METHODS Study ParticipantsĪll studies that involved human participants were conducted according to the principles described in the Declaration of Helsinki and were approved by relevant institutional review boards (Human Research Ethics Committee ). In this study, our aim was to confirm the recognition of an ESAT-6–free IGRA antigen cocktail in adolescents from a high TB burden area, define a diagnostic algorithm for the ESAT-6–free IGRA, evaluate ESAT-6–free IGRA diagnostic performance compared to QFT, and assess the variability of ESAT-6–free IGRA blood collection tubes. Several studies explored the diagnostic potential of new candidates either alone or in combination, and we recently established an ESAT-6–free IGRA antigen cocktail after screening of several candidates (TB7.7, EspJ, EspC, EspF, EccD1, PE35, and Rv2348) compared to ESAT-6 and CFP-10. However, recent advances in antigen discovery tools and M.tb antigen recognition studies in humans point to novel diagnostic antigens that could replace ESAT-6. ![]() Until recently, inclusion of ESAT-6 and CFP-10 has been considered essential for adequate immunodiagnostic sensitivity. Such a clinical trial design, one that relies on IGRA to measure M.tb infection, cannot currently be used to evaluate ESAT-6–containing vaccine candidates, since vaccine-induced immune responses are cross-reactive with those measured by IGRA, rendering the test false positive. That trial provided the first proof-of-concept efficacy signal for a subunit vaccine candidate, which is very similar to H56:IC31 but does not contain ESAT-6. We recently showed that BCG revaccination or vaccination with a novel subunit vaccine candidate (H4:IC31) may offer partial protection against sustained M.tb infection, measured by QuantiFERON-TB Gold In-tube (QFT). Vaccine efficacy to prevent established M.tb infection, as a likely predictor of prevention of TB disease, has been proposed as an innovative and cost-effective endpoint to rationalize TB vaccine development. As such, ESAT-6 is contained in many candidate vaccines against tuberculosis (TB), including the subunit vaccine H56:IC31, which is undergoing phase 2 clinical testing. ![]() ĮSAT-6 is also increasingly recognized as an important vaccine antigen with unique properties for infection containment and, potentially, for clearance. These small, highly immunodominant antigens are encoded in the region of difference 1 of the M.tb genome, which comprises many important virulence factors as components and substrates of the ESAT-6 system 1 (ESX1) type VII secretion system and are absent from bacille Calmette-Guerin (BCG), thereby, importantly, enabling distinction of M.tb infection from prior BCG vaccination. ESAT-6 and its heterodimeric complex protein CFP-10 are the principal components of immunodiagnostic tests for M.tb infection, including the interferon-gamma (IFN-γ) release assay (IGRA) and novel specific skin tests. Tuberculosis infection, diagnosis, IFN-γ release assay, qualificationĮarly secretory antigenic target-6 (ESAT-6) is an immunodominant antigen expressed by Mycobacterium tuberculosis (M.tb).
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