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Background  The current BCG vaccine induces only short-term protection against  Mycobacterium tuberculosis  ( Mtb ), suggesting its failure to generate long-lasting memory T cells. Previously, we have demonstrated that a self-adjuvanting peptide of  Mtb  (L91), successfully generated enduring memory Th1 cells. Consequently, we investigated if L91 was able to recuperate BCG potency in perpetuating the generation of memory T cells and protection against  Mtb  infected mice.    Methods  In the present study, we evaluated the potency of a self adjuvanting  Mtb  peptide vaccine L91 in invigorating BCG immune response against  Mtb  in mice. Female BALB/c mice were immunized with BCG. Later, they were boosted twice with L91 or an antigenically irrelevant lipidated influenza virus hemagglutinin peptide (LH). Further, PBMCs obtained from BCG vaccinated healthy subjects were cultured in vitro with L91. T cell responses were determined by surface markers and intracellular cytokine staining. Secretion of cytokines was estimated in the culture supernatants (SNs) by ELISA.    Results  Compared to the BCG-vaccinated controls, L91 booster significantly enhanced the percentage of memory Th1 cells and Th17 cells and reduced the mycobacterial burden in BCG primed and L91-boosted (BCG-L91) group, even after 229 days of BCG vaccination. Further, substantial augmentation in the central (CD44 hi CD62L hi CD127 hi ) and effector memory (CD44 hi CD62L lo CD127 lo ) CD4 T cells was detected. Furthermore, greater frequency of polyfunctional Th1 cells (IFN-γ + TNF-α + ) and Th17 cells (IFN-γ + IL-17A + ) was observed. Importantly, BCG-L91 successfully prevented CD4 T cells from exhaustion by decreasing the expression of PD-1 and Tim-3. Additionally, augmentation in the frequency of Th1 cells, Th17 cells and memory CD4 T cells was observed in the PBMCs of the BCG-vaccinated healthy individuals following in vitro stimulation with L91.    Conclusions  Our study demonstrated that L91 robustly reinvigorate BCG potency to invoke enduring protection against  Mtb . This novel vaccination stratagem involving BCG-priming followed by L91-boosting can be a future prophylactic measure to control TB.    Electronic supplementary material  The online version of this article (doi:10.1186/s12967-017-1301-x) contains supplementary material, which is available to authorized users.

A lipidated peptide of Mycobacterium tuberculosis resuscitates the protective efficacy of BCG vaccine by evoking memory T cell immunity