Parasitic Diseases
Hookworm disease
Disease Burden
Human hookworm infection is a soil-transmitted helminth infection caused by the nematode parasites Necator americanus and Ancylostoma duodenale. It is a leading cause of anaemia and protein malnutrition, afflicting an estimated 740 million people in the developing nations of the tropics. The largest numbers of cases occur in impoverished rural areas of sub-Saharan Africa, Latin America, South-East Asia and China. N. americanus is the most common hookworm worldwide, while A. duodenale is more geographically restricted.
Hookworm transmission occurs by skin contact with infective third-stage larvae (L3) that have the ability to penetrate through the skin, frequently entering the body through the hands, feet, arms, or legs. A. duodenale L3 also can be ingested. L3s migrate through the body and enter the lungs from which they are expelled by cough and swallowed into the intestine where they first moult twice to become adults. Adult hookworms are approximately one-centimeter-long parasites that cause host injury by attaching to the mucosa and submucosa of the small intestine and producing intestinal blood loss. The presence of between 40 and 160 adult hookworms in the human intestine results in blood loss sufficient to cause anaemia and malnutrition. The term “hookworm disease” refers primarily to the iron-deficiency anaemia with reduced host haemoglobin, serum ferritin, and protoporphyrin that results from moderate and heavy infections and is in direct correlation with the number of parasites (as measured by quantitative egg counts). In children, chronic hookworm infection has been shown to impair physical and intellectual development, reduce school performance and attendance, and adversely affect future productivity and wage-earning potential.
Unlike other soil-transmitted helminth infections, such as ascariasis and trichuriasis, in which the highest intensity infections occur primarily in school-aged children, high intensity hookworm infections also frequently occur in adult populations. This is an important health threat to adolescent girls, women of reproductive age, and to outcomes in pregnancy. Up to 44 million pregnant women are estimated to be infected with hookworm. In pregnant women, anaemia resulting from hookworm disease results in several adverse outcomes for both the mother and her infant, including low birth weight, impaired milk production, and increased risk of death for both the mother and the child.
Efforts to control hookworm infection include the sanitary disposal of faeces and educational campaigns about the proper use of latrines. At this time, the most cost-effective way to control hookworm infection has been through population-wide treatment with either albendazole or mebendazole. A resolution adopted at the 2001 World Health Assembly advocates the anthelminthic treatment of 75% of all at-risk school-aged children by 2010. In time this would become the largest health programme ever attempted. However, both children and adults usually become reinfected within a few months after deparasitation, which implies repeated and frequent use of the drugs, and there is concern that heavy and exclusive reliance on albendazole and mebendazole might lead to drug resistance. Therefore, a safe and cost-effective vaccine would provide an important new tool for the control of hookworm infection.
Vaccine
The feasibility of developing a human anti-hookworm vaccine is based on the previous success of using live, irradiated L3s as a vaccine for canine hookworm infection. The Human Hookworm Vaccine Initiative (HHVI), a programme of the Sabin Vaccine Institute, together with the George Washington University (USA), the Oswaldo Cruz Foundation (FIOCRUZ, Brazil), the Chinese Institute of Parasitic Diseases, the Queensland Institute of Medical Research (Australia), and the London School of Hygiene and Tropical Medicine (UK), has identified, isolated, cloned, and expressed the major L3 antigens, and then tested them as recombinant vaccines. The leading candidate, the Ancylostoma-secreted protein (ASP), was selected because it can be recognized in a subset of individuals who have low intensity hookworm infection, and is partially protective in laboratory hamsters and dogs against challenge with A. ceylanicum and A. caninum, respectively. With support from the Bill and Melinda Gates Foundation, as well as additional support from the NIAID, NIH, and the March of Dimes Birth Defects Foundation, the HHVI has completed manufacture of the Na-ASP-2 hookworm vaccine. A Phase I dose-escalating trial of the vaccine is tentatively planned to take place in the USA in early 2005. Further planning is in progress for a Phase IIb trial to determine the vaccine’s ability to protect against high intensity hookworm infection in Brazil. It is anticipated that industrial-scale manufacture of the vaccine will take place in Brazil.
Additional studies are in progress to develop a second antigen from adult hookworms. Candidates of choice are the haemoglobin-degrading proteases found to line the brush border membrane of the hookworm gastrointestinal tract. These have been expressed in eukaryotic expression systems such as yeasts or baculovirus, to keep their native conformation intact for better immunogenicity. Work is in progress to combine them with ASP in a multivalent vaccine.