What is Leprosy?

Leprosy, also known as Hansen’s disease, is a bacterial infection of the tissue of the skin, peripheral nervous system, mucosa, and upper respiratory tract that can cause skin lesions and serious deformity. There is an ongoing attempt to eliminate leprosy as a public health problem.

Global Burden

Leprosy

The 213,000 known remaining cases of leprosy are confined mostly to 17 countries.1 However, due to the ongoing stigma associated with the disease, the numbers may be underreported. The annual incidence has been decreasing since 2003 mainly due to timely case-finding and multidrug therapy.2 The disease is known to occur worldwide, although the greatest burden of disease is in Southeast Asia. India accounts for 50% of new cases of leprosy, with Brazil and Indonesia also reporting uncommonly high incidence rates.2

Causative Agent

Leprosy is transmitted by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis, which are related to the bacterium that causetuberculosis and Buruli ulcer. The exact mode of transmission of leprosy is still unknown. People who live in the same household as someone infected with leprosy are four times more likely to contract the infection. As such, respiratory transmission from the nasal mucosa of an infected person to the upper respiratory tract is likely.3 In the southern United States, armadillos have been reported to be a natural reservoir of leprosy and have transmitted the infection to humans on a number of occasions.4

Pathogenesis

exampleThe incubation period of leprosy is very long, ranging from two to fifteen years, which can make early treatment difficult. The primary symptoms of leprosy are progressive skin and nerve damage, which can lead to intensive disfigurement and disability.5 The WHO classifies leprosy into two categories: paucibacilliary and multibacilliary leprosy. Paucibaclliary leprosy involves a less vigorous cellular immune response and presents with fewer lesions and fewer bacilli on a skin smear. The paucibacilliary form is not detectable using a traditional skin smear. Multibacilliary leprosy is associated with a greater number of bacilli and lesions and a more vigorous immune response.6

Current Control Strategy

Because transmission is poorly understood, World Health Organization (WHO) policy focuses on the early detection of new cases and rapid treatment rather than prevention of transmission. Treating the disease early both limits the transmission of the disease and also the deformity that long-term infection can cause.2 The WHO’s “final push” strategy towards elimination emphasizes the expansion of multi drug therapy to health centers in endemic areas, aims to reduce stigma so that infected individuals will report for treatment, and encourages all patients to finish out their full course of treatment.7

Existing Products

Drugs

Historically, the treatment for leprosy since the 1930s was an anti-bacterial drug called dapsone. However, long-term monotherapy resulted in increasing drug resistance to dapsone. Currently, the WHO-recommended regimen for leprosy treatment is multidrug therapy. For paucibacillary leprosy, the regimen is rifampicin and dapsone and for multibacilliary leprosy a third drug, clofazamine, is added.8 The combination therapy is considered essential to avoid developing resistance to any one particular drug. If successful completion of the entire course of treatment is achieved, relapse rates are less than 1% for each of these regimens. However, there are emerging reports of rifampicin-resistance, which underscores the importance of completing the course of multidrug therapy.9

Vaccines

The M. welchii vaccine, a killed vaccine based on a bacterium similar to M. leprae, has been shown to have a small protective effect and has been approved in India, though it is not used on a large scale.9 The tuberculosis vaccine, BCG, is also known to provide incomplete protection against M. leprae.11

Diagnostics

Since most leprosy cases occur in rural areas with limited access to advanced equipment, diagnosis is generally based on clinical signs. Skin smear and microscopy is helpful in cases of multibacillary leprosy where the bacteria are visible, but a negative skin smear is not definitive proof that the infection is not present.12

References

  1. WHO (2012). Accelerating work to overcome the global impact of neglected tropical diseases: A roadmap for implementation.
  2. WHO (2010). Global Leprosy Situation, 2010. Weekly Epidemiological Record 35
  3. WHO. Transmission of leprosy.
  4. Truman et al. (2011). ‘Probable Zoonotic Leprosy in the Southern United States.’ The New England Journal of Medicine 364; 1626-1633
  5. Rodrigues et al. (2011). Leprosy now: epidemiology, progress, challenges and research gaps. The Lancet Infectious Diseases11(6)
  6. WHO. Classification of Leprosy.
  7. WHO. The “Final Push” strategy for elimination.
  8. WHO. MDT and drug resistance.
  9. Virendra et al (2004). Lepra Vaccine: misinterpreted myth. International Journal of Dermatology 45(2):164-167
  10. WHO. Multidrug therapy (MDT).
  11. Duthie, M. S., et al (2011) Advances and hurdles on the way toward a leprosy vaccine. Hum Vaccin. 7(11)
  12. WHO. Diagnosis of leprosy.

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.

Drugs

Analysis

The current antibiotic regimen for leprosy has no side effects and a low relapse rate when used correctly, so there are no drugs currently in development to replace MDT. However, the growing incidence of rifampicin resistance may warrant further drug development

Because leprosy is probably spread through contact with infected individuals, chemoprophylaxis of patient contacts with anti-leprosy drugs has the potential to lower the rate of transmission. Chemoprophylaxis with rifampicin has been reported to have decreased leprosy incidence after three years, but its effectiveness is not clear.1

Vaccines

Analysis

BCG, the tuberculosis vaccine, is reported to have approximately a 26% protective effect against leprosy, with increased protection after a second dose.2 A combination of BCG and killed M. leprae is also slightly more effective than BCG alone.2 A protein subunit vaccine, ICRC, underwent clinical trials in India in the 1990s and has shown a small protective effect compared to BCG.3

Diagnostics

Analysis

Because late-stage diagnosis allows for a longer period of transmission, it is crucial that more cases be detected earlier. To this end, new diagnostics for leprosy, especially rapid diagnostic tests that can be used at the point of care, are desperately needed.

References

  1. Bakker at al (2005). Prevention of leprosy using rifamicin as chemprophylaxis. The American Journal of Tropical Medicine and Hygiene72(4):44-3448
  2. Setia et al. (2006). The role of BCG in prevention of leprosy: a meta-analysis. The Lancet Infectious Diseases. 6(3): 162-170
  3. Virendra et al (2004). Lepra Vaccine: misinterpreted myth. International Journal of Dermatology 45(2):164-167

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.

The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for Mycobacterium leprae, the causative agent of Leprosy. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development.

Drugs Development Tools

Basic Research: Target IdentificationTarget ValidationScreening: Hit/Lead Identification OptimizationPre-clinical ValidationClinical Validation

Genome:Mycobacterium lepraegenome sequenced & annotated1,5

Key databases:
GenBank (AL450380)

In vitro culture:Cannot grow on bacteriological media. Limited metabolic activity detected in vitro for possible drug screening.19 Viable M. leprae can be propagated & maintained in footpads of mice.2,3,4

Gene knock-outs: No

Conditional gene knock-outs: No

Transposon mutagenesis: No

RNAi: No 

Other antisense technology:  No 

Viability assays:  Yes, RT-PCR6, radiorespirometry4, and fluorescent viability staining7  

Transcription microarrays: Yes8,9

Proteomics:Yes10,11,12 

Crystal structures:  Yes13,14,15

Whole-cell screening assays: Yes, using mouse footpad model16,17,18 or limited in vitro culture19

Enzymatic screening assays: Possible, but not used extensively

Animal models: Yes2,3

Monitoring treatment efficacy: Yes, Slit skin smear test; For PB leprosy, changes in size and number of skin lesions useful for assessing clinical improvement and differentiating between Lepra reactions vs. relapse20 

Availability of endpoints: Yes, but are varied with respect to type of Lepra reactions displayed by patient.

Availability of surrogate endpoints: Yes, but vary according to type of Lepra reaction. 

Access to clinical trial patients/sites:Yes, but low prevalence of disease and social stigma associated with diagnosis create challenges for clinical trials

Vaccines Development Tools

Basic Research: Antigen IdentificationImmune Response CharacterizationClinical Validation

See drug development tools above

Predictive animal models: Yes2,3

Detection of endogenous antigen specific response in clinical samples:Yes, IFNgamma is currently the best indicator of the antigen-specific cellular immune response of leprosy22

Natural immunity well characterized:Yes, very well-characterized. “Lepra reactions”

Surrogate markers of protection: Yes (IgG response to ML0405 and ML2331M. leprae proteins in serum)23

Challenge studies possible: No

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes. Slit skin smear test for multibacillary leprosy. “Lepromin test”: autoclavedMycobacterium leprae antigen is useful for exclusion of patients with perpherial neuropathy. Phenolic glycolipid-1 (PGL-1) IgM has liimited clinical use. 100% positive for multibacillary leprosy. Only 21 % in paucibacillary leprosy. 

Access to clinical samples: Yes, but low prevalence of disease and social stigma associated with diagnosis create challenges for clinical trials

Possible sample types: Unknown

Access to clinical trial patients/sites: Yes, but low prevalence of disease and social stigma associated with diagnosis create challenges for clinical trials 

Treatment available if diagnosed: Yes

References

  1. 1. Cole, S. T., et al. (2000) Massive gene decay in the leprosy bacillus. Nature409:1007-1011.
  2. Shepard, C. C., (1960) The experimental disease that follows the injection of human leprosy bacilli into foot pads of mice. J Exp Med112:445-454.
  3. Levy, L., Ji, B., (2006) The mouse foot-pad technique for cultivation of Mycobacterium lepraeLepr Rev. 77(1):5-24.
  4. Truman, R. W., Krahenbuhl, J. L., (2001) Viable M. leprae as a research reagent. Int J Lepr Other Mycobact Dis69(1):1-12.
  5. Scollard, D. M., et al. (2006) The continuing challenges of leprosy. Clin Microbiol Rev19(2):338-381.
  6. Martinez, A. N., et al. (2009) Molecular determination of Mycobacterium leprae viability by use of real-time PCR. J Clin Microbiol.47(7):2124-2130.
  7. Lahiri, R., et al. (2005) Application of a viability-staining method for Mycobacterium leprae derived from the athymic (nu/nu) mouse foot pad. J Med Microbiol54:235-242.
  8. Akama, T., et al. (2010) Analysis of Mycobacterium leprae gene expression using DNA microarray. Microb Pathog49(4):181-185.
  9. Akama, T., et al. (2009) Whole-genome tiling array analysis of Mycobacterium leprae RNA reveals high expression of pseudogenes and noncoding regions. J Bacteriol191(10):3321-3327.
  10. Wiker, H. G., et al. (2011) A quantitative view on Mycobacterium leprae antigens by proteomics. J Proteomics74(9):1711-1719.
  11. de Souza, G. A., et al. (2009) Validating divergent ORF annotation of the Mycobacterium leprae genome through a full translation data set and peptide identification by tandem mass spectrometry. Proteomics9(12):3233-3243.
  12. Marques, M. A., et al. (2008) Deciphering the proteomic profile of Mycobacterium leprae cell envelope. Proteomics.8(12):2477-2491.
  13. Kaushal P. S., et al. (2010) X-ray and molecular-dynamics studies on Mycobacterium leprae single-stranded DNA-binding protein and comparison with other eubacterial SSB structures. Acta Crystallogr D Biol Crystallogr. 66(Pt10):1048-1058.
  14. Grana, M., et al. (2007) The crystal structure of M. leprae ML2640c defines a large family of putative S-adenosylmethionine-dependent methyltransferases in mycobacteria. Protein Sci16(9):1896-1904.
  15. Mande S. C., et al. (1996) Structure of the heat shock protein chaperonin-10 of Mycobacterium lepraeScience.27(5246):203-207.
  16. Franzblau, S. G., et al. (1992) Double-blind evaluation of BACTEC and Buddemeyer-type radiorespirometric assays for in vitro screening of antileprosy agents. Lepr Rev. 63(2):125-133.
  17. Makarov, V., et al. (2006) Synthesis of antileprosy activity of some dialkyldithiocarbamates. J Antimicrob Chemother.57(6):1134-1138.
  18. Consigny, S., (2000) Bactericidal activities of HMR 3647, moxifloxacin, and rifapentine against Mycobacterium leprae in mice.Antimicrob Agents Chemother44(10):2919-2921.
  19. Dhople, A. M., Ortega, I., (1990) An in vitro culture method for screening new drugs against Mycobacterium leprae62(1):66-75.
  20. Rao, P.N., et al. (2011) Changes in the size and number of skin lesions in PB leprosy on treatment and follow-up. Lepr Rev.82(3):244-252.
  21. Duthie, M. S., et al (2011) Advances and hurdles on the way toward a leprosy vaccine. Hum Vaccin. 7(11): 1172-1183
  22. Sampaio, L. H., et al (2011) Evaluation of various cytokines elicited during antigen-specific recall as potential risk indicators for the differential development of leprosy. Eur J Clin Microbiol Infect Dis. 2011 Nov 12.
  23. Duthie, M. S., et al (2011) Specific IgG antibody responses may be used to monitor leprosy treatment efficacy and as recurrence prognostic markers. Eur J Clin Microbiol Infect Dis30(10):1257-65.

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.