Understanding Immunity to Tuberculosis using the TB case-contact research platform (TBCC)

Lead Research Organisation: MRC Unit, The Gambia

Abstract

Tuberculosis (TB) is a global health problem, particularly in developing countries due to over-crowded living conditions and high HIV infection rates. There has been no new vaccine for over 90 years and the current vaccine does not work in adults. There are also no diagnostic tests that can be used in health clinics without facilities such as x-ray, power or water. Unfortunately, these are the clinics that see 60% of patients.
One of the reasons we have not developed new tests and vaccines is because the bacterium that causes TB constantly changes its appearance so it cannot be easily detected by the cells in the body trying to fight it.
TB case-contact studies provide unique opportunities for the development of new tests and vaccines. When we diagnose someone with TB, we visit their home for two years to see if any of their family members (adults and children) also develop TB. We assume that if someone sleeps in the same room as the person with TB they are likely to get TB themselves (since TB is transmitted by coughing). If they don’t get TB, we can look at what types of cells are present in their blood that might have protected them. This will help us know what we should achieve with a new vaccine. We can also investigate the person with disease and see what their immune responses are like as this will help us to develop new diagnostic tests.
Through our work we hope to develop better diagnostic tests and ultimately a vaccine that will contribute to eliminate TB world-wide.

Technical Summary

Importance of the research:
Tuberculosis (TB) remains a daunting global health problem with over 9 million new cases and 1.4 million deaths each year. We urgently require new vaccines, diagnostics and treatment regimes but to achieve this we need a better understanding of the interaction between the underlying pathogen (Mycobacterium tuberculosis) and the host response to the pathogen. This can be determined using the spectrum of infection/disease states that are available to us through the TB case-contact (TBCC) platform. Our central research paradigm is that dynamic changes in host immune responses that take place during encounters with invading pathogens and during interventions such as treatment or vaccination, will allow us to reveal causal relationships with biomarkers. The MRC TB case-contact platform has been running since 2001 and has encompassed epidemiological, clinical, genetic, microbiological and immunological aspects of tuberculosis with over 80 peer-reviewed publications.

Aims of the TBCC:
Our aims are to analyse the host and pathogen at different stages of infection and disease that will inform on rational development of novel vaccines and diagnostics.

Study design:
Following diagnosis of TB, patients are consented and recruited to the TBCC platform. Subsequently, field workers visit their household to recruit and consent family members (average 10 per household). Sputum samples from index cases are studied for bacterial load, drug-resistance, strain of infection and follow-up for treatment response. At the same time, blood and other body fluids are analysed for host immune responses to TB antigens. Household contacts are tested to determine presence of latent infection (90% of infected people remain asymptomatic throughout life) and are monitored for 2 years to determine any changes in infection/disease states. Blood samples from exposed but apparently uninfected household contacts are analysed to determine what factors contribute to protective immunity to TB.

Clinical and diagnostic studies:
Our well established platform has allowed us to perform novel vaccine trials, multi-site biomarker studies; TB transmission studies; molecular typing of bacteria; implementation of new diagnostic tests such as the GeneXpert; host genetics and many more. The adult TBCC platform has also enabled the development of a pediatric TB program through Prof. Kampmann’s MRC Program Grant. Importantly, we have generated a unique and well-characterized bank of samples for future studies such as host genetics and ‘omics research and also mycobacterial strains and transmission data.

Translational research and public health benefits:
Our major translational focus is on development of new diagnostic tests for adult and pediatric TB. We have 2 patents in this regard for development of point-of-care tests. All our research has a public health focus with potential to impact on policy and practice. Importantly, we have long-standing collaborations with leaders in the TB field: the Bill and Melinda Gates funded Grand Challenges project established us as a major player in multi-site consortiums, which are essential for development of next generation diagnostics and vaccines.

Publications

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Adegbola RA (2003) Surveillance of drug-resistant Mycobacterium tuberculosis in The Gambia. 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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Adetifa IM (2007) Rising ELISPOT count prior to the onset of symptoms of full-blown tuberculosis disease. 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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Adetifa IM (2013) Interferon-? ELISPOT as a biomarker of treatment efficacy in latent tuberculosis infection: a clinical trial. in American journal of respiratory and critical care medicine

 
Description Advisory committee on MDR-TB policy and practice in The Gambia
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description Participation in advisory group on HIV/TB policy and practice in The Gambia (Global Fund)
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description Participation in generation of evidence for use of TB-LAMP for diagnosis
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
 
Description WHO guidelines on IGRA
Geographic Reach Africa 
Policy Influence Type Citation in other policy documents
Impact Impact on policy - Gambia studies referenced in WHO guidelines on use of IGRAs in high vs low burden countries providing robust evidence of IGRAs limited performance in this setting compared to low burden non BCG vaccinated tourists. References also included in WHO commissioned review of IGRA performance in children.
 
Description DGF
Amount £100,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 01/2018
 
Description GC6-2013
Amount $6,000,000 (USD)
Funding ID 43172 
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2013 
End 12/2017
 
Description GC6-74
Amount $12,000,000 (USD)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2006 
End 12/2012
 
Description LAMP TB test
Amount £16,000 (GBP)
Organisation Foundation for Innovative New Diagnostics (FIND) 
Sector Charity/Non Profit
Country Switzerland
Start 11/2013 
End 06/2015
 
Description MRC Capital funds
Amount £150,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2013 
End 06/2013
 
Description MRC mid-career grant
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2013 
End 06/2013
 
Description Mycobacterium tuberculosis antigen diversity study
Amount $2,000,000 (USD)
Funding ID R01 AI090928 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 07/2012 
End 06/2015
 
Description Screen-TB
Amount € 2,000,000 (EUR)
Funding ID DRIA2014-311 
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country Netherlands
Start 04/2016 
End 04/2019
 
Title RISK4 gene signature 
Description RNA-seq of tuberculosis incident cases and controls at 3 time-points 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? No  
Impact small gene signature is the first described to identify TB case-contacts at risk of developing active TB. This can be used for targeted therapeutic interventions 
URL https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE94438
 
Description AE-TBC 
Organisation University of Stellenbosch
Country South Africa 
Sector Academic/University 
PI Contribution This was a multi-site study (7 African field-sites, 2 European partners) for development of a rapid TB test. MRC Gambia recruited and analysed 200 subjects.
Collaborator Contribution Equal numbers of recruitment and analyses
Impact 1 manuscript to date: Ota et al., ERJ, 2014. Multi-disciplinary: immunology, clinical, microbiology
Start Year 2010
 
Description GC6-2013 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution Part of multi-site study for TB biomarkers. MRC recruited patients and their household contacts to generate incident cases - contacts who develop active TB within 2 years of recruitment. These subjects hold the key to understanding protective immunity to TB. RNA, plasma and PBMC are being analysed for biomarkers of TB 'risk'.
Collaborator Contribution Securing funding and providing resources for RNA and plasma analysis.
Impact 2 consortium papers (Sutherland et al., 2013, CMI; Sutherland et al., 2013, Plos One). RNA-seq data published in Lancet in 2016. 3 publications in 2018: AJRCCM, Nature Communications, Frontiers in Microbiology Multi-disciplinary: epidemiology, clinical, immunological, microbiological
Start Year 2007
 
Description Mask Study 
Organisation University of Leicester
Country United Kingdom 
Sector Academic/University 
PI Contribution The Mask study involves analysis of TB transmission and thus use of our TB case-contact platform to correlate patient transmission with infection status of the contacts.
Collaborator Contribution Provision of masks and analysis of all samples collected.
Impact Publications pending. Multidisciplinary project including microbiology and immunology
Start Year 2016
 
Description Mtb antigen diversity 
Organisation New York University
Country United States 
Sector Academic/University 
PI Contribution Subject recruitment, all immunology
Collaborator Contribution In silico epitope prediction
Impact 2 publications and a presentation at Keystone TB meeting 2015
Start Year 2010
 
Description Screen-TB 
Organisation University of Stellenbosch
Country South Africa 
Sector Academic/University 
PI Contribution Dr. Sutherland is site-PI for a multi-site study on development of a rapid diagnostic test for TB. This involves recruitment of 200 patients with symptoms suggestive of TB but prior to diagnosis. These patients are then diagnosed for TB or other respiratory disorders (ORD) using GeneXpert and biomarkers for TB are determined. The second stage of the project will use 'real-time' finger-prick testing of patients at the outpatients clinic to validate our diagnostic test in a 'field' setting.
Collaborator Contribution Grant co-ordinator/PI
Impact Recruitment of patients will not begin until mid-2016. Outputs will occur by 2019.
Start Year 2015
 
Description TB-Sequel 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department Faculty of Medicine
Country Germany 
Sector Academic/University 
PI Contribution Part of a multi-site study for assessing risk factors for TB-sequelae. Dr. Sutherland is Research Task 2 (host immunity) leader and Prof. Kampmann is RT5 (capacity building) leader.
Collaborator Contribution Coordination and management of grant for BMBF
Impact We have not yet initiated recruitment of study subjects. This will occur mid-2017.
Start Year 2014
 
Description TBVAC2020 
Organisation Leiden University Medical Center
Department Immunology (LUMC-I)
Country Netherlands 
Sector Hospitals 
PI Contribution For LUMC, this involved provision of RNA samples from TB-exposed household contacts. We will compare contacts who become infected to those that remain uninfected to determine early protective biomarkers. For MPIIB, this involved sending data generated from analysing RNA and plasma for bioinformatics
Collaborator Contribution For LUMC: MLPA analysis of RNA from our study subjects For MPIIB: Computational biology for metabolomics and RNA-seq data
Impact None to date
Start Year 2014
 
Description TBVAC2020 
Organisation Max Planck Society
Department Max Planck Institute for Infection Biology
Country Germany 
Sector Charity/Non Profit 
PI Contribution For LUMC, this involved provision of RNA samples from TB-exposed household contacts. We will compare contacts who become infected to those that remain uninfected to determine early protective biomarkers. For MPIIB, this involved sending data generated from analysing RNA and plasma for bioinformatics
Collaborator Contribution For LUMC: MLPA analysis of RNA from our study subjects For MPIIB: Computational biology for metabolomics and RNA-seq data
Impact None to date
Start Year 2014
 
Title Host biomarkers in Sputum for rapid TB diagnosis 
Description Use of sputum host biomarkers for diagnosis of TB. The biomarkers will be used for future development of a rapid TB test. 
IP Reference WO2015040377 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact None to date
 
Title transcriptomic signatures for identifying individuals at-risk for TB disease progression 
Description We have developed a blood-derived signature for detection of individuals at risk of TB disease progression. Identification of these individuals and subsequent TB treatment would reduce the TB burden by 4-fold. Several co-inventors are named on the application including Gerhard Walzl from Stellenbosch University (South Africa) as the submitting institute. 
IP Reference 1804019.6 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact We have received funding based on this discovery to test a fingerstick blood test for identification of at-risk household contacts.
 
Title Biomarkers in sputum for rapid TB diagnosis 
Description We are seeking to develop a lateral flow test for detection of TB using biomarkers present in sputum (phlegm), which can be rolled out in basic healthcare clinics (level 3), without x-ray or other infrastructure. We are applying for DPFS funding through MRC to continue this development. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2012
Development Status On hold
Impact Please note - these are expected impacts once the test is rolled out. 
 
Description 7th EDCTP forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk generated discussion from researchers and networking opportunities

Talk prompted discusssion for future research directions in W. Africa
Year(s) Of Engagement Activity 2014
 
Description Immunology workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact 70 post-graduate students and 15 international faculty attended an immunology workshop for West Africa. This was the first time such an event had been held in the region and consisted of lectures and practical sessions. The students also presented posters with prizes for the top 3. The event was deemed highly successful and generated mentoring and networking.
Year(s) Of Engagement Activity 2016
 
Description National Tuberculosis day 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact World Tuberculosis day is marked in the country. On this occassion a presentation was made detailing the increasing high prevalence of the disease and sensitising the community on how to detect it early for treatment. These data/talk was broadcast via the national radio and television to the entire public.

Community engagement and awareness of the TB problem, to facilitate increased health-seeking behaviours and inform the community and government of the work MRC conducts in regards to TB. This in turn facilitates continued collaboration between MRC and the National TB control program.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013
 
Description Networking 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact The meeting was organised to build on our links with the National TB control program, which is vital for our on-going TB research in The Gambia.

Increased patient recruitment. Better communication link between MRC and the external health clinics. Better community engagement for our work at MRC. Better government interactions.
Year(s) Of Engagement Activity 2013
 
Description Oral presentation at EDCTP meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Oral presentation at the EDCTP forum in Portugal, September, 2018. Presentation was on results obtained for TB/HIV biomarker analysis.
Year(s) Of Engagement Activity 2018
 
Description School engagement activity 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The purpose of this workshop was to provide awareness to adolescents on Tuberculosis in order to increase health-seeking behaviours. The results from the study have been used as pilot data for a Wellcome Trust engagement award submission.
Year(s) Of Engagement Activity 2018
 
Description TB training workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact MRC is the principal site for microbiological training for sites involved in WANETAM. We provide training in culture, smear, GeneXpert and other techniques essential for TB diagnosis.

Increasing TB diagnosis and capacity building in developing countries. Reducing the burden of TB. Providing economic benefits to developing countries.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011,2013
 
Description TB-sequel 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Kick-off meeting for health systems networks which funds 5 projects in Africa for capacity building and development. The discussions generated new avenues for future funding and ideas for sustainability of the research networks.
Year(s) Of Engagement Activity 2017
 
Description TB2016 conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact TB2016 was adjunct to AIDS2016 and was the first time a TB meeting was attached to the internationally renowned AIDS consortium. The meeting included policy makers, activists, researchers and patients from around the globe. This resulted in increased awareness of TB which is directly related to the AIDS epidemic.
Year(s) Of Engagement Activity 2016
 
Description WHO Global task force 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Dr. Ifedayo Adetifa. WHO Global Task Force on TB Impact Measurement Multi-country global workshop on TB prevalence surveys TB surveillance Workshop in Accra, Ghana, April 2013

Discussion on TB prevalence surveys in Gambia and other countries. The prevalence of TB has been accurately measured in Gambia for the first time in 50 years through the Global Fund.
Year(s) Of Engagement Activity 2013
 
Description World TB day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Each year we organise a world TB day celebration in a particular community to raise awareness for TB. The aim is to reduce stigma and increase health-seeking behaviours.
Year(s) Of Engagement Activity 2018
 
Description World TB day 2014 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact Increased engagement with communities and strengthened ties with the national TB program

sustained collaborations with the national TB program
Year(s) Of Engagement Activity 2014
 
Description oral presentation at Keystone TB in Whistler, BC 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact This talk was at an international scientific meeting, which increased networking, publicity for The Gambia and interest in Tuberculosis studies within the region.
Year(s) Of Engagement Activity 2018