MER5101, a Novel Aβ1-15:DT Conjugate Vaccine, Generates a Robust Anti-Aβ Antibody Response and Attenuates Aβ Pathology and Cognitive Deficits in APPswe/PS1ΔE9 Transgenic Mice

Active amyloid-beta (A beta) immunotherapy is under investigation to prevent or treat early Alzheimer's disease (AD). In 2002, a Phase II clinical trial (AN1792) was halted due to meningoencephalitis in similar to 6% of the AD patients, possibly caused by a T-cell-mediated immunological response. Thus, generating a vaccine that safely generates high anti-A beta antibody levels in the elderly is required. In this study, MER5101, a novel conjugate of A beta 1-15 peptide (a B-cell epitope fragment) conjugated to an immunogenic carrier protein, diphtheria toxoid (DT), and formulated in a nanoparticular emulsion-based adjuvant, was administered to 10-month-old APPswe/PS1 Delta E9 transgenic (Tg) and wild-type (Wt) mice. High anti-A beta antibody levels were observed in both vaccinated APPswe/PS1 Delta E9 Tg and Wt mice. Antibody isotypes were mainly IgG1 and IgG2b, suggesting a Th2-biased response. Restimulation of splenocytes with the A beta 1-15: DT conjugate resulted in a strong proliferative response, whereas proliferation was absent after restimulation with A beta 1-15 or A beta 1-40/42 peptides, indicating a cellular immune response against DT while avoiding an A beta-specific T-cell response. Moreover, significant reductions in cerebral A beta plaque burden, accompanied by attenuated microglial activation and increased synaptic density, were observed in MER5101-vaccinated APPswe/PS1 Delta E9 Tg mice compared with Tg adjuvant controls. Last, MER5101-immunized APPswe/PS1 Delta E9 Tg mice showed improvement of cognitive deficits in both contextual fear conditioning and the Morris water maze. Our novel, highly immunogenic A beta conjugate vaccine, MER5101, shows promise for improving A beta vaccine safety and efficacy and therefore, may be useful for preventing and/or treating early AD.