Chronic wasting disease vaccine: inducing auto-antibodies for interfering in CWD infection and prion shedding

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Prion diseases are fatal infectious neurodegenerative disorders in animals and humans caused by conversion of the cellular prion protein (PrPC) into the pathologic isoform PrPSc. Chronic wasting disease (CWD) in cervids and BSE in cattle are animal prion diseases which negatively affect economy, ecology as well as animal and possibly human health in Canada. CWD is the most contagious prion disease and affects both free-ranging and farmed deer, elk, moose and reindeer. Incidence and distribution in Canada are expanding, reaching now 6% in hunted deer in Alberta. The substantial shedding of CWD infectivity via urine, feces and saliva into the environment, combined with persistence for many years, are driving forces for CWD transmission. Due to this effective horizontal transmission and occurrence in wildlife control of disease is extremely challenging. The main research question in my group is to understand prion biology and to use this for developing therapeutic and prophylactic anti-prion strategies. Our long-term goal here is to develop a CWD vaccine. The problem with immune system-mediated approaches against prion diseases is that they do not elicit an immune response as newly generated prions are self-proteins. Our approach is unique, as it targets PrPC outside the brain, using aggregation-prone recombinant PrP for overcoming self-tolerance. This strategy results in generation of self-antibodies binding to PrPC which interfere in prion conversion. My group pioneered this concept and established a solid proof-of-concept in rodent and reindeer models that tolerance to PrP can be overcome, resulting in detectable humoral and cellular immune responses without adverse side effects and protection in CWD challenge models. The proposed work program will optimize our CWD vaccine candidates. Work in Objective 1 will focus on prion shedding. The question whether our vaccine approach reduces prion shedding is very important, as an approach which increases incubation time but does not reduce shedding would result in an overall increase of CWD infectivity in the environment. Our unit has developed innovative PrP knock-in mice which shed CWD prions efficiently and can be well infected orally. We will use them to assess the effect of vaccination on shedding, using ultra-sensitive prion conversion assays and co-housing as read-outs. Work in Objective 2 will address how vaccine design can be optimized, based on the concept that tolerance can be overcome by increasing antigen stability. Objective 3 will focus on oral antigen delivery, using nanosphere co-encapsulation of immunogens and plant-based expression systems. Work in Objective 4 will extend studies in reindeer, addressing side effects, memory and antibody secretion in milk and body fluids. We expect that work in this program will result in tools which, in the long term, help to reduce the spread of CWD, lower the zoonotic risk for the Canadian population, and protect the Canadian cervid populations.