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

背景艾滋病毒感染目前还没有治愈方法。抗逆转录病毒疗法(ART)是一种广泛可用的治疗方法，但必须每天服用，终身服用，导致副作用、耐药性、依从性和耻辱等问题。一种名为“广谱中和抗体”(或bNAbs)的新疗法似乎和ART一样有效，而且持续时间更长--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，bNAbs多年来一直导致无药物抑制，在某些情况下，还可能治愈。现在有令人信服的早期证据表明，bNAbs可以在人类体内实现持续的艾滋病毒病毒学控制。对艾滋病毒携带者(PWH)的长期非片剂缓解的影响是巨大的，特别是对难以接触到的群体和卫生基础设施欠发达的国家。BNAbs似乎分两个阶段起作用。首先是以HIV病毒为靶点的直接效应，然后是第二阶段，在这个阶段，被称为T细胞的细胞诱导持续的保护性免疫反应，从而获得长期控制--称为“疫苗效应”。目的我们的目标是确定“疫苗效应”的机制，并找出如何增强疫苗效应，以产生对威斯康星病毒最强和最持久的保护。我们的假设是，bNAbs与疫苗的结合加上短期的病毒血症(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，旨在了解解释临床上发生的事情的生物学机制。我们的目标是招募48名参与者，他们将被随机分成三组，以确定疫苗接种、治疗中断诱导的病毒血症(TIIV)和bNAbs的最佳组合。所有参与者将接受两种长效bNAbs(称为10-1074-LS和3BNC117-LS)的单剂量注射。在第一个手臂(手臂A)中，参与者将在给予bNAbs之前停止HIV治疗一小段时间(约4周--这是‘TIIV’)，让病毒重新进入血液。这可能会产生更强的疫苗效果。在第二个手臂(手臂B)中，参与者将在注射bNAb之前接受“ChAdOx1-MVA/HIVconvX”疫苗接种。这些疫苗是“二价保守的马赛克T细胞疫苗”，将杀伤T细胞集中在艾滋病毒最脆弱的部分。我们假设，bNAbs疫苗效应将增强T细胞对疫苗的特异性反应，这将有助于更强的HIV免疫控制。在第三个手臂(手臂C)，参与者既接种了TIIV，又接种了含有bNAbs的疫苗。一旦给药，所有参与者然后停止治疗，看看病毒可以被任何药物控制多长时间，只使用研究的三个分支的干预措施。这种设计允许我们看到疫苗和TIIV在多大程度上增加了bNAbs提供的保护。为了做到这一点，我们在试验开始26周后使用一种名为ELISpot的测试来测量HIV靶向T细胞免疫。这是“主要结果”。我们还使用其他T细胞免疫测试来观察许多不同的反应指标。其他成果包括临床指标，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、病毒学和遗传学参数。交付该团队是艾滋病毒治愈(Fidler，Fox，Frater)和疫苗学(Hanke，Cicconi)领域的专家，在复杂临床试验和高质量机械实验室研究的设计和分析(Liu)方面拥有良好的跟踪记录。如果研究表明，bNAb治疗后T细胞免疫增强和持续的病毒学控制，这可能会彻底改变我们治疗艾滋病毒(和其他持续感染和癌症)的方式。如果干预措施导致长期缓解--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。

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.