Hookworm, because of its high prevalence but relatively low mortality, causes a greater burden of DALYs (1·83 million) than schistosomiasis (1·76 million) or trypanosomiasis (1·60 million) (2). Two recent events have reinvigorated immunological studies on hookworms – the funding of the Human Hookworm Vaccine Initiative by the Bill and learn more Melinda Gates Foundation (http://www.sabin.org/vaccine-development/vaccines/hookworm), and the discovery that parasitic helminths, and hookworms in particular, can suppress inflammation associated with autoimmune and allergic diseases – a phenomenon that is embodied by the Hygiene Hypothesis.

Recent and past contributions to these and other aspects of hookworm immunology have involved talented researchers from many different countries, but in this review, we will focus

particularly on the work of Australian researchers. Antibodies of the isotypes IgG1, IgG4, IgM, IgD, IgA and IgE from hookworm-endemic (both the human hookworms N. americanus and the zoonotic dog hookworm Ancylostoma caninum) populations have all been shown to bind to hookworm antigens (5). In experimental hookworm infections, parasite-specific IgM is detectable 6 weeks after infection, with parasite-specific IgG detectably increased BAY 57-1293 concentration 8 weeks after infection (6–9). IgE responses in experimental human infections appear to develop slowly over a number of exposures, and the IgE response is generally undetectable in primary infections (8,9). As a result of its protective role in many helminth infections, IgE has been of particular interest to researchers. In the 1970s, David Grove and colleagues studied the role of IgE in N. americanus infections in the highlands of Papua New Guinea. They were the first to show that IgE, whether it be parasite specific or polyclonal, afforded protection against hookworm infection Ribonucleotide reductase (10,11).

Further evidence of the protective role of IgE in hookworm infection comes from vaccine studies, where levels of IgE against the vaccine candidate antigen Na-ASP-2 (ancylostoma secreted protein-2) in endemic populations from Brazil negatively correlate with infection intensity, while IgG4 against ASP-2 positively correlates with infection intensity (12). In filariasis and schistosomiasis, parasite-specific IgG4 correlates with a suppressed ‘modified TH2’ response, able to be differentiated from the parasite-killing (but often more pathogenic) IgG1 or IgE immune responses (13). A similar paradigm may exist in hookworm infection, and indeed, IgG4 specific to hookworm antigens is the best serological predictor of infection (14,15), implying a modified TH2 response is almost universal in hookworm infection. Therefore, if the immune response to hookworm is skewed away from the modified TH2 IgG4 response to a protective TH2 IgE response, immunity to the parasite may be possible.