Hepatitis B core VLP-based mis-disordered tau vaccine elicits strong immune response and alleviates cognitive deficits and neuropathology progression in Tau.P301S mouse model of Alzheimer’s disease and frontotemporal dementia

Abstract

BackgroundTruncated mis-disordered tau protein plays an important role in the pathogenesis of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Tau294–305, an epitope in the truncated tau, is essential for pathological tau-tau interaction and aggregation. A tau294–305-targeted approach may have beneficial effects in the treatment of AD and FTD.MethodsIn this study, we genetically fused tau294–305 epitope to the hepatitis B virus core protein (HBc) major immunodominant region (MIR) (with the resultant protein termed T294-HBc), and we subcutaneously immunized a Tau.P301S transgenic mouse model of FTD and AD with T294-HBc four times. The levels and characteristics of antibodies induced by T294-HBc were determined by enzyme-linked immunosorbent assay. The effect of T294-HBc on the cognitive deficits of Tau.P301S mice was tested using the Morris water maze test, novel object recognition, and a Y-maze test. Western blot analysis and IHC were applied to measure the effect of T294-HBc on tau pathologies and neuroinflammation in the mouse brains.ResultsThe results showed that T294-HBc self-assembled into HBc chimeric virus-like particles (VLPs) with tau294–305 displayed on the surface and that it induced high antibody titers specifically against the mis-disordered truncated tau. Further investigation showed that these antibodies simultaneously bound to microtubule-binding regions 1–4 (MTBR1–4) [tau263–274, tau294–305, tau325–336, tau357–368 and tau294–305(P301S)]. Moreover, T294-HBc VLP vaccination significantly ameliorated memory and cognitive decline; reduced the levels of AT8-positive tau, truncated tau monomer, and oligomer; attenuated microgliosis and astrogliosis; and rescued synaptic deficits in Tau.P301S transgenic mice.ConclusionsT294-HBc VLP vaccine elicited strong immune response and alleviated cognitive deficits and neuropathology progression in Tau.P301S mice, indicating that the T294-HBc VLP vaccine has promising therapeutic potential for the treatment of AD and FTD.

Qß Virus-like particle-based vaccine induces robust immunity and protects against tauopathy

“…For example, in that study they reported reduced levels of normal physiological tau (Tau5). 45 In contrast, in the report presented here, pT181-Qß did not reduce total soluble non-pathogenic tau species (Fig. 4d) but instead specifically reduced hyperphosphorylated tau and the ratio of insoluble/soluble tau.…”

“…Recent work, investigating pathological tau (tau 294–305 ) conjugated to a Hepatitis B-core VLP was shown to induce immunity against tau, reduce truncated tau and rescue behavior in a P301S mouse model of tauopathy. 45 However, since many modifications in tau (including phosphorylation, truncation, oligomerization, etc.) have been demonstrated to contribute to disease pathogenesis, the most effective epitope of tau for immunological targeting is still debatable.…”

Viral nanoparticles for drug delivery, imaging, immunotherapy, and theranostic applications

“…vaccination in rTg4510 mice models indicated that the vaccine candidate induced a robust and long-lived anti-pT181 antibody response leading to reduction of phosphorylated pathological tau in the hippocampus and cortex, prevention of atrophy in the hippocampus and corpus callosum, and rescue of cognitive dysfunction. It is also worth mentioning that mammalian VLPs such as HBc [169], murine leukemia virus [170], and HPV [171] have been explored with relative success as tauopathy vaccines.…”

Artificially designed hepatitis B virus core particles composed of multiple epitopes of type A and O foot‐and‐mouth disease virus as a bivalent vaccine candidate

“…However, most of these chimeric particles cannot be assembled efficiently and produced on a large scale, which limits their application for subsequent clinical production. Therefore, since HBc molecules with multiple exogenous epitopes can be efficiently expressed and assembled into VLPs in an E. coli system, VLPs‐based vaccines are more suitable for the industrialization of future vaccines . Multiple previous studies have demonstrated that HBc VLPs represent a promising presentation platform for a variety of pathogen epitopes, including the bivalent VLP HFMD vaccine candidates against EV71 and CA16 .…”

“…Therefore, since HBc molecules with multiple exogenous epitopes can be efficiently expressed and assembled into VLPs in an E. coli system, VLPs-based vaccines are more suitable for the industrialization of future vaccines. 31 Multiple previous studies have demonstrated that HBc VLPs represent a promising presentation platform for a variety of pathogen epitopes, including the bivalent VLP HFMD vaccine candidates against EV71 and CA16. 32,33 In addition to the epitope carrier platform, the recombinant multi-epitope vaccine mainly On the basis of the two B cell epitopes on FMDV VP1, a variety of epitope vaccines have been developed to induce high neutralizing antibodies titers in mice.…”