Every day approximately six thousand people die of Tuberculosis (TB). Its causative agent, Mycobacterium tuberculosis (Mtb), is an ancient pathogen that through its evolution developed complex mechanisms to evade immune surveillance and acquire the ability to establish persistent infection in its hosts. Currently, it is estimated that one-fourth of the human population is latently infected with Mtb and among those infected 3–10% are at risk of developing active TB disease during their lifetime. The currently available diagnostics are not able to detect this risk group for prophylactic treatment to prevent transmission. Anti-TB drugs are available but only as long regimens with considerable side effects, which could both be reduced if adequate tests were available to monitor the response of TB to treatment. New vaccines are also urgently needed to substitute or boost Bacille Calmette-Guérin (BCG), the only approved TB vaccine: although BCG prevents disseminated TB in infants, it fails to impact the incidence of pulmonary TB in adults, and therefore has little effect on TB transmission. To achieve TB eradication, the discovery of Mtb antigens that effectively correlate with the human response to infection, with the curative host response following TB treatment, and with natural as well as vaccine induced protection will be critical.

Over the last decade, many new Mtb antigens have been found and proposed as TB biomarkers and vaccine candidates, but only a very small number of these is being used in commercial diagnostic tests or is being assessed as candidate TB vaccine antigens in human clinical trials, aiming to prevent infection, disease or disease recurrence following treatment. Most of these antigens were discovered decades ago, before the complete Mtb genome sequence became available, and thus did not harness the latest insights from post-genomic antigen discovery strategies and genome wide approaches. These have, for example, revealed critical phase variation in Mtb replication and accompanying gene –and therefore antigen– expression patterns. In this review, we present a brief overview of past methodologies, and subsequently focus on the most important recent Mtb antigen discovery studies which have mined the Mtb antigenome through “unbiased” genome wide approaches. We compare the results for these approaches -as far as we know for the first time-, highlight Mtb antigens that have been identified independently by different strategies and present a comprehensive overview of the Mtb antigens thus discovered.