Engineered hepatitis B core virus-like particle carrier for precise and personalized Alzheimer’s disease vaccine preparation via fixed-point coupling

Abstract Heterogenous aggregates of amyloid β (Aβ) and tau protein play a key role in Alzheimer’s disease (AD) progression. As the epitope profiles of Aβ and abnormally phosphorylated tau change over the course of the disease, tailor immunotherapy to specific patient groups according to the disease stage by targeting corresponding Aβ and tau species or both of tau and Aβ might improve treatment efficacy. However, epitope peptides have low immunogenicity and peptide vaccine preparation is laborious and time-consuming. We here first constructed a platform for peptide vaccine preparation by inserting SpyCatcher into the major immunodominant region (MIR) of truncated Hepatitis B core protein (HBc)(1-149). The resulted recombinant protein HBc-SpyCatcher (HBc-S) could assemble into uniform and stable virus-like particles (VLPs), and readily bind to the SpyTag conjugated epitope peptides. Several series of peptides such as linear, cyclic and phosphorylated peptides including Aβ(1-6), Aβ(1-15), cAβ(1-7), cEP1, cEP2 from β-amyloid monomer or oligomers, T294, pTau396-404, pTau422 from tau proteins, were glued onto HBc-S VLPs, forming HBc-S-peptide (HBc-S-P) VLPs and efficiently elicited specific Th2-type immune responses. When applied to AD transgenic mice, HBc-S-pTau422 alleviated cognition deficits and neuropathology progression in Tau.P301S transgenic mice. The present study provides an easy, quick, convenient and universal platform for high-throughput peptide epitope screening and personalized peptide vaccine preparation.