tHIVconsv3 的安全性特征。 我们还将使用标准化检测来测量疫苗接种诱导的 T 细胞水平。 调查疫苗接种是否对我们的参与者中极低的艾滋病毒水平有影响。 研究将检验我们是否能够检测到淋巴结中针对 HIV 的疫苗诱导 T 细胞，以及 检查点抑制剂分子是否可以与疫苗接种配合使用，以最大限度地发挥 T 细胞功能。 第一项疫苗研究之后将进行第二项相关研究，第二项研究以第一项研究为基础。 检查马赛克疫苗（旨在增加艾滋病毒覆盖率的疫苗）是否可以进一步改善 ChAdOx1.tHIVconsv5–MVA.tHIVconsv3 的保守免疫原设计。