TBVAC2020: The quest for new and improved TB vaccines
The current vaccine against tuberculosis, Bacille Calmette Guerin (BCG) is nearly a century old and does not provide effective protection against TB, especially in high incidence settings where it is most needed. To eventually eliminate TB, we need a new, highly efficacious vaccine. The TB Vaccine Initiative consortium (TBVAC2020) has been granted 24.6 million euros from the European Horizon 2020 programme and other government sources to advance new TB vaccine candidates from discovery to clinical development.
Three TB Centre principal investigators, Hazel Dockrell, Gregory Bancroft and Helen Fletcher, are leading on three separate projects as part of a consortium of 40 research institutes, pioneering innovative approaches to vaccine development.
In three major work packages of the TBVAC2020 project, laboratory studies are focused on:
(1) safety screening of candidate TB vaccines in the SCID mouse;
(2) immune correlates of risk for TB disease in humans;
(3) infant immune responses to BCG vaccination;
(4) development of mouse models of human TB disease risk for testing of TB vaccine candidates.
ZAMBART in Zambia is one of the 11 sites testing the efficacy of the GSK candidate TB vaccine M72/AS01.
Discovery and development of TB correlates of protection
The Biomarkers of Protection work package of TBVAC2020 aims to optimise the measurement of candidate biomarkers and develop methods such as the Mycobacterial Growth Inhibition assay, which indicate the level of immunity a person has against TB. Host immune responses will be correlated with TB disease risk and the effect of helminth worm infections on mycobacterial growth inhibition will be analysed.
Standardised pre-clinical models for candidate TB vaccine evaluation
This component of the TBVAC2020 research programme at the School will provide standardised head-to-head testing of candidate TB vaccines. Testing for both safety and efficacy will be performed using immune deficient and immunocompetent mice respectively.
Diabetes associated with increased risk of TB in the United Kingdom
Researchers at the TB Centre have used UK electronic routine health records to study the association between diabetes and TB. The project used data taken from general practice consultations and records for up to six million patients over more than 20 years and produced a cohort of more than a quarter of a million patients with diabetes, who were compared with a control group and followed up for incident TB disease. Despite the UK having a very effective primary health care system that incentivises high quality care for chronic diseases such as diabetes, the increased risk of TB was still evident. The study showed that those accessing the least amount of diabetes care were at the greatest risk for TB. The findings have implications for UK national policy proposing to provide high risk groups access to TB screening and treatment in primary care settings.
Risk of tuberculosis in patients with diabetes: population based cohort study using the UK Clinical Practice Research Datalink. Louise Pealing, Kevin Wing, Rohini Mathur, David Prieto-Merino, Liam Smeeth, David A J Moore. BMC Medicine 06/2015; 13(1):135.
TB and diabetes mellitus in TANDEM
Diabetes increases the risk of TB and seems to impair response to TB treatment. The TANDEM Consortium, funded by the European Union, is investigating the links between TB and type 2 diabetes. Through field work in Peru, South Africa, Romania and Indonesia, TANDEM will determine the most cost-effective approaches to screening for diabetes in TB patients and for TB in diabetes patients. Together with partners in the Netherlands, Germany and New Zealand, molecular interactions between M. tuberculosis infection and diabetes are being elucidated using fat cells, macrophages, global gene expression analysis and genetic analysis. The TANDEM consortium is funded by a four year European Union grant award of 5.9 million euros.
TANDEM: understanding diabetes and tuberculosis. Reinout van Crevel and Hazel M. Dockrell; TANDEM Consortium. Lancet Diabetes Endocrinol, 2014; 2(4):270-2.
Mathematical modelling of vaccine response and impact of new vaccines
In an example of interdisciplinary collaboration, experimental data are being used to better inform models of vaccine immune response.
Further, modelling has been used to inform preferred product characteristics developed by partners Aeras, the Bill and Melinda Gates Foundation, TBVI and the WHO to accelerate promising TB vaccines through the pipeline and make sure the target population is ready. Mathematical modelling, produced by the TB Centre in partnership with Aeras Asia, has led to a targeted change in vaccine policy, in line with WHO goals for TB control, to ensure that TB vaccines will be as effective as possible for those who need them most.
The immunology of TB in adults and infants in Uganda
Immunology research in Uganda, in collaboration with the MRC and the Uganda Virus Research Institute, is investigating the B cell response to BCG and the role of innate immunity in protection against TB, and looking to address the question “how does maternal latent TB infection affect infant responses to BCG?”. Nested within this project is a study of the influence of epigenetics on the BCG response.