If you have a scar on one arm, chances are that it is the legacy of vaccination with BCG. Since the development of the BCG vaccine in 1921, babies and children all over the world have queued up to be vaccinated, and it remains our first line of defence against tuberculosis (TB).

BCG is so widely used with good reason, as it works extremely well at protecting children from tuberculosis. But it has a crucial shortcoming: after about ten years the resistance wanes and the body is again vulnerable to attack. Not surprisingly then, the biggest danger is not childhood tuberculosis but adult lung disease. With one-third of the world's population thought to be latently infected with Mycobacterium tuberculosis, about 2 million people dying from tuberculosis every year, and resistance to available drugs on the increase in many parts of the world, the need for a new vaccine that can help adults is pressing.

Decades of research have brought many insights into M. tuberculosis and the disease it causes, but no vaccines since BCG have even reached the stage of human trials. Now, at the University of Oxford, Dr Helen McShane is about to embark on just such a trial. She has been awarded a Wellcome Trust Clinician Scientist Fellowship to test whether her new vaccine can augment and boost BCG's protective role.

Prime and boost

Having trained in medicine, Dr McShane has worked for several years treating infectious diseases and HIV. "I had seen quite a lot of tuberculosis while doing medicine," says Dr McShane. "The HIV epidemic is making the problem worse: if you are infected with HIV you are more likely to get TB, and if you have both the clinical course for both pathogens worsens. There is a very dangerous synergy between the two."

Five years ago, Dr McShane moved to Oxford to do a PhD with Professor Adrian Hill. "At the time, most of Adrian's lab worked on malaria," she says. "They had just developed a new immunisation strategy – 'prime–boost' – and had shown that it was very good at boosting the immune response to malaria. So for my PhD I decided to apply this model to tuberculosis."

The prime–boost strategy is based on using two different vaccines, each of which includes the same protein (antigen) from a pathogen that the immune system will target and remember. In the strategy for malaria vaccines, for example, the first vaccine – the 'prime' – is a DNA vaccine encoding a malaria protein and the 'boost' is an engineered virus encoding the same protein. "So the antigen is the same but the delivery vehicles are different," says Dr McShane. "Giving two lots of DNA vaccine doesn't seem to do very much; nor does giving two lots of the virus. But if you give two vaccines where the only thing in common is the antigen, it seems to focus and enhance the immune response."

Boosting BCG

While BCG has shortcomings, for children it provides good protection against tuberculous meningitis and, in adults, leprosy. "As BCG works well, and so many people have been vaccinated with it, it would be impractical – and perhaps unethical – to stop using it," says Dr McShane. The prime-boost strategy has therefore been modified to take this into account, the plan being to give BCG as the prime and then the new vaccine as the boost.

The new vaccine is a based on MVA, shorthand for a modified vaccinia virus which has been tweaked to make it harmless to humans. "MVA doesn't replicate in anything other than bird cell lines," says Dr McShane, "so if you inject it into humans it expresses its proteins and then dies."

Dr McShane has inserted into MVA a gene that produces a protein antigen from M. tuberculosis. For the prime-boost strategy to work, the antigen had also to be found in BCG. "We chose antigen 85A for the new vaccine," says Dr McShane. "It's a highly conserved protein common to all mycobacterial species, is an enzyme involved in building the cell wall and it is actively secreted."

In mice, the new strategy works extremely well at boosting the levels of T helper lymphocytes and T killer lymphocytes, both of which are key to successful resistance to tuberculosis. BCG alone induces a small immune response, but some of the T cells will 'remember' the vaccine. When BCG is followed by MVA, which has only one antigen in common with BCG, the immune response is bigger and the subset of 'memory' cells that remember that one antigen is expanded. "In animal models what we see is high levels of immunity, higher than BCG alone, and better levels of protection," says Dr McShane. "What I'm now moving on to do – the focus of the new fellowship – is to evaluate this strategy in humans."

Testing time

To see whether the same things happen in humans as in mice, the trial will look at the immune responses to BCG or MVA alone, and to BCG followed by MVA. The volunteers in each of the three groups will, crucially, have not had BCG previously. Coincidentally, Oxfordshire is a good place to be doing the study – BCG has not been given to school children routinely for the last 20 years, with only 'at-risk' infants having been vaccinated.

This phase 1 study is likely to take two to three years, optimising the dose and the intervals. "One of the things we need to find out is when to give the second vaccine to get the best immune response," says Dr McShane. "Do you give it one month later, three months later or a year later? Then, if the vaccine works, we'll move to do a phase 1 study somewhere where tuberculosis is endemic, such as in Africa."

"There is only a certain amount you can do with animal models," Dr McShane points out. "At some point you have to start moving things along and asking 'does this work in humans?'. I'm very fortunate to be able to take the work I have been doing in the laboratory forward into clinical studies."

See also

• Programme grants: Scheme details

External links

• Dr Helen McShane: Affiliated to the Cellular Immunology and Vaccine Development Group, Nuffield Department of Clinical Medicine at the University of Oxford

Further reading

Flynn J L, Chan J (2001). Immunology of tuberculosis. Annu. Rev. Immunol. 19: 93–129.

McShane H, Brookes R, Gilbert S, Hill A V S (2001). Enhanced immunogenicity of CD4+ T-cell responses and protective efficacy of DNA-modified vaccinia virus Ankara Prime-Boost vaccination regimen for murine tuberculosis. Infection and Immunity. 69: 681–86.

Van Pinxteren L A H, Cassidy J P, Smedegaard B H C, Agger E M and Andersen P (2000). Control of latent Mycobacterium tuberculosis infection is dependent on CD8 T cells. Eur. J. Immunol. 30: 3689–98.