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A Mucosal Vaccine Formulation Against Tuberculosis by Exploiting the Adjuvant Activity of S100a4A Damage-Associated Molecular Pattern Molecule

Abil, O;Liu, S;Yeh, Y;WU, Y;Sen Chaudhuri, A;Shan Li, N;Deng, C;Xiang, Z;

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains one of the top three causes of death. Currently, the only licensed vaccine against TB is the bacillus Calmette-Guerin (BCG), which lacks efficacy in preventing and controlling pulmonary TB in adults. We aimed to evaluate a nasal TB vaccine formulation composed of the Mtb-specific vaccine antigen ESAT-6, an Mtb-associated protein that can trigger protective immune responses, and S100A4, a recently characterized novel mucosal adjuvant. Mice were intranasally given recombinant ESAT-6 in the presence or absence of S100A4 as an adjuvant. We have provided experimental evidence demonstrating that S100A4 adsorbed to ESAT-6 could induce Mtb-specific adaptive immune responses after intranasal immunization. S100A4 remarkably augmented the levels of anti-ESAT-6 IgG in serum and IgA in mucosal sites, including lung exudates, bronchoalveolar lavage fluid (BALF) and nasal lavage. Furthermore, in both lung and spleen tissues, S100A4 strongly promoted ESAT-6-specific expansion of CD4 T cells. Both CD4 and CD8 T cells from these tissues expressed increased levels of IFN-g, TNF-a, and IL-17, cytokines critical for antimicrobial activity. Antigen-reencounter-induced T cell proliferative responses, a key vaccine performance indicator, were augmented in the spleen of S100A4-adjuvanted mice. Furthermore, CD8 T cells from the spleen and lung tissues of these mice expressed higher levels of granzyme B upon antigen re-stimulation. S100A4-adjuvanted immunization may predict good mucosal protection against TB.