A model-based prion vaccine protects a transgenic mouse line carrying a Gerstmann–Sträussler–Scheinker disease mutation
Year: 2026
Type: article
Abstract: Prion diseases are transmissible, fatal, neurodegenerative disorders driven by the conformational misfolding of the cellular prion protein (PrP C ) into an infectious, aggregation-prone conformer (PrP Sc ). While the accumulation of PrP Sc represents the central pathogenic event, targeting it directly and specifically has proven difficult due to its structural heterogeneity and similarity to PrP C . Consequently, previous immunization efforts have largely focused on PrP C , though with limited success. Here, we employed a model-based approach to design a vaccine that specifically mimics immunogenic features hypothesized to be present on the surface of PrP Sc . By mimicking predicted surface residues and using an innocuous, cross-beta fibril scaffold derived from the fungal protein HET-s (218–289), we were able to generate unique, conformation-dependent epitopes not found on PrP C . We evaluated our vaccine by immunizing a genetic prion disease mouse model of Gerstmann–Sträussler–Scheinker disease, a genetic prion disorder. Vaccination was able to significantly delay the onset of disease in immunized mice (412 ± 88 days) compared to unimmunized (177 ± 17 days) and scaffold-immunized (161 ± 27 days) animals, and supplementation with adjuvants including Freund’s adjuvant (448 ± 39 days), QS-21 (479 ± 58 days), and Alum (506 ± 52 days) was able to further enhance the vaccine efficacy. To investigate the mechanism of neuroprotection, we derived a monoclonal antibody from a vaccinated mouse and mapped its discontinuous, conformation-specific epitope, comprising an aspartate–histidine pair that may be occluded in PrP C , and confirmed the antibody’s ability to differentiate between infectious and uninfected prion samples. Our study demonstrates the feasibility of a model-based approach for prion vaccine design and targeting of the infectious prion protein, providing groundwork for future development of not only potential prion therapeutic interventions, but also targeting related neurodegenerative disorders characterized by protein misfolding.
Source: Acta Neuropathologica
Authors: Andrew Fang, Xinli Tang, Madeleine Fleming, Brian Tancowny, Xiongyao Wang, YongLiang Wang, Nathalie Daude, Lyudmyla Dorosh, Shelaine C. Fleck, Vineet Rathod, Virginie Coustou, Silvia A. Cervantes, Camilo Duque Velásquez, David Westaway, Judd Aiken, Debbie McKenzie, Glenn Telling, Maria Stepanova, Sven J. Saupe, Ansgar B. Siemer, Holger Wille
Institutions: University of Alberta, Harbin Institute of Technology, University of Calgary, University of Lethbridge, Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires, University of Southern California, Neuroscience and Mental Health Institute, Colorado State University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,990
Funders: Results Driven Agriculture Research, Alberta Conservation Association, University of Alberta, Canada Foundation for Innovation, Alberta Innovates, National Institutes of Health, University of California, San Francisco, Natural Sciences and Engineering Research Council of Canada, Alberta Prion Research Institute, National Institute of Allergy and Infectious Diseases, Creutzfeldt-Jakob Disease Foundation
Awards: G1021406876, G1912914257, G2841672734, G35258784, G3708095435, Structural characterization of A-beta strain variation in AD mouse models, G491477229, Intrinsically disordered domains of α-synuclein: effect of fibril formation and fibril polymorphs, G7897779273, G8760597890, G9000187433, G9000209523, Maximizing research success in studies of naturally-occurring prion diseases, Pathogenesis, Transmission and Detection of Zoonotic Prion Diseases
OpenAlex ID: W7154705501