AADvac1 - Tau Vaccine

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AADvac1 - Tau Vaccine

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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 - 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 aggregate

Tau 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

PSP Platform Trial (NCT07173803)

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.

Platform Trial Details

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.

PSP Clinical Trial Platform

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

Platform Features

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 pathology

Timeline

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

PSP Platform Trial

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

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.

Platform Technology

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 responses

Pipeline 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 clearance

Epitope 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

PSP Platform Trial Design

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)

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📊 Evidence Profile

Evidence Balance

+0%

Certainty

30%

Debates

0

Incoming

6

Outgoing

5

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

AADvac1 - Tau Vaccine

AADvac1 - Tau Vaccine

Introduction

AADvac1 - Tau Vaccine

Introduction

Overview

Mechanism of Action

Vaccine Design

Antibody Generation

Tau Pathology Targeting

Clinical Development

Phase I Trials

Study Design

Results

Phase II Trials (ADAMANT)

Study Design

Results

PSP Platform Trial (NCT07173803)

Platform Trial Details

Rationale for PSP

Mechanism in PSP Context

Efficacy Evidence

Biomarker Effects

Clinical Outcomes

Subgroup Analysis

2024 Post-hoc Biomarker Analysis

PSP Clinical Trial Platform

Trial Design

Platform Features

Rationale for PSP

Timeline

Comparison to Other Arms

Safety Profile

Common Adverse Events

Serious Adverse Events

Immunogenicity

Competitive Landscape

Compared to Other Tau Immunotherapies

Advantages of Active Immunotherapy

Challenges and Limitations

Antibody Penetration

Patient Selection

Manufacturing

Future Directions

PSP Platform Trial

Planned Trials

Next-Generation Vaccines

Companion Diagnostics

See Also

Axon Neuroscience: Company Profile

Company Background

Leadership and Scientific Team

Platform Technology

Pipeline Overview

Tau Epitope Selection Rationale

Why pSer396/pSer404?

Epitope Mapping Studies

Mechanism Comparison with Other Tau Vaccines

ACI-35 vs AADvac1

Design Philosophy Differences

Clinical Trial Design Deep Dive

ADAMANT Trial (NCT02798930)

PSP Platform Trial Design

External Links

References

💬 Discussion