First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer's disease model

Recently, there has been an increased effort directed at developing immunotherapies targeting tau protein. Accumulating evidence, from several independent studies conducted in preclinical models of tauopathy, have shown that active and passive immunization approaches have been in reducing the burden of neurofibrillary tangles (NFTs) in the brain, slowing the progression of the behavioral phenotype or delaying the onset of motor function decline and weight loss in mouse models of tauopathy.Prior to this study the authors have previously identified structural determinants on tau protein that are essential for pathological  tau–tau interaction in Alzheimer’s disease (AD). These regulatory domains, revealed by monoclonal antibody DC8E8 represent a novel target for tau-directed therapy. A tau peptide encompassing the epitope revealed by DC8E8 was selected for the development of an active vaccine targeting structural determinants on mis-disordered tau protein that are essential for pathological tau–tau interaction. The goal of this study was to test the efficacy of the vaccine in a transgenic rat model of human tauopathies. In addition, toxicology and safety pharmacology studies were conducted under good laboratory practice conditions in multiple rodent and nonrodent species. The results show that vaccination induced a robust protective humoral immune response, with antibodies discriminating between pathological and physiological tau. Active immunotherapy reduced the levels of tau oligomers and the extent of neurofibrillary pathology in the brains of transgenic rats. Strikingly, immunotherapy has reduced AD-type hyperphosphorylation of tau by approximately 95%. Also, the tau peptide vaccine improved the clinical phenotype of transgenic animals. Toxicology and safety pharmacology studies showed an excellent safety and tolerability profile of the vaccine. The vaccine has already entered phase I clinical trial under the name AADvac1: Current Controlled Trial- NCT01850238.