Parasitic flukes (flatworms) cause enormous morbidity and mortality in developing countries. Indeed, liver flukes (Opisthorchis and Clonorchis sp.) and blood flukes (Schistosoma haematobium) are the only multi-cellular pathogens that are considered group 1 carcinogens by the International Agency for Research on Cancer. A combination of processes are thought to drive fluke infection towards cancer, including chronic inflammation caused by resident flukes and active release of excretory/secretory (ES) molecules by parasites and their subsequent entry into and potential transformation of epithelial cells. We showed that the molecular mechanisms by which these processes occur are due, at least in part, to the secretion of extracellular vesicles (EVs) that possess the hallmark features of exosomes. We used enzymatic shaving to remove proteins from the surface of fluke exosomes, and identified numerous proteins including multiple tetraspanins (TSPs). To assess the potential vaccine efficacy of EV surface proteins, we are using: (i) CRISPR-Cas9 to knock out candidate genes, and (ii) blocking exosome uptake by target cells using antibodies to recombinant EV surface proteins, such that we can prioritise proteins to test in an animal vaccine model. We produced the long extracellular loop of an O. viverrini EV surface TSP (Ov-TSP-1), and showed that antibodies blocked the uptake of fluke EVs by cholangiocytes and subsequent IL-6 production, highlighting the utility of our approach to vaccine development for this chronic infectious cancer. Pilot vaccine trials designed to assess the efficacy of the Ov-TSP-1 vaccine in a hamster model of liver fluke infection are underway.