Project Summary/Abstract (30 lines permitted) Hookworms (genera Ancylostoma and Necator) and Haemonchus contortus are related (clade V, suborder Strongylida) blood-feeding gastrointestinal nematode (GIN) parasites of humans and ruminants. In humans, hookworms are a leading cause of anemia globally and one of the most medically important parasites on earth, infecting half a billion people and causing growth stunting, cognitive impairment, malnutrition, and loss of future earnings/education/productivity. In small ruminants (e.g., sheep, goats), Haemonchus is one of the most important and devastating parasites, with infections leading to severe dehydration, anemia, lethargy, depressed low-energy behavior, rough hair coats, low weights, and poor wool and lamb production. Infections can be lethal. Drug efficacy is becoming limited for both groups of parasites, with resistance emerging in humans and widespread in sheep. Therefore, complementation of drug treatment with a prophylactic vaccine would be an enormous step forward for control and eventual elimination of blood-feeding GIN parasites. However, vaccine development against blood-feeding GINs is complicated because these parasites are masters at evading the immune system. We propose to use state-of-the art genomic, transcriptomic, and immunoinformatic techniques to identify and prioritize novel vaccine targets against blood-feeding GINs. Preliminary data are encouraging. We will use our promising preliminary data to investigate what constitutes a good vaccine against blood-feeding GINs, as well as to improve the efficacy of one vaccine candidate by altering expression platforms and adjuvants. Furthermore, we will use genomics, transcriptomics, and immunoinformatics to compare intestinal-specific genes encoding putative secreted proteins between these two blood-feeding parasites, and to compare immunomodulated genes encoding putative secreted intestinal proteins between these two nematode parasites. These comparisons will be used to identify conserved, high-value blood-feeding-specific GIN antigens. These candidate antigens will be tested first in our small animal model of human hookworm infection to identify single hookworm vaccine antigens, and/or a combination of hookworm vaccine antigens, that will engender complete or near-complete protection from infection in the laboratory. Promising antigens will be rapidly transferred to a large animal system;; sheep will be vaccinated with the corresponding H. contortus antigens and similarly assessed for protection. Immunological and mechanistic aspects of protection will be studied. Our goal is to identify one or more immunogens that can be optimized in pre-clinical studies and then advanced to human and ovine/caprine clinical trials.