The 19-kD antigen is a cell wall-associated lipoprotein present in Mycobact
erium tuberculosis and in bacille Calmette-Guerin (BCG) vaccine strains. Ex
pression of the 19-kD antigen as a recombinant protein in two saprophytic m
ycobacteria-M. vaccae and M. smegmatis-resulted in abrogation of their abil
ity to confer protection against M. tuberculosis in a murine challenge mode
l, and in their ability to prime a DTH response to cross-reactive mycobacte
rial antigens. Induction of an immune response to the 19-kD antigen by an a
lternative approach of DNA vaccination had no effect on subsequent M. tuber
culosis challenge. These results are consistent with a model in which the p
resence of the 19-kD protein has a detrimental effect on the efficacy of va
ccination with live mycobacteria. Targeted inactivation of genes encoding s
elected antigens represents a potential route towards development of improv
ed vaccine candidates.