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 HIV 感染无法治愈。抗逆转录病毒疗法（或 ART）是一种广泛使用的治疗方法，但必须终生每天服用，从而导致副作用、耐药性、依从性和耻辱等问题。一种名为“广泛中和抗体”（或 bNAb）的新疗法似乎与 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，在动物（恒河猴）研究中，bNAb 多年来已实现无药物抑制，在某些情况下甚至可能治愈。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。长期无药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。最初的直接效应是针对 HIV 病毒，随后是第二阶段，其中称为“T 细胞”的细胞诱导持续的保护性免疫反应，从而实现长期控制，称为“疫苗效应”。目的我们的目标是确定“疫苗效应”的机制，并找出如何增强它，从而为感染者提供最强、最持久的保护。我们的假设是，bNAb 与疫苗的组合加上短时间的病毒血症（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，旨在了解解释临床情况的生物学机制。我们的目标是招募 48 名参与者，他们将被随机分为三个组，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。所有参与者都将接受单剂量的两种长效 bNAb（称为 10-1074-LS 和 3BNC117-LS）。在第一组（A 组）中，参与者将短暂停止 HIV 治疗（大约 4 周 - 这就是“TIIV”），以便在给予 bNAb 之前让病毒重新进入血液。这可能会产生更强的疫苗效果。在第二组（B 组）中，参与者将在输注 bNAb 之前接种“ChAdOx1-MVA/HIVconsvX”疫苗。这些疫苗是“二价保守嵌合 T 细胞疫苗”，将杀伤性 T 细胞集中攻击 HIV 最脆弱的部分。我们假设 bNAb 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。在第三组（C 组）中，参与者同时接种 TIIV 和 bNAb 疫苗。给药后，所有参与者都会停止治疗，看看仅使用研究的三个分支中的干预措施，不使用任何药物可以控制病毒多长时间。这种设计使我们能够了解疫苗和 TIIV 在多大程度上增加了疫苗提供的保护作用。 bNAb。为此，我们在开始试验 26 周后使用 ELISpot 测试来测量针对 HIV 的 T 细胞免疫力。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更详细的免疫学、病毒学和遗传参数。交付团队是艾滋病毒治疗（Fidler、Fox、Frater）和疫苗学（Hanke、Cicconi）领域的专家，并拥有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) 方面拥有良好的记录。影响如果研究表明 T 细胞免疫力增强并持续病毒学控制bNAb 疗法，这可能会彻底改变我们治疗艾滋病毒（以及其他持续性感染和癌症）的方式。如果干预措施能带来长期缓解甚至治愈，这将对受艾滋病毒影响的人和国家产生全球影响。