Leprosy research updates: Shaping the future of global health

Transmission mechanisms and One Health approach

Despite leprosy being one of the first infectious diseases to have an identified cause and a long-standing global effort to control it, there are many scientific advances still to be made. Disease transmission mechanisms have not yet been fully understood. Leprosy is caused by M. leprae and M. lepromatosis, with transmission primarily occurring from person to person, but this mechanism is poorly understood. Zoonotic transmission, widely reported in the southeastern United States through nine-banded armadillos, has emerged as a significant concern in endemic regions of Latin America. In Brazil, approximately 10 per cent of the animals appear to be contaminated³, and hunting poses a higher risk of transmission⁴. The presence of M. leprae in the environmental reservoir further complicates efforts to achieve leprosy elimination⁵.

Diagnostic challenges

The diagnosis of leprosy is based on any of the three cardinal signs: i) the presence of skin lesions with definite loss of sensation, ii) a thickened or enlarged peripheral nerve, and iii) the presence of M. leprae in a slit-skin smear (SSS). The latter only occurs in about 20-40 per cent of cases. With decreasing expertise in clinical diagnosis and skin smear testing, the need for newer diagnostics is important.

Anti-phenolic glycolipid (PGL-I) antibodies strongly correlate to patients’ bacterial load and M. leprae DNA present in the SSS of patients and contacts⁶, rendering this host biomarker practical in detecting M. leprae infections, diagnosing multibacillary (MB) patients, and monitoring treatment⁷.

Qualitative and quantitative lateral flow tests detecting anti-PGL-I antibodies have been developed⁸ but not widely implemented as a point-of-care (POC) test. Multiple host biomarkers (αPGL-I IgM, IP-10, CRP, ApoA1, S100A12, CCL4) are required to capture the different clinical presentations across the leprosy disease spectrum⁹.

Ideally, affordable POC immunodiagnostic tests, like lateral flow assays detecting multiple biomarkers simultaneously, that recognise early stages of leprosy would play an important part in identifying individuals in need of PEP, reducing diagnostic delays and preventing misdiagnosis.

New advancements in PCR tests and M. leprae genotyping

Molecular diagnostics have significantly improved the detection and characterisation of M. leprae. PCR-based assays offer higher sensitivity and specificity, allowing early detection of M. leprae DNA in clinical and environmental samples. Recent advancements in PCR technology have led to the development of multiplex PCR assays that simultaneously amplify multiple target genes, improving diagnostic accuracy¹⁰. Given the complex nature of leprosy, a combination of molecular and biological markers enhances accuracy. Multiplex PCR assays have also been valuable for differentiating M. leprae from M. lepromatosis, which is increasingly recognised as a causative pathogen in leprosy cases. Additionally, multiplex PCR, along with other methods such as multiplex loop-mediated isothermal amplification (mLAMP) assays, have proven effective in diagnosing multiple diseases co-endemic with leprosy, simultaneously offering more cost- and time-efficient solutions¹¹. This aligns with the broader integration of leprosy diagnosis within skin-neglected tropical diseases (skin NTD), as the WHO advocates.

Expanding sample types beyond traditional SSS smears or skin biopsies which are invasive can be another key innovation. A recent study comparing blood, stool, and urine samples for paediatric leprosy diagnosis found that blood yielded the best results¹². While prior research suggested limited diagnostic utility of blood or even stool and urine, emerging technologies – such as nanoparticle-based detection – may allow us to revisit these approaches with improved sensitivity.

Beyond diagnosis, M. Leprae genotyping provides valuable epidemiological insights by tracking transmission patterns and identifying strain variations. Whole-genome sequencing (WGS) and single nucleotide polymorphism (SNP) analysis have refined our understanding of M. Leprae evolution and geographic distribution¹³. Advances in targeted sequencing approaches enable the differentiation of strains at a finer resolution, which is critical in tracing zoonotic and human-to-human transmission. These molecular tools contribute to precision in public health strategies by enabling early diagnosis, monitoring transmission routes, and guiding targeted interventions. They ultimately advance leprosy control and reduce disease burden.

Treatment challenges

Antimicrobial therapy against leprosy was introduced in the 1940s, and resistance to dapsone became a significant issue. Since 1982, the preferred leprosy multidrug therapy (MDT) has been a combination of dapsone, rifampicin, and clofazimine taken daily for up to a year. Rifampicin is the main bactericidal drug, taken once a month.

The WHO monitors the emergence of global resistance to anti-leprosy drugs. In 19 leprosy endemic countries participating in a surveillance study, molecular detection of resistance genes identified an antimicrobial resistance rate of eight per cent towards dapsone, rifampicin, and ofloxacin, with a higher percentage in relapse versus new cases¹⁴. Of additional concern are the findings that show high numbers of resistance to drugs used for second-line therapy, such as ofloxacin¹⁵. Alternatives to MDT also can include monthly ROM (rifampicin, ofloxacin, and minocycline) and moxifloxacin¹⁶; however, more trials are needed.

Bedaquiline targeting and binding with bacterial adenosine triphosphate leads to the death of mycobacteria. The long 5.5-month half-life and the higher activity compared to rifampicin make bedaquiline an attractive choice for treating leprosy. A phase 2 trial in Brazil showed that bedaquiline monotherapy for MB patients cleared M. Leprae within four wk of treatment and resulted in improvements in the appearance of skin lesions by week seven¹⁷. A phase 3, active-controlled study to assess the efficacy and safety of bedaquiline in combination with rifampicin and clofazimine for the treatment of multibacillary leprosy (CT N. 2021-006613-10) is underway.

Telacebec, a drug with established safety, tolerability, and efficacy against M. tuberculosis, has shown activity against intracellular and extracellular M. leprae at nanomolar concentrations in vitro, with activity superior to rifampicin¹⁸. Phase 2 studies are being planned, but are yet to be registered.

The management of leprosy reactions and neuritis remains a challenge. The WHO guidance document on the management of leprosy recommends a 20-wk regimen of prednisolone for the management of type 1 lepra reactions. Azathioprine, cyclosporine, and methotrexate have been used in controlled clinical trials but have failed to show higher efficacy compared to prednisolone¹⁹.

Thalidomide is the first choice for treatment for erythema nodosum leprosum (ENL); however, its limited availability, teratogenic effects, and the need for strict pregnancy prevention programmes have restricted its use in many countries. Biological drugs, including TNF-α inhibitors like etanercept and infliximab, have shown effective responses in managing ENL²⁰.

Prevention of leprosy challenges

Despite great strides in controlling leprosy and reducing the number of cases, the number of newly detected cases has plateaued over the last 10 yr. Vaccines and post-exposure chemoprophylaxis are among the strategies being trialled to interrupt transmission.

Bacillus of Calmette and Guerin (BCG) vaccine, mainly used to prevent TB meningitis, offers cross-reactivity and protection against leprosy, with decreasing efficacy over time. Revaccinating children as part of a leprosy prevention strategy in a Brazilian study showed no results, making BCG a poor candidate vaccine for leprosy control²¹.

LepVax is the first specific vaccine for leprosy²². Phase 1 trials in humans demonstrated safety and the ability to generate an immune response in healthy volunteers²². Results from ongoing trials are awaited.

Post-exposure prophylaxis is given as a single dose of rifampicin (SDR-PEP) or combined with other antibiotics like clarithromycin (SDR-PEP+)²³. Since 2018, the WHO has recommended SDR as leprosy preventive treatment for contacts of persons affected by leprosy, and a number of countries have introduced SDR-PEP for contacts of new cases as part of the leprosy control programmes despite it being less effective among household contacts, and more effective among non-blood relatives, neighbours of neighbours and other social contacts.

Single dose rifapentine (which has greater bactericidal activity than rifampicin) was shown to be protective in household contacts of index cases in a study in China²⁴. ‘Single Double Dose Rifampicin’ trialled in a cluster randomised control study (PEOPLE-trial) showed a reduction of 40 per cent in leprosy incidence in the Comoros and Madagascar²⁵. Alternative PEP-interventions, e.g., using bedaquiline as PEP (BE-PEOPLE trial), are ongoing²⁶. Major concerns of PEP are the risks associated with patient confidentiality, cost-effectiveness, the limited duration of protection, and the risks of inducing rifampicin resistance, especially when administered intermittently.

Challenges in disability management, including mental health

Leprosy is a highly stigmatising disease. This stigma is a significant barrier to its elimination. A rough estimation suggests that 3-4 million people live with visible impairments caused by leprosy, while social exclusion likely affects many more due to the disease’s label and associated disabilities. Efforts to combat stigma include human rights-based interventions such as repealing discriminatory laws and terminologies, promoting social inclusion, and providing counselling services to address the mental health impacts of diagnosis, disability, and exclusion²⁷.

Artificial intelligence in diagnosis and management

AI offers transformative potential for the diagnosis and management of leprosy. Integrated with AI, tools like the WHO Skin NTD app enable healthcare workers to identify leprosy cases early. Preliminary findings in Kenya revealed that both algorithms reached an average sensitivity of 80 per cent compared to diagnoses by certified dermatologists, highlighting AI’s capacity to enhance diagnostic accuracy and support healthcare systems in resource-limited settings²⁸.

Overall, leprosy research is shaping the future of global health by addressing diagnostic challenges, treatment limitations, and the stigma associated with the disease. Integrating AI into diagnostic tools, expanding molecular techniques, and advancing treatments for leprosy reactions and drug resistance exemplify the progress. Sustained global efforts are essential to achieve elimination, focusing on improving public health education, investing in innovative research, and ensuring access to advanced diagnostics and therapies. Together, these strategies will bridge gaps in care and empower healthcare systems to reduce the burden of leprosy worldwide.