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

1.2目前有100万美国人感染了人类免疫缺陷病毒-1（HIV）。的出现 联合抗逆转录病毒治疗（cART）成功地抑制了病毒增殖，保留了CD 4 + T细胞， 计数和延长寿命。然而，艾滋病毒感染仍然伴随着严重的污名化， 在老龄化人口中，cART治疗承担着巨大的社会健康成本。“艾滋病治愈”的定义是 使艾滋病毒感染者终身停止cART治疗的疗法。治愈不仅会带来社会和经济 这不仅会带来好处，而且也将是结束全球艾滋病毒流行病的一个关键进展。艾滋病治疗面临的挑战 策略是长寿命的静息细胞，主要是CD 4 + T细胞，携带有复制能力的病毒， 随机激活。结果是，对大多数人来说，cART的中断会导致艾滋病毒在体内反弹。 周艾滋病毒的治疗策略主要涉及联合治疗，药物驱动艾滋病毒的重新激活， 免疫疗法来检测和清除重新激活的细胞。在这项研究中，我们提出了一个首次在人类 一项新的疫苗方案的试验，旨在引发我们的免疫反应，称为CD 8 + T 细胞CD 8 + T细胞在检测病毒感染细胞方面非常有效。疫苗方案称， ChAdOx1.tHIVconsv5-MVA.tHIVconsv3由我们在牛津大学的合作者开发。一 该疫苗的先前迭代诱导了非常高的抗HIV的CD 8 + T细胞。这种疫苗的主要特点是 它将T细胞反应转移到保守的HIV区域，这些区域限制了HIV逃避免疫的能力。 反应在这项研究中，HIV感染持续抑制的参与者将依次接种以下疫苗： ChAdOx1.tHIVconsv5和MVA.tHIVconsv3。我们将彻底描述这些药物的安全性 疫苗。我们还将使用标准化的测定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参与者中非常低的HIV水平有任何影响。探索性 研究将检查我们是否可以检测到淋巴结中靶向HIV的疫苗诱导的T细胞， 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。 第一项疫苗研究之后将进行第二项相关研究。第二项研究建立在第一项研究的基础上， 研究马赛克疫苗（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。

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.