What is Schistosomiasis ?

Schistosomiasis (also known as bilharzia), is a disease caused by a parasitic worm that primarily lives in the blood. The parasite is transmitted to humans by penetration of the skin in fresh water. The majority of morbidity and mortality associated with schistosomiasis is the result of slow damage to the host organs caused by accumulation of parasite eggs in the tissues over many years.

Global Burden

Schistosomiasis

There are an estimated 240 million people infected with the parasites that cause schistosomiasis.Schistosomiasis is endemic in 74 countries (approximately 779 million people at risk2), but the highest burden is in sub-Saharan Africa accounting for approximately 90% of all cases.3 Infection is also found in the Middle East, parts of Southeast Asia, Latin America, and the Caribbean.

More than 200,000 deaths, mostly in sub-Saharan Africa are attributed to schistosomiasis each year.Morbidity, as measured in DALYs, better reflects the debilitating impact of chronic infection. Schistosomiasis is responsible for the loss of more than 1.7 million DALYs per year primarily as the result of organ damage, hemorrhage, and cancer resulting from infection. Certain estimates of disability adjusted life years (up to 70 million disability adjusted life years per annum) have shown schistosomiasis to be a more debilitating infection than even malaria.5,6

Causative Agent

parasitesSchistosomiasis is caused by five species of trematodes (a subset of flatworms and other helminthes): Schistosoma mansoniS. japonicum, S. haematobiumS. intercalatum, and S. mekongiS. mansoniS. japonicum, and S. haematobium are the most significant species for human disease but vary in geographical distribution.

 
Parasite Geographic distribution
S. mansoni Latin America and the Caribbean
S. japonicum Far East
S. haematobium Africa and the Middle East
life cycle Schistosoma spp. parasites are transmitted to humans when the free living cercariae penetrate the skin in fresh water. Cercariae are produced by the intermediate hosts of the parasite, freshwater snails. Snails become infected with the parasites when eggs produced by the adult worms reach the water via contamination with feces or urine from infected humans. Under the correct conditions of light and fresh water, the eggs hatch producing the free swimming miracidia that can infect the snail. The miracidia form sporocysts in the snail tissue and eventually produce cercariae that are released back into the water. Each species of Schistosoma prefers a different genus of snails.
 
Parasite Snail genus
S. mansoni Biomphalaria spp.
S. japonicum Oncomelania spp.
S. haematobium Bulinus spp.

Pathogenesis

The free living cercarial form of the Schistosoma spp. parasite penetrates human skin in fresh water. The cercariae travel through the tissue to the blood stream. Adult male and female worms mature and mate in the veins of the liver before moving to their final destination, the veins that drain to the intestine (S. mansoni and S. japonicum) or the bladder (S. haematobium). The female adult worm begins to produce 200-2000 eggs per day. Eggs are shed into the feces or urine and circulate in the blood vessels until they become lodged in various organs. The accumulation of eggs in the various tissues and organs of the body can cause severe damage including bleeding and cancer. It is the accumulated damage caused by the eggs rather than the parasites themselves that causes the majority of mortality and morbidity associated with the disease.

Current Control Strategy

The primary control strategy employed for schistosomiasis is mass drug administration (MDA) with the drug praziquantel (see next section on Existing Medications for details). In 2008, 17.5 million people were treated for schistosomiasis representing just over 2% of the entire estimated at risk population.2,3 While this is a significant advance, it falls far short of the World Health Organization (WHO) goal of treating 75% of school age children (approximately 71 million children total) by 2010.

Other components of control strategies include avoidance of fresh water known to harbor the snail vector, vector control by removal of snails that can harbor the parasites, and environmental controls to reduce human waste contamination of waterways with snails to halt transmission to the intermediate host. Although these strategies to control transmission were largely successful in China, flooding, transfer of responsibilities from national to local control programs, and a shift in focus from transmission to morbidity control with MDA have resulted in some resurgence of transmission.7,8 Although transmission-based control strategies may still be valuable in certain contexts, they may be more difficult to implement and sustain in resource limited settings.

Existing Products

Drugs

Praziquantel is the standard of care for the treatment of schistosomiasis. It is highly effective and can be used in MDA. Unlike medications used in MDA for other helminth infections, praziquantel (Merck) donations were limited to 200 million tablets over 10 years beginning in 2008 for a few high burden, least developed countries.9 As part of the 2012 London Declaration, Merck announced that it would increase its commitment to donation of 50 million tablets per year indefinitely to support schistosomiasis control.10 While this donation is important and essential for schistosomiasis control, a key focus of the schistosomiasis community is to increase access to praziquantel and improve the reach of schistosomiasis MDA programs.

Vaccines

There is currently no vaccine for the prevention of schistosomiasis.

Diagnostics

The current standard method for the diagnosis of schistosomiaisis is microscopic evalution of stool or urine samples for the presence of eggs using the Kato-Katz technique. This method only detects on the order of 20-30% of infections as eggs do not appear immediately in stool or urine upon infection.

In regions with S. haematobium infection, a dipstick test for parasite antigens in the urine is available for use in the field. Similar rapid tests using urine for S. mansoni and S. japonicum are not likely to be possible due to differences in the pathology of these organisms, but the possibility of rapid tests using stool samples should be considered.

Other immune-based and nucleic acid amplification-based tests are used in settings with laboratory facilities, but these are not practical for use in the field where MDA programs are taking place.

References

  1. WHO, Neglected Tropical Diseases: PCT databank.
  2. Hotez PJ (2009) “Mass Drug administration and integrated control for the world’s high-prevalence neglected tropical diseases.” Clinical Pharmacology & Therapeutics 85: 659-664.
  3. WHO (2010) First WHO report on neglected tropical diseases 2010: working to overcome the global impact of neglected tropical diseases.
  4. WHO: Schistosomiasis Fact Sheet.
  5. Gray, D.J. et al. Schistosomiasis elimination: lessons from the past guide the future. Lancet Infect. Dis. 10, 733-736 (2010).
  6. King,C.H. Parasites and poverty: the case of schistosomiasis. Acta Trop. 113, 95-104 (2010).
  7. Utzinger J et al. (2005) “Conquering schistosomiasis in China: the long march.” Acta Tropica 96: 69-96.
  8. Xiao-Nong Z et al. (2005) “The public health significance and control of schistosomiasis in China – then and now.” Acta Tropica96: 97-105.
  9. WHO: Schistosomiasis strategy.
  10. WHO (2012) “Accelerating Work to Overcome the Global Impact of Neglected Tropical Diseases: A Roadmap for Implementation.” Geneva, Switzerland.

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Drugs

Analysis

There is one product currently in clinical stage development for schistosomiasis, Co-Arinate FDC®. Co-Arinate is an ACT that is in development by Dafra Pharmaceuticals for the treatment of malaria; however, it is not WHO prequalified for the treatment of malaria at this time. In a recent phase III clinical trial to evaluate the efficacy of Co-Arinate for the treatment of S. haematobium in children, Co-Arinate was found to be safe and have partial efficacy but was determined to be inferior to treatment with praziquantel.1 This study suggested that further studies examining the efficacy of ACTs in children with schistosomiasis is warranted. Given the partial efficacy of Co-Arinate, it may be worthwhile to evaluate ACTs that have been more rigorously evaluated through more widespread use for malaria than Co-Arinate.

There are several additional pre-clinical and discovery stage programs for schistosomiasis therapeutics including development of a drug currently in use for the treatment of leishmaniasis, miltefosine, and inhibitors of the enzyme thioredoxin glutathione reductase (TGR). Phenotypic screening to identify novel inhibitors is also ongoing.

Vaccines

Analysis

There are currently three vaccines in clinical development for schistosomiasis. The most advanced product is the Bilhvax vaccine that is currently in phase III development. However, no published data are available from Phase I and II trials. This vaccine is a recombinant protein-based vaccine that is currently being evaluated for the prevention of re-infection with S. haematobium after praziquantel treatment. Inconsistent protective efficacy and marked polymorphism limits the value of tetraspanin-2 as a vaccine target for S. japonicum. Further, prophylactic efficacy proof of concept studies for SmTSP-2 has only been performed in the mouse model. In case of Sm-p80 proof of concept studies have been performed both in rodent nad nonhuman primate models. Immunogenic epitopes of Sm-p80 which may play a role in vaccine-mediated protection are conserved in the three species of schistosomes. Thus Sm-p80 based vaccine formulation is postulated to have potential for cross-species protection for both intestinal and urinary schistosomiasis. Lack of prevailing Sm-p80-specific IgE in high risk/infected human populations from schistosome-endemic areas — minimizing the risk of hypersensitivity reaction following vaccination with Sm-p80 in humans.

Another vaccine is in phase I development by Fiocruz for the prevention of S. mansoni. The vaccine is also a recombinant protein vaccine and has the added benefit of providing some cross protection against Fasciola hepatica, a related parasite that is also on the WHO neglected disease list.

Diagnostics

Analysis

Sensitive, rapid diagnostics that can be used in the field in conjunction with MDA are needed. These tests are needed for two of the most significant species of schistosomes, S. mansoni and S. japonicum, and should be simple for a minimally trained health volunteer to administer and interpret.  The most advanced test in the pipeline for schistosomiasis rapid diagnosis is a urinary dipstick test that has been plagued with efficacy problems for nearly a decade. 

References

  1. Sissoko MS et al. (2009) “Efficacy of artesunate + sulfamethoxypyrazine/pyrimethamine versus praziquantel in the treatment of schistosoma haematobium in children.” PLoS ONE 4: e6732.

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The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for schistosomiasis. 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 schistosomiasis are quite limited.

Drugs Development Tools

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

Genome: Sequenced and annotated, S. mansoni only 

Key databases:Shistosoma mansoni Database 

In vitro culture:Partial, snail and mouse in vivo culture required for portions of life cycle

S. mansoni most commonly used laboratory strain, however, the NIAID contract facility provides various life cycle stages and infected animals for all three organisms: NIAID Schistosomiasis Resource Center

Gene knock-outs: No, conditional gene knock-outs: No, but some transgene overexpression possible via viral vectors

Transposon mutagenesis: Development in progress 

RNAi: Yes 

Other antisense technology: Possibly

Viability assays: Yes 

Transcription microarrays: Yes

Proteomics: Yes 

Crystal structures:Yes

Whole-cell screening assays: Yes, medium throughput phenotypic screens

Enzymatic screening assays: Yes

Animal models: Yes, mouse model used most frequently for S. mansoni and S. japonicum. A baboon model has also been used.

Hamster model for S. haematobium but more reliable animal models are being developed (baboon)

Monitoring treatment efficacy: Yes, laboratory assays but not point of care tests

Availability of endpoints: Yes, egg reduction 

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 (Baboons)

Detection of endogenous antigen specific response in clinical samples: Yes 

Natural immunity well characterized: Minimal understanding

Surrogate markers of protection: No 

Challenge studies possible: Theoretically possible, but do not appear to be in use

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes 

Access to clinical samples: Yes, from MDA program monitoring

Possible sample types: Blood, urine or stool (depending on species)

Access to clinical trial patients/sites: Yes 

Treatment available if diagnosed: Yes

References

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