Genetic Modification of the BCG Vaccine to Overcome Its Limited Efficacy in Adults: A Specialized Review

Abstract While the Bacillus Calmette-Guérin (BCG) vaccine protects against severe childhood tuberculosis, it does not consistently protect against adult pulmonary tuberculosis, the main driver of global transmission and mortality. This review summarizes the scientific rationale and evolution of genetic engineering approaches to address BCG's immunological limitations, from initial strategies such as overexpressing Mycobacterium tuberculosis antigens and immunomodulatory cytokines to second-generation methods using subtractive and integrative genomic editing. Key candidates, such as VPM1002—engineered for phagosomal escape and improved CD8 + T-cell activation via MHC-I cross-presentation—and MTBVAC, a live-attenuated M. tuberculosis strain with a broad antigenic repertoire, are now in advanced clinical trials within a diverse pipeline monitored by WHO. These advances constitute a paradigm shift in vaccine design. However, adoption remains challenged by major barriers: the lack of immune correlates of protection, complex regulatory pathways for GMOs, and significant economic and manufacturing hurdles. Genetic modification offers the most feasible route to an effective adult TB vaccine, but its promise depends on overcoming obstacles in the translational landscape and aligning with the WHO's End TB Strategy.