title: Refinement of a DNA based Alzheimer's disease epitope vaccine in rabbits.
abstract: We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope vaccine comprising three copies of a short amyloid-β (Aβ) B cell epitope, Aβ 11 fused with the foreign promiscuous Th epitope, PADRE (p3Aβ 11-PADRE) was immunogenic in mice. However, since DNA vaccines exhibit poor immunogenicity in large animals and humans, in this study, we sought to improve the immunogenicity of p3Aβ 11-PADRE by modifying this vaccine to express protein 3Aβ 11-PADRE with a free N-terminal aspartic acid fused with eight additional promiscuous Th epitopes. Generated pN-3Aβ 11-PADRE-Thep vaccine has been designated as AV-1955. We also delivered this vaccine using the TriGrid electroporation system to improve the efficiency of DNA transfection. This third-generation DNA epitope vaccine was evaluated for immunogenicity in rabbits in comparison to the parent construct p3Aβ 11-PADRE. AV-1955 vaccination induced significantly stronger humoral immune responses in rabbits compared with p3Aβ 11-PADRE vaccine. Anti-Aβ 11 antibodies recognized all forms of human β-amyloid peptide (monomers, oligomers and fibrils), bound to amyloid plaques in brain sections from an AD case and reduced oligomer- and fibril-mediated cytotoxicity ex vivo. These findings suggest that AV-1955 could represent an effective DNA epitope vaccine for AD therapy, pending safety and efficacy studies that are currently being conducted in Rhesus monkeys.
authors: Department of Molecular Immunology; Institute for Molecular Medicine; Huntington Beach, CA, USA.
authors: Anahit
authors: A
authors: Ghochikyan
authors: Hayk
authors: H
authors: Davtyan
authors: Irina
authors: I
authors: Petrushina
authors: Armine
authors: A
authors: Hovakimyan
authors: Nina
authors: N
authors: Movsesyan
authors: Arpine
authors: A
authors: Davtyan
authors: Anatoly
authors: A
authors: Kiyatkin
authors: David H
authors: DH
authors: Cribbs
authors: Michael G
authors: MG
authors: Agadjanyan
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000906:Antibodies / Q000097:blood; D001921:Brain / Q000473:pathology; D018985:Epitopes, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000906:Antibodies; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic
keywords: Alzheimer’s disease; DNA vaccine; T helper epitope; electroporation; humoral immune responses
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