A lipid nanoparticle-mRNA vaccine provides potent immunogenicity and protection against Mycobacterium tuberculosis

Mycobacterium tuberculosis remains the largest infectious cause of mortality worldwide, even with over a century of widespread administration of the only licensed tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG). mRNA technology remains an underexplored approach for combating chronic bacterial infections such as TB. We have developed a lipid nanoparticle (LNP)-mRNA vaccine encoding for a fusion protein of two immunogenic TB antigens, termed mRNA ^CV2 . In C57BL/6 mice intramuscularly vaccinated with mRNA ^CV2 , high frequencies of polyfunctional, antigen-specific Th1 CD4 ⁺ T cells were observed in the blood and lungs, which was associated with the rapid recruitment of both innate and adaptive immune cells to lymph nodes draining the site of immunisation. mRNA ^CV2 vaccination provided significant pulmonary protection in M. tuberculosis -infected mice, reducing bacterial load and inflammatory infiltration in the lungs. As BCG is widely administered in infants in TB endemic countries, new TB vaccines should be able to boost the effects of BCG. Importantly, mRNA ^CV2 enhanced immune responses and long-term protection when used to boost BCG-primed mice. These findings, which provide the first report of a highly protective LNP-mRNA vaccine for TB, highlight the potential of the LNP-mRNA platform for TB control and support further research to facilitate translation to humans.