Refinement of a DNA based Alzheimer disease epitope vaccine in rabbits

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.