Global Health Primer

What is Onchocerciasis (River Blindness)?

Onchocerciasis is a skin and eye disease caused by the parasitic worm, Onchocerca volvulus. The infection is spread by blackflies that breed in fast-flowing water, giving it the common name “river blindness.” Onchocerciasis is the second leading cause of infectious blindness worldwide. There is no vaccine available to prevent O. volvulus infection. Aggressive vector control and drug delivery programs have dramatically decreased disease incidence over the past thirty years.

Global Burden


Countries endemic for onchocerciasis
(WHO, 2002)

Worldwide, there are an estimated 37 million people infected with O. volvulus and 90 million people remain at risk.1 Approximately half a million people are visually impaired due to the disease and 270,000 have been blinded.2 Onchocerciasis is found primarily in West and Central Africa, with 99% of infected individuals living in 30 endemic countries. The disease is also prevalent in Yemen and in a handful of Latin American nations.3

Onchocerciasis has traditionally been a major factor in decreasing the economic prosperity of affected regions. In the 1970s, the disease had blinded almost half of men over age 40 in some African communities.2 The unrelenting itching can cause psychological problems, reduce productivity, and stigmatize infected individuals. The association of the disease with fast-flowing streams left fertile farmland abandoned. During this time period, economic losses resulting from onchocerciasis were estimated at $30 million per year.2 The three-decade long Onchocerciasis Control Program in West Africa, which ended in 2002, used insecticide and drug administration to successfully treat an estimated 40 million infections and to prevent 600,000 cases of blindness; this program reversed the annual loss of ~1 million disability adjusted life years and made 25 million hectares of land safe for resettlement.3,4

Causative Agent and Transmission

Image

Simulium spp. of flies that transmit
onchocerciasis. (photo: WHO)

O. volvulus is filarial nematode worm that is transmitted to humans by blackflies of the genus Simulium. The blackfly acquires immature O. volvulus larva (termed microfilariae) by biting the skin of an infected individual. The microfilariae develop in the fly over a period of two weeks and then migrate to its mouthparts. The infectious larvae are then transmitted to a new human host during the next blood meal. Once inside the subcutaneous tissue, larvae form nodules and begin maturing into adult worms – a process that can take up to one year. The male and female adults, which can measure up to a meter in length, live coiled in mating frequently pairs within the nodules in the skin. The female worms produce progeny microfilariae in numbers of up to 1000 per day for a lifespan of 15 years. Microfilariae migrate throughout the body, including to the skin, where they are accessible to the bite of the blackfly. Death of the microfilariae in the sensitive organs of the skin and eye leads to the major symptoms of onchocerciasis, which usually appear between 9 months and 2 years after initial infection.

Image

O. volvulus life cycle.
Click to view

Because the microfilariae cannot develop further inside the human body, the number of adult worms present in an individual is related to the number of times they have been bitten by infected blackflies. For this reason the disease is often not contracted by a single bite, and the most severe symptoms result from years of repeated exposure. Travelers spending less than three months in endemic areas are at little or no risk for the disease. For those who have been exposed, however, symptoms may appear years after leaving the endemic region, as the long-lived adult worms continue to produce microfilariae.5,6

 

Pathogenesis

The pathogenesis of onchocerciasis is caused by the microfilariae. These immature larvae migrate throughout the body, especially to the skin and eyes. Death of the microfilariae in these tissues results in an inflammatory immune reaction and causes a variety of pathologies.  In the skin, the disease can manifest as rashes, lesions, and disfiguring conditions such as depigmentation, skin scaling, and atrophy. The death of microfilariae in the skin causes itching, which is so severe that it is estimated to account for 60% of the disease burden.3 In the eyes, microfilariae can cause inflammation and bleeding, leading to itching, redness, and eventually vision impairment or blindness. Morbidity caused by onchocerciasis can reduce life expectancy by up to 15 years.2

Bacteria of the Wolbachia genus have been found to live inside O. volvulus worms. The relationship is symbiotic, as these bacteria are necessary for female worm fertility. Wolbachia also contribute to onchocerciasis pathogenesis, asthe release of bacteria upon death of the microfilariae contributes to the severity of the inflammatory response.7

Current Control Strategy

Several coordinated and aggressive control programs have been highly successful at limiting the burden of onchocerciasis over the past three decades. The Onchocerciasis Control Program in West Africa (1974-2002) began to control the disease vector through the aerial spread of insecticides. Following the donation of the drug ivermectin (Mectizan) by Merck in 1988, the program initiated mass treatment in high-risk communities. Merck recently committed to the continuation of unlimited donation of ivermectin through 2020.10 The African Program for Onchocerciasis Control was initiated in 1995 to limit the spread of the disease in the remaining endemic African regions. This program is directed by the affected communities themselves, who distribute the medication, and monitor coverage. The Onchocerciasis Elimination Program for the Americas aims to reduce the burden of disease in Latin America through mass drug treatment campaigns.

Since ivermectin kills the microfilariae, but does not impact the adult worms, the treatment does not cure infection but merely relieves or delays its symptoms. Microfilariae will remain suppressed for about 6 months following treatment. Continuing success in the fight against Onchocerciasis therefore requires maintaining high treatment coverage with the drug for the lifespan of the adult worm.3

 

Existing Products

Drugs

Onchocerciasis can be treated with an annual dose of ivermectin (Mectizan, Merck). This medication kills the parasite larva (microfilariae), relieves the severe skin itching, and stops the damaging effects on the eye caused by the disease.2 Since it does not affect the adult worms, this drug does not cure infection. The effectiveness of ivermectin may be threatened by a decreased response of the adult worm to the embryostatic effects of the drug. Also, ivermectin treatment cannot be used in regions that are co-endemic for another filarial parasite, Loa loa, due to the observation of serious adverse events.

Antibiotics that target the bacteria Wolbachia aim to kill the adult worms that rely on this endosymbiont. For example, doxycycline alone, or added to ivermectin, has been found to significantly reduce female worm viability and the number of microfilariae in the skin within 6 weeks of treatment.8 Short courses of antibiotics (rifampin and azithromycin) were not effective at reducing the number of worms, but these antibiotics may be a useful addition to other treatment regimens.9 It is unclear what role antibiotics will play in future onchocerciasis control programs.

Vaccines

There are currently no vaccines for the prevention of onchocerciasis.

Diagnostics

There are two predominant diagnostic techniques used for onchocerciasis:

  • Skin biopsies (“snips”) or examination of excised nodules: Visualizing microfilariae in a skin sample is the standard diagnostic test for onchocerciasis. This technique is highly specific, but has poor sensitivity during the early stages of infection before significant numbers of microfilariae have been produced. Several samples should be taken and there is low acceptance.
  • Serological assays: Antibodies specific for the parasite can be found in the blood, but may not indicate active infection. Assays for O. volvulus antibodies include the Ov16 card test (to detect IgG4 targeting Ov16 antigen), ELISA to detect antibodies against cocktails of recombinant antigens (e.g., Ov20 and Ov33 or Ov7, Ov11 and Ov16), and dot blot assay using native adult parasite antigens.6 These are currently available only in a research setting and are not approved for clinical diagnosis. Ov16 ELISA is used in the Onchocerciasis Elimination Program in the Americas to determine if transmission has been eliminated.

 

References

  1. Disease and Mortality in Sub-Saharan Africa. 2nd edition. Jamison DT, Feachem RG, Makgoba MW, et al., Eds. Washington (DC): World Bank; 2006.
  2. WHO: Priority Eye Diseases
  3. WHO (2010) Working to overcome the global impact of neglected tropical diseases: First WHO report on neglected tropical diseases.
  4. Basáñez MG, Pion SD, Churcher TS, Breitling LP, Little MP, Boussinesq M. River blindness: a success story under threat? PLoS Med. 2006 Sep;3(9):e371
  5. CDC: Onchocerciasis FAQs
  6. Medscape: Onchosariasis
  7. Saint Andre A et al. (2002) The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Science.  295:1892-5.
  8. Hoerauf A et al (2009) “Efficacy of 5-week doxycycline treatment on adult Onchocerca volvulus.” Parasitology Research 104: 437-447.
  9. Hoerauf A et al (2008) “Effects of 6-week azithromycin treatment on the Wolbachia endobacteria of Onchocerca volvulus.” Parasitology Research 103: 279-286. 
  10. 10. Uniting to Combat Neglected Tropical Diseases (Jan 2012). Table of Commitments.

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Drugs

PIPELINE

Product/Research ProgramDevelopersDiscoveryPre-clinicalPhase IPhase IIPhase III
MoxidectinWorld Health Organization

 

 

 

 

 

ClosantelScripps Research Institute

 

 

Flubendazole (Oncho)Drugs for Neglected Diseases Initiative
McGill University
Michigan State University

 

 

Oxaboroles (oncho)Anacor Pharmaceuticals

 

EmodepsideBayer AG

 

On Hold

ANALYSIS

New product needs for onchocerciasis include macrofilaricides and/or drugs that can be used in combination with ivermectin to shorten the timeframe for mass drug administration. A major focus is on repurposing antihelminth drugs that are currently in use in animals for the treatment of onchocerciasis in humans. One animal antihelminth, moxidectin (Pfizer), underwent human clinical trials and two others, emodepiside (Bayer) and closantel (multiple generic manufacturers), have demonstrated efficacy in vitro.1,2 Unfortunately, moxidectin has the same mechanism of action as ivermectin and is unlikely to be useful if drug resistance to ivermectin develops. In contrast, emodepiside and closantel have unique mechanisms of action relative to ivermectin and target GPCRs and chinases, respectively. New repurposing efforts are targeting flubendazole as a potential macrofilaricide clinical candidate for the treatment of onchocerciasis and lymphatic filariasis in areas where loiasis is coendemic.10

 

Vaccines

PIPELINE

Product/Research ProgramDevelopersDiscoveryPre-clinicalPhase IPhase IIPhase III
Anti-L3 vaccine (LSTM)Liverpool School of Tropical Medicine

 

Anti-L3 vaccine (NYBC)New York Blood Center

 

There are no vaccines in clinical development for onchocerciasis, but several research groups are exploring recombinant protein vaccines that use antigens from the L3 larval stage of the parasite. Protective immunity against O. volvulus L3 larva has been demonstrated in humans, mice, and cattle and several recombinant antigens capable of partial protection in mice have been identified. Because of the success of mass drug administration campaigns with ivermectin, investment in vaccines has been minimal. If drug resistance to ivermectin is detected or if mass drug administration proves to take 15 years due to the long life span of the adult worm, a vaccine would prove to be more valuable.

Diagnostics

PIPELINE

Product/Research ProgramDevelopers Technology Phase of Development
Oncho-C27 antigen dipstickMinistry of Technical Scientific Research
University of Dschang
University of Yaounde I

Clinical

Diethylcarbamazine (DEC) patch testCollege of Dermatology, University of Nigeria
World Health Organization

Clinical

Multi-antigen luciferase immunoprecipitation systems (LIPS)National Institutes of Health

Pre-clinical

DNA detection test stripsBernard Nocht Institute for Tropical Medicine

Pre-clinical

Paper chromatography hybridization assayWashington University in St. Louis, School of Medicine

Pre-clinical

Ov16 Rapid Immunochromatographic Card TestPATH

Pre-clinical

Metabolomics-based biomarker discovery programScripps Research Institute

Pre-clinical

ANALYSIS

There are four types of diagnostic in development for onchocerciasis:

  • Antigen-based detection: Detection of parasite antigens can indicate active infection. The oncho-C27 dipstick assay can detect the C27 antigen in urine and tears in as little as 3 hours. The test showed good sensitivity and specificity during testing in Cameroon.3 PATH is also developing the OV16 rapid diagnostic test that is based on detection of antibodies to a parasite antigen.
  • Immune response test: The Diethylcarbamazine (DEC) patch delivers a drug into the skin, which causes a localized dermal reaction if the worms are present.4 DEC is not used as part of mass drug administration for onchocerciasis due to this reaction.
  • Nucleic acid amplification tests: PCR of material from skin can increase diagnostic sensitivity.5-8 Unfortunately, PCR is costly and requires specialized equipment, limiting the utility of this test in endemic regions.
  • Metabolomics-based tests: A recent study used liquid chromatography-mass spectrometry to identify 14 biomarkers in the blood that correlate with O. volvulus infection.9 Additional research will be needed to determine if these biomarkers can be developed into diagnostic assays that can be used in the field.
  • Luciferase immunoprecipitation system (LIPS) to differentially diagnose onchocerciasis from other filarial infections (including the lymphatic filariasis species and Loa Loa). NIH researchers developing the test believe that it may be feasible for point of care use. 

References

  1. Hoerauf A (2008) “Filariasis: new drugs and new opportunities for lymphatic filariasis and onchocerciasis.” Curr Opin Infect Dis 21: 673-681.
  2. Gloeckner C et al. (2010) “Repositioning of an existing drug for the neglected tropical disease Onchocerciasis.” PNAS 107: 3424-3429.
  3. Ayong LS et al. (2005) “Development and evaluation of an antigen detection dipstick assay for the diagnosis of human onchocerciasis.” Trop Med Int Health 10: 228-233.
  4. WHO clinical trail: “To determine the safety, tolerability and systemic absorption of Diethylcarbamazine (DEC) from a "patch" applied locally to the skin for the diagnosis of Onchocerca volvulus infection.” More information available here.
  5. Zhang S et al. (2000) “Paper chromatography hybridization: a rapid method for detection of Onchocerca volvulus DNA amplified by PCR.” Am J Trop Med Hyg 63: 85-89.
  6. Pischke S et al (2002) An internal control for the detection of Onchocerca volvulus DNA by PCR-ELISA and rapid detection of specific PCR products by DNA Detection Test Strips Trop Med Int Health 7: 526-531.
  7. Rodríguez-Pérez MA et al. (2006) “Large-scale entomologic assessment of Onchocerca volvulus transmission by poolscreen PCR in Mexico.” Am J Trop Med Hyg 74: 1026-33.
  8. Tang TH et al. (2010) “Nested PCR to detect and distinguish the sympatric filarial species Onchocerca volvulus, Mansonella ozzardi and Mansonella perstans in the Amazon Region.” Mem Inst Oswaldo Cruz 105: 823-828.
  9. Denery JR et al. (2010) “Metabolomics-based discovery of diagnostic biomarkers for onchocerciasis.” PLoS Neglected Tropical Diseases 4: pii: e834.
  10. Mackenzie CD et al. (2012) “Elimination of onchocerciasis from Africa: possible?” Cell 28(1):16-22.

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 or contact us at globalhealthprimer@bvgh.org.

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

Drug Development Tools

Basic Research: Target Identification Target Validation Screening: Hit/Lead Identification Optimization Pre-clinical Validation Clinical Validation
Genome:
cDNA assembly sequences available for nuclear genome.

Complete mitochondrial genome has been sequenced.

Key databases:
Wellcome Trust | Sanger Institute

Broad Institute Genome Index

In vitro culture: Adult worms and larvae can survive in vitro; L3 molting occurs in vitro.
No onchocercal cell line exists.
Gene knock-outs: No

Conditional gene knock-outs: No

Transposon mutagenesis: No

RNAi: Yes

Other antisense technology: Yes

Viability assays: Yes, e.g., MTT (3-(4,5 dimethylthiazol-2yl)-2,5 diphenyl tetrazolium bromide) staining of L3 larvae.

Transcription microarrays: Yes, but only limited studies have been performed

Proteomics: Yes, but only limited studies have been performed

Crystal structures: Yes
Whole-cell screening assays: Yes, eg. Molting assay of L3 larvae.

Enzymatic screening assays:
Yes
Animal models: O. volvulus infects chimpanzees, gorillas, and cynomolgus monkeys but does not cause ocular disease.

Cytomegalous monkeys can also be infected with O. lienalis.

Mangabey monkeys and patas monkeys can be infected with Onchocerca spp.

Onchocerca spp. infect dogs and cause ocular symptoms.

Cattle can be infected with O. ochengi.

Mice are infectable with Onchocerca spp.
Monitoring treatment efficacy: Yes

Availability of endpoints:
Yes. Sustained absence of microfilariae in skin biopsies

Killing of adult worms (macrofilaricidal or curative effects)

Availability of surrogate endpoints:
  No

Access to clinical trial patients/sites:
  Yes

 

Vaccine Development Tools

Basic Research: Antigen Identification Immune Response Characterization Clinical Validation
See drug development tools above Predictive animal models: Non-human primates and bovine models are best available.

Detection of endogenous antigen specific response in clinical samples: Yes, e.g., antibodies

Natural immunity well characterized: Yes, protective immunity targets the infectious larva (L3). Concomitant immunity develops with age.
Surrogate markers of protection: No

Challenge studies possible:
Control programs have used
volunteers exposed to wild blackflies to collect the insects for study.

 

Diagnostic Development Tools

Basic Research: Biomarker Identification Biomarker Validation Clinical Validation
See drug development tools above Biomarkers known: No metabolite biomarkers were recently mapped, but remain to be validated

Access to clinical samples: Yes

Possible sample types:
Skin, blood
Access to clinical trial patients/sites: Yes

Treatment available if diagnosed:
Yes, ivermectin

 

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 or contact us at globalhealthprimer@bvgh.org.

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