Childhood tuberculosis: Integrating tools for improved diagnosis and vaccines

儿童结核病：整合工具以改进诊断和疫苗

• 批准号: MC_EX_MR/K011944/1
• 负责人: Beate Kampmann
• 金额: $ 254.84万
• 依托单位: MRC Unit the Gambia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_EX_MR%2FK011944%2F1
• 关键词: Childhood; tuberculosis; Integrating; tools; improved

Tuberculosis still causes significant disability and death in many countries in the world, including half a million deaths in children each year. The diagnosis of TB is more difficult in children, as often it cannot be confirmed by "gold standard" methodology, which means showing presence of the TB bacilli in a patient, usually in their sputum. This is rarely possible in children, since they have fewer bacteria, often don't cough up sputum and still get very sick. They often don't receive treatment in time or not at all. Apart from looking for the TB bacilli, we hence use other more indirect tools to make a diagnosis, including observations of TB cases in the community and evidence that the host's immune system has been exposed to TB (patient) by doing a skin test. There are new technologies which can now be applied to blood samples of patients to see if their immune system expresses a characteristic "signature" of TB. However, these have not been used in children yet.TB often occurs in households, which is where children are particularly likely to catch it from an infected adult. But not everyone gets it when exposed to a coughing "index case", which is the coughing person with active TB. It is likely that many factors like the organism in question, the conditions of the household and also the responses of the immune system of the individual child play a role. We have a large gap in our understanding of the transmission, susceptibility and what kind of immunity is needed to fend off the TB bacteria. This is why we have so far failed to make a better vaccine than the current vaccine, BCG, which is not fully protective. If we understand the mechanisms that underlie susceptibility and protection, this would be very useful for any trials of new vaccines, but also for the diagnosis, as we could look for specific markers associated with TB disease and protection. Such markers could also be used in vaccine or treatment trials, instead of purely relying on the bacteriologically confirmed cases, which is the current approach. This approach is very costly since it needs a very large number of children to participate in vaccine or treatment trials, as most of them will never show up with confirmation by bacteria and yet get sick with what we think is TB.In our project, we will develop and test novel approaches by using new methods in the microbiology and immunology laboratory and have brought together a strong team of internal and external experts to be able to use all the state-of-the art available methodology.In particular, we want to evaluate some of the new technologies to diagnose TB on the "signature" it leaves in the body and to use a statistical approach to bring together the individual pieces of the jigsaw that makes up TB diagnosis in children. We will also study children who do and do not get TB after exposure to the bacillus in their household, as the group who does not contract the disease or infection might hold the key to what is really protective against TB. This knowledge will be very important for making an improved vaccine, which can essentially mimic such protective mechanisms. With the help of more advanced statistical analysis of all the factors that contribute to a TB diagnosis we would like to come up with algorithms for the diagnosis that are just or nearly as good as the gold standard. We wish to conduct this project in the Gambia, where there is still a lot of TB. Thanks to the MRC Unit in The Gambia, we benefit from all the tools in the lab and field to collect samples and data for a very comprehensive assessment of every case. Our long-term goal with this project is to enable the research community to develop a better diagnostic approach to childhood TB and understand how we should design the ideal vaccine against TB.

在世界上许多国家，结核病仍然造成严重的残疾和死亡，包括每年50万儿童死亡。结核病的诊断在儿童中更为困难，因为通常无法通过“金标准”方法确诊，这意味着在患者体内（通常在其痰液中）显示结核杆菌的存在。这在儿童身上很少发生，因为他们的细菌较少，通常不会咳痰，但仍然会病得很重。他们经常得不到及时的治疗，或者根本不接受治疗。因此，除了寻找结核杆菌外，我们还使用其他更间接的工具进行诊断，包括观察社区中的结核病例，以及通过皮肤试验证明宿主免疫系统接触过结核（患者）的证据。现在有一些新技术可以应用于患者的血液样本，以观察他们的免疫系统是否表现出结核病的特征“特征”。然而，这些还没有用于儿童。结核病通常发生在家庭中，儿童特别容易从受感染的成年人那里感染结核病。但并不是每个人在接触咳嗽“指数病例”时都会感染，即咳嗽的活动性结核病患者。很可能有很多因素在起作用，比如有问题的生物体、家庭条件以及孩子个体免疫系统的反应。我们对结核病的传播、易感性和需要什么样的免疫力来抵御结核病细菌的理解存在很大差距。这就是为什么我们迄今未能研制出比目前的卡介苗更好的疫苗的原因，卡介苗没有完全的保护作用。如果我们了解易感性和保护作用的机制，这将对任何新疫苗的试验都非常有用，而且对诊断也很有用，因为我们可以寻找与结核病和保护作用相关的特定标记。这种标记物也可以用于疫苗或治疗试验，而不是像目前的方法那样纯粹依赖于细菌学上的确诊病例。这种方法非常昂贵，因为它需要非常多的儿童参与疫苗或治疗试验，因为他们中的大多数人永远不会得到细菌的证实，但却患上了我们认为是结核病的疾病。在我们的项目中，我们将在微生物学和免疫学实验室使用新方法开发和测试新方法，并汇集了一个强大的内部和外部专家团队，能够使用所有最先进的方法。特别是，我们希望评估一些新技术，根据结核病在体内留下的“印记”来诊断结核病，并使用统计方法将构成儿童结核病诊断的各个部分结合起来。我们还将研究在家庭中接触这种杆菌后患结核病和不患结核病的儿童，因为不感染这种疾病或不感染这种疾病的群体可能掌握着真正预防结核病的关键。这一知识对于制造改进的疫苗非常重要，这种疫苗基本上可以模仿这种保护机制。在对所有有助于结核病诊断的因素进行更先进的统计分析的帮助下，我们希望提出与黄金标准一样或几乎一样好的诊断算法。我们希望在冈比亚开展这个项目，那里仍然有很多结核病。感谢冈比亚的MRC单位，我们从实验室和现场的所有工具中受益，收集样本和数据，对每个病例进行非常全面的评估。我们这个项目的长期目标是使研究界能够开发出一种更好的儿童结核病诊断方法，并了解我们应该如何设计出理想的结核病疫苗。

项目成果

Meta-Analysis Identification of Highly Robust and Differential Immune-Metabolic Signatures of Systemic Host Response to Acute and Latent Tuberculosis in Children and Adults.

• DOI: 10.3389/fgene.2018.00457
• 发表时间: 2018
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Bah SY;Forster T;Dickinson P;Kampmann B;Ghazal P
• 通讯作者: Ghazal P

Licensed Bacille Calmette-Guérin (BCG) formulations differ markedly in bacterial viability, RNA content and innate immune activation.

• DOI: 10.1016/j.vaccine.2019.11.060
• 发表时间: 2020-02-24
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Angelidou A;Conti MG;Diray-Arce J;Benn CS;Shann F;Netea MG;Liu M;Potluri LP;Sanchez-Schmitz G;Husson R;Ozonoff A;Kampmann B;van Haren SD;Levy O
• 通讯作者: Levy O

Why the Convention on the Rights of the Child must become a guiding framework for the realization of the rights of children affected by tuberculosis.

• DOI: 10.1186/s12914-016-0105-z
• 发表时间: 2016-12-08
• 期刊: BMC international health and human rights
• 影响因子: 3
• 作者: Basu Roy R;Brandt N;Moodie N;Motlagh M;Rasanathan K;Seddon JA;Detjen AK;Kampmann B
• 通讯作者: Kampmann B

The influence of paediatric HIV infection on circulating B cell subsets and CXCR5(+) T helper cells.

• DOI: 10.1111/cei.12618
• 发表时间: 2015-07
• 期刊: Clinical and experimental immunology
• 影响因子: 4.6
• 作者: Bamford A;Hart M;Lyall H;Goldblatt D;Kelleher P;Kampmann B
• 通讯作者: Kampmann B