Leprosy or Hansen’s disease is a complex ancient infectious disease, caused by M.leprae and M.lepromatosis. The most believed frequent mode of transmission is airborne and therefore those in close contact with a new leprosy case are at the most risk of developing the disease although this depends on immunity heterogeneity. Despite leprosy has been the first infectious disease where the pathogen agent was identified, research and development have failed in the creation of reliable diagnostic tests for infection and disease. Therefore, the World Health Organization (WHO) recommends clinical cardinal signs and the ancient slit skin smear (SSS) for the diagnosis of the disease, and no diagnostic test for diagnosis of infection is currently recommended. Both clinical and laboratory skills and expertise are key for ensuring the reliability of diagnosis, which is dwindling due to the sustained decrease of leprosy prevalence worldwide. Nevertheless, the incidence has plateaued in the last decade around 200,000 new cases at the global scale and the highly effective treatment with multidrug therapy (MDT) has been insufficient to stop transmission. In 2018, the WHO has recommend single-dose rifampicin (SDR) as post-exposure prophylaxis (PEP) for the contacts of new leprosy patients without signs of leprosy disease. The protection of PEP is around 60% and is based on the pivotal COLEP trial in Bangladesh. The Leprosy post-exposure prophylaxis with single-dose rifampicin (LPEP) study has documented the feasibility of PEP under programmatic conditions, and there is also evidence that PEP is cost-effective. Nevertheless, operational challenges for the most cost-effective approach to the provision of PEP for the high-risk population without causing harm to the persons eligible for SDR, and avoiding the increase of prevalence of rifampicin resistance, remain. In this Ph.D., we developed and estimated the effectiveness of innovative active case detection strategies based on Geographic Information Systems-based (GIS-based) technologies for stopping transmission of M. leprae in high-priority countries i.e. Comoros, India, and Madagascar. We discussed the latest evidence of the natural history of leprosy and the most recent control strategies in Chapter 1. In chapter 2, we analyzed door-to-door screening for leprosy in four endemic villages of Comoros that received SDR-PEP and we calculated the spatial risk of contracting leprosy for contacts including the protective effect of SDR-PEP for those who received it. We found 114 new cases among 5760 contacts screened (2.0% prevalence), in addition to the 39 cases detected in the two preceding years. There were statistically significant associations of incident leprosy with physical distance to index cases ranging from 2.4 (95% confidence interval (95% CI) 1.5–3.6) for household contacts to 1.8 (95% CI 1.3–2.5) for those living at 1–25 m, compared to individuals living at ≥75 m. The effect of SDR-PEP appeared protective but did not reach statistical significance due to the low numbers. Chapter 3, describes the protocol of Post ExpOsure Prophylaxis for Leprosy in the Comoros and Madagascar (PEOPLE), a cluster-randomized trial to assess the effectiveness of three modalities of implementing PEP. In the PEOPLE trial, four annual door-to-door surveys will be performed in four arms. All consenting permanent residents will be screened for leprosy. Leprosy patients will be treated according to international guidelines and eligible contacts will be provided with SDR-PEP. Arm-1 is the comparator where no PEP will be provided. In arms 2, 3, and 4, SDR-PEP will be administered at a double dose (20 mg/kg) to eligible contacts aged two years and above. In arm 2, all household members of incident leprosy patients are eligible. In arm 3, not only household members but also neighborhood contacts living within 100-m of an incident case are eligible. In arm 4, such neighborhood contacts are only eligible if they test positive for anti-PGL-I, a serological marker. Incidence rate ratios calculated between the comparator arm 1 and each of the intervention arms will constitute the primary outcome. In chapter 4, we describe the findings of the baseline survey of the first year of the PEOPLE trial in Comoros and Madagascar. We also assessed clustering at the village level fitting a purely spatial Poisson model by Kulldorff’s spatial statistic and measured the distance risk of contact to the nearest leprosy patient. There were 455 leprosy patients; 200 (44.0%) belonged to 2735 households included in a cluster. Thirty-eight percent of leprosy patients versus 10% of the total population live 25 m from another leprosy patient. Risk ratios for being diagnosed with leprosy were 7.3, 2.4, 1.8, 1.4, and 1.7, for those in the same household, at 1–