Thus, hookworms may release molecules that actively Palbociclib ic50 attract and expand NK cells during infection and stimulate IFN-γ release through an undefined NK receptor. This has been proposed as an immune evasion strategy as the IFN-γ released could cross-regulate the otherwise protective TH2 response. The first hookworm vaccine was developed in 1965 against the dog hookworm A. caninum and consisted of irradiated larvae (50). Although this vaccine gave good protection against experimental and field challenge, it was withdrawn

from veterinary use after concerns with efficacy and shelf life were raised. In the 1980s, David Grove and Simon Carroll switched their focus from human immunity to vaccines using A. ceylanicum infection in dogs Erlotinib solubility dmso as a model for the human disease. They showed that dogs that were chronically infected then treated with an anthelmintic were resistant to reinfection (51), highlighting for the first time that immunity to reinfection could occur, at least in the A. ceylanicum/dog relationship. Carroll and Grove then went on to explore the protective efficacy of hookworm extracts and showed that protection against A. ceylanicum infection in dogs by vaccination with adult worm aqueous somatic extracts when formulated with Freund’s adjuvants (52), kicking off efforts to develop vaccines based on soluble molecules

rather than whole parasites. More recently, recombinant vaccines have been found to exert partial efficacy in the dog hookworm model using A. caninum, stimulating human trials with orthologous N. americanus antigens presently underway. The first recombinant vaccine to show efficacy against hookworm was ancylostoma secreted protein-1 (Ac-ASP-1), which conferred partial protection in mice challenged with A. caninum (53,54). ASPs are a large family of proteins, which are the most highly expressed products of in vitro activated Farnesyltransferase larvae (55),

with the related ASP-2 protein discovered shortly after ASP-1 (56). However, mice are not a permissive host for hookworms, and ASP-1 did not confer protection in permissive hosts including hamsters (57) and dogs (58). ASP-2, by contrast, appeared to show similar protection to that of irradiated larvae (57), and in human hookworm-endemic populations, IgE specific to ASP-2 negatively correlated with hookworm burden, thus highlighting its potential as a vaccine candidate in animal models and endemic regions (12). An Na-ASP-2 vaccine is currently in development: it has been shown to raise effective and safe immune responses in unexposed individuals (59) and is currently in phase I clinical trials in Brazil being conducted by researchers (including ourselves) at The Human Hookworm Vaccine Initiative – see http://www.sabin.org/vaccine-development/vaccines/hookworm.