Tuberculosis (TB) is a global health problem, killing 1.5 million of people every year. The only currently available vaccine, Mycobacterium bovis BCG, is effective against severe childhood forms, but it demonstrates a variable efficacy against the pulmonary form of TB in adults. Many of these adult TB cases result from the reactivation of an initially controlled, latent Mycobacterium tuberculosis (MTB) infection. Effective prophylactic vaccination remains the key long-term strategy for combating TB. Continued belief in reaching this goal requires unrelenting innovation in the formulation and delivery of candidate vaccines. It is also based on the assumption, that the failure of recent human vaccine trials could have been due to a sub-optimal vaccine design and delivery, and therefore should not erode the key principle that a TB vaccine is an attainable target. This proposal focuses on mucosal vaccination, which has been considered in the past, but not implemented efficiently. The innovation of the proposal is focused on several important aspects of vaccine development and testing, including the use of novel technologies for vaccine delivery, novel ways of specific targeting of mucosal immune cells and tissues, the use of polypeptides incorporating early and latent MTB antigens and putative CD8+ T cell epitopes, and application of novel tools for identifying early predictors and correlates of vaccine-induced protection. The overall objective is to design a vaccine that will induce a broad-ranging immune response to MTB both systemically and in the mucosa of the lungs, and provide the currently missing links in protective immunity to this pathogen.