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- Title
MER5101, a Novel Aßl-15:DT Conjugate Vaccine, Generates a Robust Anti-Aß Antibody Response and Attenuates A/3 Pathology and Cognitive Deficits in APPswe/PSlΔE9 Transgenic Mice.
- Authors
Bin Liu; Frost, Jeffrey L.; Jing Sun; Hongjun Fu; Grimes, Stephen; Blackburn, Peter; Lemere, Cynthia A.
- Abstract
Active amyloid-β (Aß) 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 --6% of the AD patients, possibly caused by a T-cell-mediated immu-nological response. Thus, generating a vaccine that safely generates high anti-Aß antibody levels in the elderly is required. In this study, MER5101, a novel conjugate of A/31-15 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/PSlΔE9 trans-genic (Tg) and wild-type (Wt) mice. High anti-Aß antibody levels were observed in both vaccinated APPswe/PSlΔE9 Tg and Wt mice. Antibody isotypes were mainly IgGl and IgG2b, suggesting a Th2-biased response. Restimulation of splenocytes with the Aßl-15:DT conjugate resulted in a strong proliferative response, whereas proliferation was absent after restimulation with Aßl-15 or Aßl-40/42 peptides, indicating a cellular immune response against DT while avoiding an Aß-specific T-cell response. Moreover, significant reductions in cerebral Aß plaque burden, accompanied by attenuated microglial activation and increased synaptic density, were observed in MER5101 -vaccinated APPswe/PSlΔE9 Tg mice compared with Tg adjuvant controls. Last, MER5101-immunized APPswe/PSlΔE9 Tg mice showed improvement of cognitive deficits in both contextual fear conditioning and the Morris water maze. Our novel, highly immunogenic Aß conjugate vaccine, MER5101, shows promise for improving Aß vaccine safety and efficacy and therefore, may be useful for preventing and/or treating early AD.
- Subjects
ALZHEIMER'S disease treatment; AMYLOID; IMMUNOTHERAPY; VACCINES; CLINICAL trials; IMMUNOGLOBULINS; COGNITION disorders; LABORATORY mice
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 16, p7027
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5924-12.2013