TB vaccine trial is step forward though results 'not what hoped'

The clinical trial was the first to evaluate the ability of a new TB vaccine to prevent the disease since BCG, the 90 year-old vaccine that is familiar to many and is used extensively throughout the world.

The study involved almost 2,800 babies in South Africa and the findings are published in the medical journal The Lancet.

Professor Helen McShane, who first developed the MVA85A vaccine 15 years ago at Oxford University's Jenner Institute and is senior author on the Lancet paper, says despite the disappointing results, getting to this point marks a step forward for the field and there is much to be learned from the results.

'The primary endpoint of the trial was safety, and we met this endpoint and found the vaccine to be safe,' she says. 'However, unfortunately, we saw no statistically significant evidence of increased protection against TB above and beyond BCG alone.

'The results from this study should let us know far more about the type and level of immune response required, and that will boost future efforts to develop an effective TB vaccine by Oxford and other researchers throughout the world.'

TB is the second leading infectious disease killer in the world. In 2011 there were approximately 8.7 million new cases of TB and 1.4 million deaths worldwide.

'The TB epidemic in our country is devastating – half a million South Africans develop the disease every year,' says Professor Willem Hanekom, director of the South African TB Vaccine Initiative (SATVI) which carried out the trial. 'Prevention by an effective vaccine would be the best way to get the epidemic under control.'

The only existing vaccine against TB is the Bacille Calmette-Guérin vaccine, or BCG. BCG was created 90 years ago and approximately 100 million newborns are vaccinated globally with BCG each year. But the vaccine does not prevent TB affecting the lungs, the most common form of the disease in adolescents and adults, and the disease remains a global epidemic.  

The MVA85A vaccine candidate is designed to boost immune responses already primed by the BCG vaccine, so generating a stronger immune response against TB. Earlier trials showed the vaccine to be safe and to produce consistently powerful immune responses in adults.

This new trial was important because as well as assessing safety, for the first time it would look at efficacy. That is, whether the immune responses generated by MVA85A would actually improve infants' protection against TB beyond that given by BCG alone.

The trial took place in South Africa and involved almost 2800 healthy babies, all of whom had received BCG at birth. Half received a single dose of MVA85A at 4-6 months of age and the other half received a placebo. The babies were monitored for up to 3 years for any signs of TB disease.  

The researchers found 39 cases of TB in the placebo group and 32 in the MVA85A group. That’s a vaccine efficacy of 17.3%, but the difference is not statistically significant, so it's not possible to say whether the vaccine had any effect above that of BCG alone.

Writing independently about the study in the Lancet, Christopher Dye of the World Health Organisation and Paul Fine from London School of Hygiene and Tropical Medicine, say that the findings are not a 'terminal prognosis' for MVA85A and suggest several questions have yet to be answered, including whether MVA85A, working as a booster to BCG, might protect adolescents and adults against TB in a way that it cannot protect infants.

They add: 'Now is a key moment in tuberculosis vaccine research. Trials such as [this] are at last generating hard evidence about protection against tuberculosis in human beings, the most important goal of immunisation. If the history of tuberculosis vaccine research teaches us anything, it is to expect surprises. We need to go on playing the high-stakes game.' 

The trial data show that the MVA85A vaccine boosted the babies' immune responses against TB modestly, and this was found to be insufficient to offer extra protection against the disease.

But these immune responses in babies were much lower than those previously seen in adults in other trials of the vaccine. The researchers say that it’s not possible to know from this trial whether the MVA85A vaccine might work in adults.

'We can do a lot looking at this data in more detail, and also by analysing blood samples taken from all the babies soon after vaccination,' adds Professor McShane. 'We can look for biological signals that correlate with TB risk. We can understand more about the type and level of immune response the body needs to generate against TB. Does it just need to be a greater immune response, or a particular type, or something completely different?'

The study in South Africa showed it is possible to conduct a large efficacy trial in infants in an area of high TB incidence with robust measures for detecting disease – something that should greatly benefit future testing of TB vaccine candidates, says Professor McShane.

'This is the first efficacy trial of a new TB vaccine in infants since BCG was last tested in 1968,' she says. 'We have done it, and that's an important move forward for the field.

'I remain immensely proud that our work at Oxford University over 15 years, along with our partners, has seen us be first to bring a new TB vaccine to this point. As well as our own work, there are a dozen or so other TB vaccines in development, and everyone in the field will benefit from seeing this data. After all, it's only by doing this kind of trial that we can find out what does and doesn't work and eventually reach our goal.'

'Developing a vaccine against TB, just like developing vaccines against malaria and HIV, is complex, difficult, and a long road. The early vaccine trials for malaria and HIV also did not show efficacy, but the findings from those trials led to improvements in vaccines and both these fields now have vaccines showing some degree of efficacy.'

Dr Ted Bianco, director of technology transfer at the Wellcome Trust, who have funded the vaccine's development from the start, says: 'It is no mean feat to design and implement a trial of this kind and obtain a result as unequivocal as this. It is only through the difficult business of evaluating candidate vaccines in humans that we will really move forward in understanding how we might improve on BCG. I stand in admiration of the professionalism of this international team that understands the importance of well executed science, irrespective of the result one might have hoped for.'

The Phase IIb study was conducted by the University of Cape Town's South African Tuberculosis Vaccine Initiative (SATVI) and was sponsored by Aeras, a nonprofit organisation for TB vaccine development. Funding was provided by Aeras, the Wellcome Trust and the Oxford-Emergent Tuberculosis Consortium (OETC), a joint venture between the University of Oxford and pharmaceutical company Emergent BioSolutions.