The impact of maternal infection with Mycobacterium tuberculosis on the infant response to BCG immunisation

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Infectious and Tropical Diseases

Abstract

Tuberculosis (TB) is still a very important health problem in sub-Saharan Africa. Many people are infected with Mycobacterium tuberculosis (M.tb) (the bacterium that causes tuberculosis) in these countries, but the infection is kept in check by the immune system and the people remain healthy. We call this latent infection. Usually, only about 10% of infected individuals will progress to having the active form of the disease in their lifetime. However, when people do get the active disease, they can infect many other people, and so the cycle continues. TB kills approximately 2 million people every year, and another 10 million people become infected with M.tb every year.

One way to eradicate TB would be to immunise everyone with an effective vaccine. Unfortunately, to date there is only one licensed vaccine, BCG, which was first introduced almost 100 years ago. BCG is given in many countries at, or around the time of birth. In sub-Saharan Africa, this immunisation schedule has been very effective at preventing some of the more severe (and deadly) forms of the disease in children, but the vaccine does not protect against the more common, active pulmonary form of the disease (the disease affecting the lungs) that occurs in adolescents and adults. By contrast, in countries such as the UK, BCG immunisation gives up to 80% protection against active pulmonary disease in adolescents and adults. We do not know why BCG should give poorer protection against pulmonary TB in sub-Saharan African countries compared to European countries, and our study is aimed at understanding this phenomenon.

Since latent M.tb infection is more prevalent in sub-Saharan Africa than in the UK (for example), we think that part of the answer may lie in whether a mother has an underlying, latent M.tb infection. We think that this infection in a pregnant woman may affect the developing baby's own immune system. For example, if the baby is exposed to maternal M.tb infection while in the womb, when its immune system is developing, the immune system may regard the presence of Mtb infection as "normal" and fail to mount a suitable reaction to the infection. In such a case, when the baby is born and is given the BCG vaccine, the baby may not respond in the same way as a baby who was born of a mother without a latent M.tb infection (such as mothers in the UK).

Our study will therefore look at the infant immune response to the BCG vaccine. We will examine immune responses in babies born in sub-Saharan Africa from mothers who do and don't have a latent M.tb infection, and we will compare their results with results from babies born of mothers in the UK, where M.tb infection is much less common. These results will give us a good idea of whether maternal M.tb infection status affects the infant response to BCG. If it does, then we may have to think about testing young women for the infection, and treating them before or during pregnancy.

Technical Summary

We propose that the poor effectiveness of BCG in sub-Saharan Africa may be due to maternal Mycobacterium tuberculosis (M.tb) infection, which is endemic in this setting. If maternal M.tb infection influences the infant response to BCG, the timing, magnitude, or quality of the BCG-specific immune response may be altered in infants of M.tb-infected women compared to those without such exposure. Such effects may be manifested as a delayed peak in response to BCG immunisation, or a lower overall recruitment of BCG-specific immune cells in the priming phase, leading to a lower set point of BCG-specific immunological memory, and as differences in the effector response profile.

We will therefore conduct longitudinal studies to examine the timing, magnitude and quality of the initial response to BCG immunisation, and will follow infants to age one year in order to assess the establishment of BCG-specific immunological memory. To investigate the effects of maternal M.tb infection, we will compare these parameters between infants of mothers infected with M.tb, and infants of uninfected mothers, in Uganda. We will also explore mechanisms by which such effects may be mediated by studying differences in dendritic cell profiles, mRNA-Seq profiles and in circulating molecules - such as chemokines and cytokines - that may control the immunological milieu and hence, ultimately, effector cell function. To investigate whether maternal M.tb infection contributes significantly to the association between latitude and response to BCG immunisation we will compare infant responses between Uganda and the UK and assess whether differences are qualitatively similar to those between infants of mothers with and without M.tb infection.

Planned Impact

1. The primary, long-term, intended beneficiaries of our research are the populations of TB endemic countries. If our study shows that maternal M.tb infection affects the infant response to BCG the next step will be to investigate the benefits of treatment of latent tuberculosis in young women, before or during pregnancy, for the response to BCG immunisation in their infants. These further studies will be designed to inform local, national and international guidelines on the treatment of M.tb infection (latent or otherwise) in young women before, or during pregnancy, to allow for a better protective vaccine outcome in infants and children in TB endemic settings. This will have a knock-on effect of potentially decreasing the large burden of latent M.tb infection, thereby decreasing the number of latently infected adults and thus driving down the burden of TB. This would have obvious benefits for any endemic country by decreasing morbidity and mortality associated with M.tb infection, and of having healthier adults contributing to the health and wealth of the nation.

2. In addition, there will be particular immediate and long-term beneficiaries in Uganda.
i. The mothers and their infants participating in the study will benefit, during the critical first year of the infant's life, from the excellent, free medical care provided by the research clinic.
ii. The staff of Entebbe Hospital, with whom the research team collaborates, will benefit from on-going training in research methods and good clinical research practice, as well as from salary enhancement in appreciation of their contribution to the work.
iii. The research team. The Co-infection Studies Programme has a strong track record in research capacity building, having developed a research team trained in good clinical research practice now numbering 40 strong, and having contributed to research training for 20 Masters, 12 PhD students and 5 post-doctoral fellows, as well as numerous school-leaver and undergraduate internships. The proposed work will continue to act as a platform for such research capacity development.
iv. Technology and skills transfer. The London team will support the transfer of new techniques to Uganda, particularly the use of Luminex assays, which are just being established in Uganda, thus enhancing capacity in cutting edge immunology research. The analysis of complex immunological data is of increasing importance given availability of techniques, such as Luminex and microarray, which can produce results on hundreds or thousands of outcomes from a small amount of material. Dr Emily Webb will work with statisticians in Uganda on the analysis of Luminex data using principal component analysis. Ugandan trainees will also have the opportunity to learn about the analysis of microarray data through the collaboration with VGTI: this project is one of several currently in progress between VGTI and the Uganda Virus Research Institute and together with other projects, will contribute to the development of bioinformatics expertise at the MRC Uganda Unit.

Publications

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Cose S (2015) Immunology in Africa. in Tropical medicine & international health : TM & IH

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Dockrell HM (2016) Towards new TB vaccines: What are the challenges? in Pathogens and disease

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Elliott A (2015) Capacity for science in sub-Saharan Africa. in Lancet (London, England)

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Mawa PA (2015) The impact of maternal infection with Mycobacterium tuberculosis on the infant response to bacille Calmette-Guérin immunization. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

 
Description Immunomodulation and Vaccine/Co-Infections Programme
Amount £918,513 (GBP)
Funding ID MC_UP_1204/15 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2017 
End 01/2018
 
Description Makerere University / UVRI Centre of Excellence for Infection and Immunity Research and Training
Amount £4,442,596 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Strategic Award
Sector Charity/Non Profit
Country United Kingdom
Start 08/2015 
End 07/2020
 
Description Population differences in vaccine response: the role, reversibility and mediators of immunomodulation by chronic parasitic infections in the tropics
Amount £2,319,188 (GBP)
Funding ID MR/R02118X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2018 
End 04/2022
 
Title Infant BCG database 
Description We have generated a sample archive and database of multiple samples from infants throughout the first year of life, who received BCG at birth. This database includes physical samples (PBMCs, DNA, RNA and plasma) as well as analysis databases in whole blood stimulation and flow cytometry. 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact None as yet, although samples are being sent to collaborators in the UK to undertake DNA methylation studies, as well as RNASeq studies. Results for this dataset should be available later in the year. 
 
Description Co-supervision with colleagues from Witwatersrand 
Organisation University of the Witwatersrand
Department School of Public Health
Country South Africa 
Sector Academic/University 
PI Contribution We are jointly supervising PhD student Lawrence Lubyayi who is using data form this project for his PhD
Collaborator Contribution We are jointly supervising PhD student Lawrence Lubyayi who is using data form this project for his PhD
Impact Draft paper
Start Year 2017
 
Description Early versus late BCG vaccination in HIV-1 exposed infants in Uganda 
Organisation Makerere University
Department School of Public Health
Country Uganda 
Sector Academic/University 
PI Contribution Dr Steve Cose was invited to collaborate on the above funded clinical trial, as the Immunologist for the trial. The trial is funded by the Research Council for Norway, and has now funded a PhD student. Dr Cose is formally registered as a PhD supervisor for the student. This collaboration and PhD student has come as a direct result of his work in Uganda on our MRC Project grant, and our international reputation for undertaking studies on tuberculosis. Our lab will serve as the research lab for all immunological outputs and analysis.
Collaborator Contribution The senior authors for this clinical trial (NCT02606526) are leading epidemiologists who conceived the idea and obtained funding. The primary outcomes for this trial are to compare the risk of severe illness during the first 14 weeks of life, in infants given BCG at birth compared to those given BCG at 14 weeks. Secondary outcomes are to examine the immunological mechanisms behind any effect - in particular the hypothesis that BCG induces trained immunity in the innate immune system, and that giving BCG at birth results in a lower incidence of recorded severe illness events in this group of children. The lead authors will undertake the epidemiological analyses and trial co-ordination.
Impact None as yet.
Start Year 2016
 
Description Early versus late BCG vaccination in HIV-1 exposed infants in Uganda 
Organisation University of Bergen
Department Department of Earth Science
Country Norway 
Sector Academic/University 
PI Contribution Dr Steve Cose was invited to collaborate on the above funded clinical trial, as the Immunologist for the trial. The trial is funded by the Research Council for Norway, and has now funded a PhD student. Dr Cose is formally registered as a PhD supervisor for the student. This collaboration and PhD student has come as a direct result of his work in Uganda on our MRC Project grant, and our international reputation for undertaking studies on tuberculosis. Our lab will serve as the research lab for all immunological outputs and analysis.
Collaborator Contribution The senior authors for this clinical trial (NCT02606526) are leading epidemiologists who conceived the idea and obtained funding. The primary outcomes for this trial are to compare the risk of severe illness during the first 14 weeks of life, in infants given BCG at birth compared to those given BCG at 14 weeks. Secondary outcomes are to examine the immunological mechanisms behind any effect - in particular the hypothesis that BCG induces trained immunity in the innate immune system, and that giving BCG at birth results in a lower incidence of recorded severe illness events in this group of children. The lead authors will undertake the epidemiological analyses and trial co-ordination.
Impact None as yet.
Start Year 2016
 
Description MRC/UVRI Uganda Unit - London School of Hygiene & Tropical Medicine 
Organisation MRC/UVRI Uganda Research Unit on AIDS
Country Uganda 
Sector Public 
PI Contribution I and my research team are based at the MRC/UVRI Unit. I lead a research programme there. In 2018 the Unit became a part of the London School of Hygiene and Tropical Medicine so this ceased to be a collaboration in the earlier sense of the word.
Collaborator Contribution The MRC/UVRI Unit hosts the research, providing facilities, administration and research support
Impact This collaboration has resulted in more than 80 research publications, several research grants, two Wellcome Trust funded and one EDCTP funded research capacity building grants, much training at undergraduate, Masters, PhD and post-doctoral level.
 
Description Entebbe Mother and Baby Study meeting for participants and community representatives 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Potential participants and community members were made aware of the planned research

Strong interest in the community in participating in the study
Year(s) Of Engagement Activity 2014
 
Description Immunology Conference SA 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A poster presentation of some of our preliminary work on this grant. The presentation garnered a lot of interest from experts in the field, with a good discussion and suggestions for further work.
Year(s) Of Engagement Activity 2015
 
Description Keystone TB Conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Abstract and poster submitted for the upcoming Keystone conference "Tuberculosis Co-Morbidities and Immunopathogenesis", to be held at Keystone, CO, USA, Feb 28 - Mar 3. No outcomes or impacts as yet.
Year(s) Of Engagement Activity 2016
 
Description LSHTM TB Centre 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Invited to give a presentation to the LSHTM TB Centre Annual retreat, to update the Centre on preliminary results of our grant. The talk generated a good discussion at the time, and in several outbreak sessions afterwards. Several discussions were based around establishing new collaborations to examine other areas of research, for example using our data for mathematical modelling.
Year(s) Of Engagement Activity 2015
 
Description MRC Quinquennial Review 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Supporters
Results and Impact A formal group of funders and scientific board members attended a three day Review of the MRC Unit, to assess the next five years of funding. Dr Stephen Cose presented a poster of our work to members, which resulted in an application (ultimately unsuccessful) to the 2016 GCRF round.
Year(s) Of Engagement Activity 2016
 
Description Meeting with policy makers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact Meeting with the manager of the Uganda Tuberculosis Control Programme to share results.
Year(s) Of Engagement Activity 2018
 
Description Open Day for Secondary Schools 
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 Schools
Results and Impact We led an Open Day at the Uganda Virus Research Institute, in collaboration with Makerere University. About 900 senior secondary students attended with their teachers. The guest of honour was the Minister of State for Education and Sports (Higher Education).
Year(s) Of Engagement Activity 2018
URL http://www.muii.org.ug/
 
Description Poster Presentation - by Dr Stephen Cose, British Society for Immunology 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A student undertaking the research component of his MSc (LSHTM) cam to Uganda to undertake a study on acquisition of CMV within our funded infant study. The results of this study were presented at the British Society for Immunology.
Year(s) Of Engagement Activity 2016
 
Description Presentation of proposed research to the director of the Uganda National Tuberculosis control programme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact Information regarding planned work on BCG research was shared with policy makers in the host country for the work.

The leader of the national TB control programme became aware of relevant work.
Year(s) Of Engagement Activity 2014
 
Description Research Seminar (Lahore, Pakistan) by Dr Stephen Cose 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Dr Cose gave a research seminar on our work in Uganda during a visit to Forman Christian College, Lahore, Pakistan. My presentation generated a lot of debate throughout the audience, and has resulted in discussions to start a collaboration with colleagues in Pakistan. A PhD student form the lab in Pakistan is currently visiting the MRC/UVRI Unit in Uganda to learn flow cytometric techniques.
Year(s) Of Engagement Activity 2017
 
Description TB Conference - Keystone 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr Stephen Cose presented preliminary data from our funded study at the Keystone conference in Vancouver, Canada. This data generated a lot of interest and discussion after presentation.
Year(s) Of Engagement Activity 2016