Childhood tuberculosis: Integrating tools for improved diagnosis and vaccines

Lead Research Organisation: MRC Unit, The Gambia

Abstract

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. 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. We now have a candidate biosignature which has been patented and will be evaluated in additional cohorts.

Technical Summary

Tuberculosis causes significant morbidity and mortality in children worldwide. Bacteriological confirmation of TB in children is rare and lack of suitable alternative diagnostics is a major bottleneck to progress in identifying patients in need of treatment and in clinical trials of new vaccines and therapies. The MRC Unit, The Gambia can make a significant contribution in this field, since it has a track record in TB research, established data collection tools and state-of-the art laboratory facilities. Suitable cohorts of children with TB disease, infected and controls can be predicted. Our team of local and international investigators is developing and evaluating existing and new tools based on both host immune response and microbiology. We also work with new external collaborators, who are highly experienced in statistical analysis. We are testing samples from TB-affected children (exposed, infected or diseased) identified in household cohorts by using a combined approach of host and pathogen signatures and cellular and molecular methods, such as GeneXpert and biosignatures (ERJ 2015, IUATLD 2016). We characterise host responses associated with protection against infection in TB-exposed children who remain uninfected and who can serve as a model for protective immunity (MRC PhD studentship). We have expaned our existing epidemiological database to include the epidemiological and microbiological context of household transmission and its impact on host responses. We are developing a novel statistical approach to design prediction algorithms for the diagnosis of childhood TB. Translation to Policy: Our research activities have doubled the notification figures for childhood TB in The Gambia. We have developed and patented a novel diagnostic biosignature. Integration of measurable host responses into diagnostic algorithms is informing not only the diagnosis of the individual patient but also facilitate clinical trials of new vaccines and drugs. Understanding of protective immune mechanisms will guide vaccine design. Epidemiological datasets that link TB exposure, infection and disease can serve as a model for public health and TB control. We are working with the NLPT to transfer the household contact tracing into the national program.

Planned Impact

Tuberculosis remains a global emergency and affects and continues to kill adults and children in large numbers worldwide.
Our project proposal has been developed to address a critical bottleneck for patient management and clinical trials of new vaccines and drugs alike: a) the problem of accurate diagnostics for tuberculosis (TB) in children and b) the absence of markers of protection which can be used as endpoints for TB vaccine trials. This bottleneck is widely acknowledged by the scientific community and international TB program officers, and remains at the center of international research efforts. This was highlighted in the special supplement to the Journal of Infectious Disease, published on World TB Day 2012 and dedicated to basic research but also implementation obstacles for TB globally.
Without a better diagnostic approach, which doesn't exclusively rely on bacteriological confirmation, children are not likely to be included in any studies of improved treatment for TB, and any ongoing vaccine trials will continue to require large and expensive cohorts of patients to be followed prospectively over a long period of time. This is prohibitively expensive and will preclude the evaluation of promising vaccine candidates as there simply are not enough field sites available that can provide both sizeable paediatric cohorts and have the laboratory and clinical capacity to follow them up in clinical trials.
Our research program will impact on areas of discovery, development and delivery within childhood tuberculosis. All of these are required and have merit in driving forward the agenda to improve the diagnosis and treatment of individual cases of TB in children and ultimately also facilitate clinical trials for new treatments and vaccines.
Discovery: the identification of new biomarkers and host/pathogen signatures will drive the development of point-of care tests for TB by identifying new leads in either metabolomics, cytokine or gene signatures, which are amenable to further development with the help of industry partners and not-for profit organisations such as FIND/PATH. To understand mechanisms of protection against infection opens up a key avenue for vaccine design and evaluation, as ultimately, only a TB vaccine that prevents infection and disease will have the desired public health impact for TB control.
Development: we expect that the evaluation of recently identified biosignatures from adult populations will confirm preliminary results also in children and will then stimulate the development of more user-friendly versions of assays, including translation into nanotechnological and lateral flow-based assays, again partnering with industry in the future.
Delivery: The assessment of impact of epidemiological components for household transmission and the analysis of additional laboratory assays built into the diagnostic algorithms will lend support for the planning of interventions and mobilisation of resources for policy makers in TB and the national TB programs in a variety of settings, depending on resources available. The aim of this particular objective is to develop further policy links and share the algorithms and toolbox concept with our partners in NLTP in resource-poor and -rich settings. We anticipate that these algorithms could be tailored according to available resources and require to be evaluated in a variety of populations (+/- HIV). We will then liaise with experts in cost-effectiveness analysis (i.e. Imperial College Business school, HPA, WHO) to quantify the potential need for resources, depending on the algorithm chosen. This will allow the TB program decision makers to develop more appropriate predictions of impact depending on the settings that wish to adapt them.Through close links between our research and the National Leprosy and TB program (NLTP), the experience in The Gambia will inform international TB control efforts via communication channels such as the StopTB partnership and WHO.

Publications

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Afolabi MO (2015) A multimedia consent tool for research participants in the Gambia: a randomized controlled trial. in Bulletin of the World Health Organization

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Andreas NJ (2015) Human breast milk: A review on its composition and bioactivity. in Early human development

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Bah SY (2017) Immune oxysterols: Role in mycobacterial infection and inflammation. in The Journal of steroid biochemistry and molecular biology

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Basu Roy R (2019) Tuberculosis susceptibility and protection in children. in The Lancet. Infectious diseases

 
Description Assistance to the National TB program
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact The training program in childhood tuberculosis which was established through my program grant has led to a doubling of the notification of cases of childhood TB in the country. It has also led to the request for our involvement to assist the National Leprosy and TB Program of The Gambia in their preparation for the application for funding to the Global Fund. This request for funding was granted and now also includes more provision of services for children.
 
Description Book chapter in new book on childhood TB
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact I am the author of the chapter on immunology in the new book on childhood and adolescent TB recently published by Starke and Donaldson- this textbook is virtually the only available textbook and to be asked to author a chapter pays tribute to my international standing in the field.
 
Description ECDC advocacy workshop
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Raising the profile of paediatric tuberculosis in international organisations such as ECDC and WHO has led to the inclusion of recommendations specifically for children in the guidelines.
 
Description Implementation of prophylaxis for TB exposed children in 4 SSA countries
Geographic Reach Africa 
Policy Influence Type Participation in a national consultation
Impact Implementation of the recommended prophylactic therapy with INH has been hindered in most SSA countries due to lack of knowledge and experience. Engagement in our research project has enabled governmental organisations (National TB programs) to roll out IPT at sentinel sites and gain experience with a number of different approaches and assess the cascade of care where patients might get lost. This leads ot improvement of services for patients and families.
 
Description NIH case-definition workshop
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Description New classification of childhood tuberculosis
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact the NIH-commissioned workshop of which I was an invited member drafted a new case classification for research in childhood tuberculosis. This classification is now standard to attract funding for diagnostic-related research in this area.
 
Description Press panel RCPCH
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Guideline Title NIH Classification of childhood TB
Description Update of classification for childhood TB
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact The definitions for childhood TB have facilitate the notifications of the condition to the WHO and the rise of age-disaggregated data in the reports to the Who has been phenomenal. The reporting of childhood TB in The Gambia rose by 60% since I initiated the childhood TB research program.
 
Description WHO advisory board
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact improvements in delivery of clinical services to children exposed to TB by advocating contact tracing for vulnerable groups in the WHO guideline document to which I contributed
 
Description guidelines for use of IGRA in children
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact our research has clearly identified the correct use of IGRA for the the diagnosis of TB in children. We were commissioned to publish our guidelines in a UK Education?actice Journal, which has an international audience
 
Description work cited in international guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
Impact rational use of resources
 
Description GCRF
Amount £580,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 04/2019
 
Description German Government- BMBF- International collaborations
Amount € 2,000,000 (EUR)
Organisation German Federal Ministry of Education and Research 
Sector Public
Country Germany
Start 07/2016 
End 06/2021
 
Description MRC Program grant
Amount £2,000,000 (GBP)
Organisation MRC Harwell 
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 01/2018
 
Description MRC studentship Dr Togun
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 01/2016
 
Description Networks of Excellence EDCTP
Amount € 3,066,638 (EUR)
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 03/2017 
End 03/2020
 
Description PhD studentship Dr Egere
Amount € 20,000 (EUR)
Organisation Ludwig Maximilian University of Munich (LMU Munich) 
Sector Academic/University
Country Germany
Start 10/2013 
End 09/2016
 
Description PhD studentship Dr Saikou Bah
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2012 
End 09/2016
 
Description PhD studentship for Dr Basu-Roy
Amount £250,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2013 
End 08/2016
 
Title design of a public health contact tracing model for TB control in the community 
Description the contact tracing model was developed by my TB research group to facilitate the linking of index cases to childhood contacts. it has been developed in collaboration with public health england and an adapted version also in use at the MRC Unit in The Gambia. 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact contact tracing and chemoprophylaxis for children is now part of the activities of the National TB program in the Gambia 
 
Title reporter gene mycobacteria 
Description I generated a new generation of reporter-gene tagged mycobacteria in my lab which facilitates studies of host/pathogen interaction 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact new assay for high throughput of drug screening set up 
 
Title R4KA database 
Description 4-country research database for implementation of the project, data integrity and data sharing on a regular basis 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact able to share data across the platform of the study and enable data quality control 
 
Title database for TB contacts in households 
Description This database links index cases and contacts affected by tuberculosis 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact The set up of the database in The Gambia is also a useful tool for the TB research at Imperial College and has been shared in an anonymised way with all ethical approvals 
 
Description British Columbia University 
Organisation University of British Columbia
Department Department of Pediatrics
Country Canada 
Sector Academic/University 
PI Contribution provided support for field sample collections and vaccinations, plus laboratory facilities
Collaborator Contribution access to protocols
Impact publication, presentation at international meeting, visibility
Start Year 2014
 
Description GCRF Foundation Award partner 
Organisation National Institute for Medical Research, Tanzania
Department NIMR Mbeya Research Centre
Country Tanzania, United Republic of 
Sector Public 
PI Contribution Grant Facilitates Recruitment site for childhood GCRF grant, MRC Gambia provides training
Collaborator Contribution sample collection, policy development
Impact ongoing
Start Year 2017
 
Description GCRF Foundation Award partner 
Organisation University of Jos
Country Nigeria 
Sector Academic/University 
PI Contribution Grant Facilitates Recruitment site for childhood GCRF grant, MRC Gambia provides training
Collaborator Contribution Recruitment of patients and biosamples for collaborative childhood TB work
Impact capacity building , research skills
Start Year 2017
 
Description GCRF Foundation award partner 
Organisation University of Bamako
Country Mali 
Sector Academic/University 
PI Contribution Grant Facilitates Recruitment site for childhood GCRF grant, MRC Gambia provides training
Collaborator Contribution Able to recruit patients to collaborative project
Impact ongoing
Start Year 2017
 
Description IIDMM UCT 
Organisation University of Cape Town
Department Institute of Infectious Disease and Molecular Medicine (IIDMM)
Country South Africa 
Sector Academic/University 
PI Contribution joint supervision of PhD students academic links in the field of TB grant money to UCT
Collaborator Contribution access to lab and field
Impact joint publications joint grant applications
Start Year 2009
 
Description IMPALA 
Organisation Liverpool School of Tropical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on assessment of child lung health
Collaborator Contribution Training and expertise
Impact new collaboration
Start Year 2018
 
Description Jos 
Organisation University of Jos
Department Department of Paediatrics
Country Nigeria 
Sector Academic/University 
PI Contribution We engaged Dr Ebonyi as our partner in the research project and devised the protocol and data system to be implemented on site. We shared our training materials
Collaborator Contribution The partners in Jos have enabled implementation of the GCRF work and facilitated close links with the Nigerian National TB Control Program and have led training activities in Nigeria for chidlhood TB as well as informed documentation of implementation of IPT.
Impact derived documents now used in National TB programs
Start Year 2017
 
Description Levy Lab 
Organisation Boston Children's Hospital
Department Levy Laboratory
Country United States 
Sector Hospitals 
PI Contribution set up of systems vaccinology research for studies of EPI vaccines
Collaborator Contribution bioinformatics support
Impact several publications and a grant submission to the nIH
Start Year 2014
 
Description Oxford Vaccine Group 
Organisation University of Oxford
Department Oxford Vaccine Group
Country United Kingdom 
Sector Academic/University 
PI Contribution mutual engagement in Vaccinology research
Collaborator Contribution joint supervision of PhD student
Impact new collaboration
Start Year 2014
 
Description Staten Serum Institute Denmark 
Organisation The Statens Serum Institute (SSI)
Country Denmark 
Sector Public 
PI Contribution application of reagents in research studies
Collaborator Contribution availability of reagents to our research study
Impact joint publications
Start Year 2006
 
Description TB-CDRC 
Organisation Johns Hopkins University
Department Division of Infectious Diseases
Country United States 
Sector Academic/University 
PI Contribution I act a s the director of paediatric studies in this consortium which has a large grant from the NIH to conduct research into TB diagnostics
Collaborator Contribution regular input into paediatric study design and review of evolving concept sheets
Impact consensus statement on TB diagnostics classification for children- see publications list
Start Year 2010
 
Description Tanzania 
Organisation National Institute for Medical Research, Tanzania
Department NIMR Mbeya Research Centre
Country Tanzania, United Republic of 
Sector Public 
PI Contribution Identification of children in households affected by TB through protocols, data collection tools and teaching
Collaborator Contribution recruitment of children affected by TB and samples for biomarker studies
Impact samples currently undergoing evaluation for novel diagnostics
Start Year 2017
 
Description UCAD 
Organisation University Cheikh Anta Diop de Dakar
Country Senegal 
Sector Academic/University 
PI Contribution Professor Mboup and Professor Gaye are partners in our West African Global Health Research initiative and a number of members of their respective departments are now involved in our research
Collaborator Contribution exchange of ideas and potential for join grant applications
Impact scientific workshops
Start Year 2016
 
Description UNiversity of Bamako 
Organisation University of Bamako
Country Mali 
Sector Academic/University 
PI Contribution Identification of children in households affected by TB through protocols, data collection tools and teaching
Collaborator Contribution Implementation of contact tracing for children with TB via the National TB program sample collections for biomarker evaluations
Impact Implementation of contact tracing for children with TB via the National TB program
Start Year 2017
 
Description University of Jos, Nigeria 
Organisation University of Jos
Department Department of Paediatrics
Country Nigeria 
Sector Academic/University 
PI Contribution A paediatrician form Jos is developing a research project under my supervision and received funding via Imperial College in 2016. He is now also a collaborator on the Foundation GCRF award
Collaborator Contribution set up of validators cohorts for childhood TB research
Impact Foundation Award MRC
Start Year 2015
 
Description University of Munich 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Country Germany 
Sector Academic/University 
PI Contribution Collaborative grant award from the German ministry to conduct research into lung sequelae of TB
Collaborator Contribution LMU is the grant holder and chose my TB program at MRC and the TBCC as a partner site in this 5-counry multicentre study.
Impact the study is just starting, the website is being developed
Start Year 2016
 
Title Patent for TB biomarker signature 
Description this patent application is a direct result of the work conducted on my MRC program grant. it protects a diagnostic biosignature for childhood TB which can now be taken forward for further evaluation and potentially developed into a POC test. 
IP Reference P10280GB 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact only just filed
 
Description Community sensitisation events 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact The community sensitisation events are regularly conducted to inform past, present and future participants in our research on the results of previous studies and upcoming new research studies and clinical trials. They serve as a link to the community decision makers and are well supported by community members and MRC researchers.

Increased participation in clincial trials and ongoign research
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
 
Description INMIS media interveiw 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact as part of the International Symposium for neonatal and maternal immunisations hick I organised in The Gambia I gave a television interview to the national media which was broadcasted on the same day
Year(s) Of Engagement Activity 2015
 
Description Inaugural lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Travel with T cells, now on YouTube

inerest in academic medicine by GCSE-level students, several University students requesting mentorship
Year(s) Of Engagement Activity 2012
 
Description Kick of meeting Mali , Bamako University 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Kick off meeting for the GCRF award engaged University of Bamako practitioners and the National TB program
Year(s) Of Engagement Activity 2017
 
Description Lancet personal profile 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Personal Profile in The Lancet entitled" Professor Beate Kampmann: Advocate for Childhood Tuberculosis"

invitations to present work at various international meetings
Year(s) Of Engagement Activity 2012
 
Description World TB Day community activities 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact For the World TB day on March 24th we coordinated joint activities with the NLTP of The Gambia in a coastal community. Schoolchildren and lay audience as well as healthcare workers and patents participated.
Year(s) Of Engagement Activity 2016
URL http://www.mrc.gm/mrc-unit-tb-research-world-tb-day-celebration/