mRNA vaccine development for tuberculosis: antigen design, immune mechanisms, and translational challenges

The persistent global burden of tuberculosis (TB) and the context-dependent efficacy of the Bacillus Calmette-Guérin (BCG) vaccine necessitate the development of innovative prophylactic strategies. mRNA vaccine platforms have emerged as a transformative toolkit, offering unprecedented versatility in antigen design and manufacturing scalability. This inclusive innovation review synthesizes the molecular engineering and immunological mechanisms of mRNA TB vaccines, evaluating their capacity to address the unique challenges posed by the intracellular lifestyle of Mycobacterium tuberculosis (Mtb). mRNA platforms realistically offer superior endogenous antigen production for CD8⁺ T-cell activation and the flexibility to encode multi-stage fusion antigens targeting both active and latent bacilli. However, significant constraints remain; mRNA technology alone cannot resolve the spatial sequestration of Mtb within necrotic granulomas or the "recruitment lag" of systemic immunity to the lung parenchyma. Achieving sterile protection requires a transition toward mucosal delivery systems capable of inducing lung T_RM cells. Furthermore, translational success must be measured beyond classical interferon-gamma (IFN-γ) readouts, prioritizing correlates of protection that reflect site-specific immunity, safety in latently infected populations, and the deployment of thermostable formulations in endemic regions. By integrating mRNA constructs into heterologous prime-boost regimens and host-directed therapies, the field moves toward a precision vaccinology framework capable of curtailing the TB epidemic.