In 1962, Dr. Norman Stoll of the Rockefeller foundation referred to human hookworm infection ('hookworm') as the "The Great Infection of Mankind" and today, almost half a century later, this remains the case . Hookworm is still highly endemic globally, with approximately 576 million cases . Necator americanus is considered the most common hookworm worldwide. In the developing regions of sub-Saharan Africa, Asia, and the Americas, hookworm is an important cause of iron-deficiency anemia and protein malnutrition; it is considered the second most important parasitic disease next to malaria . Both of these pathologic processes result from the blood-feeding activities of adult hookworms in the host small intestine. It is estimated that approximately 25 adult N. americanus hookworms cause the loss of approximately 1 ml of blood daily . Two populations are particularly vulnerable to developing hookworm anemia – children and women of reproductive age, including pregnant women . In children, chronic hookworm anemia results in impaired growth and cognitive development , and a recent economic analysis suggests that these processes result in significant wage earning losses . In pregnant women, hookworm is a major contributor to severe anemia in pregnancy, low birth weight, and increased maternal morbidity and mortality .
In response to the increasing awareness of hookworm as a major public health threat, the World Health Organization and other international agencies currently advocate global efforts to control hookworm morbidity through the regular and periodic use of anthelmintics . In areas of high hookworm transmission it is recommended to administer anthelmintics, usually a single dose of either albendazole or mebendazole, two-three times annually. Although this 'deworming' approach would lead to important morbidity reduction, there are larger concerns about its sustainability given 1) the high rates of hookworm re-infection following drug treatment , 2) the diminishing efficacy of the drug with repeated use , possibly because of drug resistance , and 3) the high prevalence and intensity of hookworm infection among adult populations, most notably women of reproductive age .
In response to these concerns, an international product development partnership known as The Human Hookworm Vaccine Initiative  was initiated to develop an anti-hookworm vaccine aimed at reducing worm burdens and intensity, as an alternative or complementary approach to deworming [1, 13, 14]. The HHVI has identified promising vaccine candidates from both the adult stages of hookworms, as well as the infective larval stages [13, 15]. Ultimately, the HHVI is working to develop multivalent vaccine comprised of at least one larval and one adult antigen. The larval antigen, ASP-2, pdb-code 1U53 , has undergone pilot scale manufacture, and Phase 1 clinical testing , while two adult antigens, including an aspartic protease (APR-1)  and a glutathione-S-transferase (GST)  are at earlier stages of development.
The GST superfamily is comprised of widely distributed isoenzymes that perform functions as diverse as the detoxification of electrophilic compounds to protecting against peroxidative damage . GSTs are homodimers that catalyze the nucleophilic addition of reduced glutathione to various diverse electrophilic substrates consequently facilitating their inactivation, and extrusion [20, 21]. GSTs are a major detoxification system for helminths, which have limited detoxification enzymes and apparently lack the cytochrome P-450 dependent reactions [22–24]. Thus, GSTs are critical to the survival of adult helminths in the host. Inhibition of GSTs will deprive parasitic helminths of their major detoxification and defense against oxidative stress, making hookworm GSTs a viable target for the design of novel vaccines as well as anthelmintics. A 28 kDa GST from Schistosoma haematobium, the etiologic agent of urinary schistosomiasis is undergoing clinical trials in Africa .
In preclinical studies conducted in laboratory dogs and hamsters challenged with infective hookworm larvae, Ac-GST-1, a GST from the canine hookworm, Ancylosotma caninum demonstrated promise as vaccines that reduce adult worm burden and fecundity of female worms . Based on these laboratory animal vaccine trials, enzymatic and structural studies were initiated recently to provide new insights into the roles of hookworm GSTs as functional vaccines. In order to clarify the role of hookworm GSTs as possible drug and vaccine targets, we have undertaken X-ray structural analysis of the Na-GST-1 and Na-GST-2, two of the three known GSTs from N. americanus. We present here first structures of human hookworm GSTs.