Hookworms are parasitic nematodes (roundworms) that are transmitted via contact with contaminated soil. Soil-transmitted helminths infections are amongst the most prevalent human infections worldwide and afflict primarily the poorest and most disadvantaged communities. The hookworm species that most commonly infects humans is Necator americanus, whereas Ancylostoma duodenale and Ancylostoma ceylanicum are more focally clustered in certain regions.
Hookworm infection is one of the most common chronic infections of humans and affects more than 700 million people in tropical countries, in particular in Southeast Asia, China, sub-Saharan Africa and the Americas.
The areas most afflicted are impoverished rural areas, where approximately 3.2 billion people worldwide are at risk of hookworm infection.
Hookworm infection is spread via eggs that are shed in the feces of an infected host and contaminate soil in areas with poor sanitation. Within one or two days, hookworm larvae hatch from the eggs. The first larval stage, called L1 or rhabditoform larvae, is not infective and feeds on the microbial content of the soil. After two molds, the larvae develop into the infectious L3 or filariform larvae, which stop feeding on bacteria and have much increased their mobility.
Upon contact with human skin, the infectious larvae penetrate the skin and travel via the blood stream to the lung, where they are coughed up and swallowed. Eventually the larvae settle in the small intestine, where they mature to male and female adult hookworms and attach themselves to the intestinal wall to feed on blood.
Adult hookworms can live in the human intestine for many years. Heavy hookworm infections cause severe intestinal blood loss that results in chronic iron-deficiency anemia and malnutrition, which is particularly devastating for pregnant women and children. Hookworm infection of pregnant women can result in severe anemia, increased maternal morbidity and prematurity or even loss of the fetus, whereas children with a medium or heavy hookworm burden suffer from growth retardation, and can develop intellectual, cognitive and educational deficits. As they grow into adulthood, many children with chronic hookworm infections experience a substantial decrease income-earning potential. As a result, countries with a high prevalence of hookworm infections suffer from reduced productivity and poor socioeconomic development.
Development of a Human Hookworm Vaccine
The general approach to hookworm control worldwide has been the frequent and repeated administration of benzimidazole anti-hookworm drugs to infected individuals in high-prevalence areas.
However, this approach is limited by high re-infection rates and the development of drug-resistant hookworm populations. These concerns have prompted interest in alternative and more permanent tools for hookworm control, such as the development of a vaccine. Developing a vaccine against a relatively large, multicellular organism is however particularly challenging.
The adult hookworm living in the human intestine is dependent on the digestion of hemoglobin from erythrocytes (red blood cells) for use as an energy source. The current strategy for the development of a vaccine against human hookworm infection is focused on parasitic enzymes required for blood feeding, hemoglobin digestion and heme detoxification.
Hookworms digest hemoglobin via a proteolytic cascade that begins with the enzyme aspartic protease 1 (APR-1), which cleaves the intact hemoglobin and allows for further hydrolysis of the fragments by other proteases. Vaccination with recombinant APR-1 has protected animals from infection in challenge studies.
Another antigen from the hookworm blood digestion pathway that is a promising vaccine target is glutathione S-transferase-1 (GST-1), an enzyme that binds and detoxifies the toxic oxygen byproducts of the hemolysis. Hamsters immunized with recombinant GST-1 of N. americanus (Na-GST-1) and later challenged with infectious larvae were significantly protected compared to unimmunized animals.
The aim is to induce antibodies against these two enzymes that are essential for the hookworm blood feeding pathway, thereby reducing both host blood loss and the number of hookworms attached to the gut. Both vaccine candidates are currently in phase 1 clinical trials designed to evaluate their safety and immunogenicity. The goal is to license a hookworm vaccine that is comprised of both antigens, Na-APR-1 and Na-GST-1, by 2020. If both recombinant vaccine candidates are shown to be safe and immunogenic in the current phase 1 trials in adults and children, they will be combined to one product and tested in phase 2 and 3 trials in hookworm endemic areas in Brazil and Sub-Saharan Africa to evaluate their efficacy in preventing hookworm infections.