Tuberculosis caused by infection with Mycobacterium tuberculosis or Mycobacterium bovis remains one of the most important infectious diseases of man and animals. The current vaccine M. bovis Calmette-Guérin (BCG) demonstrates variable efficacy and so a more robust strategy to either replace, or more likely supplement it, is required. Prime-boost strategies where immunity induced by BCG is boosted by a second heterologous vaccine represent a promising avenue of research. We have evaluated the ability of a protein subunit vaccine using the antigen Rv3019c to either prime or boost immunity induced by BCG in a murine M. bovis challenge model. Despite the induction of anamnestic T cell responses, we report that antigen-independent immune stimulation with adjuvant in conjunction with BCG could enhance the level of protection induced by BCG alone. Importantly this improved protection correlated with pre-infection frequencies of ex vivo IFN-gamma producing cells in the spleen, providing a possible surrogate correlate of protection for future vaccination studies.