A model-based prion vaccine protects a transgenic mouse line carrying a Gerstmann-Sträussler-Scheinker disease mutation.

Abstract

Prion diseases are transmissible, fatal, neurodegenerative disorders driven by the conformational misfolding of the cellular prion protein (PrP) into an infectious, aggregation-prone conformer (PrP). While the accumulation of PrPrepresents the central pathogenic event, targeting it directly and specifically has proven difficult due to its structural heterogeneity and similarity to PrP. Consequently, previous immunization efforts have largely focused on PrP, 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. 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. 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, 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.