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

目前有120万美国人感染了人类免疫缺陷病毒-1(HIV)。……的到来 联合抗逆转录病毒疗法(CART)成功地抑制了病毒的增殖，保留了CD4+T细胞 计数并延长寿命。然而，艾滋病毒感染仍然与严重的耻辱有关，并且是终生的 在人口老龄化的情况下，CART治疗承担着巨大的社会健康成本。“治愈”的定义是 将艾滋病毒感染者从终生购物车中解救出来的疗法。治愈不仅会有社会和经济上的 这不仅是有益的，而且将是在结束全球艾滋病毒流行方面取得的关键进展。艾滋病治疗面临的挑战 策略是长寿的静息细胞，主要是CD4+T细胞，含有复制能力强的病毒，这种病毒可以 随机重新激活。结果是，对于大多数人来说，CART的中断会导致HIV在体内反弹 几周。艾滋病毒的治疗战略主要包括联合疗法、推动艾滋病毒重新激活的药物和 以免疫为基础的治疗，以检测和清除重新激活的细胞。在这项研究中，我们提出了一种人类第一人 一种新的疫苗方案的试验，旨在诱导我们的免疫反应，称为CD8+T 细胞。CD8+T细胞在检测病毒感染细胞方面非常有效。疫苗方案被称为， ChAdOx1.tHIVconv5-MVA.tHIVconv3是我们牛津大学的合作者开发的。一个 这种疫苗的前一次迭代诱导了非常高的CD8+T细胞来对抗HIV。这种疫苗的主要特点是 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 回应。在这项研究中，感染艾滋病毒的耐受抑制的参与者将依次接种 ChAdOx1.tHIVconv5和MVA.tHIVconv3。我们将彻底描述这些产品的安全性 疫苗。我们还将使用标准化的分析方法来测量接种疫苗和 调查接种疫苗是否会对参与者中非常低的艾滋病毒水平产生任何影响。探索性的 研究将检验我们是否能在淋巴结中检测到疫苗诱导的针对HIV的T细胞，以及 检查点抑制分子是否可以与疫苗接种一起使用，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。第二项研究建立在第一项研究的基础上，通过 研究马赛克疫苗(旨在增加艾滋病毒覆盖率的疫苗)是否可以进一步改进 ChAdOx1.tHIVconv5-MVA.tHIVconv3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.