WHO Tuberculosis day 2014

March 24th 2014 marks World Tuberculosis (TB) day. This day commemorates the day in 1882 when Dr Robert Koch announced that he had discovered the cause of TB. This year’s World Health Organization (WHO) TB Day campaign focuses on the 'missed' 3 million to ensure that everyone suffering from TB has access to diagnosis, treatment and cure.

The Nuffield Department of Medicine asked Professor Helen McShane, a Wellcome Trust Senior Clinical Fellow and Professor in Vaccinology, to explain why TB is still such a huge problem and how her research developing an improved TB vaccine, is aiming to improve this situation.

Q: Why is it important to raise public awareness of TB? How many people are affected by TB each year?

Helen McShane: TB remains a very significant cause of both death and disease throughout the world. The latest WHO figures show 8.6 million new cases and 1.3 million deaths throughout the world in 2012. In addition, about one third of the world’s population (2 billion people) are estimated to be latently infected with TB. These people are at risk of reactivation of this latent TB, should they become immunocompromised for any reason. Globally the commonest cause of immunosuppression is co-infection with HIV and the geographical overlap between the HIV and TB epidemics, particularly in sub-Saharan Africa, has had a devastating impact. Interesting, the latest WHO report shows that there has been some progress in this area and that in the last 10 years TB incidence has been very slowly falling overall in the world. However, the pace of change is much too slow.

Q: Why do we need an alternative to the Bacille Calmette-Guérin (BCG) vaccine?

HM: BCG is one of the world’s most widely used vaccines. It has been given to over 3 billion people throughout the world. It was developed in 1921, almost 100 years ago, and remains the only licensed vaccine for the prevention of TB. BCG is given pretty throughout the world in infancy, as soon after birth as possible. When BCG is given at birth it does protect against disseminated disease (TB that has spread outside of the lungs), and particularly TB meningitis in children. It is very effective at doing that. What BCG is not nearly as good at is protecting against lung disease, particularly in young adults and adolescents, which is where the burden of transmission is, which is therefore responsible for fuelling the epidemic. We need a better vaccine to be given either at birth or perhaps in adolescence, when BCG is starting to wane.

Q: Can you tell us about the MVA85A vaccine?

HM:In terms of what is happening in vaccine development there are two broad strategies. Some groups are developing replacements for BCG. The idea here is that we can make BCG better. Some of that is about making BCG safer, since BCG is a live attenuated vaccine we can’t give it to people or babies who are infected with HIV. The other strategy is to develop a booster vaccine to be given at a later point in time. You would give BCG as it is and then boost later on in infancy or later on in adolescence, when we know that the effects of BCG are starting to wane. That is the strategy that most work in this field has been focusing on to date and it is the strategy that we have been focusing on here in Oxford; MVA85A is an example of a booster vaccine to be given after BCG.

Q: Can you tell us about the results from last year’s trial?

HM: We reported the results of a very large Phase IIb efficacy trial in South African babies in February last year (2013). This was a trial where all the babies received BCG at birth and then half of the babies were boosted with MVA85A at between 4 and 6 months of age. What we found was that the vaccine was safe but it stimulated relatively weak immune responses and there was no improvement in protection over BCG alone. I think this tells us many important things. One of which is that we need to design more potent vaccines, particularly in the target populations. Since that trial, the field has moved away from infant vaccination and is more focused on vaccinating adolescents as they are responsible for transmission. A vaccine that worked in adolescents would have a greater impact on the epidemic though reducing transmission. We know that the immunogenicity of MVA85A and other vaccines is better in adolescents than it is infants, so we are doing some studies at the moment in Oxford where we are looking at different routes of immunisation. One of these is immunising directly into the airways as we have some animal data that shows that this is the best way to protect against TB. This makes sense as this is how TB enters the body. We are also doing some work with other vaccines and working with other vaccine developers to combine vaccines, as it may well be that you need to combine different sorts of vaccines to induce the most potent immune response.

Q: How has our understanding of TB and future vaccine strategies improved?

HM: The real challenge in the field of TB is that we don’t know how well any of the animal models represent human disease and that is a bit of a chicken and egg situation - we won’t know how well these animal models represent human efficacy until we have a vaccine that works in humans. I think what we have learnt over the past ten years, in part from our efficacy trial and in part from other groups, is that these animal models need to be refined. There are many different groups working on this, including mine. I also think that we need better models by which we test vaccines. In other vaccine fields we use human challenge models to facilitate vaccine development. We are working in Oxford on a human BCG challenge model to see if such a model would be a useful tool in selecting promising vaccines that should go forward for further trials. The other major challenge is that we don’t have a biomarker or an immunological correlate of protection, with which we could guide vaccine design and development; so again more work is needed with that. One of the things that we are doing with the samples from the infant trial is lots of detailed immunology studies, so that we can try and understand why some children got TB and other children didn’t. If we can understand the differences in immune responses between these children then perhaps that information would steer us towards a new vaccine design..

Q: Do you think that TB will ever be eradicated in our lifetime?

HM: I think that eradication is a very big word. I believe that the reason we could eradicate other diseases, such as smallpox, is that there was no latent phase. With 2 billion people latently infected, eradication within my lifetime is not feasible. But I think if we can maintain the momentum this whole field has gained over the last ten years there is a huge amount that we can do to work towards eradicating TB. Ultimately, I would think that in the next 20 years we may have a deployable vaccine.