The recent publication of a Phase IIb efficacy trial of the tuberculosis vaccine candidate MVA85A represents the long awaited outcome of the hopes and investment of a global research endeavour seeking a giant leap in tuberculosis control. MVA85A, a modified vaccinia virus expressing the Mycobacterium tuberculosis (Mtb) 85A antigen, is designed to improve on the currently available vaccine Bacillus Calmette-Guerin (BCG) and is the first among a number of novel vaccine candidates to enter a Phase IIb efficacy trial in infants. Given that the immunological rationale underpinning the development of MVA85A is shared by 9 out of 14 vaccines in clinical trials, the lack of efficacy in this recent pivotal trial is a significant setback to the tuberculosis vaccine community.1 The results of this trial therefore have far reaching implications for the current dominant approach to vaccine development and highlight several gaps in the current strategy.

In a randomised placebo-controlled trial, 2797 BCG vaccinated infants at a trial site in South Africa were enrolled between 4–6 months of age and administered either one intradermal dose of MVA85A or a placebo. The participants were actively followed every 3 months to identify tuberculosis infection or disease for a median of 24 months. Although, MVA85A induced strong antigen-specific CD4 multicytokine secreting T cell responses 28 days after vaccination, there was no evidence of increased efficacy against tuberculosis disease or infection over and above that of BCG. The disappointment in the failure of this vaccine in infants, which has been 15 years in the making, needs to be tempered by the opportunity to learn lessons and consider alternative strategies. In the words of Winston Churchill, ‘Success consists of going from failure to failure …