What is Leishmaniasis ?

Leishmaniasis is a widespread parasitic disease transmitted by the bite of an infected sandfly. The disease occurs in three forms, cutaneous leishmaniasis, mucocutaneous leishmaniasis, and visceral leishmaniasis, each of which varies in incidence and severity. The three predominant forms of leishmaniasis can affect the skin, mucosa, and/or internal organs resulting in severe disfigurement, disability, or death.

Global Burden

Leishmaniasis

Leishmaniasis is endemic in 88 countries across 4 continents with approximately 350 million people currently at risk for infection.1,2  Each year it is estimated that 1.6 million new infections occur as well as 47,000 deaths.

Leishmaniasis occurs in three forms that differ in incidence and geographic distribution as summarized in the table below.2

Disease Form Infections (per year) Geographic Distribution
Cutaneous leishmaniasis (CL) 1,100,000 90% of cases in Afghanistan, Algeria, Brazil, the Islamic Republic of Iran, Peru, Saudi Arabia, Sudan, and the Syrian Arab Republic
Mucocutaneous leishmaniasis (MCL) 35,000 90% of cases in Brazil, Peru, and the Plurinational State of Bolivia
Visceral leishmaniasis (VL)/Kala-azar 500,000 90% of cases in Bangladesh, Brazil, Ethiopia, India, Nepal, and Sudan

Organ damage and death associated with untreated visceral disease, as well as disfiguring damage to the mucosa and skin resulting from the mucocutaneous and cutaneous diseases, contribute to the morbidity associated with leishmaniasis. Morbidity as measured in DALYs across World Health Organization (WHO) regions are summarized in the table below.

WHO Region DALY (in thousands)3
Africa 328
Americas 45
Eastern Mediterranean 281
Southeast Asia 1,264
Western Pacific 51
Total: 1,969

The economic impact of leishmaniasis has not been estimated.

Causative Agent

parasiteLeishmaniasis is caused by protozoan parasites of the genus Leishmania. Upon taking a blood meal, an infected sandfly injects the leishmania parasites into the skin. The parasites are taken up by macrophages where they differentiate into an intracellular form, known as an amastigote, and replicate.

life cycleLeishmania spp. parasites are all transmitted through the bite of sandflies of the genus Phlebotomus (Africa, Middle East, and Asia) or Lutzomyia (Americas). Sandflies become infected by taking up parasite infected macrophages when ingesting the blood of an infected host. Ingested parasites transform from the intracellular amastigote form to the extracellular promastigote form in the midgut of the fly before being transmitted via a subsequent blood meal. Interestingly, leishmaniasis is primarily a zoonosis; the majority of transmission occurs from infected animals to humans via the sandfly rather than from humans to humans. The large animal reservoir for leishmaniasis has implications for control strategies.

 

Pathogenesis

Cutaneous leishmaniasis is characterized by skin lesions that are formed at the site of initial infection by the sandfly bite. As parasites replicate inside and eventually lyse macrophages and endothelial cells in the skin, direct cellular damage occurs. There are over 15 species or subspecies of Leishmania parasites that cause cutaneous disease. Most cutaneous lesions heal slowly over the course of several months without medication. However, the open wounds associated with untreated disease leave the host susceptible to other infections.

For unknown reasons, certain species of Leishmania parasites migrate beyond the site of initial sandfly bite to cause more extensive disease. Mucocutaneous disease occurs when parasites migrate to mucosal surfaces, generally of the nose or mouth. As with cutaneous lesions, parasites replicate in the tissues causing damage. However, unlike the cutaneous form of the disease, mucocutaneous lesions are not self-limiting and can result in permanent damage or loss of the nose, soft palate, or lips. Mucocutaneous disease is the least common form of leishmaniasis and is primarily limited to South America. The majority of disease is caused by a single subspecies of the parasite, Leishmania baziliensis braziliensis.

Following initial infection, a sub-set of parasite species can also migrate to organs throughout the body resulting in visceral leishmaniasis (also known as kala-azar). Severe damage to the liver and spleen commonly cause massive enlargement of these organs. Without treatment, death occurs within two years. The parasite species responsible for the majority of visceral disease vary geographically:

  • Indian subcontinent and Africa: L. donavani
  • Mediterranean: L. infantum
  • Central and South America: L. chagasi

Current Control Strategy

Control strategies for leishmaniasis have been difficult. There are several factors limiting progress towards disease control:

  • Large animal reservoir of parasites
  • Growing sandfly resistance to common insecticides
  • Bednets are only effective if frequently re-treated with insecticide as sandflies are significantly smaller than other insect vectors and can often pass through the mesh of untreated nets

Despite these challenges, the current control strategy for leishmaniasis includes:1

  • Early diagnosis and prompt treatment of disease
  • Vector control through indoor residual spraying and long-lasting insecticide treated nets (LLITN)
  • Detection and containment of epidemics

Existing Products

Drugs

There are several drugs available for the treatment of leishmaniasis, but many of the newer medications are not yet available in all endemic areas. Drug resistance is a concern in regions using monotherapies for treatment.

Drug Dosing Availability Comments
Pentavalent antimonials:Sodium stibogluconate, SSG Meglumine antimoniate 30+ days of IM or IV injections All endemic regions Toxic side effects and drug resistance are common
AmBisome®, liposomal amphotericin B 1-5 days IV injection Approved in 1997 in US for VL

Used in India to replace more toxic traditional formulation of amphotericin B 

Seeking registration and adoption in Africa with DNDi
 
Miltefosine 28 days, oral Approved in India in 2003 for VL

Seeking registration and adoption in Africa with DNDi
Only oral drug for VL; side effects generally limited and include diarrhea or vomiting
Paromomycin 21 days, IM injection Approved in 2006 in India for VL

Seeking registration and adoption in Africa with iOWH and DNDi
 

There is an intensive effort underway, primarily through DNDi, to register and encourage adoption of newer, safer visceral leishmaniasis medications outside of India. This is primarily being done through more extensive clinical trials of combination therapies of the drugs listed above.

Vaccines

There is currently no vaccine approved for the prevention of leishmaniasis.

Some informal vaccination efforts for the prevention of cutaneous leishmaniasis have been conducted in endemic areas through a process known as "leishmanisation." This process involves inoculating an area of skin (usually an area hidden by clothing) using live parasites from the active lesion of another person. Although difficult to standardize and extremely variable in outcome, this strategy does provide some protection.

Diagnostics

Several tests, including rapid tests for use at the point of care, are available for leishmaniasis.

Indication Diagnostic Method What is detected Characteristics
VL rK39 Dipstick Qualitative detection of antibodies to members ofL. donovani complex in human serum Sensitivity: >95% in India; less sensitive in East Africa

Specificity: >95% in India

Specimen: serum

Storage: room temperature (20-28°C)
VL Direct Agglutination Test (DAT) Qualitative detection of antibodies to Leishmania donovani, Leishmania infantum or Leishmania chagasiin in human blood, serum or plasma Sensitivity: High sensitivity including in HIV+ patients

Specificity: Unknown

Specimen: serum, plasma (taken on heparin), whole blood on filter paper (Whatman 3)

Storage: refrigerator (2-8°C), cold chain required
VL Kala-azar Latex Agglutination Test (KAtex) Qualitative detection of a low molecular weight, heat-stable, carbohydrate antigen in the urine of VL patients Sensitivity: 50-75%

Specificity: >95%

Specimen: urine

Storage: refrigerator (2-8°C)
VL, CL Culture Detection of live parasites grown from tissue samples Sensitivity: Varies depending on tissue sample

Specificity: >95%

Specimen: Tissue samples (skin scraping, aspirate, or biopsysnip for CL or organ/bone marrow aspirate for VL)

Storage: Requires advance laboratory setting
VL, CL PCR Detection of parasite DNA from tissue samples Sensitivity: Varies depending on tissue sample

Specificity: >95% in India

Specimen: Tissue samples (skin scraping, aspirate, or biopsysnip for CL or organ/bone marrow aspirate for VL)

Storage: Requires advance laboratory setting

Developing new leishmaniasis diagnostics is complicated by the fact that over a dozen parasite species complexes are responsible for multiple clinical syndromes in different geographic areas. It is unlikely that a single test or format will be satisfactory for all indications. Rapid tests of cure following treatment of VL that do not require difficult to obtain organ or bone marrow aspirate are still needed.

References

  1. WHO Leishmaniasis, available here.
  2. WHO (2010) First WHO report on neglected tropical diseases 2010: working to overcome the global impact of neglected tropical diseases.
  3. WHO (2004) Global Burden of Disease.

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Drugs

Analysis

The primary focus of new drug development for leishmaniasis is improved efficacy and simplified treatment for visceral disease. It is possible that significant progress can be made through improving access to existing therapies and developing novel combination therapies that both reduce the risk for drug resistance and shorten treatment courses. In line with these priorities, the majority of clinical stage candidates in development for leishmaniasis include new combinations and new formulations of existing drugs. Efforts are also being directed towards expansion of registration and use of existing products.

There is only one new chemical entity (NCE) in clinical stage development for visceral leishmaniasis, sitamaquine. However, potential renal toxicity observed in a phase II trial has raised uncertainty regarding whether or not this product will remain in active development.

There is a greater diversity among programs in the pre-clinical and discovery stages of development for leishmaniasis. Novel oral formulations of amphotericin B are in development as are NCEs spanning several drug targets and classes of molecules (including DNA damage inducers, natural products, lipid biosynthesis inhibitors, boron based molecules, 2-quinoline analogs, and others). Establishment of novel oral combination therapies, preferably in short course single pill formulations, has the potential to replace both existing therapies and the combinations of injectable/oral therapies currently in development.

 StrengthsWeaknessesOpportunitiesRisks
Combination therapies (Multiple existing drugs)
Most advanced program:  Phase III Reduced risk for drug resistance Potential to reduce treatment time and improve safety Based on extensively evaluated, approved single medicationsPotentially involves complicated combinations of injections and oral drugsExpansion of use of newer drugs from India to other parts of Asia, Africa, and Latin America Potential for future multi-drug, single formulations to simplify treatmentPotential oral treatments in pre-clinical and discovery stage development may eventually replace combinations of injectable drugs
New formulations (Existing drugs)
Most advanced program:  Amphomul, Phase IIINew formulation of existing approved VL treatment  Potential for single injection cure  Not orally availableDevelopment of combination single injection cureMay not be an improvement over AmBisome, currently available injectable liposomal formulation of amphotericin B Oral formulations of amphotericin B in pre-clinical development may replace this product
8-aminoquinolines (Target unknown)
Most advanced program:  Sitamaquine, Phase II Once daily oral dosing showed efficacy in phase II trial Only NCE in clinical development Concern over possible renal adverse events Development of combination therapies with approved oral VL drug (Miltefosine) Will not be adopted until at least as safe as on market products

Vaccines

Analysis

Patients who have been treated and subsequently cured of leishmaniasis generally have strong protective immune responses towards the parasite. This suggests that development of a preventative vaccine should be possible. Furthermore, despite the diversity of parasite species that can cause leishmaniasis, serological differentiation of infection between different species has not been possible, thus suggesting a universal vaccine that can protect against multiple species is an achievable goal.

Development of whole cell, killed leishmania vaccines was pursued from the 1930s through the 1980s. The greatest success was observed in studies in Brazil and Iran in the 1980s where efficacy rates as high as 50% were observed.1 Unfortunately, efficacy was highly variable across these studies, and ultimately these vaccine development programs were abandoned. Live vaccines are not being pursued at this point, although several factors may contribute to revisiting this approach along with whole cell, killed leishmania vaccines in the future, including:

  1. Subsequent studies of the whole cell, killed vaccines as therapeutic, as opposed to preventive vaccines, showed improved efficacy when combined with therapeutics
  2. New understanding of how human immune responses differ between sandfly delivered parasites and needle delivered parasites
  3. Progress towards development and understanding of other whole cell, killed and live attenuated vaccines for parasitic diseases, such as malaria
  4. Availability of improved adjuvants, which are more powerful than the BCG adjuvant used in these original studies.

The most advanced active vaccine development program for leishmaniasis is a series of recombinant protein vaccines in development by the Infectious Disease Research Institute (IDRI) in Seattle, WA. The protein antigen used in these vaccines is a combination of TSA, LmSTI1, and LeIF proteins from the parasite. The polyprotein antigen has been optimized slightly across three generations of this vaccine, called LEISH-F1 + MPL-SE (LEISH-111F + MLP-SE), LEISH-F2 + MPL-SE, and LEISH-F3 + GLA-SE (the current active product, phase I). Clinical trials for the first and second generation vaccines were primarily carried out as therapeutic trials for CL or a condition known as post kala-azar dermal leishmaniasis (PKDL) that is characterized by parasite infection re-occuring in the skin after treatment of visceral disease. These particular clinical trial settings were evaluated in part to more rapidly assess efficacy of these vaccines. However, the ultimate goal of IDRI, and others working on leishmaniasis vaccine development, is to develop and obtain approval for a preventive vaccine for VL.

Other vaccines in pre-clinical development are exploring newer vaccine technologies such as peptide antigen vaccines, DNA vaccines, and viral vector vaccines. Many of these newer technologies are also being assessed as potential preventive vaccines for dogs, an important animal reservoir for Leishmania spp. parasites. Animal reservoir vaccination may serve as an interesting tool to evaluate the safety and efficacy of novel vaccine technologies as a precursor to human clinical trials.

Diagnostics

Diagnostics

Analysis

The following represent a summary of key gaps in leishmaniasis diagnostics:

  • Test of cure in symptomatic individuals with a confirmed diagnosis of VL. Although the clinical response to efficacious treatment can be readily observed, predicting late relapses remains difficult. Because of lasting immune responses following treatment, serological tests such as rK39 and DAT remain positive for months and cannot be used to predict relapses. Bone marrow or organ tissue samples needed to detect reduced parasite burden after VL treatment are difficult and dangerous to obtain in a resource poor setting. Therefore, simplified test of cure assays using easily obtained specimens such as peripheral blood or saliva that can be performed in low resource settings represent a diagnostic need. In particular there is a need for biomarkers that predict long lasting clinical cure in drug trials for VL.
  • A diagnostic test for Leishmania infection is needed to identify who in endemic areas is infected from those who are not. This distinction is essential if long term plans for regional elimination in the Indian subcontinent are to be realized. Previous attempts at using crude parasite lysates as a skin test antigen to detect delayed type hypersensitivity have proven unreliable. Immune responses, either serologic or cell mediated, and / or sensitive parasite assays using peripheral blood are needed to rapidly screen large populations.

References

  1. Modabber F (2010) Leishmaniasis vaccines: past, present, and future. International Journal of Antimicrobial Agents 36S: S58-S61.

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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 leishmaniasis. 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. The tools for leishmaniasis are generally well developed.

Drugs Development Tools

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

Genome: Sequenced and annotated (L.braziliensisL. infantum, L. major, and L. Mexicana

Key databases:TriTrypDB 

In vitro culture: Yes,L. major most common species used in laboratories

Gene knock-outs: Yes

Conditional gene knock-outs: Yes 

Transposon mutagenesis: Possible

RNAi: Yes 

Other antisense technology: Yes

Parasite viability assays: Yes

Transcription microarrays: Yes

Proteomics: Yes 

Crystal structures:Yes

Whole-cell screening assays: Yes, HTS with either automated image analysis or transfected amastigotes

Enzymatic screening assays: Yes

Animal models: Yes, mouse, hamster, dog, and monkey models available

Monitoring treatment efficacy:Yes, but challenging for VL

Availability of endpoints: Yes, clearance of parasitemia 

Availability of surrogate endpoints: No 

Access to clinical trial patients / sites: Yes

Vaccines Development Tools

Basic Research: Antigen IdentificationImmune Response CharacterizationClinical Validation

See drug development tools above

Predictive animal models: Yes, no animal models exactly reproduce human response but mouse model and hamster model (better for VL) most commonly used

Detection of endogenous antigen specific response in clinical samples:Yes, not fully characterized 

Natural immunity well characterized:  No, natural immunity after parasite cure exists but is still the subject of study

Surrogate markers of protection: No

Challenge studies possible:  Potentially, challenge studies using CL were performed in the 1980s, but not currently used

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes 

Access to clinical samples: Yes 

Possible sample types:  Blood, skin, organ, and bone marrow aspirate

Access to clinical trial patients/sites:Yes

Treatment available if diagnosed: Yes

References

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.