Mincle receptor agonist UM-1098 and TLR4 agonist INI-2002 combination adjuvant enhances Th1 responses and provides protection against Mycobacterium tuberculosis challenge in mice

Adjuvants targeting pattern recognition receptors (PRRs) can selectively skew the immune responses towards a Th1, Th2 or Th17 phenotype following vaccination. However, for diseases such as tuberculosis (TB), mixed Th cell responses, especially Th1/Th17 are considered important for protection. Hence, the potential of combining adjuvants to achieve mixed and synergistic immune responses warrants further investigation. Herein, we evaluated the combination of a Mincle and a Toll-like receptor (TLR) 4 agonist for its capacity to induce greater and more protective Th1/Th17 responses than use of either adjuvant individually. Stimulation of human PBMCs with the synthetic UM-1098/INI-2002 adjuvant combination led to synergistic IL-1β and TNF-α production. Importantly, vaccination of mice with the Mycobacterium tuberculosis (Mtb) antigen M72 and the UM-1098/INI-2002 combination resulted in significantly greater Th1 responses than vaccination with either adjuvant alone. On the other hand, Th17 responses induced by M72 and the UM-1098/INI-2002 combination were not significantly greater than Th17 responses induced by vaccination with either adjuvant alone. A virulent Mtb challenge in mice demonstrated protection after vaccination with M72 combined with UM-1098, INI-2002 or the combination adjuvants. Additionally, mice vaccinated with either UM-1098 or INI-2002 alone or their combination had significantly greater numbers of pulmonary CD4⁺/CD44^high/IL-17A⁺ cells post challenge than naïve mice or mice vaccinated with the clinical benchmark, BCG. In summary, this study demonstrates that the combination of synthetic Mincle and TLR4 agonists has promise for enhancing Th1/Th17 immunity to co-administered antigens and could be particularly effective for enhancing immunity to bacterial pathogens.