Evaluating novel diagnostics and enabling preventive measures for childhood tuberculosis between the UK and partners in Sub-Saharan Africa

Lead Research Organisation: MRC Unit, The Gambia

Abstract

This project aims to develop and validate better diagnostic tools for children with TB (Find and Treat), as well as looking at implementation of preventive therapy for those already infected but not yet ill, but who might progress to disease if not receiving the recommended intervention- (Screen and Prevent).
Importance of TB in LMIC:
Around 1 million children fall ill from TB each year and 140 000 die. Many countries struggle to deliver the age-stratified notifications for TB in children to the WHO, and there is reluctance to engage in diagnosing and treating TB in children in many settings, as staff feel ill equipped to confirm a "gold standard" diagnosis, based on microbiological evidence. This
situation is pertinent in Africa and continues to lead to unnecessary morbidity and mortality and a reservoir of cases for the future. The roadmap for the elimination of TB sets priorities for achieving global TB control and within this effort, childhood TB has been identified as a neglected problem, but of great importance for overall TB control (WHO Global Plan for TB).
This requires two interventions: 1. to appropriately diagnose the cases and place on treatment -find and treat- and 2. to prevent secondary cases in TB-exposed children, which can be done successfully by delivering preventive medication-screen and prevent.
Why is it more difficult to diagnose TB in children?
Due to the limited number of mycobacteria contained in their sputa, conventional microbiological diagnostics perform poorly in children. Unless more sensitive diagnostics for paucibacillary disease can be developed, it is unlikely that the current situation of two thirds of children receiving treatment for TB without a confirmed diagnosis will change. Host-derived biosignatures in blood or urine therefore hold promise for development into point-of care tests for childhood TB.
What do we want to do?
We have considerable experience in the management of childhood TB in both the UK and The Gambia, and this project aims to involve new partners in Africa to find and treat children with TB using existing and new diagnostics. We have already developed such new tests but they need to be further validate also in children who have HIV or malnutrition. We will therefor recruit a large prospective court of children likely o have TB to validate the new diagnostics.
In addition, we want to work the National TB programs (NTP) in the partner countries to implement a preventive strategy, as supported by the WHO but not implemented on the ground. We want to understand the bottlenecks within the care path and train members of the NTP to recognise TB in children and take the necessary preventive steps to avoid secondary
cases in families. Based on the UK model, we have already established a screen-and-prevent- program of contact screening for children exposed to TB in their households in The Gambia, which has the support of the NTP. Our find and treat and screen and prevent activities have increased the case notifications by 50% over the last 3 years. This approach now requires full integration into the NTP programs in other countries and systematic evaluation to determine its long term
impact on national TB figures also in our partner countries. It could serve as an important model for the WHO strategy to improve prevention of TB worldwide but each country might have specific requirements and our project will deliver data from 4 different African settings to inform the recommendations.
We expect that our work can improve TB control and that we can create a network of excellence with specialist knowledge for childhood TB in Africa, as we have already done in Europe.

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 for enrolment into clinical trials of new vaccines and therapies. As shown by our ongoing work, suitable
cohorts of children with TB disease, infected and controls can be reliably recruited and their specimens analysed, and our expertise can now be extended to the new sites in Africa. Supported by the state-of-the art technologies, bioinformatics and public health expertise available to the PI in the UK, our team of local and international investigators will further develop
and evaluate existing and new tools based on both host immune response and microbiology to build similar expertise in other LMIC where childhood TB remains a major problem.
Building on our previous MRC-supported work, we will test samples from children suspected to have TB by using a combined approach of cellular and molecular methods to validate protein and transcriptome -based diagnostic biosignatures. In this period of available funding, we will also set up pilot sites to administer preventive treatment to childhood contacts and translate our knowledge from the UK and the MRCG to the new partners in Africa. Translation into Policy: Integration of measurable host responses into diagnostic algorithms for patient care will not only secure the diagnosis of the individual patient but also facilitate clinical trials of new vaccines and drugs at participating sites. This project will build capacity for such future studies by creating a network of excellence for childhood TB. Epidemiological datasets that link TB exposure, infection and disease can serve as a model for public health and TB control and enable the wider roll out of IPT in the countries via the national TB programs with whom this proposal is engaging, as recommended by the WHO.

Publications

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

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Egere U (2017) In reply. in The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease

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Kampmann B (2018) Evaluating UK National Guidance for Screening of Children for Tuberculosis. A Prospective Multicenter Study. in American journal of respiratory and critical care medicine

 
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 Improve notification of Childhood TB
Geographic Reach Africa 
Policy Influence Type Participation in a national consultation
Impact Increased notification encouraged the NLTP in The Gambia to implement contact tracing.
 
Description Participation in NIH workshop on reserach agenda for latent TB infection- represnted paediatric components
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description NIH- Biomarkers for Childhood TB
Amount $2,500,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 02/2020 
End 01/2024
 
Description NIH- Biomrker Award PI Levin
Amount $2,000,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 01/2018 
End 12/2023
 
Description UKRI-GCRF
Amount £150,000 (GBP)
Organisation United Kingdom Research and Innovation 
Department Global Challenges Research Fund
Sector Public
Country United Kingdom
Start 04/2020 
End 03/2021
 
Description WANETAM- network
Amount € 2,000,000 (EUR)
Organisation European Commission H2020 
Sector Public
Country Belgium
Start 04/2018 
End 04/2022
 
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 
 
Description Collaboration with the MRC/GCRF funded network Validate , University of Oxford, UK 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution The MRC/GCRF funded sister "Networks in Vaccine R&D" Hic-Vac, BactiVac, IntVetVacc, Validate and IMPRINT support each other by exchange of knowledge, administrative issues, the network PIs supporting network meeting by presenting their own networks and joint presentation of the networks during the BSI meeting 2017 (please refer to Engagement activities for more details).
Collaborator Contribution The MRC/GCRF funded sister "Networks in Vaccine R&D" Hic-Vac, BactiVac, IntVetVacc, Validate and IMPRINT support each other by exchange of knowledge, administrative issues, the network PIs supporting network meeting by presenting their own networks and joint presentation of the networks during the BSI meeting 2017 (please refer to Engagement activities for more details).
Impact Joint meeting attendance, exchange of knowledge on reporting to funders and administrative matters.
Start Year 2017
 
Description GCRF Foundation Award partner 
Organisation National Institute for Medical Research, Tanzania
Department NIMR Mbeya Research Centre
Country Tanzania, United Republic of 
Sector Academic/University 
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 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 NIH grant for biomarkers of chidlhood TB diagnostics 
Organisation University of San Francisco
Country United States 
Sector Academic/University 
PI Contribution this recently awarded NIH grant will allow us ot contribute stored samples form the MRC program grant and GCRF award to the validation of childhood TB diagnostic markers and to prospectively recruit a new cohort of children with TB and community controls
Collaborator Contribution The grant is led by the colleagues from the University of San Francisco and we are research partners with a sub contract.
Impact none yet
Start Year 2020
 
Description Tanzania 
Organisation National Institute for Medical Research, Tanzania
Department NIMR Mbeya Research Centre
Country Tanzania, United Republic of 
Sector Academic/University 
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 UKRI-GCRF award for partenrship in chidlhood TB sequelae (just awarded) 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution This GCRF grant is held by my postdoc Dr Togun and myself at MRCG@LSHTM. We have small salary portions on it only as overall garnt small and money needed for the activities- hence we give time in lieu to set up this new collaboration to establish a platform to study lung outcome in chidlren who are/were affected by TB
Collaborator Contribution This GCRF award has established a partnership with Dr Kevin Mortimer at Liverpool University and his team. The grant is held at MRC Gambia at teh LSHTM. Whilst he has a small salary contribution, his team is contributing in kind in order to set things up for the more substantial application next year.
Impact not yet
Start Year 2020
 
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 WANETAM network 
Organisation West African Network for TB, AIDS and Malaria
Country Senegal 
Sector Charity/Non Profit 
PI Contribution The WANETAM network is an EDCTP funded network across partners in West Africa. My group leads the TB workpackage which has created a platform for the conduct of childhood TB research and funds research and career development for paediatricians and NLTP in the region to invest in better diagnosis and management of childhood TB. Most activities are led by my post doc Dr Toyin Togun who achieved his PhD under the original program grant form MRC to myself, I therefore see this as an impactful outcome.
Collaborator Contribution Partners in 7 West African countries are making contributions by dedication time and personnel to the aim of the network package, which is to achieve better diagnosis and management of childhood TB in the region.
Impact ongoing, only started in 2019, training delivered, all Ethics through in all countries, MSc student appointed, database designed and shared- now recruiting
Start Year 2019
 
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 Engagement with local schoolchidlrne aroufn TB in the community 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Several schools have been invited to workshops and information sessions at the MRC Unit to talk about TB, the symptoms, stigma-related issues- these activities are led by a member of our team, Dr Owalabi, who also received small funding for Public engagement from the LSHTM.
Year(s) Of Engagement Activity 2019,2020
 
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 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 World TB Day in conjucntion with National TB Program the Gambia 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Each year our team collaborated with the National TB program in teh Gambia to stage events around World TB Day and to give visibility to all of the TB control activities. These events are always attended by national TV and radio and written up in national newspapers as well as publicised via the mRC comms channels. World TB Day is an international event.
Year(s) Of Engagement Activity 2019,2020