The ΔfbpA attenuated candidate vaccine from Mycobacterium tuberculosis, H37Rv primes for a stronger T-bet dependent Th1 immunity in mice

The Delta fbpA candidate vaccine derived from Mycobacterium tuberculosis (H37Rv) (Mtb) protects mice better than BCG against tuberculosis, and we investigated the hypothesis that Delta fbpA may induce a stronger Th1 immunity. Since T-bet transcription factor regulates Th1 immunity, mice infected with Delta fbpA, BCG vaccine and related mycobacteria were analyzed for T-bet positive T cells. Mouse dendritic cells (DCs) or macrophages were also pulsed with excretory-secreted antigens (ES; Antigen-85B, ESAT-6 and CFP10) and cocultured with T cells from immunized or naive mice and tested for in vitro induction of T-bet and IFN-gamma. In both models, Delta fbpA mutant induced a stronger response of T-bet(+)CD4 T cells, which correlated with an increased expansion of IFN-gamma(+)CD4 T cells in vivo and in vitro. When DCs pulsed with ES antigens were allowed to stimulate T cells, ESAT-6 and CFP-10 failed to induce a recall expansion of T-bet(+)IFN-gamma(+)CD4 T cells from BCG vaccinated mice. Thus, deletion of RD1 in BCG seems to reduce its ability to induce T-bet and induce stronger Th1 immunity. Finally, mice were vaccinated with Delta fbpA and BCG and challenged with virulent Mtb for evaluation of protection and T cell expansion. Delta fbpA vaccinated mice showed a rapid and stronger expansion of CD4(+)CXCR3(+) IFN-gamma(+) T cells in the lungs of Mtb challenged mice, compared to those which had BCG vaccine. Delta fbpA immunized mice also showed a better decline of the Mtb bacterial counts of the lungs. Mtb derived Delta fbpA candidate vaccine therefore induces qualitatively better T-bet dependent Th1 immunity than BCG vaccine. (C) 2011 Elsevier Ltd. All rights reserved.