Sunday, 26 June 2011

TUBERCULOSIS: Helen McShane and a new vaccine for tuberculosis

22 Jun, 2011 : Chrissie Giles is Senior Science Writer at the Wellcome Trust, where she writes, commissions and edits news and feature articles and is editor of ‘Wellcome News’ and ‘Big Picture’ magazines. Her work has been published by a number of publishers and charities, including Nature Publishing Group, the ‘Guardian’, the British Heart Foundation and IPC Media.

Helen McShane Image credits: University of Oxford, Wellcome Library

Helen McShane

To mark the 75th anniversary of the death of Henry Wellcome and the founding of the Wellcome Trust, we are publishing a series of 14 features on people who have been significant in the Trust’s history. In our ninth piece, Wellcome Trust Senior Science Writer Chrissie Giles looks at Helen McShane, who has developed the first tuberculosis vaccine to come to human trials since BCG in the 1920s.

Dr Helen McShane is talking about the PhD students and postdocs she’s supervised in her lab when she breaks off, mid-sentence. “An email has just pinged in,” she says. “It reads: ‘We have just vaccinated baby number 2784. That’s it: we have completed enrolment.’ That’s really exciting!” The delight is clear in her voice. The study she’s referring to is the largest infant trial of a tuberculosis vaccine to date, what’s known as a phase IIb efficacy trial, being run in South Africa. The vaccine under investigation, MVA85A, is the most clinically advanced tuberculosis (TB) vaccine candidate for decades.
There is already a vaccine approved for TB, which has been in use since 1921, but it’s not enough. Across the world, 5000 people die every day from TB. Every second, someone else becomes infected with the bacterium that causes the disease. Why has it taken 90 years to get this far with a new candidate vaccine and what role has McShane – a Wellcome Trust Senior Clinical Fellow and Reader in Vaccinology at the Nuffield Department of Clinical Medicine at the University of Oxford – played in the process?
It was 1992 when McShane, a newly qualified junior doctor, stepped on to ward 6 in Hove General Hospital, Brighton. This ward was for people diagnosed with an emerging infection that was sweeping through the gay population – human immunodeficiency virus (HIV). She describes a ward of very sick patients who died soon after admission. “When one patient died, another who was just as ill arrived to take their place,” she said. “At that time, the only treatment for HIV/AIDS was treatment of infections and palliative care.”
This stark introduction into the world of infectious diseases had a career-changing impact on the young medic, who – for reasons that with hindsight, she says, aren’t completely clear – had always thought she’d be a GP.
A year in Oxford as a registrar in infectious diseases followed her time in Brighton, after which she “toyed with the idea of research” but decided that she wasn’t ready. Her next job, as a registrar in HIV and genito-urinary medicine in London, gave her hands-on experience working with TB, as she learned how to use an endoscope to examine the upper airways and lungs of people who were HIV-positive and also had TB. People with HIV are over 20 times more likely to develop TB if infected with the bacterium responsible than people without HIV. The combination is lethal: TB is the biggest cause of death of people with HIV.
“It was then that I started to think that I was ready to do research – but what on?” says McShane. “Although I was training to be an HIV physician, I recognised that lots of people were doing HIV research. I also thought that, in many ways, TB is a more interesting bug.” She applied for a Clinical Training Fellowship from the Medical Research Council and began to study for a PhD on immune responses in people with TB, with Professor Adrian Hill at the University of Oxford. “As I arrived in the laboratory, Adrian had just started a malaria vaccine programme and had got some very interesting results,” McShane says. “The obvious thing to do was to ask if we could apply his prime-boost approach to TB. It was rather a significant change to my project!”

Boosting BCG
Unlike her colleagues working on malaria, McShane was tackling a disease for which there was already a vaccine – BCG (Bacille Calmette-Guérin). First used in humans 90 years ago, BCG is an attenuated strain of Mycobacterium bovis, which causes TB in cattle. This is a close relative of M. tuberculosis, the bug that causes TB, which is carried by 1 in 3 people across the world.
As vaccines go, BCG is far from perfect. While it protects against the most serious type of TB in children, it provides variable protection against pulmonary TB, the most common form in adults. And the closer someone lives to the equator – where TB is most prevalent – the less likely BCG is to work. “Although BCG doesn’t protect against adult lung disease, it does protect rather well against severe disease in children,” McShane says. “It’s because of that that everyone in the field thinks that BCG – in some form – is here to stay.”
A key feature of Hill’s work to develop a malaria vaccine is the concept of prime-boost. This means that two different vaccines containing the same antigen (a component of a bacterium or other foreign substance that sparks an immune response) are given to a patient several weeks apart. This approach gives a greater response of immune cells called T cells, a reaction that is felt to be important in terms of protecting against TB and other infectious diseases such as malaria and HIV. So, if you’re aiming to develop a new TB vaccine, either you choose to use BCG as your priming immunisation and develop a booster vaccine – the approach most TB vaccine groups are taking – or you choose to develop a genetically modified (recombinant) strain of BCG that’s better than the existing one.
McShane chose the first option, and used her PhD to begin the process of trying to discover a vaccine that could be given after BCG to produce a greater degree of protection against all forms of TB. Of the potential vaccines investigated in her PhD, one has become the most clinically advanced candidate TB vaccine in the world. Its name is MVA85A. It is based on a modified version of the vaccinia virus (which is the smallpox vaccine) called modified vaccinia Ankara (MVA); this is used widely in vaccine development across diseases such as malaria, flu and measles. 85A is an antigen of M. tuberculosis that is secreted when M. tuberculosis divides, and is also found in BCG and all other strains of mycobacterium sequenced to date.
With her thesis complete and MVA85A a promising candidate ripe for further investigation, McShane applied for and was awarded a Wellcome Trust Clinician Scientist Fellowship. This allowed her to finish her clinical training and qualify as a consultant as well as continue her lab research. It meant a lot for the progress of the vaccine project too. “The Clinician Scientist Fellowship was absolutely pivotal, as it bridged me from my PhD into doing the first-in-man clinical studies with MVA85A,” she says.

A new vaccine
While McShane’s project was making progress, the broader field of TB vaccines was largely stagnant. The last real policy-changing work came in the shape of BCG, first used in humans in 1921, 80 years before McShane was awarded her Wellcome Trust Fellowship. “In contrast to HIV and malaria, there were no new TB vaccines in clinical trial at this point,” she says. “This was partly due to a lack of investment.” TB is a disease of poverty, and hence one for which the commercial market for potential drugs is uncertain. This led to a lack of industry involvement in TB drug development. Funding from the public sector and philanthropic organisations over the 20th century has also been poor. One estimate suggests that TB, a disease that’s been killing people for thousands of years, has garnered just 5 per cent of the funding put behind research into HIV/AIDS, which emerged 25 years ago.

French anti-TB poster featuring Albert Calmette, co-discoverer of the BCG vaccine, 1934. French anti-TB poster featuring Albert Calmette, co-discoverer of the BCG vaccine, 1934.

McShane recognises that the decades of neglect around the funding of research into vaccines, diagnostics and treatments for TB are coming to an end. Pharmaceutical companies, including GSK and Crucell, are currently working on vaccines. Still, though, funding for TB lags behind that for HIV. Searching on the US National Institutes of Health global clinical trials registry at produces 543 results for the term ‘HIV vaccine’, compared with 89 for ‘TB vaccine’.
It’s not just underfunding that has limited progress in developing a new TB vaccine: significant fears remain about whether such a thing can be safe. These concerns stem from the fact that one-third of the world’s population is thought to carry M. tuberculosis, although most do not have active TB disease. Billions of people are also exposed to bacteria related to M. tuberculosis, which are found in our surroundings, including in soil, streams and rivers, especially in tropical areas. This exposure to mycobacteria is thought to have the potential to affect the immune response triggered by a TB vaccine and could lessen its effectiveness.
McShane was acutely aware of the potential problems with safety. “The team at the time – just me and a postdoc – took a very cautious, stepwise approach,” she says. “We had a candidate that we believed to be safe, but we used the support of the Wellcome Trust to test it very carefully.” The research began in the safest possible population: people in the UK (where exposure to environmental mycobacteria is lower than nearer the equator) who had not previously received BCG vaccination. Next came a trial in those who had been vaccinated with BCG. Finally, the team moved on to people with latent TB infection, who carry the bacteria but don’t have active disease.
Having shown that the vaccine was safe in these groups, they also needed to ensure that it worked in the places where it is most needed. So, in parallel with the studies in the UK, McShane had been setting up some overseas collaborations. “The first UK trial with MVA85A began in September 2002. In 2003, once we had safety data from this study, we began a trial in Gambian adults, through funding from the European Commission,” she says. The results were positive, showing that MVA85A was safe and very effective at triggering an immune response. “Then in 2005, we started some work in South Africa with the University of Cape Town.” As in the Gambia, trials of the vaccine here showed that it generated a powerful T-cell response and was safe. McShane’s team also began a collaboration with researchers in Senegal in 2006.
Work continued in Oxford, including a study that found that the boosting effects of MVA85A were as great when given shortly after BCG vaccination as when given ten years later.
Steadily, MVA85A cleared each of the clinical hurdles in the process of developing a new drug. Next came the large efficacy trials, known in clinical trial circles as phase IIb – the subject of the email McShane was so pleased to receive. With a £4 million Strategic Translation Award from the Wellcome Trust and £4m matching funding from Aeras, a non-profit organisation working to develop TB vaccines (then called the Aeras Global TB Vaccine Foundation), McShane and her colleagues began an efficacy trial in South African babies at the TB vaccine research site of the South African Tuberculosis Vaccine Initiative (SATVI) of the University of Cape Town.
“We began vaccinating for this trial in July 2009,” says McShane. The team has now recruited 2784 babies, all born in Worcester, a town in the Western Cape around 120 km from Cape Town. “It’s a very fixed population there, people don’t move around very much, so our retention in the trial is very good.” For the study, every baby enrolled is vaccinated with BCG at birth. Between four and six months of age they are then randomly assigned to receive either MVA85A or placebo. Every three months, the babies will be examined for any signs of TB disease. Any baby with symptoms or who has been in contact with adults with infectious TB will be admitted to hospital for case verification.
“The endpoint of this trial is safety and immunogenicity, but also efficacy,” McShane says. “We’ll be seeing how many children who got both vaccines get TB, and will compare this to the number who received placebo and get the disease.” The study is expected to be completed in 2012. If the trial is successful, development of MVA85A will continue via a Joint Venture between the University of Oxford and Emergent BioSolutions called the Oxford Emergent Tuberculosis Consortium. This Consortium will work in collaboration with Aeras to further develop this vaccine towards licensure.

Asking questions
McShane will continue to be involved in the future of MVA85A but will also work on a number of other research projects with her group in Oxford. What questions does she want to answer? “We need better tools to select which vaccines go forward into large efficacy trials,” she says. “For most diseases we don’t know what an immune response in an animal model means in terms of protection in humans. So, to test if your vaccine works, you’re stuck with these big efficacy trials.” Not only are these time-consuming and very expensive, but, for some diseases, there is a limited pool of suitable sites and populations for such trials. “To date, there are 14 TB candidate vaccines that have reached early-stage clinical testing – the world just doesn’t have the capacity to fund or carry out efficacy trials for each of those. We need a better way to screen out the ones that won’t be successful.”
In many areas of research on infectious disease, human challenge models – that is, exposing people to the bacterium, virus or parasite of interest – have been an extremely useful tool for looking at whether vaccines work. These models have been used to study diseases including influenza, malaria and typhoid, which either can be treated fully over a short period of time or are self-limiting. Not like TB.
“Obviously we can’t give people virulent TB,” says McShane, “but we do give people BCG, which is a live, replicating mycobacterium.” The idea is, she explains, that a vaccine that works against TB should work against BCG as well. “I want to see if we can give BCG as an injection in the arm, biopsy that site and then look at how much BCG is left.” This would, she suggests, provide a surrogate of a TB challenge model, which would give researchers a handle on whether the vaccine works or not – and, if it does, potentially help them raise funding for an efficacy trial.
Her team is also looking at different routes of vaccination, including as an aerosol that you breathe in. “TB enters the body via the lungs so perhaps the best way to induce a protective immune response is to deliver a vaccine straight to the lungs too.” Her lab will also be investigating more of the basic biology around TB, including the immune response to infection.
Alongside her research responsibilities, McShane is a Consultant in HIV and Genito-urinary Medicine and has clinical duties that include holding weekly clinics for these conditions. “I did an HIV clinic yesterday and it’s constantly rewarding how one can have a discussion about how we can treat the disease now and the things we can do,” she says. “In 20 years, HIV has changed from a fatal condition to a chronic illness treated in the outpatient setting. It’s extraordinary what’s changed for HIV in my professional lifetime.”
As the team in South Africa fill in the details of the vaccination of baby number 2784, MVA85A comes a step closer to becoming the world’s second ever TB vaccine. It could be just a matter of years before people are describing a change as great as that seen in HIV for the field of TB.

Extra: Hasn’t that been eradicated?
When she started working on TB, the question everyone would ask Helen McShane was: “Hasn’t that been eradicated?” In the UK, you’d be forgiven for thinking that TB was a problem of the past. Now, the number of cases per year is just a fifth of the 50 000 seen in the 1950s.
It was in the 1950s that the Medical Research Council performed a large-scale trial of BCG in schoolchildren. BCG (Bacille Calmette-Guérin) is the only TB vaccine currently in use in the world. The results of this study led to the introduction of vaccination in schools in 1953. The experience of having BCG and the six-needled Heaf test that precedes it will likely be familiar to anyone over 16 who went to school in the UK. Twenty years of follow-up for the original trial has shown that the efficacy of the BCG vaccine is high in the UK population.
Combined with a significant improvement in the living standards and public health of people in the UK, the introduction of BCG led to a fall in TB in the second half of the 20th century. The UK school vaccination programme was halted in the mid-2000s. Now, babies deemed at high risk are the only ones to receive BCG. Criteria for vaccination include living somewhere where the incidence of TB is at least 40 cases per 100 000, and living with adults or parents who have lived in a country with this incidence.
While UK cases are still few compared with the burden of disease seen in many other parts of the world, including South Asia and sub-Saharan Africa, TB is an increasing problem in the UK. The number of cases per year has been slowly rising over the 1990s and 2000s to just over 9000 cases in 2009, and the number of drug-resistant cases of TB nearly doubled between 2000 and 2009.

Further reading
Ibanga HB et al. Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design. Lancet Infect Dis 2006;6(8):522-8.
Ota M et al. Sci Transl Med 2011 [in press].
McShane H et al. Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat Med 2004;10(11):1240-4.
Scriba TJ et al. Modified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cells. Eur J Immunol 2010;40(1):279-90.

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