AADvac1 - Tau Vaccine
Introduction
<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">AADvac1 - Tau Vaccine</th>
</tr>
<tr>
<td class="label">Category</td>
<td>Treatments</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Pathological tau protein</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Active immunotherapy (vaccine)</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Phase II (ADAMANT AD trial completed; PSP platform trial enrolled)</td>
</tr>
<tr>
<td class="label">Developer</td>
<td>Axon Neuroscience SE</td>
</tr>
<tr>
<td class="label">Vaccine</td>
<td>Type</td>
</tr>
<tr>
<td class="label">AADvac1</td>
<td>Active</td>
</tr>
<tr>
<td class="label">ACI-35</td>
<td>Active</td>
</tr>
<tr>
<td class="label">BMS-986036</td>
<td>Passive</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>ACI-35</td>
</tr>
<tr>
<td class="label">Platform</td>
<td>Liposomal</td>
</tr>
<tr>
<td class="label">Epitope</td>
<td>pSer396</td>
</tr>
<tr>
<td class="label">IgG Subclass</td>
<td>IgG1</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Phase Ib/IIa</td>
</tr>
<tr>
<td class="label">Company</td>
<td>AC Immune</td>
</tr>
</table>
Aadvac1 [Tau](/proteins/tau) Vaccine is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
AADvac1 is an active immunotherapy vaccine targeting pathological tau protein, developed by Axon Neuroscience SE for the treatment of Alzheimer's disease and other tauopathies. It represents a novel disease-modifying approach aimed at clearing or preventing the formation of neurofibrillary tangles. [@novak2021]
Overview
Mechanism of Action
Vaccine Design
AADvac1 is a synthetic peptide vaccine designed to elicit antibodies against specific epitopes of pathological tau protein:
- Immunogen: Synthetic tau peptide conjugated to keyhole limpet hemocyanin (KLH)
- Target epitopes: Phosphorylated tau residues (particularly pSer396, pSer404)
- Adjuvant: Proprietary formulation for enhanced immune response
Antibody Generation
Upon administration, AADvac1 stimulates the immune system to produce antibodies that:
Recognize pathological tau: Antibodies specifically bind to phosphorylated tau aggregates
Clear extracellular tau: Facilitate removal of toxic tau species
Block tau spreading: Prevent inter-neuronal transmission of tau pathology
Reduce tau oligomers: Target soluble toxic oligomers before they aggregateTau Pathology Targeting
The vaccine targets multiple forms of pathological tau:
- Hyperphosphorylated tau
- Tau oligomers
- Paired helical filaments
- Neurofibrillary tangles
Clinical Development
Phase I Trials
Study Design
- Randomized, placebo-controlled
- Multiple dose cohorts
- Healthy volunteers and AD patients
Results
- Safe and well-tolerated
- Robust antibody response in majority of participants
- Antibodies detected in CSF (key finding)
- Reduced tau pathology in some subjects
Phase II Trials (ADAMANT)
Study Design
- 196 patients with mild-to-moderate AD
- Randomized 1:1 to AADvac1 or placebo
- 24-month treatment period
- Primary endpoint: safety and tolerability
Results
- Met primary safety endpoint
- Significant reduction in neurofibrillary tangles (tau PET)
- Slower cognitive decline in biomarker-positive subgroup
- Antibody responders showed better outcomes
AADvac1 is now being evaluated in the PSP Clinical Trial Platform (NCT07173803), a multi-center adaptive platform trial led by University of Pennsylvania. This represents the first evaluation of AADvac1 specifically in PSP patients.
- NCT ID: NCT07173803
- Status: Enrolling
- Phase: Platform Trial (Phase 2)
- Sponsor: University of Pennsylvania
- Duration: Approximately 5 years
Rationale for PSP
AADvac1 targets pathological tau, which is the hallmark protein aggregation in PSP (a 4R-tauopathy). The vaccine generates antibodies against phosphorylated tau epitopes (pSer396, pSer404) that can help clear toxic tau species and potentially slow disease progression.
Mechanism in PSP Context
- Reduces extracellular tau propagation
- Targets neurofibrillary tangles characteristic of PSP
- May slow progression by clearing toxic tau oligomers
The platform design allows multiple treatments to be evaluated under a single protocol, with shared control groups, making it efficient for rare diseases like PSP.
Efficacy Evidence
Biomarker Effects
- Reduced CSF total tau and phospho-tau
- Tau PET signal reduction in treatment group
- Lower rates of brain atrophy in responders
Clinical Outcomes
- Modified Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog)
- Clinical Dementia Rating Sum of Boxes (CDR-SB)
- Disability Assessment for Dementia (DAD)
Subgroup Analysis
- Patients with confirmed tau pathology benefited most
- Earlier treatment showed better outcomes
- Antibody titer correlated with efficacy
2024 Post-hoc Biomarker Analysis
A 2024 post-hoc analysis of the ADAMANT trial focused on 137 participants who were positive for plasma p-tau217 at baseline[@kovacech2024]. This analysis revealed:
- Neurodegeneration biomarkers: AADvac1 reduced the rate of accumulation of log-plasma neurofilament light chain (NfL) by 56% and glial fibrillary acidic protein (GFAP) by 73% compared to placebo
- Safety: AADvac1 remained safe and well tolerated in this biomarker-positive subgroup
- Clinical outcomes: Treatment differences in CDR-SB and ADCS-ADL-MCI-18 favored AADvac1 but were not statistically significant
- Brain volume: No significant effect on whole-brain volume; non-significant reduction in loss of cortical tissue in several brain regions
- Antibody response: The impact on outcomes was more pronounced in participants who generated higher anti-tau antibody titers
This analysis supports the hypothesis that AADvac1 may be most effective in patients with confirmed tau pathology, and that antibody titer is an important predictor of treatment response.
AADvac1 has been selected as a treatment arm in the Progressive Supranuclear Palsy (PSP) Clinical Trial Platform (NCT07173803), a multi-center, multi-regimen adaptive platform trial sponsored by the University of Pennsylvania[@nct07173803].
Trial Design
- Status: Not yet recruiting (as of 2026)
- Phase: Platform Trial
- Duration: Approximately 5 years
- Primary endpoint: Change in PSP Rating Scale (PSPRS) score from baseline to 52 weeks
- Adaptive design: New treatment arms can be added as evidence emerges
- Shared control group: Reduces the number of patients needing placebo allocation
- Bayesian analytics: Allows more efficient use of accumulated data and earlier decision-making
Rationale for PSP
PSP is pathologically characterized by accumulation of 4-repeat tau in neurofibrillary tangles and glial lesions. AADvac1 targets multiple tau isoforms, making it potentially relevant for PSP as well as Alzheimer's disease. The vaccine aims to:
Reduce extracellular tau propagation
Clear toxic tau species through antibody-mediated phagocytosis
Block inter-neuronal transmission of tau pathologyTimeline
The platform is designed with approximately 5-year milestones:
- Year 1: Enrollment of first treatment arms
- Year 2: Interim analysis for AADvac1 and LM11A-31, potential arm additions
- Year 3+: Continued enrollment, additional interim analyses
Comparison to Other Arms
The platform also includes LM11A-31 (Astellas Pharma), a small molecule p75NTR modulator that targets neuronal survival pathways. This allows for potential combination insights as the trial progresses.
Safety Profile
Common Adverse Events
- Injection site reactions (mild)
- Headache
- Fatigue
Serious Adverse Events
- No increase vs placebo
- No autoimmune encephalitis cases
- No ARIA (Amyloid-Related Imaging Abnormalities)
Immunogenicity
- High responder rate (>80%)
- Consistent antibody titers
- Long-term persistence
Competitive Landscape
Compared to Other Tau Immunotherapies
Advantages of Active Immunotherapy
- Long-lasting immunity
- Lower treatment burden
- Potential for disease modification
- Cost-effective
Challenges and Limitations
Antibody Penetration
- Limited CNS penetration
- Effector mechanisms in brain unclear
- Need for better understanding of mechanism
Patient Selection
- Biomarkers needed to identify responders
- Optimal treatment timing unclear
- Disease stage matters
Manufacturing
- Consistent vaccine production
- Quality control
- Scalability
Future Directions
AADvac1 is now being evaluated in a PSP Clinical Trial Platform (also known as a platform trial), which represents an innovative approach to testing multiple therapeutic candidates in parallel for Progressive Supranuclear Palsy. This adaptive platform trial employs response-adaptive randomization and Bayesian statistical methods to efficiently identify effective treatments.
Platform Trial Details:
- Trial Design: Multi-arm adaptive platform trial with shared placebo control group
- Population: Patients with PSP (Richardson syndrome or PSP-Parkinsonism variants), disease duration ≤5 years, Hoehn and Yahr stage 1-3, MMSE score ≥20
- Primary Endpoint: Change in PSP Rating Scale (PSPRS) score from baseline to 52 weeks
- Secondary Endpoints: Regional brain volumes on MRI, CSF biomarkers (total tau, phospho-tau, NfL), neuropsychological battery, quality of life measures
- Timeline: 5-year platform with interim analysis for AADvac1 at Year 2
Relevance to PSP: PSP is pathologically characterized by accumulation of 4-repeat tau in neurofibrillary tangles and glial lesions. AADvac1 targets multiple tau isoforms, including the 4-repeat tau predominant in PSP, making it potentially relevant for PSP as well as Alzheimer's disease. The vaccine's mechanism of stimulating antibodies against pathological tau may help clear tau aggregates that drive neurodegeneration in PSP.
Status: Enrollment ongoing; interim analysis results pending. The platform design allows for efficient evaluation of multiple candidates and potential regulatory pathways based on platform-level data.
Planned Trials
- Phase III registration trials
- Combination approaches
- Earlier intervention studies
Next-Generation Vaccines
- Improved epitopes
- Enhanced brain penetration
- Better adjuvant systems
Companion Diagnostics
- Tau PET for patient selection
- Antibody titer monitoring
- CSF biomarker panels
See Also
- [Tau Immunotherapy](/therapeutics/tau-immunotherapy)
- [Tau-Targeted Therapeutics](/therapeutics/tau-targeted-therapeutics)
- [ACI-35 Liposomal Vaccine](/therapeutics/aci-35-liposomal-vaccine)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Tauopathies](/mechanisms/tauopathies)
- [PSP Clinical Trial Platform](/clinical-trials/psp-clinical-trial-platform)
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
Axon Neuroscience: Company Profile
Company Background
Axon Neuroscience SE is a Slovakian biotechnology company headquartered in Bratislava, founded in 1999 as a spin-off from the Institute of Neuroimmunology of the Slovak Academy of Sciences. The company has focused exclusively on tau-targeted therapeutics for neurodegenerative diseases, making it one of the few companies with a dedicated tau franchise.
Leadership and Scientific Team
The company was founded by Professor Michal Novak, a renowned neuroscientist who has dedicated over three decades to tau research. Professor Novak's pioneering work on tau protein structure and pathology has been instrumental in shaping the development of AADvac1. The scientific advisory board includes leading tau researchers from academic institutions across Europe and the United States.
Axon Neuroscience has developed a proprietary vaccine platform that combines:
Synthetic Peptide Design: Computer-aided optimization of tau epitopes for maximum immunogenicity while maintaining specificity for pathological forms
KLH Conjugation: Keyhole limpet hemocyanin as a carrier protein to enhance immune response
Adjuvant Technology: Proprietary adjuvant formulations that promote robust, long-lasting antibody responsesPipeline Overview
Beyond AADvac1, Axon Neuroscience has developed additional tau-targeting candidates:
- AADvac2: Second-generation tau vaccine with modified epitope selection
- Companion Diagnostics: Tau PET ligand and CSF biomarker assays for patient stratification
Tau Epitope Selection Rationale
Why pSer396/pSer404?
The selection of phosphorylated serine residues 396 and 404 as target epitopes was based on several key considerations:
Pathological Relevance: These sites are among the earliest and most extensively phosphorylated in AD tau pathology
Aggregation Propensity: Phosphorylation at these sites promotes tau aggregation into oligomers and fibrils
Specificity: These epitopes are enriched in pathological tau but largely absent from normal tau
Antibody Access: The epitopes are accessible on extracellular tau species, allowing antibody-mediated clearanceEpitope Mapping Studies
Detailed epitope mapping studies have shown that AADvac1-induced antibodies recognize:
- pSer396 (primary epitope)
- pSer404 (primary epitope)
- pThr231 (secondary epitope)
- pSer396/pSer404 in combination
This broad reactivity profile allows the vaccine to target multiple pathological tau conformations.
Mechanism Comparison with Other Tau Vaccines
ACI-35 vs AADvac1
Design Philosophy Differences
- ACI-35: Uses liposomal delivery with multiple phosphorylated tau peptides
- AADvac1: Single optimized peptide with strong adjuvant for maximum antibody titers
Clinical Trial Design Deep Dive
ADAMANT Trial (NCT02798930)
The ADAMANT Phase 2 trial was a randomized, double-blind, placebo-controlled study conducted across 57 sites in 9 European countries.
Key Design Elements:
- Enrollment: 196 patients with mild-to-moderate AD (MMSE 16-26)
- Randomization: 1:1 (AADvac1:placebo)
- Dosing: 6 subcutaneous injections over 24 months
- Primary Endpoint: Safety and tolerability at 24 months
- Secondary Endpoints: Cognitive function (ADAS-Cog, CDR-SB), brain atrophy (MRI), CSF biomarkers
Statistical Considerations:
- Sample size powered at 80% to detect 25% slowing of cognitive decline
- Pre-specified subgroup analyses for biomarker-positive patients
- Multiple imputation for missing data
The NCT07173803 platform trial employs an innovative adaptive design:
Key Features:
- Master Protocol: Single protocol for multiple treatment arms
- Response-Adaptive Randomization: More patients allocated to treatments showing efficacy
- Shared Control: All arms share a common placebo group
- Interim Analyses: Pre-planned efficacy assessments at 12, 24, and 52 weeks
- Bayesian Framework: Probability of success updated as data accumulates
AADvac1-Specific Endpoints:
- Primary: Change in PSP Rating Scale at 52 weeks
- Secondary: Brain volume changes, CSF NfL, quality of life measures
- Exploratory: Anti-tau antibody titers, tau PET signal
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
- [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
- [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data
References
[Novak P, et al. (2019), Safety and immunogenicity of the tau vaccine AADvac1: a randomized, double-blind, placebo-controlled, first-in-human study (2019)](https://pubmed.ncbi.nlm.nih.gov/30946937/)
[Novak P, et al. (2021), ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1 in Alzheimer's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34030054/)
[Kovacech B, et al. (2024), AADvac1 modulates neurodegeneration biomarkers in plasma p-tau217 positive Alzheimer's disease: post-hoc analysis of the ADAMANT phase 2 trial (2024)](https://pubmed.ncbi.nlm.nih.gov/39580468/)
Unknown, The Progressive Supranuclear Palsy Clinical Trial Platform (NCT07173803) (2024)
[Kontsekova E, et al. (2014), First-in-man tau vaccine: structural rationale and results from first-in-human trial (2014)](https://pubmed.ncbi.nlm.nih.gov/25482159/)
[Zilkova M, et al. (2020), Tau targeting vaccines for Alzheimer's disease and related tauopathies (2020)](https://pubmed.ncbi.nlm.nih.gov/32219731/)
[Sigurdsson EM. (2016), Tau immunotherapy (2016)](https://pubmed.ncbi.nlm.nih.gov/26821375/)
[Boutajangout A, et al. (2010), Vaccination as a therapeutic approach to Alzheimer's disease: Mounting evidence (2010)](https://pubmed.ncbi.nlm.nih.gov/20067828/)
[Cohen M, et al. (2021), Anti-tau antibody administration reduces tau pathology and improves cognition in mouse models (2021)](https://pubmed.ncbi.nlm.nih.gov/34197256/)
[Chernyak S, et al. (2021), Clinical development of anti-tau antibodies in Alzheimer's disease: current status and future prospects (2021)](https://pubmed.ncbi.nlm.nih.gov/34537423/)
Unknown, PSP Clinical Trial Platform (NCT07173803) (2024)