The tuberculin skin test (TST) is a simple and inexpensive test to determine whether individuals have been exposed to Mycobacterium tuberculosis. This test is not always reliable, however, in people previously immunized with BCG and/or who have been exposed to environmental mycobacterial species due to a reaction to purified protein derivative (PPD) used in the skin test. An issue with BCG, therefore, is that the resulting sensitization to PPD in some individuals compromises the diagnostic use of the skin test. The ability to induce protective immune responses without sensitizing to the tuberculin skin test will be important properties of next-generation tuberculosis (TB) vaccine candidates. We show here that guinea pigs immunized with the candidate TB vaccine ID93/GLA-SE, currently in clinical trials, do not react to intradermal PPD administration. In contrast, positive DTH responses to both ID93 and components thereof were induced in ID93/GLA-SE-immunized animals, indicating robust but specific cellular responses were present in the immunized animals. Noninterference with the TST is an important factor for consideration in the development of a vaccine against M. tuberculosis.T uberculosis (TB) remains a huge global health problem, with nearly 1.3 million deaths and more than 8.5 million people developing TB in 2012 due, in part, to the lack of an effective vaccine for the prevention of pulmonary tuberculosis in adults (1). The bacillus Calmette-Guérin (BCG) vaccine, in widespread use for more than 60 years, appears to have minimal impact on the worldwide incidence, despite demonstrating reasonable efficacy against severe complications of infant TB (2). The identification of individuals infected with the tuberculosis bacilli, particularly in epidemiological studies, has been traditionally done using a tuberculin skin test (TST). This test is based on the delayed-type hypersensitivity (DTH) reaction elicited by Mycobacterium tuberculosis antigens (tuberculin). Intradermal (i.d.) injection of purified protein derivative (PPD) of tuberculin, which is a cell-free purified protein fraction from M. tuberculosis diluted in PBS (or buffer), polysorbate Tween 80 (as a stabilizer) and phenol (as a preservative), results in a DTH response in most immunocompetent infected individuals peaking 48 to 72 h after injection. Although this is a relatively simple and inexpensive way to identify individuals that have been exposed to tuberculosis, there are drawbacks to the TST. One of the biggest drawbacks results from a large complement of proteins within PPD that are expressed by BCG (3), which can compromise the ability of this test to distinguish between BCG-vaccinated and M. tuberculosis-exposed people in countries where BCG is routinely used. A subset of people vaccinated with BCG revert to a PPD-negative status over time: there is little effect on the TST if BCG is given only once at birth and if the TST is performed 10 years or more after BCG vaccination (4). If, however, BCG is given as a booster vaccination as a part of t...