title: Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial.
abstract: BACKGROUND
  Neurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimer's disease. Immunotherapy targeting pathological tau proteins is therefore a promising strategy for disease-modifying treatment of Alzheimer's disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial.
  
  
  METHODS
  We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50-85 years with mild-to-moderate Alzheimer's disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov, number NCT01850238; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov, number NCT02031198.
  
  
  RESULTS
  This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 [53%] vaccinated patients [92 individual events]). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres.
  
  
  CONCLUSIONS
  AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1.
  
  
  BACKGROUND
  AXON Neuroscience SE.
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia. Electronic address: petr.novak@axon-neuroscience.eu.
authors.forename: Petr
authors.initials: P
authors.lastname: Novak
authors.affiliation: Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, Graz, Austria.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schmidt
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Eva
authors.initials: E
authors.lastname: Kontsekova
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Norbert
authors.initials: N
authors.lastname: Zilka
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Branislav
authors.initials: B
authors.lastname: Kovacech
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Rostislav
authors.initials: R
authors.lastname: Skrabana
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Vince-Kazmerova
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Katina
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Lubica
authors.initials: L
authors.lastname: Fialova
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Michal
authors.initials: M
authors.lastname: Prcina
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Parrak
authors.affiliation: University Clinic of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Dal-Bianco
authors.affiliation: University Clinic of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Brunner
authors.affiliation: University Clinic of Neurology, Christian-Doppler-Clinic, Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Staffen
authors.affiliation: Social and Medical Centre East, Danube Hospital, Karl Landsteiner Institute for Memory and Alzheimer Research, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Rainer
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Matej
authors.initials: M
authors.lastname: Ondrus
authors.affiliation: Division of General Neurology, Department of Neurology, Medical University Graz, Graz, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ropele
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Smisek
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Roman
authors.initials: R
authors.lastname: Sivak
authors.affiliation: Karolinska Institute Alzheimer Disease Research Centre and Clinical Trial Unit, Geriatric Clinic, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.affiliation: AXON Neuroscience SE, Bratislava, Slovakia.
authors.forename: Michal
authors.initials: M
authors.lastname: Novak
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000628:therapy*; D023582:Alzheimer Vaccines / Q000009:adverse effects / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D016875:tau Proteins / Q000276:immunology*
chemical_list: D023582:Alzheimer Vaccines; D016875:tau Proteins