Prion diseases are infectious, conformational neurodegenerative disorders characterized by the structural modification of the prion protein, PrPC, into a pathological conformer, PrPSc. Currently there is no effective therapy for this group of diseases. The outbreak of bovine spongiform encephalopathy and the resulting emergence of a new human prion disease vCJD, highlight the public health threat from prion diseases. Although the original outbreak of vCJD is waning, there is the possibility of further outbreaks from current asymptomatic carriers of the disease. In the USA an ongoing threat from prion disease is from chronic wasting disease (CWD). High rates of infection among deer and elk populations have been report, with experimental data indicating that this disease is transmissible to primates. In the prior funding of this grant we reported on the first successful in vivo active and passive immunization approaches for prion diseases using wild-type animals. In the last funding cycle we also developed an in vitro tissue culture model of prion disease, and showed that it is a valuable tool to screen for therapeutically active anti-PrP antibodies. Our recent preliminary results indicate that using our novel mucosal immunization approach we are able to completely prevent prion disease among animals with a high anti-PrP titer. We also have shown that anti-PrP antibodies that are active in our tissue culture model of prion infection, can significantly delay prion infection and reduce severity of disease. In our planned studies we will further develop our active and passive immunization approaches, to bring them closer to veterinary and human clinical use for both prion infection prevention and potential treatment of symptomatic disease. The specific aims of this proposal are to : 1): Development of the optimal oral vaccination method in wild-type mice and transgenic mice expressing elk, sheep or human PrP; 2) Characterization of the immune response in successfully vaccinated animals and the development of monoclonal antibodies (Mabs) to mouse and human PrP from these mice. Mabs will be tested for therapeutic efficacy in tissue culture models of scrapie and human sporadic CJD prion infection and 3) Passive immunization studies using existing Mabs and antibodies generated from successfully vaccinated mice to determine the mechanisms responsible for therapeutic effects and to investigate if any will be effective in both human and scrapie prion infection in the pre- symptomatic incubation period and in symptomatic disease.