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Name: AADvac1
Synonyms: Axon peptide 108 conjugated to KLH
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease, Progressive Nonfluent Aphasia
U.S. FDA Status: Alzheimer's Disease (Phase 2), Progressive Nonfluent Aphasia (Phase 1)
Company: Axon Neuroscience SE


This is an active vaccine designed to elicit an immune response against pathologically modified forms of tau protein. It targets four similar epitopes in the microtubule binding repeats of the mid-domain of tau. The approach was inspired by research that began several decades ago on tau cleavage generating N-terminally truncated fragments that trigger tangle formation (Feb 2013 newsPaholikova et al., 2015). 

The AADvac1 vaccine consists of a synthetic peptide derived from amino acids 294 to 305 of the tau sequence, i.e., KDNIKHVPGGGS, coupled to keyhole limpet hemocyanin. AADvac1 uses aluminum hydroxide as an adjuvant. At the 2014 AAIC conference in Copenhagen, preclinical studies were reported as having met safety requirements for up to six months in rats, rabbits, and dogs; a paper reported that the vaccine reduced tau pathology and improved sensorimotor function in transgenic rats (Aug 2014 newsKontsekova et al., 2014).

In other preclinical work, a monoclonal antibody targeting this epitope prevented tau-tau oligomerization, blocked pathological tau spreading through the brain, and facilitated uptake of extracellular tau by microglia (Kontsekova et al., 2014Weisová et al., 2019Zilkova et al., 2020).


In May 2013, Axon Neuroscience began a first-in-man Phase 1 trial at four sites in Austria to evaluate AADvac1 in 30 patients with clinically diagnosed mild to moderate Alzheimer’s disease. Three subcutaneous, monthly injections of a single dose were assessed for safety, tolerability, and immunogenicity; some exploratory assessment of cognition was also done. A three-month, double-blind, placebo-controlled phase was followed by another three months of open-label monthly dosing. The treatment group received a total of six injections; placebo participants received three. After that, patients could enroll in a follow-up open-label extension lasting a further 18 months.

At the July 2015 AAIC conference, the company announced results. Twenty-four patients had been randomized to AADvac-1 and six to placebo, according to Reinhold Schmidt of the University of Graz. Two withdrew due to adverse events, of whom one—a patient with a viral infection followed by epileptic seizure—was considered to be possibly related to the study medication. Overall, AADvac1 in this study was safe and well-tolerated, Schmidt said. In a majority of participants, repeat injections induced increasing antibody titers. Sera from immunized patients reacted with pathological tau from human brain. Mean ADAS-cog scores remained stable over six months. The results were later published (Novak et al., 2017).

The 18-month open-label extension enrolled 26 patients, of whom 20 completed. Antibody titers declined in the six months after last injection; booster doses restored IgG levels. The scientists saw no additional treatment-related serious adverse events, but reported a trend toward lower hippocampal atrophy and better performance on some cognitive tests in patients with higher IgG responses (Novak et al., 2018Novak et al., 2019).  

In March 2016, a 24-month Phase 2 safety trial began enrolling 185 patients with mild to moderate AD and an MRI consistent with this diagnosis. Initially, the inclusion criteria included indications of medial temporal lobe atrophy; during the study the criteria were changed to medial temporal lobe atrophy and/or a positive AD biomarker profile of amyloid and tau in CSF. The study lists 30 exclusion criteria. It compared six monthly subcutaneous injections followed by five quarterly boosters of 40 micrograms of vaccine with the adjuvant aluminum hydroxide to placebo. The primary outcome was safety; secondary outcomes included cognitive and clinical batteries as well a measure of immunogenicity. FDG PET, MRI volumetry, and CSF biochemistry were exploratory outcomes. The study was conducted in Austria, Czechia, Germany, Poland, Romania, Slovakia, Slovenia, and Sweden, and was completed in June 2019.

In a September 2019 press release, Axon Neuroscience announced initial results, and presented more details at the 2020 virtual AAT-AD/PD Focus Meeting (Apr 2020 conference news). The company published full results after peer-review (Novak et al., 2021). According to their reports, the treatment was safe and well-tolerated. Injection site reactions and transient confusion were the adverse events seen more often in the treated group compared to placebo. Two people in the active group died, of causes deemed unrelated to the vaccine. Of 196 participants enrolled, 163 completed the trial. More than 95 percent of immunized participants developed tau antibodies specific for the peptide antigen. Antibody was detected in CSF, at concentrations averaging 0.3 percent of serum. The elicited antibodies bound aggregated tau in autopsy brain tissue from AD, progressive supranuclear palsy, corticobasal degeneration, or frontotemporal dementia patients, and impeded neuronal uptake of pathologic tau in cell assays.

In this trial, AADvac-1 reportedly slowed the increase in blood NfL. In vaccinated participants, blood NfL rose 12.6 percent between baseline and two years versus a 27.7 percent rise in the placebo group (p=0.0035). Twenty treated patients and seven on placebo provided CSF. The former had a significant reduction of pTau217, and a trend toward reduction in CSF pTau181 and total tau, compared with placebo. In the trial as a whole, treatment produced no cognitive benefit. A preplanned age subgroup analysis indicated a trend toward slower decline with treatment than placebo on the CDR-SB, MMSE, and ADL among younger participants. In this group, treatment led to greater reductions in plasma NfL than in the group as a whole, and a statistically significant slowing of cortical atrophy. An unplanned post hoc analysis of the subgroup of participants deemed most likely to harbor Aβ and tau pathology found the vaccine slowed decline on the CDR-SB and the ADCS-MCI-ADL. In a post hoc substudy of diffusion tensor MRI in 20 people, white-matter integrity was preserved with treatment compared with control.

Later, one-third of participants in ADAMANT were found to be negative for tau biomarkers. A post hoc analysis of 119 participants predicted to be amyloid- and tau-positive—by way of using a machine learning model or CSF biomarkers—found slowing of the CDR-SB and ADCS-MCI-ADL in the treated group compared to placebo. Higher antibody titers correlated with clinical response and slowing of brain atrophy (Cullen et al., 2023). Another subgroup analysis, presented at the 2023 CTAD conference, included 136 participants judged to be amyloid-positive based on MRI or on pTau217 measured retrospectively in stored baseline blood samples. This analysis found a slowing of decline on the CDR-SB in treated patients at several time points, reductions in plasma NfL and GFAP, and slowing of brain atrophy. All these changes were more pronounced in those with higher antibody titers. The company said it is planning a larger Phase 2b study of the vaccine.

In July 2017, Axon Neuroscience started a two-year, open-label Phase 1 pilot trial of two doses of AADvac1 in 33 people with nonfluent/agrammatic variant primary progressive aphasia (PPA) between the ages of 18 and 85. Participants receive either 40 or 160 micrograms of AADvac1 in a series of six subcutaneous injections spaced six weeks apart, followed by five booster shots spaced 13 weeks apart. Primary outcomes include adverse events and measures of immunogenicity such as anti-AADvac1 antibody titer and subclass. Secondary outcomes include change in CSF biomarkers such as neurogranin, phosphorylated neurofilament heavy chain protein, ubiquitin, tau, phospho-tau pT181, N-terminal tau, amyloid β1-40, amyloid-β1-42, α-, β-, and γ-synuclein, YKL-40, MCP-1; change in serum biomarkers such as neurofilament light; MRI, as well as a range of clinical measures including the Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR-SB) and others. The trial was to run at three sites in Germany until November 2020.

For details on AADvac1 trials, see

Clinical Trial Timeline

  • Phase 1
  • Phase 2
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034
Axon Neuroscience SE NCT01850238
Axon Neuroscience SE NCT02031198
Axon Neuroscience SE NCT02579252

Last Updated: 20 Dec 2023


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News Citations

  1. Active Tau Vaccine: Hints of Slowing Neurodegeneration
  2. Truncated Tau Triggers Tangles, Transmits Pathology
  3. Therapies Take Aim at Tau

Paper Citations

  1. . Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017 Feb;16(2):123-134. Epub 2016 Dec 10 PubMed.
  2. . FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease. Alzheimers Res Ther. 2018 Oct 24;10(1):108. PubMed.
  3. . AADvac1, an Active Immunotherapy for Alzheimer's Disease and Non Alzheimer Tauopathies: An Overview of Preclinical and Clinical Development. J Prev Alzheimers Dis. 2019;6(1):63-69. PubMed.
  4. . ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nat Aging. 1, 2021, pp521-34. Nat Aging.
  5. . N-terminal truncation of microtubule associated protein tau dysregulates its cellular localization. J Alzheimers Dis. 2015;43(3):915-26. PubMed.
  6. . 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. Alzheimers Res Ther. 2014;6(4):44. Epub 2014 Aug 1 PubMed.
  7. . Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer's disease. Alzheimers Res Ther. 2014;6(4):45. Epub 2014 Aug 1 PubMed.
  8. . Therapeutic antibody targeting microtubule-binding domain prevents neuronal internalization of extracellular tau via masking neuron surface proteoglycans. Acta Neuropathol Commun. 2019 Aug 7;7(1):129. PubMed.
  9. . Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation. Acta Neuropathol Commun. 2020 May 29;8(1):74. PubMed.

External Citations

  1. Phase 1 trial
  2. press release
  3. Cullen et al., 2023

Further Reading


  1. . Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways. J Neuroinflammation. 2012;9:47. PubMed.
  2. . The self-perpetuating tau truncation circle. Biochem Soc Trans. 2012 Aug;40(4):681-6. PubMed.
  3. . Misfolded truncated protein τ induces innate immune response via MAPK pathway. J Immunol. 2011 Sep 1;187(5):2732-9. PubMed.
  4. . Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in Alzheimer's disease. Curr Alzheimer Res. 2010 Dec;7(8):708-16. PubMed.
  5. . Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation. Acta Neuropathol Commun. 2020 May 29;8(1):74. PubMed.