Pre-existing immune-suppression and emergence of drug resistance and disease relapse are the major setbacks in the treatment of drug sensitive and drug resistant tuberculosis (Sharma et al., 2009). So far, protective potential of candidate vaccines against tuberculosis has been evaluated by ability to induce T cells to secrete IFN-γ. However, in many forms of active tuberculosis patients, increased number of IFN-γ+ T cells and soluble IFN-γ is present. Therefore, IFN-γ alone is essential but not sufficient for protective immunity against M. tuberculosis as TNF-α is critical for granuloma formation. Critical role of TNF-α is further substantiated by increased risk of developing active TB in latent TB infection individuals following anti-TNF-α therapy in Rheumatoid Arthritis patients. Thus, currently it is widely thought that effector T cells simultaneously producing these two cytokines, at the least (IFN-γ +TNF-α+) are crucial for efficient granuloma formation and protective immunity, supposedly to be elicited by any vaccine against tuberculosis. We have previously demonstrated the impact of inhibiting PD-1 in restoring protective poly-functional T cells (PFTs) as well as IFN-γ response (Singh et al., 2013, Singh et al., 2017, Singh et al., 2014, Singh et al., 2012). Inhibiting PD-1 pathway boosts poly-functional T cells, which are more protective in tuberculosis than IFN-γ alone, as evident by our human in vitro PD-1 blocking experiments and reduced CFU counts in our in vitro Monocyte Derived Macrophages (MDMs) model experiment. In vivo mouse M.tb infection model demonstrated significant reduction in bacterial burden in ATT along with anti-PD-1 treated groups relative to control. The bacterial burden corroborated with histo-pathological findings and poly-functional T cell response and improving bacterial containment in both lungs and spleen of infected mice. Moreover, we have seen in the peripheral blood of TB patients that anti-PD-1 enhances the poly-functional T cell response induced by ID-93 in vitro. Therefore, the role of PFTs is emerging as a critical element for protective immunity in tuberculosis. This necessitates development of adjunct therapeutic vaccines which can elicit robust poly-functional T cell response along with dominant IFN-γ response, which can work synergistically with anti-TB chemotherapy. Therefore, we propose that targeting the checkpoint inhibitors like PD-1 will enhance the efficacy and provide strong synergistic immune clearance of M. tuberculosis along with chemotherapy. Inhibition of PD-1 in our anti-TB therapeutic vaccine trial will be appropriate for several reasons. Firstly, Nivolumab (anti-PD-1) has already been approved by FDA as an adjunct immunotherapy along with the treatment in renal cell carcinoma, metastatic melanoma, non-small cell lung cancer etc (Guo et al., 2017) showing promising results and is already therapeutic modality and in protocol. Its adverse effects, dose tolerance etc are already known and standardized. Secondly, the adverse inflammatory reactions such as pneumonitis, uveitis, colitis etc only develop after 2-4 months and clinically manageable (Medina and Adams, 2016). Moreover, risk of such complications will be significantly less in tuberculosis, as we propose use of much lower dosage (0.5-1mg/Kg of body weight as opposed to up to 10mg/Kg used in many cancers) (Agrawal et al., 2015). This will be more so, because we propose 3 doses only during the intensive phase of chemotherapy i.e. first 8 weeks of therapy, as we need to rescue the immunity just to push the bacillary clearance at the early phase so as to bridge the gap between immune response and bacillary load, hoping the effective chemotherapy would effectively clear the bacilli subsequently. Thirdly, repurposing anti-PD-1 therapy as adjunct immunotherapy in TB patient doesn’t require any clearance from regulatory authority in India as it is already in standardized clinical practice for other diseases and has already undergone all the required trials for safety, toxicity, efficacy both in animal models and patients.

With the anti-PD1 treatment, there might be a possibility of Immune reconstitution inflammatory syndrome (IRIS) which happens when the immune function recovers too quickly. Overworking of the immune system can sometimes lead to inflammation throughout the body and can sometimes flare up as a severe disease in the form of IRIS. Common symptoms of IRIS include fever, lymph nodes swelling, rashes and lesions on the skin, pneumonia, breathing difficulties etc. However with a very low dose of anti-PD-1 that is proposed in this study, chances of development of IRIS are rare. Data safety monitoring board (DSMB) will be formed for proper control and regulation of any such instances. Any symptoms of IRIS or anti-PD-1 toxicity or side effects will be taken care of by this DSMB and patient will be withdrawn from the trial. Appropriate measures and treatment will be carried out to ensure proper safety of the trial participant.