Development of a multivalent, PrP(Sc)-specific prion vaccine through rational optimization of three disease-specific epitopes.
Prion diseases represent a novel form of infectivity caused by the propagated misfolding of a self-protein (PrP(C)) into a pathological, infectious conformation (PrP(Sc)). Efforts to develop a prion vaccine have been complicated by challenges and potential dangers associated with induction of strong immune responses to a self protein. There is considerable value in the development of vaccines that are specifically targeted to the misfolded conformation. Conformation specific immunotherapy depends on identification and optimization of disease-specific epitopes (DSEs)(1) that are uniquely exposed upon misfolding. Previously, we reported development of a PrP(Sc)-specific vaccine through empirical expansions of a YYR DSE. Here we describe optimization of two additional prion DSEs, YML of β-sheet 1 and a rigid loop (RL) linking β-sheet 2 to α-helix 2, through in silico predictions of B cell epitopes and further translation of these epitopes into PrP(Sc)-specific vaccines. The optimized YML and RL vaccines retain their properties of immunogenicity, specificity and safety when delivered individually or in a multivalent format. This investigation supports the utility of combining DSE prediction models with algorithms to infer logical peptide expansions to optimize immunogenicity. Incorporation of optimized DSEs into established vaccine formulation and delivery strategies enables rapid development of peptide-based vaccines for protein misfolding diseases.
Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan Canada S7 N 5E5, Canada; Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E3, Canada.
Kristen
K
Marciniuk
Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E3, Canada.
Pekka
P
Määttänen
Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E3, Canada; School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan Canada S7N 5E5, Canada.
Ryan
R
Taschuk
Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC V5Z 3P1, Canada.
T Dean
TD
Airey
Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E3, Canada.
Andrew
A
Potter
Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC V5Z 3P1, Canada.
Neil R
NR
Cashman
Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E3, Canada; School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan Canada S7N 5E5, Canada.
Philip
P
Griebel
Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan Canada S7 N 5E5, Canada; Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E3, Canada. Electronic address: scott.napper@usask.ca.
Scott
S
Napper
D000818:Animals; D000906:Antibodies / Q000097:blood; D000918:Antibody Specificity; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D005260:Female; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018620:PrPSc Proteins / Q000276:immunology*; D017096:Prion Diseases / Q000517:prevention & control*; D017433:Protein Structure, Secondary; D012756:Sheep; D014612:Vaccines / Q000276:immunology*; D022223:Vaccines, Subunit / Q000276:immunology
D000906:Antibodies; D018985:Epitopes, B-Lymphocyte; D018620:PrPSc Proteins; D014612:Vaccines; D022223:Vaccines, Subunit
Disease-Specific Epitopes; Prion diseases; Protein Misfolding; Self-Epitope; Vaccine