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Prototype Alzheimer’s Disease Vaccine Using the Immunodominant B Cell Epitope from -Amyloid and Promiscuous T Cell Epitope Pan HLA DR-Binding Peptide¹

Michael G. Agadjanyan^2,*, Anahit Ghochikyan^*, Irina Petrushina, Vitaly Vasilevko, Nina Movsesyan^*, Mikayel Mkrtichyan^*, Tommy Saing and David H. Cribbs^2,3,,

^* Institute for Molecular Medicine, Department of Immunology, Huntington Beach, CA 92647; Institute for Brain Aging and Dementia, Department of Neurology, University of California, Irvine, CA 92697

Immunization of amyloid precursor protein transgenic mice with fibrillar -amyloid (A) prevents Alzheimer’s disease (AD)-like neuropathology. The first immunotherapy clinical trial used fibrillar A, containing the B and T cell self epitopes of A, as the immunogen formulated with QS21 as the adjuvant in the vaccine. Unfortunately, the clinical trial was halted during the phase II stage when 6% of the participants developed meningoencephalitis. The cause of the meningoencephalitis in the patients that received the vaccine has not been definitively determined; however, analysis of two case reports from the AN-1792 vaccine trial suggest that the meningoencephalitis may have been caused by a T cell-mediated autoimmune response, whereas production of anti-A Abs may have been therapeutic to the AD patients. Therefore, to reduce the risk of an adverse T cell-mediated immune response to A immunotherapy we have designed a prototype epitope vaccine that contains the immunodominant B cell epitope of A in tandem with the synthetic universal Th cell pan HLA DR epitope, pan HLA DR-binding peptide (PADRE). Importantly, the PADRE-A_1–15 sequence lacks the T cell epitope of A. Immunization of BALB/c mice with the PADRE-A_1–15 epitope vaccine produced high titers of anti-A Abs. Splenocytes from immunized mice showed robust T cell stimulation in response to peptides containing PADRE. However, splenocytes from immunized mice were not reactivated by the A peptide. New preclinical trials in amyloid precursor protein transgenic mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse events that occurred in the first clinical trial.

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