Two mRNA TB vaccines show promise in animal studies

Tuberculosis is caused by Mycobacterium tuberculosis (Mtb) and remains a target for improved vaccines. In a preclinical effort led by Louis S. Ates, researchers designed and tested two new mRNA-LNP-based vaccine candidates named BNT164a1 and BNT164b1. Both candidates encode the same eight Mtb antigens that are expressed across different stages of infection: Ag85A, Hrp1, ESAT-6, RpfD, RpfA, HbhA, M72, and VapB47. The two vaccine constructs differ in their mRNA chemistry: BNT164a1 utilizes nucleoside-unmodified mRNA, while BNT164b1 utilizes N1-methyl pseudouridine-modified mRNA. The team used a prime-boost immunization strategy in multiple rodent models to evaluate whether these mRNA vaccines could generate immune responses against a broad set of Mtb antigens. This work represents a focused attempt to apply mRNA-LNP technology to tuberculosis by combining multiple antigens in a single vaccine format and testing safety and immune activity before moving into human trials.

The researchers tested prime-boost immunization with BNT164a1 and BNT164b1 in three mouse strains: C57BL/6, BALB/c, and HLA-A2.1/DR1 humanized mice. Across these strains, the candidates elicited antibody and/or T-cell responses against all eight encoded antigens. Safety was assessed in a rat toxicity study, which reported a favorable safety profile for the candidates. Efficacy was evaluated in murine aerosol challenge models using two Mtb strains; both BNT164 candidates significantly reduced bacterial burdens in these challenge experiments. Analysis of the infected lung tissue showed that BNT164 protection correlated with granuloma infiltration by CD8 + T cells with memory precursor phenotypes, linking a specific cellular response to protection in the models. Following these preclinical results, BNT164a1 and BNT164b1 became the first mRNA-based TB vaccines to enter phase I/II clinical trials (NCT05537038, NCT05547464).

Taken together, the findings reported by Louis S. Ates and colleagues show that mRNA-LNP vaccines encoding multiple Mtb antigens can be immunogenic, well tolerated and effective in reducing bacterial load in rodent models. The use of two mRNA chemistries—nucleoside-unmodified mRNA for BNT164a1 and N1-methyl pseudouridine-modified mRNA for BNT164b1—demonstrates that different mRNA formulations can be brought forward for comparative testing. The correlation between protection and granuloma infiltration by CD8 + T cells with memory precursor phenotypes points to a measurable immune signature associated with efficacy in these preclinical systems. Importantly, these candidates have progressed into early human testing, marking a step from animal models toward clinical evaluation. The results support further investigation of multi-antigen mRNA approaches for tuberculosis and provide a foundation for the ongoing phase I/II studies listed above.