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

Abstract

Tauopathies, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD) are progressive neurodegenerative diseases clinically characterized by cognitive decline and could be caused by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles (NFTs) inside neurons. There is currently no FDA-approved treatment that cures, slows or prevents tauopathies. Current immunotherapy strategies targeting pTau have generated encouraging data but may pose concerns about scalability, affordability, and efficacy. Here, we engineered a virus-like particle (VLP)-based vaccine in which tau peptide, phosphorylated at threonine 181, was linked at high valency to Qß bacteriophage VLPs (pT181-Qß). We demonstrate that vaccination with pT181-Qß is sufficient to induce a robust and long-lived anti-pT181 antibody response in the sera and the brains of both Non-Tg and rTg4510 mice. Only sera from pT181-Qß vaccinated mice are reactive to classical somatodendritic pTau in human FTD and AD post-mortem brain sections. Finally, we demonstrate that pT181-Qß vaccination reduces both soluble and insoluble species of hyperphosphorylated pTau in the hippocampus and cortex, avoids a Th1-mediated pro-inflammatory cell response, prevents hippocampal and corpus callosum atrophy and rescues cognitive dysfunction in a 4-month-old rTg4510 mouse model of FTD. These studies provide a valid scientific premise for the development of VLP-based immunotherapy to target pTau and potentially prevent Alzheimer’s diseases and related tauopathies.

Factors That Govern the Induction of Long-Lived Antibody Responses

“…Subsequent studies demonstrated that vaccines consisting of self-antigens arrayed on the surface of the VLPs could effectively induce anti-self antibody responses [52,53], that this ability is critically dependent on the density of the self-antigens displayed on VLPs [54,55], and that these interactions may be mediated by binding to surface-expressed IgD on naïve B cells [56]. These findings have led to the development of vaccine candidates that induce antibodies against self-antigens involved in chronic diseases, including angiotensin II (hypertension) [57], PCSK9 (cardiovascular disease) [58], amyloid-beta and hyper-phosphorylated tau (Alzheimer's Disease) [59,60], and others [61]. Several of these vaccines have been tested in human clinical trials [62].…”

“…tau (Alzheimer's Disease) [59,60], and others [61]. Several of these vaccines have been tested in human clinical trials [62].…”

Tauopathy Analysis in P301S Mouse Model of Alzheimer Disease Immunized with DNA and MVA Poxvirus-Based Vaccines Expressing Human Full-Length 4R2N or 3RC Tau Proteins

“…Another factor to consider is the cellular location of the antigen, in our case the tau protein. The tau protein is an intracellular protein and the anti-tau antibodies enter in the brain [28,29] and can be internalized in neurons [30]. However, the most likely hypothesis is that its mechanism of action consists in eliminating extracellular tau and, therefore, blocking transcellular spreading [51].…”

“…Therefore, future experiments will be performed to evaluate the expression by MVA of other tau isoforms or optimized tau fragments with a diminished microtubule stabilization, such as the C-terminal region of tau that has also been described as the most immunogenic region [55,58], or other regions as the N-terminal domain. Moreover, some tau fragments have been used with success in active immunization against AD [4,55], as well as a phosphorylated tau peptide bound to VLPs [29].…”

“…Active immunotherapeutic approaches include the whole tau molecule, tau in aggregated or modified forms or synthetic tau peptides, such as ACI-35 [25] and AADvac1 [26]. Most of the passive immunotherapeutic approaches consist of monoclonal anti-tau antibodies, such as 8E12, RO7105705 and BIIB092 [27], and it has been recently described that anti-tau antibodies enter the brain [28,29] and can be internalized in neurons via Fcγ receptors [30]. Moreover, in addition to conventional vaccines, gene-based methods have been used to induce the expression of proteins to activate the cellular immune response upon delivery of DNA vectors [31].…”