<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">ACI-35 Liposomal Vaccine</th>
</tr>
<tr>
<td class="label">Candidate</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">ACI-35</td>
<td>Active vaccine (pSer396/404)</td>
</tr>
<tr>
<td class="label">ACI-35.030</td>
<td>Enhanced formulation</td>
</tr>
<tr>
<td class="label">Anti-tau antibodies</td>
<td>Passive immunization</td>
</tr>
<tr>
<td class="label">Aspect</td>
<td>Advantages</td>
</tr>
<tr>
<td class="label">Dosing</td>
<td>Infrequent (monthly to yearly)</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>Long-lasting immunity</td>
</tr>
<tr>
<td class="label">Cost</td>
<td>Lower long-term cost</td>
</tr>
<tr>
<td class="label">Flexibility</td>
<td>Memory responses</td>
</tr>
<tr>
<td class="label">Aspect</td>
<td>Advantages</td>
</tr>
<tr>
<td class="label">Dosing</td>
<td>Immediate effect</td>
</tr>
<tr>
<td class="label">Consistency</td>
<td>Defined dosing</td>
</tr>
<tr>
<td class="label">Safety</td>
<td>Reversible</td>
</tr>
</table>
<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">ACI-35 Liposomal Vaccine</th>
</tr>
<tr>
<td class="label">Candidate</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">ACI-35</td>
<td>Active vaccine (pSer396/404)</td>
</tr>
<tr>
<td class="label">ACI-35.030</td>
<td>Enhanced formulation</td>
</tr>
<tr>
<td class="label">Anti-tau antibodies</td>
<td>Passive immunization</td>
</tr>
<tr>
<td class="label">Aspect</td>
<td>Advantages</td>
</tr>
<tr>
<td class="label">Dosing</td>
<td>Infrequent (monthly to yearly)</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>Long-lasting immunity</td>
</tr>
<tr>
<td class="label">Cost</td>
<td>Lower long-term cost</td>
</tr>
<tr>
<td class="label">Flexibility</td>
<td>Memory responses</td>
</tr>
<tr>
<td class="label">Aspect</td>
<td>Advantages</td>
</tr>
<tr>
<td class="label">Dosing</td>
<td>Immediate effect</td>
</tr>
<tr>
<td class="label">Consistency</td>
<td>Defined dosing</td>
</tr>
<tr>
<td class="label">Safety</td>
<td>Reversible</td>
</tr>
</table>
ACI-35 is a liposome-based therapeutic vaccine targeting phosphorylated tau proteins, developed by [AC Immune](/companies/ac-immune) SA in collaboration with [Janssen](/companies/janssen) Pharmaceuticals. It represents one of the most advanced active immunization strategies for Alzheimer's disease (AD) and other tauopathies, including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and frontotemporal dementia (FTD) [1]. Unlike passive antibody therapies that require repeated infusions, ACI-35 stimulates the patient's own immune system to generate anti-tau antibodies, potentially providing sustained protection with periodic booster vaccinations. [@immune2023]
The vaccine targets phosphorylated tau at the Ser396/404 epitope, which is a key pathological modification found in neurofibrillary tangles (NFTs) in AD and related tauopathies. By generating antibodies against these pathological tau species, ACI-35 aims to slow or halt the progression of tau-driven neurodegeneration. This page provides a comprehensive overview of ACI-35's mechanism of action, clinical development, comparison to other tau immunotherapies, and future directions [2]. [@pulanco2022]
[Tau](/proteins/tau) protein is a microtubule-associated protein that stabilizes neuronal axons under normal conditions. In AD and other tauopathies, tau becomes hyperphosphorylated, aggregates into neurofibrillary tangles, and propagates throughout the brain in a pattern that correlates with clinical decline. The phosphorylation at serine 396 and serine 404 (pSer396/pSer404) is particularly relevant because: (1) these sites are among the earliest and most extensively modified in AD; (2) antibodies against pSer396/404 preferentially recognize pathological tau over normal tau; and (3) this epitope is accessible for antibody binding in both extracellular tangles and intracellular tau aggregates [3]. [@schindowski2006]
The rationale for targeting phosphorylated tau rather than total tau stems from the need to selectively eliminate pathological species while sparing normal tau function. Total tau antibodies risk disrupting physiological tau's role in microtubule stabilization and axonal transport, potentially causing unintended adverse effects [4]. [@yu2021]
ACI-35 employs a sophisticated liposome-based delivery system that offers several advantages over traditional peptide vaccines. Liposomes are spherical vesicles composed of phospholipid bilayers that can encapsulate hydrophilic and hydrophobic compounds. In ACI-35, the phosphorylated tau peptide antigens are displayed on the liposome surface, presenting them to the immune system in a format that stimulates robust antibody responses while minimizing risks associated with direct peptide administration [5]. [@watkins2020]
The liposome platform provides: (1) Safety - Liposomes are biodegradable and non-toxic, reducing the risk of adverse immune reactions; (2) Immunogenicity - The multivalent display of antigens on liposome surfaces enhances B-cell activation compared to soluble peptides; (3) Stability - Liposomes protect the peptide antigens from degradation; and (4) Customizability - Liposome composition can be optimized for desired immune responses [6]. [@crispin2021]
The vaccine includes monophosphoryl lipid A (MPL), a detoxified derivative of bacterial lipopolysaccharide that acts as a toll-like receptor 4 (TLR4) agonist. MPL provides the danger signals necessary to activate innate immunity and drive robust adaptive immune responses. By engaging [TLR4](/entities/tlr4) on dendritic cells and other antigen-presenting cells, MPL enhances antigen presentation, T-cell help, and ultimately antibody production against the tau peptide antigens [7]. [@mpl2019]
Following vaccination, anti-phospho-tau antibodies circulate in the bloodstream and can enter the central nervous system through mechanisms including: (1) antibody binding to peripheral tau that crosses the [blood-brain barrier](/entities/blood-brain-barrier); (2) antibody uptake by peripheral macrophages that traffic to the brain; and (3) potentially, direct antibody entry through Fc receptor-mediated transport by endothelial cells [8]. [@barducci2022]
Once in the brain, anti-tau antibodies can: (1) Bind extracellular tau - Antibodies recognize and bind to phosphorylated tau released from [neurons](/entities/neurons), preventing its uptake by other neurons and propagation; (2) Opsonize tau aggregates - Antibody-coated tau species become targets for microglial phagocytosis through Fc receptor-mediated recognition; (3) Block templated seeding - Antibodies may prevent pathological tau from acting as seeds that template the aggregation of endogenous tau [9]. [@liu2020]
The first-in-human study of ACI-35 enrolled patients with mild-to-moderate AD (MMSE 16-28) in a randomized, placebo-controlled design. The trial tested multiple dose levels to establish safety, tolerability, and immunogenicity. Key findings included [10]: [@aci2021]
Safety and tolerability: ACI-35 demonstrated a favorable safety profile with no serious adverse events attributable to the vaccine. The most common adverse events were mild-to-moderate injection site reactions, consistent with other therapeutic vaccines. Importantly, no cases of meningoencephalitis or other serious inflammatory CNS events were observed, which had been a concern with earlier active immunization approaches [11]. [@aci2021a]
Immunogenicity: Over 90% of participants who received ACI-35 generated robust anti-phospho-tau antibody responses. Antibody titers were dose-dependent, with higher doses producing greater responses. The antibody responses were sustained over the study duration, with evidence of memory B-cell responses suggesting long-term immunity could be achieved with booster vaccinations [12]. [@aci2021b]
Target engagement: Antibodies generated by ACI-35 showed high specificity for phosphorylated tau peptides at the Ser396/404 epitope, with minimal binding to non-phosphorylated tau. Importantly, antibodies were detected in the cerebrospinal fluid (CSF) of vaccinated subjects, demonstrating that the immune response could reach the target organ [13]. [@aci2022]
Biomarker effects: Exploratory biomarker analyses showed trends toward reduced CSF tau levels in vaccinated subjects, suggesting target engagement and potential disease-modifying effects. These findings require validation in larger trials [14]. [@aci2022a]
Based on the encouraging Phase 1b results, ACI-35 has advanced to Phase 2 clinical testing. The Phase 2 program is evaluating: (1) Multiple dose regimens to optimize antibody titers; (2) Clinical efficacy endpoints in larger patient populations; (3) Biomarker correlations to understand mechanisms; (4) Expansion to additional tauopathies beyond AD [15]. [@aci2023]
ACI-35 is one of several tau-targeting immunotherapies in development: [@aadvac2022]
AADvac1 (Axon Neuroscience) targets tau phosphorylated at threonine 231 (pThr231). This vaccine has completed Phase 2 trials showing safety and immunogenicity, with trends toward slower cognitive decline in antibody responders. The different target epitope (pThr231 vs pSer396/404) means the two vaccines could potentially be complementary [16]. [@semorinemab2022]
Semorinemab (Genentech/Roche) is a passive antibody therapy targeting tau's mid-region. Phase 2 trials showed mixed results, with some biomarker changes but no significant cognitive benefit in the overall population [17]. [@tilavonemab2023]
Tilavonemab (AbbVie) targets N-terminal tau and failed to meet efficacy endpoints in Phase 2, highlighting the challenges of tau immunotherapy [18]. [@biib2022]
BIIB080 (Biogen/Ionis) is an antisense oligonucleotide (ASO) that reduces tau production at the RNA level, offering an alternative approach to antibody-mediated tau clearance [19]. [@phosphotau2020]
The pSer396/404 targeting provides selectivity for pathological tau species. This specificity may improve the therapeutic window by avoiding interference with normal tau function while maximizing effects on disease-relevant targets [20]. [@liposome2021]
The liposome delivery system offers advantages including: (1) Enhanced immunogenicity reducing the need for frequent boosters; (2) Improved safety through reduced reactogenicity; (3) Flexibility to display different antigen configurations; and (4) Established manufacturing scalability [21]. [@tauopathies2022]
While initially developed for AD, ACI-35's mechanism is relevant to any tauopathy characterized by pSer396/404 tau pathology, including PSP, CBS, and certain FTD subtypes. This broad applicability could enable expansion to multiple indications [22]. [@active2021]
Active immunization produces memory immune responses that can be boosted periodically, potentially providing sustained therapeutic benefit without the need for monthly infusions required by passive antibody therapies [23]. [@vaccine2020]
Not all patients respond equally to vaccination. Factors influencing antibody responses include age-related immune decline, genetic factors, and baseline immune status. Strategies to enhance response rates are needed [24]. [@cns2021]
Achieving adequate antibody concentrations in the CNS remains challenging. While CSF antibodies were detected in Phase 1, the relationship between peripheral antibody levels and CNS efficacy requires further investigation [25]. [@epitope2019]
长期 vaccination could potentially induce antibodies against additional tau epitopes through epitope spreading, which could enhance or potentially complicate therapeutic effects [26]. [@clinical2022]
Phase 1 trials were not designed to demonstrate clinical efficacy. Larger trials with adequate statistical power are needed to determine whether ACI-35 can slow cognitive decline in AD and other tauopathies [27]. [@combination2023]
Combination approaches: Combining ACI-35 with other disease-modifying therapies targeting amyloid (e.g., [lecanemab](/entities/lecanemab), donanemab) or other mechanisms could provide complementary benefits [28]. [@companion2022]
Biomarker development: Developing companion diagnostics to identify patients most likely to respond and to monitor treatment effects will be important for personalized medicine approaches [29]. [@psp2021]
Expanded indications: Initial focus on AD may be followed by trials in PSP, CBS, and other tauopathies where tau pathology is more diffuse and antibody penetration may be more relevant [30]. [@nextgen2023]
Next-generation formulations: Improved liposome compositions and adjuvant systems may further enhance immunogenicity and reduce variability in antibody responses [31].
AC Immune SA is a Swiss biotechnology company headquartered in Lausanne, founded in 2003 as a spin-off from the École Polytechnique Fédérale de Lausanne (EPFL). The company specializes in neurodegenerative disease therapeutics, with a particular focus on Alzheimer's disease and tauopathies. AC Immune has developed a proprietary technology platform for creating misfolded protein-targeting biologics, including antibodies, vaccines, and small molecules.
The company is led by Dr. Andrea Pfeifer, Chief Executive Officer, who has been instrumental in steering the company's pipeline development. The scientific team includes world-renowned experts in protein misfolding, amyloid biology, and neuroimmunology. AC Immune's academic founders and collaborators include leading researchers from Swiss and international institutions.
AC Immune's core technology platform centers on:
AC Immune has established key collaborations to advance its pipeline:
ACI-35 liposomes are composed of:
The liposome manufacturing process involves:
Critical quality attributes include:
The Phase 1b trial was a randomized, double-blind, placebo-controlled, dose-escalation study conducted at multiple sites in the United States and Europe.
Key Design Elements:
Primary Endpoints:
The Phase 1b trial demonstrated a favorable safety profile:
Antibody Response Rates:
ACI-35 represents a middle ground:
The pSer396/404 epitope was selected based on:
The synthetic peptide antigen includes:
ACI-35 has received regulatory support for accelerated development:
The development pathway includes:
Regulatory agencies require:
AC Immune maintains collaborations with:
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