What is Soil-Transmitted Helminths: Hookworm?

Hookworm is a parasitic roundworm of the small intestine that is transmitted through contaminated soil. When hookworm eggs are passed in human feces, they are shed into the surrounding environment, where the eggs hatch and penetrate through the skin of exposed individuals. Although most patients are asymptomatic, heavy worm burdens lead to anemia, diarrhea, abdominal pain, weight loss and loss of appetite. While hookworm is associated with a relatively small number of deaths, chronic anemia caused by the disease is associated with significant morbidity.

Global Burden

Soil-Transmitted Helminths: Hookworm

Hookworm is found throughout the tropics and subtropics. It is estimated that 600-700 million people are infected worldwide, resulting in the loss of approximately 1.1-22.1 million DALYs annually and 65,000 lives annually.1,2 Hookworm infection is commonly seen in the same places as ascariasis and trichuriasis.

WHO Region DALY (in thousands)3
Africa 377
Americas 20
Eastern Mediterranean 43
Southeast Asia 286
Western Pacific 364
Total: 1,090

The economic impact of hookworm is difficult to estimate. However, retrospective studies of the effects of hookworm control and treatment in the United States demonstrated that children cured of hookworm were more likely to attend school and on average earned 45% higher incomes as adults as compared to children who grew up with hookworm.1

Causative Agent

hookwormHookworm is caused by two organisms, Necator americanus and Ancylostoma duodenaleN. americanuscauses 85% of hookworm infections and is found throughout the Americas, sub-Saharan Africa, Southeast Asia, China, and Indonesia. A. duodenale is restricted to the Middle East, North Africa, and India.

 
life cycleHumans are infected with hookworm when free-living larval stages of the worm in the soil penetrate the skin. The larvae travel through the blood stream to the lungs where they migrate up the trachea and, through coughing and subsequent swallowing, pass through the stomach to the small intestine. Female hookworms in the small intestine shed eggs into the stool of the host. When latrines or toilets are not available, eggs from the feces of infected hosts contaminate the soil and water. In the soil, the eggs hatch and develop through three larval stages before infecting a new host through penetration of the skin. Unlike the intensity of infections by other types of STH, the severity of hookworm infection tends to increase with age.

Pathogenesis

The adult hookworm when located in the small intestine burrows into the intestinal lining rupturing capillaries to access the host’s blood. The worm survives by feeding on this blood. Blood loss through intestinal damage and worm feeding lead to the anemia associated with hookworm. Worms can survive in the intestine for 1-18 years.

Children and pregnant women are particularly susceptible to iron deficiency anemia (IDA) as the result of hookworm infection. In children IDA can lead to impaired neurological development and cognitive function. In pregnant women IDA can lead to low infant birth weight and even infant death.

Current Control Strategy

Current control strategies for hookworm include a combination of mass drug administration (MDA) — one to two times per year based on the prevalence of STH in school-age children — with benzimidazoles (albendazole or mebendazole) and improvement of sanitation to reduce fecal contamination in the local environment.

Existing Products

Drugs

Mass drug administration programs primarily use albendazole (single dose efficacy approximately 75%) for the treatment of hookworm. Mebendazole and pyrantel pamoate can also be used but are significantly less effective.2 Albendazole is also used for MDA to treat lymphatic filariasis and other soil transmitted helminths such as ascariasis and trichuriasis providing crossover treatment for hookworm. In lymphatic filariasis, programs to treat adult populations will likely decrease in the carriage and transmission of hookworm.

Vaccines

There is currently no vaccine approved for the prevention of hookworm. Vaccines in development are discussed in the next section.

Diagnostics

Diagnosis of hookworm relies on microscopic examination of feces for egg contamination. This has an overall low sensitivity for hookworm diagnosis as eggs in stool are not visible until 8 weeks after infection with N. americanus or 38 weeks after infection with A. duodenale. Furthermore, hookworm eggs are difficult to distinguish from the eggs of other worm infections and need to be looked at in fresh stool for best results.

References

  1. WHO (2010) First WHO report on neglected tropical diseases 2010: working to overcome the global impact of neglected tropical diseases.
  2. Hotez PJ et al. (2010) “Developing vaccines to combat hookworm infection and intestinal schistosomiasis.” Nature Reviews Microbiology 8: 814-826.
  3. Keiser J, Utzinger J (2008) "Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis.” JAMA 299: 1937–48

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Drugs

The development of novel or combination drugs for hookworm is not important if resistance is not found. Although drug resistance is possible, it has not yet been detected. At this point in time, resources are focusing more heavily on improving the coverage of mass drug administration among school children and vaccines to prevent hookworm infection. A new system to detect, test, and respond to resistance is under development by the WHO.

Future drug discovery programs will most likely focus on the repurposing of veterinary medications for worm infections, new combination therapy programs, or discovery of single products that can target multiple parasitic or neglected diseases in a single dose.

Vaccines

Analysis

Currently, there is one vaccine, Na-GST-1, in phase I clinical development, and another, Na-APR-1 in pre-clinical development for hookworm. Both of these vaccines target the parasite blood feeding pathway.

In a phase 1 study conducted in hookworm-naive adults living in the US, Na-ASP-2 adjuvanted with Alhydrogel was well-tolerated and immunogenic . However, in a parallel phase 1 trial of this vaccine in adults living in a hookworm endemic area of Brazil, vaccination with a single dose of Na-ASP-2 (10 µg) resulted in generalized urticarial reactions in several volunteers. Subsequent analysis showed that the urticarial reactions were associated with elevated levels of IgE antibodies specific for Na-ASP-2, present before receiving immunization from their previous hookworm infection. A survey of adults and children from the same hookworm-endemic area revealed that a significant proportion had elevated levels of IgE to Na-ASP-2.1 Development of Na-ASP-2 as a vaccine candidate was halted in 2007/2008. In order to avoid the risk of negative allergic reactions in the future, the inventors of this vaccine decided to shift their strategy from focusing on protein antigens from larval stage worms to focusing on antigens associated with worm blood feeding, though substantial animal model work remains to validate this approach

Diagnostics

New point-of-care diagnostics for hookworm are needed for use in parallel with mass drug administration (MDA) programs. A key challenge of MDA is determining when mass treatment should stop. Diagnostics that can be used in extremely rural areas by minimally trained community volunteers (potentially those already involved in the MDA program) are needed to determine when transmission of hookworm has been interrupted in a village. The same diagnostics should be used to monitor communities to ensure reintroduction does not occur.

The majority of ongoing diagnostic development is focusing on optimizing microscopic detection of eggs rather than novel tests. Biomarker discovery and immune response profiling associated with vaccine programs may inform novel diagnostic development.

References

  1. Bethony JM, Cole RN, Guo X, Kamhawi S, Lightowlers MW, Loukas A, Petri W, Reed S, Valenzuela JG, Hotez PJ. Vaccines to combat the neglected tropical diseases. Immunol Rev. 2011 Jan;239(1):237-70.

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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 hookworm. 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 available for human hookworm research and development are not extensive.

Drugs Development Tools

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

Genome: Necator americanus genome sequencing is in progress

Key databases: Nematode.net

In vitro culture: Larval stages from eggs isolated from infected people

Gene knock-outs: No

Conditional gene knock-outs: No

Transposon mutagenesis: No

RNAi: No

Other antisense technology: No

Viability assays: Yes, using adultAncylostoma caninum(dog hookworm) motility

Transcription microarrays: Limited, primarily only forAncylostoma caninum(dog hookworm)

Proteomics: Limited, primarily only forAncylostoma caninum(dog hookworm)

Crystal structures: Limited, available for antigens being pursued for vaccine development

Whole-cell screening assays: No

Enzymatic screening assays: Limited

Animal models: Yes

A. ceylanicum or A. caninum infection of dogs

A. ceylanicum infection of hamsters

Ancylostoma spp. andN. americanus in mice but non-physiological due to lack of intestinal blood feeding

Hamster adapted N. americanus

Monitoring treatment efficacy: Yes, indirectly through egg counts in stool and effects on anemia

Availability of endpoints: Indirect measurements of parasite survival including egg counts in stool and anemia, and direct measurements of fecal blood loss

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: Several models with limited relevance

Detection of endogenous antigen specific response in clinical samples: Yes

Natural immunity well characterized: No, studies ongoing but complex

Surrogate markers of protection: Surrogate markers of infection and immunity

Challenge studies possible: No, although clinical infections were performed in '70s and '80s to study immunology 

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: Stool & blood

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.