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Background & objectives Although multi-drug therapy has decreased the burden of disease, leprosy is yet to be eliminated. Accelerating progress requires optimal use of existing tools, advanced diagnostic tests, newer drugs, and vaccines. The search for a vaccine with therapeutic and preventive potential is ongoing, but evidence on effectiveness and safety is lacking. This systematic review and meta-analysis will evaluate and compare the clinical efficacy, immunogenicity, and safety of leprosy vaccines in humans. Methods In June 2024, three databases were systematically searched with updated search keywords. Randomized controlled trials (RCTs) pertaining to leprosy vaccines for humans which evaluated either therapeutic or prophylactic vaccines in leprosy with a placebo or active comparator arm, with full-text access, were included in the study. There were no restrictions on language, country or date. For the risk of bias assessment in the studies included, the revised Cochrane risk-of-bias 2 tool for RCTs was used. A P value (two-sided) of <0.05 was considered as significant for all tests; however for heterogeneity, a one-sided P value of <0.1 was considered as statistically significant. The quality of generated evidence specific to the desired outcomes were assessed using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). The study protocol was registered in PROSPERO (ID: CRD42024561651). Results A total of 2163 studies were retrieved from different databases. After removing duplicates and full text screening, 12 articles were finally selected. Out of these studies, eight used leprosy vaccines on prophylactic basis, while four used leprosy vaccines on therapeutic basis. In therapeutic use of leprosy vaccine, Ramu's score was found to be significantly protective [-3.06 (95% confidence interval (CI): -3.96 to -2.16)] among the recipients of the therapeutic leprosy vaccine. Bacterial index was found to be insignificant [-0.26 (95% CI: -1.54 to 1.03)] among the recipients of therapeutic leprosy vaccine. In subgroup analysis among the eight prophylactic vaccine studies, pooled relative risk was found to be 0.61 (95% CI: 0.41 - 0.91). Interpretation & conclusions The findings of this meta-analysis suggest that both prophylactic and therapeutic leprosy vaccines were significantly better compared to the placebo. Leprosy vaccine in the form of Mw/Mycobacterium welchii/MIP along with combination of World Health Organization (WHO) multi-drug therapy (MDT) or Bacillus Calmette-Guerin (BCG) vaccine along with second line treatment with rifampicin were found to be protective among the recipients.