A lung-oriented controlled human infection model using live BCG to evaluate tuberculosis immunopathogenicity and vaccine efficacy (TB-CHIM).

结核病是人类已知的最致命的疾病之一。在过去的两个世纪里，它已经导致超过10亿人死亡，目前是全球最大的传染病杀手。2016年，新诊断的结核病病例超过1000万例，死亡170万人(全球每分钟有3人死于结核病！)。在世界上的一些地区，比如撒哈拉以南非洲，这种疾病已经失控。结核病最常影响肺部，并通过吸入咳嗽飞沫传播，这些飞沫进入宿主的肺部，最终到达感染扎根的气囊(肺泡)。然而，如果有人吸入了结核病细菌，并不一定意味着他们会患上活动性结核病。在大多数人(约90%到95%)中，免疫系统能够在细菌发展成疾病之前杀死或遏制细菌。然而，在大约5%-10%的人中，细菌繁殖导致结核病。免疫系统是复杂的，有许多相互作用的组件。然而，这些成分如何在肺部共同作用以杀灭细菌和防止疾病发展尚不清楚。因此，目前尚不清楚为什么一些人感染了这种疾病，而另一些人则受到了保护。这主要是因为到目前为止，大多数研究都涉及动物模型和来自人类血液隔室的细胞，这与人类肺部发生的情况很不接近。然而，现在有几条证据表明，一种名为记忆T细胞的白细胞，如果经过“训练”，可以迅速识别和杀死结核病细菌。新的研究还表明，曾经被认为没有保护作用的抗体可以与其他细胞相互作用，杀死结核病细菌。我们的目标是研究这些特定的成分以及它们如何防止人类肺部疾病的发展。这将给我们提供如何设计针对结核病的保护性干预措施的线索。根除结核病的最好方法是开发有效的疫苗。然而，目前在许多国家使用的卡介苗疫苗只对儿童预防结核病，对成年人几乎没有保护作用，特别是在结核病常见的国家。大约有20种新疫苗正在评估中，但开发过程非常漫长(10年至15年)和昂贵(从开始到结束约8亿GB)，大多数疫苗将在人体试验的后期阶段失败。因此，我们需要一种新的有效和更负担得起的方法，涉及较少的患者，以选择最好的疫苗来进行更大规模的人体研究。另一个悬而未决的问题是如何最好地接种疫苗。传统上，疫苗是通过皮肤注射给药的，但直接将疫苗吸入肺部可能会更好地激活对结核病等空气传播感染的保护反应。我们拟议的研究将试图解决这些未得到满足的需求和悬而未决的问题，方法是用一种活的减弱的结核病菌株(称为卡介苗)直接感染不同组试验参与者的肺部(每组显示对结核病的易感性不同)，并检查感染前后的免疫反应。这被称为受控人类感染模型(CHIM)。这样的模型更准确地反映了一个人是如何自然感染结核病的。ChIM过去曾被用于开发其他疾病的疫苗，如霍乱和疟疾，并取得了巨大成功。我们最近完成了一项由盖茨基金会和SA-MRC资助的研究，使用类似的模型，我们用卡介苗和来自结核病细菌的不同蛋白质的混合物(称为PPD)感染健康人的肺部，并在3天后检测肺部的免疫反应。我们已经在近100名参与者中确定了这一CHIM的安全性。我们现在需要利用这些成果，通过使用这个模型来询问免疫系统的哪些特定方面是保护的，完善系统以最终确定一个可用于对新的候选疫苗进行分类的模型，并确定接种新疫苗的最佳途径。

Tuberculosis (TB) is one of the deadliest diseases known to man. It has killed over 1 billion people in the last 2 centuries and is currently the biggest infectious disease killer globally. In 2016 there were over 10 million newly diagnosed TB cases and 1.7 million people died (worldwide 3 people die from TB every minute!). In some parts of the world, like Sub-Saharan Africa, the disease is out of control. TB most commonly affects the lungs and is transmitted through the inhalation of cough droplets, which enter the host's lung and eventually reach the air sacs (alveoli) where the infection takes root. However, if someone inhales TB bacteria it does not necessarily mean that they will develop active TB disease. In most people (~90 to 95%), the immune system is able to either kill or contain the bacteria before they develop disease. However, in ~5-10% of people, the bacteria multiply leading to TB disease. The immune system is complex with many interacting components. However, how these components work together in the lung to kill the bacteria and prevent disease development is poorly understood. Thus, it remains unclear why some people get the disease while others are protected. This is mainly because most research, up to now, involved animal models and cells from the human blood compartment, which poorly approximate what happens in the human lung. However, several lines of evidence now suggest that a type of white blood cell called a memory T-cell, if "trained", can rapidly recognise and kill the TB bacteria. New research also suggests that antibodies, once thought to have no role in protection, can interact with other cells to kill TB bacteria. We aim to investigate these specific components and how they can protect against development of disease in the human lung. This will give us clues how to design protective interventions against TB.The best way to eradicate TB is by developing an effective vaccine. Yet the current vaccine used in many countries, BCG, only protects against TB in children and offers little protection in adults, especially in countries where TB is common. About 20 new vaccines are being evaluated but the development process is very long (10 to 15 years) and expensive (about £800 million from start to finish) and most vaccines will fail in the late stages of human testing. Thus, we need a new efficient and more affordable approach, involving small numbers of patients, to choose the best vaccines to move to larger human studies. Another unresolved issue is how best to administer the vaccine. Traditionally, vaccines are given by injection in the skin but inhaling it directly into the lungs may better activate the protective responses against airborne infections like TB.Our proposed study will attempt to address these unmet needs and unresolved questions by directly infecting the lungs of different groups of test participants (each group showing a different level of susceptibility against TB) with a live weakened strain of TB (called BCG) and examining the immune response before and after infection. This is called a controlled human infection model (CHIM). Such a model more accurately reflects how a person is naturally infected with TB. CHIM has been used in the past to develop vaccines for other disease such as cholera and malaria with great success. We have recently completed a study funded by the Gates Foundation and SA-MRC using a similar model where we have infected the lungs of healthy persons with BCG and a mixture of different proteins from TB bacteria (called PPD) and examined the immune response in the lungs after 3 days. We have established the safety of this CHIM in close to 100 participants. We now need to leverage these gains by using this model to now interrogate which specific aspects of the immune system are protective, refine the system to finalise a model that can be used to triage new vaccine candidates, and to determine the best route by which to administer new vaccines.