Mycobacterium tuberculosis defective in phthiocerol dimycocerosate translocation provides greater protective immunity against tuberculosis than the existing bacille Calmette-Guérin vaccine.

We demonstrate that Mycobacterium tuberculosis that is unable to export the complex lipid phthiocerol dimycocerosate has a decreased capacity to replicate in mice and affords sustained protective immunity against M. tuberculosis infection Protection was significantly better than that provided by the existing vaccine, Mycobacterium bovis bacille Calmette-Guérin (BCG), and this improved protective efficacy was maintained for at least 24 weeks after vaccination. Protection afforded by this attenuated strain coincided with a number of factors that were not associated with BCG vaccination: long-term persistence of the strain within the host, sustained and potent induction of antimycobacterial interferon-gamma-secreting cells equal to that induced by virulent M. tuberculosis, and elicitation of T cells recognizing dominant M. tuberculosis antigens absent from BCG. These results suggest that the BCG vaccine may be too attenuated to afford effective protective immunity against tuberculosis, and vaccine strains that can provide sustained delivery of mycobacterial antigens are promising antituberculosis vaccine candidates.