Vaccine development against Mycobacterium tuberculosis: a PRISMA-guided systematic review of conventional and computational multi-epitope approaches.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health burden despite widespread Bacillus Calmette-Guérin vaccination, which provides inconsistent protection against adult pulmonary TB. This systematic review, conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, synthesizes recent advances in TB vaccine development, encompassing conventional live-attenuated and protein subunit vaccines as well as computationally designed multi-epitope vaccines (MEVs). A comprehensive literature search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar for studies published between January 2020 and December 2024 identified 847 records, of which 63 met inclusion criteria for qualitative synthesis. Clinical-stage development remains dominated by conventional platforms, with M72/AS01E demonstrating 54% efficacy in a Phase 2b trial and advancing to Phase 3 evaluation, representing the most promising next-generation candidate to date. In parallel, immunoinformatics and reverse vaccinology (RV) approaches have enabled rational MEV design, including constructs such as PP13138R and PP19128R, which exhibit strong antigenicity and immunogenicity in silico and in vitro. Novel hypothetical protein antigens, including Rv3899c, Rv1509, Rv0574c, and Rv0790c, have also emerged as potential targets. However, no computationally designed MEV has yet progressed to clinical evaluation, highlighting a significant translational gap between predictive modeling and experimental validation. TB vaccine research is increasingly transitioning toward rational, computationally guided strategies, but integration of computational discovery with rigorous preclinical and clinical validation remains essential to accelerate the development of effective next-generation TB vaccines.