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While the accumulation of PrP\n                    <jats:sup>Sc<\/jats:sup>\n                    represents the central pathogenic event, targeting it directly and specifically has proven difficult due to its structural heterogeneity and similarity to PrP\n                    <jats:sup>C<\/jats:sup>\n                    . Consequently, previous immunization efforts have largely focused on PrP\n                    <jats:sup>C<\/jats:sup>\n                    , 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\n                    <jats:sup>Sc<\/jats:sup>\n                    . By mimicking predicted surface residues and using an innocuous, cross-beta fibril scaffold derived from the fungal protein HET-s (218\u2013289), we were able to generate unique, conformation-dependent epitopes not found on PrP\n                    <jats:sup>C<\/jats:sup>\n                    . We evaluated our vaccine by immunizing a genetic prion disease mouse model of Gerstmann\u2013Str\u00e4ussler\u2013Scheinker disease, a genetic prion disorder. Vaccination was able to significantly delay the onset of disease in immunized mice (412\u2009\u00b1\u200988 days) compared to unimmunized (177\u2009\u00b1\u200917 days) and scaffold-immunized (161\u2009\u00b1\u200927 days) animals, and supplementation with adjuvants including Freund\u2019s adjuvant (448\u2009\u00b1\u200939 days), QS-21 (479\u2009\u00b1\u200958 days), and Alum (506\u2009\u00b1\u200952 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\u2013histidine pair that may be occluded in PrP\n                    <jats:sup>C<\/jats:sup>\n                    , and confirmed the antibody\u2019s 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.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03015-4","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T10:21:18Z","timestamp":1776421278000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A model-based prion vaccine protects a transgenic mouse line carrying a Gerstmann\u2013Str\u00e4ussler\u2013Scheinker disease mutation"],"prefix":"10.1007","volume":"151","author":[{"given":"Andrew","family":"Fang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinli","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine","family":"Fleming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Tancowny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongyao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YongLiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Daude","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyudmyla","family":"Dorosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelaine C.","family":"Fleck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vineet","family":"Rathod","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Coustou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia A.","family":"Cervantes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilo Duque","family":"Vel\u00e1squez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Westaway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judd","family":"Aiken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie","family":"McKenzie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn","family":"Telling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Stepanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven J.","family":"Saupe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ansgar B.","family":"Siemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Wille","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"3015_CR1","doi-asserted-by":"publisher","first-page":"19812","DOI":"10.1074\/jbc.RA118.004810","volume":"293","author":"DH Abdelaziz","year":"2018","unstructured":"Abdelaziz DH, Thapa S, Brandon J, Maybee J, Vankuppeveld L, McCorkell R et al (2018) Recombinant prion protein vaccination of transgenic elk PrP mice and reindeer overcomes self-tolerance and protects mice against chronic wasting disease. 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Similar patent applications are pending in Canada, the European Union, Japan and Hong Kong. HW is a co-founder of Solenoid Biosciences LLC, which will attempt to commercialize structure-based vaccines for Alzheimer\u2019s and Parkinson\u2019s disease. The remaining authors declare that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All animal experiments were performed in accordance with the ethics guidelines from the University of Alberta Animal Care and Use Committee (ACUC) according to guidelines from the Canadian Council on Animal Care (CCAC). The research protocols of this study were approved under AUP00002852, titled \u201cVaccines for neurodegenerative diseases\u201d, AUP00000884, titled \u201cStructural biology of infectious mammalian prions\u201d, and AUP00000424, titled \u201cProduction of antibodies for neurodegenerative disease research\u201d.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"41"}}