ICF: AbVax Combination vaccination and broadly neutralising antibody therapy in HIV to induce a protective Tcell vaccinal effect, a mechanistic study

ICF：AbVax 联合疫苗接种和广泛中和 HIV 抗体疗法诱导保护性 T 细胞疫苗效应，一项机制研究

• 批准号: MR/Y008847/1
• 负责人: Alexander Frater
• 金额: $ 304.51万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY008847%2F1
• 关键词: ICF; AbVax; Combination; vaccination; broadly

BackgroundThere is no cure for HIV infection. Antiretroviral therapy (or ART) is a widely available treatment, but has to be taken daily, for life, causing issues around side-effects, resistance, adherence and stigma. A new therapy called 'broadly neutralising antibodies' (or bNAbs) appears to work as well as ART and lasts much longer - one dose can last 6 months. Excitingly, in studies with animals (rhesus macaques), bNAbs have resulted in drug-free suppression for years and, in some cases, possible cures. There is now compelling early evidence showing that bNAbs can achieve sustained HIV virological control in humans. The impact of long-term tablet-free remission for people living with HIV (PWH) is enormous, particularly for hard to reach groups and countries with less developed health infrastructures.BNAbs appear to work in two stages. An initial direct effect in which the HIV viruses are targeted, followed by a second stage in which the induction of a sustained protective immune response by cells called 'T cells' confers longer term control - called the 'vaccinal effect'. AimOur aim is to determine the mechanism under-pinning the 'vaccinal effect' and to find out how it can be enhanced to induce the strongest and most durable protection for PWH. Our hypothesis is that a combination of bNAbs with a vaccine combined with a short period of viraemia (virus in the blood) will produce the most sustained immune protection. DesignAbVax is an early stage clinical trial designed to understand the biological mechanisms which explain what happens clinically. We aim to recruit 48 participants, who will be randomised across three arms to determine the best combination of vaccination, treatment interruption induced viraemia (TIIV) and bNAbs. All participants will receive a single dose of the two long-acting bNAbs (called 10-1074-LS and 3BNC117-LS). In the first arm (Arm A) participants will stop HIV therapy for a short time (about 4 weeks - this is the 'TIIV') to allow the virus to re-enter the blood before the bNAbs are given. This may induce a stronger vaccinal effect. In the second arm (Arm B), participants will receive vaccination with the "ChAdOx1-MVA/HIVconsvX" vaccines before bNAb infusions. These vaccines are "bivalent conserved mosaic T cell vaccines" which focus killer T cells on the most vulnerable parts of HIV. We hypothesise that the bNAbs vaccinal effect will enhance the T cell specific response to the vaccines, which will contribute to a stronger HIV immune control. In the third arm (Arm C), participants have both the TIIV and the vaccines with the bNAbs. Once dosed, all participants then stop therapy to see how long the virus can be controlled off any drugs, using just the interventions in the three arms of the study.This design allows us to see how much the vaccine and TIIV add to protection provided by bNAbs. To do this we measure HIV-targeting T cell immunity 26 weeks after starting the trial using a test called an ELISpot. This is the 'Primary Outcome'. We also use other tests of T cell immunity to look at many different measures of the response. Other outcomes include clinical measures such as duration of virological remission following treatment interruption and further detailed immunological, virological and genetic parameters.DeliveryThe team are experts in the fields of HIV cure (Fidler, Fox, Frater) and vaccinology (Hanke, Cicconi) and have strong track records in the design and analysis (Liu) of complex clinical trials and high-quality mechanistic laboratory studies.ImpactIf the study demonstrates boosted T cell immunity and sustained virological control following bNAb therapy, this could revolutionise the way we treat HIV (and other persistent infections and cancers). Should the intervention result in long-term remission - or even cure - this would have global impact for people and countries impacted by HIV.

背景艾滋病病毒感染目前尚无治愈方法。抗逆转录病毒疗法（或ART）是一种广泛使用的治疗方法，但必须每天服用，终身服用，导致副作用，耐药性，依从性和耻辱感等问题。一种名为“广泛中和抗体”（或bNAbs）的新疗法似乎与ART一样有效，并且持续时间更长-一剂可以持续6个月。令人兴奋的是，在对动物（恒河猴）的研究中，bNAb已经导致多年的无药物抑制，在某些情况下，可能治愈。现在有令人信服的早期证据表明，bNAb可以在人类中实现持续的HIV病毒学控制。长期无片剂缓解对艾滋病毒感染者（PWH）的影响是巨大的，特别是对于难以接触到的群体和卫生基础设施欠发达的国家。BNAb似乎分两个阶段发挥作用。最初的直接效果是靶向HIV病毒，随后是第二阶段，在第二阶段中，被称为“T细胞”的细胞诱导持续的保护性免疫反应，从而获得更长期的控制-称为“疫苗效应”。目的我们的目的是确定机制的基础上的“疫苗效应”，并找出如何可以提高诱导最强大和最持久的保护PWH。我们的假设是，bNAb与疫苗结合短期病毒血症（血液中的病毒）将产生最持久的免疫保护。DesignAbVax是一项早期临床试验，旨在了解解释临床发生的生物学机制。我们的目标是招募48名参与者，他们将被随机分配到三个组中，以确定疫苗接种、治疗中断诱导的病毒血症（TIIV）和bNAb的最佳组合。所有受试者将接受单剂量的两种长效bNAb（称为10-1074-LS和3BNC 117-LS）。在第一组（A组）中，参与者将在短时间内（约4周-这是“TIIV”）停止HIV治疗，以使病毒在给予bNAb之前重新进入血液。这可能会产生更强的疫苗效应。在第二组（B组）中，受试者将在bNA B输注前接受“ChAdOx 1-MVA/HIVconsvX”疫苗接种。这些疫苗是“二价保守嵌合T细胞疫苗”，将杀伤性T细胞集中在HIV最脆弱的部位。我们假设bNAbs疫苗效应将增强T细胞对疫苗的特异性应答，这将有助于更强的HIV免疫控制。在第三组（C组）中，参与者具有TIIV和具有bNAb的疫苗。一旦给药，所有参与者然后停止治疗，看看多久可以控制任何药物的病毒，只使用研究的三个分支中的干预措施。这种设计使我们能够看到疫苗和TIIV增加了多少bNAb提供的保护。为此，我们在试验开始后26周使用称为ELISpot的测试来测量HIV靶向T细胞免疫力。这就是“主要成果”。我们还使用T细胞免疫的其他测试来观察许多不同的反应措施。其他结果包括临床指标，例如治疗中断后病毒学缓解的持续时间，以及进一步详细的免疫学、病毒学和遗传参数。交付该团队是艾滋病毒治疗领域的专家（Fidler，Fox，Frater）和疫苗学（汉克，Cicconi），并在复杂临床试验的设计和分析（Liu）方面有着良好的记录，如果这项研究证明bNAb治疗后T细胞免疫力增强和病毒学控制持续，这可能会彻底改变我们治疗HIV（和其他持续性感染和癌症）的方式。如果干预导致长期缓解-甚至治愈-这将对受艾滋病毒影响的人和国家产生全球影响。