mRNA-based tuberculosis vaccines BNT164a1 and BNT164b1 are immunogenic, well tolerated and efficacious in rodent...

We designed and preclinically tested two mRNA-lipid-nanoparticle-based vaccine candidates to protect against tuberculosis. BNT164a1 and BNT164b1 encode the same eight Mycobacterium tuberculosis antigens expressed across different infection stages: Ag85A, Hrp1, ESAT-6, RpfD, RpfA, HbhA, M72 and VapB47. BNT164a1 utilizes nucleoside-unmodified mRNA, whereas BNT164b1 utilizes N¹-methylpseudouridine-modified mRNA. Prime-boost immunization with BNT164 candidates elicited antibody and/or T cell responses against all antigens in three mouse strains (C57BL/6, BALB/c and HLA-A2.1/DR1 humanized mice). The candidates demonstrated favorable safety profiles in a rat toxicity study and significantly reduced bacterial burdens of two M. tuberculosis strains in murine aerosol challenge models. BNT164 protection was correlated with granuloma infiltration by CD8⁺ T cells with memory precursor phenotypes. In conclusion, BNT164a1 and BNT164b1 were immunogenic, well tolerated and efficacious in preclinical models and have entered phase 1/2 clinical trials ( NCT05537038 , NCT05547464 ).