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Background  Previously we have shown that Ag85B-TB10.4 is a highly efficient vaccine against tuberculosis when delivered in a Th1 inducing adjuvant based on cationic liposomes. Another Th1 inducing adjuvant, which has shown a very promising profile in both preclinical and clinical trials, is IC31®. In this study, we examined the potential of Ag85B-TB10.4 delivered in the adjuvant IC31® for the ability to induce protection against infection with  Mycobacterium tuberculosis . In addition, we examined if the antigen dose could influence the phenotype of the induced T cells.    Methods and Findings  We found that vaccination with the combination of Ag85B-TB10.4 and IC31® resulted in high numbers of polyfunctional CD4 T cells co-expressing IL-2, IFN-γ and TNF-α. This correlated with protection against subsequent challenge with  M.tb  in the mouse TB model. Importantly, our results also showed that both the vaccine induced T cell response, and the protective efficacy, was highly dependent on the antigen dose. Thus, whereas antigen doses of 5 and 15 µg did not induce significant protection against  M.tb , reducing the dose to 0.5 µg selectively increased the number of polyfunctional T cells and induced a strong protection against infection with  M.tb . The influence of antigen dose was also observed in the guinea pig model of aerosol infection with  M.tb.  In this model a 2.5 fold increase in the antigen dose reduced the protection against infection with  M.tb  to the level observed in non-vaccinated animals.    Conclusions/Significance  Small changes in the antigen dose can greatly influence the induction of specific T cell subpopulations and the dose is therefore a crucial factor when testing new vaccines. However, the adjuvant IC31® can, with the optimal dose of Ag85B-TB10.4, induce strong protection against  Mycobacterium tuberculosis . This vaccine has now entered clinical trials.

Protection and Polyfunctional T Cells Induced by Ag85B-TB10.4/IC31® against Mycobacterium tuberculosis Is Highly Dependent on the Antigen Dose