Title : Recombinant BCG vaccine as a potent anti tuberculosis vaccine candidate
Abstract:
Tuberculosis (TB) is a significant global health challenge; it has been responsible for more human lives lost than any other infectious disease. BCG is the only pre-emptive vaccine against tuberculosis. However, the variable efficacy of BCG is well acknowledged fact which prompted to develop alternative vaccine against tuberculosis.
Previous works from our lab have shown immunomodulatory role of an important Mtb protein which induces anti-inflammatory cytokines in host and gives survival advantage to bacteria. We have shown that it inhibits phagosomal acidification and antigen presentation. Interestingly, this protein is also highly expressed in BCG, which prompt us to ask whether it can influence the effectiveness of the BCG vaccine. We know T cells form an important part of adaptive immunity and especially in case of immunity against intracellular pathogen like Mycobacterium tuberculosis. The development and differentiation of T cells highly influence by the cytokines it experiences during the antigen presentation process. We hypothesized that deleting the gene might boost the immunogenicity, strengthen adaptive immunity thus effectiveness of the BCG vaccine.
We have generated a recombinant BCG strain by deleting our gene of interest from its genome. In in vitro infection condition the recombinant BCG strain induces higher proinflammatory cytokines compared to BCG pasture strain. It also improves the phagosomal acidification and antigen presentation in in vitro antigen presentation assay. Intracellular survival assay showed that the new strain is easily killed inside macrophage, hence processed and presented by macrophages or dendritic cells. This improved antigen presentation and differential cytokines might improve the T cell activation and differentiation towards T helper type 1. In in vivo mice vaccination study, we found that T cells from rBCG vaccinated mice produce more IL-2 and IFN-γ compared to BCG vaccine group after in vitro stimulation. This indicate that T helper cells are more differentiated in rBCG vaccinated condition compared to BCG pasture strain.
In summery we have developed a recombinant BCG strain which has potential to improve the anti tb T helper 1 type immune response which is a key regulator of anti-tb immune response. We are also trying to understand how nuances in cytokines influence T cell differentiation and how tuning the cytokines balance influence the adaptive immunity and T cell memory generation.
