title: 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.
abstract: Active amyloid-β (Aβ) 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 immunological response. Thus, generating a vaccine that safely generates high anti-Aβ antibody levels in the elderly is required. In this study, MER5101, a novel conjugate of Aβ1-15 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/PS1ΔE9 transgenic (Tg) and wild-type (Wt) mice. High anti-Aβ antibody levels were observed in both vaccinated APPswe/PS1ΔE9 Tg and Wt mice. Antibody isotypes were mainly IgG1 and IgG2b, suggesting a Th2-biased response. Restimulation of splenocytes with the Aβ1-15:DT conjugate resulted in a strong proliferative response, whereas proliferation was absent after restimulation with Aβ1-15 or Aβ1-40/42 peptides, indicating a cellular immune response against DT while avoiding an Aβ-specific T-cell response. Moreover, significant reductions in cerebral Aβ plaque burden, accompanied by attenuated microglial activation and increased synaptic density, were observed in MER5101-vaccinated APPswe/PS1ΔE9 Tg mice compared with Tg adjuvant controls. Last, MER5101-immunized APPswe/PS1ΔE9 Tg mice showed improvement of cognitive deficits in both contextual fear conditioning and the Morris water maze. Our novel, highly immunogenic Aβ conjugate vaccine, MER5101, shows promise for improving Aβ vaccine safety and efficacy and therefore, may be useful for preventing and/or treating early AD.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Frost
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Hongjun
authors.initials: H
authors.lastname: Fu
authors.forename: Stephen
authors.initials: S
authors.lastname: Grimes
authors.forename: Peter
authors.initials: P
authors.lastname: Blackburn
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Lemere
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D016466:CHO Cells / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000276:immunology / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D003214:Conditioning, Classical / Q000502:physiology; D006224:Cricetinae; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004168:Diphtheria Toxoid / Q000276:immunology*; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D005239:Fear; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000276:immunology / Q000628:therapy; D006801:Humans; D007114:Immunization / Q000379:methods*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D047468:Immunoprecipitation; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology; D053764:Presenilin-1 / Q000235:genetics; D013154:Spleen / Q000166:cytology; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D016207:Cytokines; D004168:Diphtheria Toxoid; D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1