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

Abstract

Immunization of amyloid precursor protein transgenic mice with fibrillar β-amyloid (Aβ) prevents Alzheimer’s disease (AD)-like neuropathology. The first immunotherapy clinical trial used fibrillar Aβ, containing the B and T cell self epitopes of Aβ, 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-Aβ Abs may have been therapeutic to the AD patients. Therefore, to reduce the risk of an adverse T cell-mediated immune response to Aβ immunotherapy we have designed a prototype epitope vaccine that contains the immunodominant B cell epitope of Aβ in tandem with the synthetic universal Th cell pan HLA DR epitope, pan HLA DR-binding peptide (PADRE). Importantly, the PADRE-Aβ1–15 sequence lacks the T cell epitope of Aβ. Immunization of BALB/c mice with the PADRE-Aβ1–15 epitope vaccine produced high titers of anti-Aβ 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 Aβ 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.

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

“…37,38,40 In parallel, we conducted therapeutic studies by immunization of 16-19-month-old Tg2576 mice (n = 6). Control animals of the same age were injected with adjuvant alone (n = 5).…”

“…30,35,36 In fact, we recently pointed out that active Ab-vaccines tested in clinical trials so far have produced ambivalent results due to their inadequate immunogenicity. 31 To support our position and suggest an effective future clinical trials protocol, we decided for the first time to test the efficacy of our proteinbased epitope vaccine (EV) composed of three copies of immunogenic N-terminal epitope of Ab [37][38][39][40][41] and two Th epitopes from tetanus toxoid (TT) in preventive and therapeutic settings in parallel. More specifically, to simulate disease stages in humans (i.e., prodromal, mild to moderate, and severe AD), we studied the immunogenicity and efficacy of EV (reduction of Ab pathology and cognitive impairments) in Tg2576 mice that, at the start of vaccination, possess low, moderate, and high AD-like pathology.…”

Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Aβ antibody response with Alum to Quil A adjuvant switch

“…A prototype epitope AD vaccine was synthesized exactly as we have described previously [36]. Briefly, the N-terminus of the immunodominant B cell epitope of Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] was synthesized in tandem with a promiscuous foreign T cell epitope, PADRE (aK-Cha-VAAWTLKAAa, where "a" is D alanine and "Cha" is L-cyclohexylalanine) as Multiple Antigenic Peptides (MAP), which contain a core matrix of 4 branching lysines [42,43] to generate PADRE-Aβ 1-15 -MAP molecules (Invitrogen Inc., CA).…”

“…To reduce the risk of an adverse T cell-mediated immune response to Aβ-immunotherapy, we developed an epitope vaccine, PADRE-Aβ 1-15 -MAP, and demonstrated that immunizations with this vaccine induced high titers of anti-Aβ antibodies, but not anti-PADRE antibodies. Formulation of our immunogen in the Th2-type adjuvant, Alum, was performed to direct the antibody response toward a Th2 phenotype in an attempt to avoid a strong Th1 humoral response, while maintaining potentially beneficial anti-Aβ antibody response [36]. Alum, however, is much less potent than the majority of Th1-type adjuvants including saponin (QS21) [19,[37][38][39][40], sometimes as much as 200-fold [41].…”

“…In the present study, we compared the immunogenicity of our novel prototype epitope vaccine that contains the immunodominant B cell epitope of Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] in tandem with the synthetic universal helper T cell epitope, PADRE (PADRE-Aβ 1-15 -MAP) [36] formulated in Th1-type adjuvant (Quil A) or Th2-type adjuvant (Alum). To identify an acceptable adjuvant formulation for use in future pre-clinical and clinical trials, we tested the use of different combinations of Quil A and Alum in BALB/c and C57BL/6 mice of two different haplotypes H-2 d and H-2 b , respectively.…”