Development of a dual Aβ‐tau vaccine for the prevention of Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterized by two pathological hallmarks, Aβ plaques and tau tangles. Several antibodies targeting Aβ plaques showed signs of slowing clinical decline in AD. Antibodies targeting tau epitopes and vaccines targeting either Aβ or tau are in earlier clinical development stages. Since Aβ and tau may act synergistically in the cause and/or progression of disease, targeting both concomitantly may lead to better efficacy for prevention of AD. Here we describe the development of our dual Aβ‐tau vaccine for AD aimed to clear pathogenic Aβ and block tau transmission.MethodA variety of linear immunogens containing both Aβ and tau peptides separated by various linkers and dendritic cell cleavage sites were screened in mice and guinea pigs for the generation of balanced titers to Aβ and tau. A subset was also evaluated in cynomolgus monkey. Animals were immunized intramuscularly with peptide‐conjugated immunogens formulated with an appropriate adjuvant. Bleeds were taken 1‐2 week after each injection. Serum titers were determined against Aβ and tau. Fresh frozen human AD or control brain sections were stained with sera from immunized and control animals. The neutralizing activity of immune sera was also assessed against soluble Ab oligomers. T‐cell reactivity was also investigated.ResultWe found dual vaccine constructs that provided balanced and immunogenic responses against Aβ and tau proteins. Immune sera bound avidly to Aβ plaques and tau tangles in human AD brain sections at concentrations expected to be achieved in CNS under in vivo conditions. Immune sera also inhibited the binding of soluble Aβ aggregates to hippocampal neurons. Immunogens did not elicit cytotoxic T‐cell responses to Aβ or tau.ConclusionWe developed dual vaccine constructs that induce optimally balanced titers against Aβ and tau in cynomolgus monkeys. Antibodies were immunoreactive to both Aβ plaques and neurofibrillary tau tangles in human AD brain sections and blocked the binding of soluble Aβ aggregates to neurons, without eliciting T‐cell responses to Aβor tau. These results support the development of a dual Aβ‐tau vaccine with the ability to target pathogenic Aβ and tau for the prevention of AD.