Abstract
BackgroundAggregated amyloid-β peptide 1–42 (Aβ42), derived from the cellular amyloid precursor protein, is one of the pathological hallmarks of Alzheimer’s disease (AD). Although active immunization against Aβ42 peptide was successful in AD mouse models and led to removal of plaques and improved memory, a similar clinical trial in humans (Aβ42 peptide immunization with QS-21 adjuvant) was stopped in phase II, when 6% of the treated patients developed encephalitis. Currently ongoing passive immunizations with the injection of preformed monoclonal antibodies against different epitopes within the Aβ1–42 peptide, which do not lead to activation of the immune system, have shown some effects in slowing AD pathology. Active DNA Aβ42 immunizations administered with the gene gun into the skin are noninflammatory because they activate a different T-cell population (Th2) with different cytokine responses eliciting a different humoral immune response. We present our findings in rhesus macaques that underwent the DNA Aβ42 immunization via gene gun delivery into the skin.MethodsSix rhesus monkeys received two different doses of a DNA Aβ42 trimer vaccine. The humoral immune response was analyzed from blood throughout the study, and cellular immune responses were determined in peripheral blood mononuclear cells (PBMCs) after three and six immunizations.ResultsDNA Aβ42 trimer immunization led to high titer antibody responses in the nonhuman primate (NHP) model. Antibodies generated in the rhesus monkeys following DNA Aβ42 immunization detected amyloid plaques consisting of human Aβ42 peptide in the brain of the triple-transgenic AD mouse model. T-cell responses showed no interferon (IFN)-γ- and interleukin (IL)-17-producing cells from PBMCs in Enzyme-Linked ImmunoSpot assays after three immunization time points. At six immunization time points, IFN-γ- and IL-17-producing cells were found in immunized animals as well as in control animals and were thus considered nonspecific and not due to the immunization regimen. IFN-γ and IL-17 secretion in response to Aβ42 peptide restimulation became undetectable after a 3-month rest period.ConclusionsIntradermal DNA Aβ42 immunization delivered with the gene gun produces a high antibody response in NHPs and is highly likely to be effective and safe in a clinical AD prevention trial in patients.
Highlights
Aggregated amyloid-β peptide 1–42 (Aβ42), derived from the cellular amyloid precursor protein, is one of the pathological hallmarks of Alzheimer’s disease (AD)
Anti-Aβ antibodies produced after DNA Aβ42 immunization detect a wide variety of epitopes on the Aβ1–42 peptide, including N-terminal truncated Aβ a
The adult cohort (6–10 years old) analyzed in this study developed a strong antibody response in all animals, and we predict, on the basis of data derived from the use of this immunization protocol in aged mice and rabbits, that DNA Aβ42 immunization will lead to strong humoral immune responses in patients with AD [24, 34]
Summary
Aggregated amyloid-β peptide 1–42 (Aβ42), derived from the cellular amyloid precursor protein, is one of the pathological hallmarks of Alzheimer’s disease (AD). Active immunization against Aβ42 peptide was successful in AD mouse models and led to removal of plaques and improved memory, a similar clinical trial in humans (Aβ42 peptide immunization with QS-21 adjuvant) was stopped in phase II, when 6% of the treated patients developed encephalitis. Immunotherapy has the rationale that immunization induces an immune response that is able to clear plaque and tangles, which has high potential to treat these two hallmarks and has been successful in mouse AD models [1,2,3]. In a first clinical trial in which full-length Aβ1–42 peptide was stopped in 2002 in phase II, when 6% of the immunized patients developed meningoencephalitis that was due to inflammatory T-cell responses likely caused by the adjuvant, which was used to enhance the immune response and antibody production [4,5,6,7].
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