Clinical trial reveals TB vaccine candidate does not protect infants against disease or infection

The most advanced tuberculosis vaccine candidate, MVA85A, does not provide protection in preventing TB disease in infants previously vaccinated with BCG, according to the results of a phase IIb clinical trial published today in the 'Lancet'.

The vaccine was well tolerated and had a good safety profile but induced only modest immune responses that were not sufficient to protect against TB disease or infection with the causative agent, the bacteria Mycobacterium tuberculosis.

MVA85A is a TB vaccine candidate designed to boost immune responses already primed by the Bacille Calmette-Guérin (BCG) vaccine, the currently licensed and widely used TB vaccine. Although BCG prevents some severe forms of TB in children, it has failed to control the global TB epidemic (despite widespread administration), and there is an urgent need for a more effective vaccine.

This is the first study to evaluate MVA85A's ability to prevent TB disease after BCG vaccination and was begun in 2009. The trial, in infants without TB disease or HIV infection, involved a 'prime-boost' strategy that used MVA85A to boost immune responses already primed by the BCG vaccine.

The study, conducted at the University of Cape Town's South African Tuberculosis Vaccine Initiative (SATVI), enrolled nearly 2,800 HIV-negative infants in the Western Cape province of South Africa. All of the infants that participated received BCG at birth, then one half of the infants received a single dose of MVA85A at 4–6 months of age and the other half received a placebo. Approximately 93 per cent of the infants enrolled completed the study and have been monitored for up to 37 months for any signs of TB disease.

The study was successful in that the vaccine was well tolerated and there was no evidence of any harm to the trial participants; however, the results reveal that a single dose of MVA85A is not sufficient to confer statistically significant protection against TB disease or infection in infants who had been vaccinated at birth with BCG. There were 32 cases of TB disease in the infants that received BCG and MVA85A compared with 39 cases of disease among those receiving BCG with a placebo vaccine.

Professor Helen McShane, a Wellcome Trust Senior Clinical Research Fellow at the University of Oxford and the original developer of the vaccine, said: "Although the results of this first efficacy trial of a new TB vaccine are not what we had hoped for, further analysis of the data should reveal a great deal about how the body's immune system protects against TB and what is necessary to develop an effective vaccine.

"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 us and others. The difficulty of this task is one reason why there has not been a new TB vaccine since BCG was developed more than 90 years ago, but one is needed and we're not about to give up now."

Dr Ted Bianco, Director of Technology Transfer at the Wellcome Trust, said: "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."

Funding for this clinical trial was provided by: Aeras, a nonprofit biotech with a social mission to develop TB vaccines; The Wellcome Trust; and the Oxford-Emergent Tuberculosis Consortium (OETC), a joint venture between the University of Oxford and Emergent BioSolutions. This phase IIb study was sponsored by Aeras and conducted by the University of Cape Town's South African Tuberculosis Vaccine Initiative (SATVI). The vaccine was originally developed and investigated by the University of Oxford.

The researchers remain hopeful that MVA85A may protect in other populations, such as adults or those infected with HIV. Future studies will be needed to determine whether the MVA85A immune response can be improved or whether MVA85A combined with other vaccines merits further evaluation.