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World TB Day: what next for prevention and treatment?

24 Mar, 2015

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TB remains a global problem with 1.5 million deaths and 9 million cases per year. On World TB Day, Wellcome Trust Senior Science Portfolio Developer Marta Tufet looks back at the history of TB prevention and treatment, explains what the Wellcome Trust is doing to support research in this area, and asks what more needs to be done to make an impact on this stubborn disease…

At 13 I moved to France mid-school term and mid-TB vaccination campaign. All the kids were lined up at the school’s gym and one by one a nurse inserted a needle into our forearms – the Tuberculin skin test to see whether we would mount a localised immune response, an indication that there had been exposure to the bacteria. To this day the memory remains vivid – not speaking a word of French at the time, it presented an excellent communication opportunity. I eagerly held out my arm and gestured other kids to do the same and compare who had the biggest reaction. To my surprise, I had nothing to show for it. A few days later, my newfound friends and I – those of us with still no lump on our forearms – were lined up again at the gym, and this time given the Bacille Calmette-Guerin (BCG) Vaccination, developed in the 1920s, with the aim of protecting us against the most serious form of TB.

BCG vaccination was mandatory for school children in France between 1950 and 2007, before a shift to selective vaccination. Similarly, the UK ran a universal immunisation campaign from 1953-2005. Today the WHO recommends that BCG be given to all children born in countries with a high prevalence of TB. But despite these multiple vaccination campaigns TB remains a global problem with 1.5 million deaths and 9 million cases per year.

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Marta (centre, wearing a yellow dress) at school in France where she received her BCG vaccination. 

Unfortunately, it would seem that for the past 90 years we have been relying on a vaccine that is far from perfect. Although BCG can protect against the severe extrapulmonary form of TB in children, it is unreliable in protecting against pulmonary TB, which accounts for the majority of TB cases globally. Moreover, BCG’s efficacy diminishes the closer you live to the equator, where TB is most prevalent. The vaccine is also not safe in infants who are infected with HIV, yet HIV is considered the single most important factor in the increase of TB in many countries, increasing the likelihood of a TB infection turning into active disease.

Because of these problems, we need a new more effective vaccine, which is easier said than done.  The complexities of TB disease, comprising both latent (without symptoms) and active states, the lack of adequate animal models, limited financial resources and poor coordination are just some of the contributing factors for why we are not any closer to a modern TB vaccine now than we were 15 years ago.

Most vaccine efforts have focused on the same model of understanding TB immunology as was used to develop the BCG vaccine. However, even the most promising TB vaccine to date, MVA85A, has failed to demonstrate significant efficacy in clinical trials. Since then, many researchers and funders feel the need to go back to the drawing-board to re-evaluate our understanding of what constitutes an essential and sufficient immune response to TB before pursuing new vaccine efforts.

Prevention aside, TB is in fact treatable with a mixture of antibiotics over a duration of 6-9 months. Regrettably, access to drugs in poorer countries is still an obstacle and detecting TB in the first place is not easy. Furthermore, these drugs are now threatened by the emergence of resistance. We can blame poor adherence to courses of treatment, falsified or poor quality drugs, or even the bacteria’s evolutionary prowess, but the reality remains strikingly worrying: in 2013 alone, 480,000 people developed multi-drug resistant TB, and for these individuals there is unfortunately little hope.

Today on world TB day we are being asked to “gear up to end TB” and at the Trust we are committed to support research towards this aim. Putting an end to TB will require more than our traditional investments in basic research towards vaccine and drug development.

To address this, the Welcome Trust, in partnership with the Medical Research Council (MRC) and the Department For International Development (DFID), have also been supporting a number of global health trials tackling multiple angles: from improved diagnosis, to optimized treatment regimens, to socioeconomic interventions:

  • The STAMP trial led by Stephen Lawn at the London School of Hygiene and Tropical Medicine (LSHTM) aims to improve treatment in patients with HIV and TB by determining whether the addition of a new urine-based test to the standard diagnosis strategy can reduce mortality in Malawi and South Africa.
  • The TRUNCATE-TB trial led by Patrick Phillips at University College London (UCL) aims to determine whether treatment for drug-sensitive TB can be improved whilst at the same time reducing the drive towards new cases of multi-drug resistant TB in multiple Asian countries by optimizing regimens at the individual level.
  • The TB fast-track trial led by Alison Grant at LSHTM aims to see whether you can reduce early mortality by using point-of-care technology to rapidly identify individuals presenting for HIV treatment at high risk of TB and ensuring they start TB treatment.
  • Diana Gibb at the MRC clinical trials unit is investigating whether a shorter treatment for children with milder forms TB is just as effective as the currently recommended treatment, which has been largely based on research conducted only in adults. This would not only be advantageous for the child but also for the over-burdened health systems, reducing the number of clinic visits children would need to make to take their drugs.
  • Carlton Evans at Imperial College is evaluating the impact of socioeconomic interventions for reducing poverty, improving access to TB care and consequently reducing the risk of future TB in Peru.

On top of this research, we also need new strategies to reduce the reservoir of latently infected individuals, from which new cases can arise. Current diagnostic tests cannot predict who will develop active disease, and in any case the current treatment options available are not adequate given the scale of the intervention that would be required – a third of the world’s population is currently predicted to be latently infected with TB.

20 years after my BCG vaccination, I was again tested for TB on moving to Seattle. I waved my arm again in front of my American colleagues and this time it was clear that I had the largest skin reaction from the Tuberculin test, a testimony to my BCG vaccination status (the US has never used mass immunization of BCG, relying instead on the detection and treatment of TB instead). A subsequent test, not affected by vaccination status, also came back positive. As I was not showing any signs of active disease it was concluded that between 1994-2014 I had most likely been exposed to TB. The risk of this progressing to full blown disease is about 5-10%. It would seem I have now joined a third of the world’s population in harbouring latent TB.

More information about World TB Day can be found here

Image credit: NIAID, Mycobacterium tuberculosis Bacteria, the Cause of TB on Flickr

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