Abstract
ABSTRACT We designed and preclinically tested two mRNA-LNP-based vaccine candidates to protect against tuberculosis (TB). BNT164a1 and BNT164b1 encode the same eight Mycobacterium tuberculosis ( Mtb ) antigens expressed across different infection stages: Ag85A, Hrp1, ESAT-6, RpfD, RpfA, HbhA, M72, and VapB47. BNT164a1 utilizes nucleoside-unmodified mRNA, while BNT164b1 utilizes N1-methyl pseudouridine-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 Mtb strains in murine aerosol challenge models. BNT164 protection 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 are the first mRNA-based TB vaccines to enter phase I/II clinical trials ( NCT05537038 , NCT05547464 ).
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ABSTRACT
We designed and preclinically tested two mRNA-LNP-based vaccine candidates to protect against tuberculosis (TB). BNT164a1 and BNT164b1 encode the same eight Mycobacterium tuberculosis (Mtb) antigens expressed across different infection stages: Ag85A, Hrp1, ESAT-6, RpfD, RpfA, HbhA, M72, and VapB47. BNT164a1 utilizes nucleoside-unmodified mRNA, while BNT164b1 utilizes N1-methyl pseudouridine-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 Mtb strains in murine aerosol challenge models. BNT164 protection 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 are the first mRNA-based TB vaccines to enter phase I/II clinical trials (NCT05537038, NCT05547464).
Competing Interest Statement
All authors are employees at BioNTech SE and may hold stock options. U.Ş. is a management board member and stock owner of BioNTech SE (Mainz Germany). N.A, S.S., A.V., M.D and U.Ş. are inventors on International Patent Application PCT/EP2022/071816, which relates to tuberculosis vaccine candidates. N.A, L.S.A., S.S., A.C., A.V., J.D., M.D and U.Ş. are inventors on patents or patent applications relating to mRNA technology and vaccines.
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