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Efficacy and Safety of A Liposome-Based Vaccine against Protein Tau, Assessed in Tau.P301L Mice That Model Tauopathy
Open accessAbstract
Progressive aggregation of protein Tau into oligomers and fibrils correlates with cognitive decline and synaptic dysfunction, leading to neurodegeneration in vulnerable brain regions in Alzheimer's disease. The unmet need of effective therapy for Alzheimer's disease, combined with problematic pharmacological approaches, led the field to explore immunotherapy, first against amyloid peptides and recently against protein Tau. Here we adapted the liposome-based amyloid vaccine that proved safe and efficacious, and incorporated a synthetic phosphorylated peptide to mimic the important phospho-epitope of protein Tau at residues pS396/pS404. We demonstrate that the liposome-based vaccine elicited, rapidly and robustly, specific antisera in wild-type mice and in Tau.P301L mice. Long-term vaccination proved to be safe, because it improved the clinical condition and reduced indices of tauopathy in the brain of the Tau.P301L mice, while no signs of neuro-inflammation or other adverse neurological effects were observed. The data corroborate the hypothesis that liposomes carrying phosphorylated peptides of protein Tau have considerable potential as safe and effective treatment against tauopathies, including Alzheimer's disease.
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“Active tau immunization has been shown to reduce tau pathology by targeting single185, 187, 189–193 or multiple194 phospho-epitopes, the amino terminus195, full-length normal and mutant tau196, 197, or aggregated tau198.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [190]
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“ACI-35, a liposomal vaccine, constituting tau protein fragments with several phosphorylated serine residues decreased soluble tau protein phosphorylation at S396 and induced antibody formation in P301L mice (Theunis et al., 2013).”
BackgroundComparison of Tau and Amyloid-β Targeted Immunotherapy Nanoparticles for Alzheimer’s Disease
Mashal, Y., Abdelhady, H. G., & Iyer, A. K. (2022) · Biomolecules · doi:10.3390/biom12071001 · Cited by 21
“Metallic (gold) poly(amidoamine) (PAMAM) dendrimer nanocomposite (3D-AuPAMAM) 2–100 Antibody (CAb), antibody (HRPDAb) Direct determination of tau [43]”
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Rajanna, S., Gundale, P. P., & Mahadevaiah, A. D. (2025) · Dementia & Neuropsychologia · doi:10.1590/1980-5764-dn-2024-0204 · Cited by 20
“No significant safety signals were reported, but the modest adverse event rate suggests potential for further refinement 56 .”
Davidson, R., Krider, R. I., Borsellino, P., Noorda, K., Alhwayek, G., & Vida, T. A. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45110553 · Cited by 17
“030, is a liposomal (MPLA) vaccine developed to target the amino acids 393–408, with a particular emphasis on pS396 and pS404 [148–150].”
BackgroundRahimi, A., Sameei, P., Mousavi, S., Ghaderi, K., Hassani, A., Hassani, S., & Alipour, S. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04143-2 · Cited by 18
“The antibodies from AADvac1 target the microtubule-binding region of tau, decrease tau aggregation, and promote tau clearance, while the antibodies from ACI 35 decrease phosphorylated tau [63–65].”
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“There are several active vaccines approaches which have obtained a certain effect in clinical trials, such as ACI-35 vaccine which could reduce the hyperphosphorylated pathological Tau (64 kDa) and AADvac1 vaccine which could target misfolded Tau in AD (Kontsekova et al. 2014a; Theunis et al. 2013).”
BackgroundEmerging amyloid and tau targeting treatments for Alzheimer’s disease
Khan, A., Corbett, A., & Ballard, C. G. (2017) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2017.1326819 · Cited by 16
“Preclinical data showed ACI-35 to elicit clinical improvement and exert no adverse outcomes [124].”
BackgroundThe development of biological therapies for neurological diseases: moving on from previous failures
Qosa, H., & Volpe, D. A. (2018) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2018.1437142 · Cited by 15
“Compared to full length tau which caused severe inflammatory reactions, active immunization with tau fragments showed improved safety and efficacy in reducing taupathy in taupathy mouse models [27,28].”
BackgroundRecent Trends in Active and Passive Immunotherapies of Alzheimer’s Disease
Alshamrani, M. (2023) · Antibodies · doi:10.3390/antib12020041 · Cited by 17
“In tau P301L transgenic mice and wildtype mice, ACI-35 evoked fast and robust polyclonal antibody reactions specific to p-tau [134].”
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Dunning, E. E., Decourt, B., Zawia, N. H., Shill, H. A., & Sabbagh, M. N. (2024) · Neurology and Therapy · doi:10.1007/s40120-024-00614-9 · Cited by 20
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Intranasal gene therapy for the treatment of neurological disorders
Dhas, N. L., Mehta, T. A., Sharma, S., Garkal, A., Yadav, D., Hariharan, K., Shamjetshabam, B., Khot, S. V., Kudarha, R. R., Bangar, P., et al. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822522-6.00017-5 · Cited by 13
Role of Tau protein in long COVID and potential therapeutic targets
Marwaha, B. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1280600 · Cited by 11
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Theunis, C., Adolfsson, O., Crespo‐Biel, N., Piorkowska, K., Pihlgren, M., Hickman, D. T., Gafner, V., Borghgraef, P., Devijver, H., Pfeifer, A., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160695 · Cited by 12
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“…brainstem tauopathy causes lethal upper-airway breathing defects that can be mitigated genetically by GSK3b overexpression or pharmacologically by increased O-GlcNAc-ylation (Terwel et al., 2008; Dutschmann et al., 2010; Borghgraef et al., 2013; Theunis et al., 2013; Crespo-Biel et al., 2014).”
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“…2011; Collin et al., 2014; Dai et al., 2015; Ittner et al., 2015; Kontsekova et al., 2014a; Kontsekova et al., 2014b; Sankaranarayanan et al., 2015; Theunis et al., 2013; Umeda https://doi.org/10.1016/j.expneurol.2018.02.004 Received 19 August 2017; Received in revised form 31 January 2018;…”
InfluentialChukwu, J. E., Congdon, E. E., Sigurdsson, E. M., & Kong, X. (2019) · mAbs · doi:10.1080/19420862.2019.1574530 · Cited by 12
Immune modulations and immunotherapies for Alzheimer’s disease: a comprehensive review
Mahdiabadi, S., Momtazmanesh, S., Perry, G. L., & Rezaei, N. (2021) · Reviews in the Neurosciences · doi:10.1515/revneuro-2021-0092 · Cited by 13
Tau immunotherapy in Alzheimer’s disease and progressive supranuclear palsy
Karimi, N., Catak, F. B., Arslan, E. O., Saghazadeh, A., & Rezaei, N. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109445 · Cited by 11
Arévalo-Villalobos, J. I., Rosales‐Mendoza, S., & Zarazúa, S. (2016) · Expert Review of Vaccines · doi:10.1080/14760584.2016.1229602 · Cited by 11
“This vaccine is currently under evaluation in a phase Ib clinical trial [36].”
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Islam, M. R., Rabbi, M. A., Hossain, T., Sultana, S., & Uddin, S. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00360 · Cited by 10
García‐Arriaza, J., Marín, M. Q., Merchán‐Rubira, J., Mascaraque, S. M., Medina, M., Ávila, J., Hernández, F., & Estéban, M. (2020) · Vaccines · doi:10.3390/vaccines8010127 · Cited by 11
Recent Advancements in Strategies for Abnormal Protein Clearance in Alzheimer's Disease
Zhuang, J., Gao, J., Yin, Y., Gong, B., Ji, W., Chen, X., Li, P., Cheng, W., Zhao, Y., & He, B. (2022) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557522666220214092824 · Cited by 10
Targeting tau in Alzheimer’s Disease: rationale, approach and challenges
Aslanyan, A., Foiani, M. S., Giovannucci, T. A., McDade, E., Duff, K., Mummery, C. J., Schöll, M., Wildsmith, K. R., & Paterson, R. W. (2026) · Molecular Neurodegeneration · doi:10.1186/s13024-026-00925-5 · Cited by 10
“Animal models showed reduction in both soluble and insol-uble tau as well as improved clinical parameters such as body weight retention, delayed motor phenotypes and extended lifespan with significant inflammatory response [149, 161].”
Tau and β-Amyloid Relevant Pathology as a Central Therapeutic Target in Alzheimer’s Disease
Strużyńska, L., Adamiak, K., & Sidoryk‐Wȩgrzynowicz, M. (2026) · Biomolecules · doi:10.3390/biom16040595 · Cited by 9
“According to the hypothesis linking the pathogenesis of AD with tau protein, a key element of the neurodegenerative process is tau hyperphosphorylation, which leads to the formation of NFTs [38,39].”
Klaver, A. C., Coffey, M. P., Bennett, D. A., & Loeffler, D. A. (2017) · Translational Neurodegeneration · doi:10.1186/s40035-017-0100-x · Cited by 9
Diverse influences on tau aggregation and implications for disease progressionPreprint
Alstyne, M. V., Pratt, J., & Parker, R. (2025) · Genes & Development · doi:10.1101/gad.352551.124 · Cited by 11
Recent advances in Alzheimer’s disease pathogenesis and therapeutics from an immune perspective
Nguyen, T.-D., Dang, L. N., Jang, J., & Park, S. (2023) · Journal of Pharmaceutical Investigation · doi:10.1007/s40005-023-00631-0 · Cited by 9
“In an animal experiment, this vaccine was found to stimulate the immune system to produce high titers of polyclonal IgG antibodies against tauopathies (Theunis et al. 2013).”
BackgroundGancia, P., & Pomero, G. (2010) · PubMed · Cited by 8
Tau-based therapies for Alzheimer’s disease: Promising novel neuroprotective approaches
Sayas, C. L. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814037-6.00005-7 · Cited by 9
Hsueh, S. C. C., Aina, A., Roman, A. Y., Cashman, N. R., Peng, X., & Plotkin, S. S. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00567 · Cited by 8
Alzheimer’s Disease Pharmacology
Plascencia‐Villa, G., & Perry, G. L. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00018-9 · Cited by 6
The engagement of microglia in tau-targeted immunotherapy in Alzheimer’s disease
Palova, D., Csokova, N. T., Markova, K., Kontseková, E., Kováčech, B., & Žilková, M. (2021) · General Physiology and Biophysics · doi:10.4149/gpb_2021029 · Cited by 6
“In summary, tau-targeting vaccines recognize different tau species and have been suggested to act through various mechanisms: by preventing tau aggregation and cell-to-cell spreading (Theunis et al. 2013; Albayram et al. 2017; Courade et al. 2018; Novak et al. 2018; Albert et al. 2019; Weisova et al. 2019), by facilit…”
BackgroundRoy, R., Bhattacharya, P., & Borah, A. (2022) · Current Drug Metabolism · doi:10.2174/1389200223666220526094802 · Cited by 6
Clinical Biomarkers and Novel Drug Targets to Cut Gordian Knots of Alzheimer's Disease
Mir, R. H., Masoodi, M. H., Shah, A. J., Mohi-ud-din, R., Sabreen, S., Wani, T. U., Jan, R., Javed, M. N., & Mir, P. A. (2022) · Current Molecular Pharmacology · doi:10.2174/1874467215666220903095837 · Cited by 6
Dale Schenk One Year Anniversary: Fighting to Preserve the Memories
Overk, C., & Masliah, E. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-171071 · Cited by 5
“Theresultingantibodies boundpathologicaltauinthebrain[130].”
Future Treatment of Alzheimer Disease
Keskin, A. O., Durmaz, N., Uncu, G., Erzurumluoglu, E., Yıldırım, Z., Tuncer, N., & Adapınar, D. Ö. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.85096 · Cited by 6
“ACI-35 is a synthetic peptide spanning the human protein tau sequence 393–408, phosphorylated at S396 and S404 [72].”
BackgroundResultInfluentialAn update on clinical trials targeting human tauopathies
Moussa, C.-H., Javidnia, M., & Kurd-Misto, B. T. (2017) · Clinical Trials in Degenerative Diseases · doi:10.4103/2542-3975.216580 · Cited by 5
Recent Advancements in the Early Diagnosis and Treatment of Alzheimer's Disease
Wu, Y., Fu, L., Li, Q., Gao, X., Zhang, Y., Jin, C., Ding, F., Hong, S. C., Cai, H., & Li, Y. (2023) · Advanced Therapeutics · doi:10.1002/adtp.202300181 · Cited by 4
Metadata
- Authors
- Theunis, C., Crespo-Biel, N., Gafner, V., Pihlgren, M., López-Deber, M. P., Reis, P., Hickman, D. T., Adolfsson, O., Chuard, N., Ndao, D. M., Borghgraef, P., Devijver, H., Van Leuven, F., Pfeifer, A., & Muhs, A.
- Affiliations
- KU Leuven (BE)
- AC Immune (Switzerland) (CH)
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-08-19
- Volume
- 8
- Issue
- 8
- Pages
- e72301
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3747157
- OpenAlex
- W2090968981
- Cited by
- 259
- References
- 78
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 25 · 2023: 17 · 2022: 22 · 2021: 23 · 2020: 25 · 2019: 23 · 2018: 27 · 2017: 22 · 2016: 19 · 2015: 13 · 2014: 16 · 2013: 1
- FWCI
- 11.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, tau immunotherapy, tauopathy, Alzheimer's disease, vaccine safety, neuroinflammation, tau aggregation
- MeSH terms
- Animals, Brain, Disease Models, Animal, Humans, Liposomes, Mice, Transgenic, Peptides, Phosphoproteins, Phosphorylation, Psychomotor Performance, Vaccination, tau Proteins, Treatment Outcome, Alzheimer Vaccines, Tauopathies, Mice, Antibodies, Neutralizing
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