PROJECT SUMMARY / ABSTRACT No prophylactic or therapeutic regimen is known for any prion disease. The BSE outbreak in cattle with the subsequent emergence of a new and transmissible human prion disease (vCJD) highlights the public health threat from prion diseases. The commonalities among mammalian prion diseases are quite remarkable 1. The ongoing and expanding major threat from prion disease in North America is chronic wasting disease (CWD). CWD is an emergent rapidly spreading disease in cervids 2 with uncertain zoonotic potential 3. Approximately 9 million Americans hunt deer and elk 4 with an estimated 7,000-15,000 CWD- infected cervids consumed annually (increasing 20%/yr) 5. As hunting is a roughly $26 billion (per annum) 4 industry, CWD also represents an enormous potential health and economic threat. We have developed novel vaccine strategies which show promise in animal models 6-8 and have established a carefully-graded CWD challenge 9,10 in tandem with a longitudinal monitoring system in our unique indoor-housed white-tailed deer facility 10-14, permitting CWD vaccine assessment in the native host. We propose 3 aims to determine the ability of homologous or heterologous immunization strategies to protect deer from CWD infection and mitigate prion shedding. In Aim 1 we will determine the efficacy and safety of CWD vaccines that have complementary targets, a highly innovative and rationally designed vaccine which targets PrPSc 8,15 and a second vaccine strategy which aims at eliminating the substrate for prion conversion 7,16, and whether combining the vaccines is more effective. In Aim 2 we will determine if these vaccine strategies, alone or in combination, protect deer from CWD infection. Aim 3 will further determine if vaccination reduces prion shedding in excreta and secreta (urine, feces and saliva) of CWD challenged deer, thereby reducing infection between cervids and environmental contamination. The translational impact of the results of these studies will: a) develop prototype vaccine candidates for prion diseases b) provide management tools for the cervid industry and wildlife management c) mitigate the risks of zoonotic transmission of cervid prions. Thereby, this research will have immediate impacts in both human and animal health.