Owing to its highly immunodominant nature and ability to induce long-lived memory immunity, ESAT-6. a prominent antigen of Mycobacterium tuberculosis, has been employed in several approaches to develop tuberculosis vaccines Here, for the first time, we combined ESAT-6 based recombinant BCG (rBCG) and DNA vaccine (DNAE6) in a prime boost approach Interestingly, in spite of inducing an enhanced antigen specific IFN-gamma response in mice, a DNAE6 booster completely obliterated the protection imparted by rBCG against tuberculosis in guinea pigs Analysis of immuncipathology and cytokine responses suggests involvement of an exaggerated immunity behind the lack of protection imparted by this regimen (C) 2009 Elsevier Ltd All rights reserved