Development of the food supplement Nyaditum resae as a new tool to reduce the risk of tuberculosis development

Nyaditum resae (NR) is a galenic preparation of heat-killed Mycobacterium manresensis (hkMn). This is a new species that belongs to the Mycobacterium fortuitum complex, and it is present in drinking water—thus, regulatorily speaking, it is considered a food supplement. Preclinical studies in the murine model of active tuberculosis (TB) in the C3HeB/FeJ strain have demonstrated that daily administration of NR containing 103–106 hkMn for 14 days was able to stop the progression toward active TB [1]. The mechanism of action was linked to the induction of low dose tolerance and was related to the increase of Tuberculin Purified Protein Derivative (PPD) memory-specific Tregs (CD4+CD25+CD39+ cells) after ex vivo incubation of splenocytes for 7 days. This increase of Tregs was related to the increase of interleukin (IL)-10 in the spleen and in the reduction of IL-17 in the lungs, where there was also a reduction in bacillary load and the pathology caused by a reduction of neutrophiles' infiltration [2]. Two randomized, double-blind placebo-controlled clinical trials (CTs) have been conducted in humans. The NYADATREG study (Clinicaltrials.gov identifier NCT02076139; 2013–2014) was aimed to evaluate the safety and the immunogenicity of two concentrations of NR (containing 104 hkMn and 105 hkMn) versus placebo (all administered orally everyday for 14 days) in tuberculin-positive and tuberculin-negative volunteers (total n = 51). The results demonstrated an excellent safety record, with no differences between groups in terms of adverse effects. A significant increase in PPD-specific memory regulatory T cells was also detected in both NR groups [3]. The NYADAPETRICS study (Clinicaltrials.gov identifier NCT02581579) is evaluating the safety and immunogenicity of NR 105 hkMn (capsule format, orally) in the pediatric population. Currently, an efficacy study (randomized, double-blinded, placebo-controlled CT) is being conducted in Georgia. This NYADAGEORG trial includes close contacts of active TB cases with positive sputum not tributaries of chemoprophylaxis (