Abstract
BackgroundNumerous pre-clinical studies and clinical trials demonstrated that induction of antibodies to the β-amyloid peptide of 42 residues (Aβ42) elicits therapeutic effects in Alzheimer's disease (AD). However, an active vaccination strategy based on full length Aβ42 is currently hampered by elicitation of T cell pathological autoreactivity. We attempt to improve vaccine efficacy by creating a novel chimeric flu vaccine expressing the small immunodominant B cell epitope of Aβ42. We hypothesized that in elderly people with pre-existing memory Th cells specific to influenza this dual vaccine will simultaneously boost anti-influenza immunity and induce production of therapeutically active anti-Aβ antibodies.MethodsPlasmid-based reverse genetics system was used for the rescue of recombinant influenza virus containing immunodominant B cell epitopes of Aβ42 (Aβ1-7/10).ResultsTwo chimeric flu viruses expressing either 7 or 10 aa of Aβ42 (flu-Aβ1-7 or flu-Aβ1-10) were generated and tested in mice as conventional inactivated vaccines. We demonstrated that this dual vaccine induced therapeutically potent anti-Aβ antibodies and anti-influenza antibodies in mice.ConclusionWe suggest that this strategy might be beneficial for treatment of AD patients as well as for prevention of development of AD pathology in pre-symptomatic individuals while concurrently boosting immunity against influenza.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in the elderly which is clinically characterized by progressive loss of memory and general cognitive decline
Chimeric and wild-type viruses were rescued in Madin-Darby canine kidney (MDCK)/ 293T cell co-cultures, and the identity of the rescued viruses was confirmed by RT-PCR and restriction/ sequence analysis of the hemagglutination assay (HA) gene segment containing the engineered foreign sequence as previously described [27]
Generation and characterization of chimeric viruses expressing Ab1-10 or Ab1-7 peptides Previous approaches to develop AD active vaccines based on full-length b-amyloid have resulted in pathological autoimmunity [8,9,14,15,16]
Summary
Alzheimer’s disease (AD) is the most common form of dementia in the elderly which is clinically characterized by progressive loss of memory and general cognitive decline. One possible way to avoid these side effects is the replacement of the self-T helper epitope(s) present in the Ab42 peptide by a foreign epitope (s) while leaving self-B cell epitope(s) of Ab42 intact Another important, but overlooked, result from the AN1792 clinical trial was that the majority of AD patients generated only low titers of anti-Ab antibodies, and approximately 50% of the patients failed to produce a measurable antibody response [12,17]. Chimeric influenza viruses expressing the B cell epitope of Ab may induce anti-viral immunity, and generate higher titers of anti-Ab antibodies in adult individuals with pre-existing influenza virus-specific memory Th cells. We hypothesized that in elderly people with pre-existing memory Th cells specific to influenza this dual vaccine will simultaneously boost anti-influenza immunity and induce production of therapeutically active anti-Ab antibodies
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