At the sharp end

Everyone over a certain age remembers the six-pin TB test, followed almost inevitably by the BCG vaccination: most of us probably still have a small scar to prove it. The vaccine was so successful in the UK that in some areas it ceased to be routinely given to children. But tuberculosis remains a major global health problem, particularly in the developing world, and cases have risen to more than 8,000 a year in the UK. At the same time BCG, developed more than 80 years ago, is not fully effective – though it does protect against the worst manifestations of the disease.

In 2007 Dr Helen McShane of Oxford’s Centre for Clinical Vaccinology and Tropical Medicine (CCVTM) began field trials in South Africa with a new vaccine she had developed: the first to reach this stage since BCG. The vaccine works in tandem with BCG, rather than replacing it. After being ‘primed’ with BCG, patients receive a ‘boost’ a few weeks later in the form of modified virus that contains a protein from the tuberculosis bacterium. ‘This vaccine is safe and stimulates very high levels of the type of immune response we think we need to protect against TB’, says Dr McShane.

In April 2009, a Phase IIb proof of concept efficacy trial with MVA85A in BCG vaccinated infants commenced in South Africa. This trial will enrol approximately 2,800 infants and will look at safety, immunogenicity, and also efficacy at preventing TB disease.

The ‘prime-boost’ strategy was developed by Dr McShane’s former PhD supervisor, Professor Adrian Hill, in his search for a malaria vaccine. The idea is to show the body the same antigen – a protein that provokes an immune response – carried by two different vehicles, producing a greater response than either would on its own. Malaria is caused not by a bacterium but by a parasite with a complex life cycle that makes it especially difficult for the immune system to tackle, and equally difficult to devise a vaccine. Using the ‘prime-boost’ approach – a DNA vaccine followed by a modified virus – Professor Hill first showed vaccine-induced protection against malaria mediated by the cellular arm of the immune system in healthy volunteers in Oxford. Subsequent trials have been performed in Kilifi in Kenya, and in collaboration with the Medical Research Council’s laboratories in the Gambia where malaria is the biggest killer of young children. The latest generation of malaria vaccine uses a simian adenovirus to generate more powerful protective immunity and this approach is now in phase II trials in Oxford.

The goal of a vaccine for HIV/AIDS is equally challenging, but Professor Andrew McMichael of the Weatherall Institute for Molecular Medicine has also developed candidate prime-boost vaccines that have undergone field trials in Kenya. His colleague Dr Lucy Dorrell is investigating whether the vaccine might enable HIV-positive people to come off their anti-retroviral medication either temporarily or permanently. Professor McMichael is the only scientific leader from an institution outside the US to be involved in the $300-million Center for HIV-AIDS Vaccine Immunology, funded by the US National Institutes of Health.

Within one institution, Oxford combines clinical understanding of disease, the basic research necessary to discover target antigens, expertise in constructing vaccines, an industry-standard Clinical BioManufacturing Facility and extensive experience in designing and implementing clinical trials. It is unique among universities in developing vaccines for these challenging diseases and taking them all the way to trials in the field.