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Cited by 111Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Safety, tolerability and immunogenicity of an active anti-Aβ40 vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial

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Lacosta, Ana-María, Pascual-Lucas, María, Pesini, Pedro, Casabona, Diego, Pérez-Grijalba, Virginia, Marcos-Campos, Iván, Sarasa, Leticia, Canudas, Jesus, Badi, Hassnae, Monleón, Inmaculada, San-José, Itziar, Munuera, Josep, Rodríguez-Gómez, Octavio, Abdelnour, Carla, Lafuente, Asunción, Buendía, Mar, Boada, Mercè, Tárraga, Lluis, Ruiz, Agustín, Sarasa, Manuel·2018·Alzheimer's Research & Therapy
DOI 10.1186/s13195-018-0340-8PMC PMC5789644
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Abstract

Immunotherapy targeting the amyloid-β (Aβ) peptide is a promising strategy for the treatment of Alzheimer’s disease (AD); however, none of the active or passive vaccines tested have been demonstrated to be effective to date. We have developed the first active vaccine against the C-terminal end of Aβ40, ABvac40, and assessed its safety and tolerability in a phase I clinical trial. A randomised, double-blind, placebo-controlled, parallel-group, phase I study of ABvac40 was conducted with patients aged 50–85 years with mild to moderate AD. Participants were entered into three separate groups according to time of study entry and were randomly allocated to receive ABvac40 or placebo (overall ratio 2:1). The first group received two half-doses of ABvac40 or placebo, whereas the second and third groups received two and three full doses, respectively. All treatments were administered subcutaneously at 4-week intervals. Patients, carers and investigators were blind to treatment allocation throughout the study. The primary objective was to assess the safety and tolerability of ABvac40 by registering all adverse events (AEs). All patients who received at least one dose of treatment were included in the safety analysis. The secondary objective was to evaluate the immunogenicity of ABvac40 by titration of specific anti-Aβ40 antibodies in plasma. Twenty-four patients were randomly allocated: 16 patients to the ABvac40 group and 8 patients to the placebo group. All randomised patients completed the study, therefore the intention-to-treat and safety populations were identical. Overall, 71 AEs affecting 18 patients were recorded: 11 (69%) in the ABvac40 group and 7 (88%) in the placebo group (p = 0.6214). Neither incident vasogenic oedema nor sulcal effusion (amyloid-related imaging abnormalities corresponding to vasogenic oedema and sulcal effusions) nor microhaemorrhages (amyloid-related imaging abnormalities corresponding to microhaemorrhages and hemosiderin deposits) were detected throughout the study period in the ABvac40-treated patients. Eleven of 12 (~92%) individuals receiving three injections of ABvac40 developed specific anti-Aβ40 antibodies. ABvac40 showed a favourable safety and tolerability profile while eliciting a consistent and specific immune response. An ongoing phase II clinical trial is needed to confirm these results and to explore the clinical efficacy of ABvac40. ClinicalTrials.gov, NCT03113812 . Retrospectively registered on 14 April 2017.

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Fig. 1 Study design
Fig. 1 Study designCC BY · PubMed Central
Fig. 2 Trial profile. IP Initial protocol, AP Amended protocol, ITT Intention to treat, PP Per protocol, * Major protocol deviations
Fig. 2 Trial profile. IP Initial protocol, AP Amended protocol, ITT Intention to treat, PP Per protocol, * Major protocol deviationsCC BY · PubMed Central
Fig. 3 Evolution over time of the immune response of initial protocol (IP) and amended protocol (AP) patients (left and right panels, respectively) from baseline to the final visit (a and b) and during the 1-year open-label follow-up (c). The levels of anti-amyloid-β40 (Aβ40) antibodies in plasma are represented as the optical density (OD) in the titration enzyme-linked immunosorbent assays performed in 96-well plates coated with the Aβ1–40 peptide. Pre-adsorption of plasma samples with Aβ33–40 peptide (b) resulted in a reduction of > 91% of the signal compared with non-pre-adsorbed samples (a), suggesting that the signal corresponded to specific anti-Aβ40 antibodies. The levels of specific anti-Aβ40 antibodies remained elevated in AP patients in the ABvac40 group for up to 56 weeks after the last immunisation (c). Data are mean ± SEM
Fig. 3 Evolution over time of the immune response of initial protocol (IP) and amended protocol (AP) patients (left and right panels, respectively) from baseline to the final visit (a and b) and during the 1-year open-label follow-up (c). The levels of anti-amyloid-β40 (Aβ40) antibodies in plasma are represented as the optical density (OD) in the titration enzyme-linked immunosorbent assays performed in 96-well plates coated with the Aβ1–40 peptide. Pre-adsorption of plasma samples with Aβ33–40 peptide (b) resulted in a reduction of > 91% of the signal compared with non-pre-adsorbed samples (a), suggesting that the signal corresponded to specific anti-Aβ40 antibodies. The levels of specific anti-Aβ40 antibodies remained elevated in AP patients in the ABvac40 group for up to 56 weeks after the last immunisation (c). Data are mean ± SEMCC BY · PubMed Central
Fig. 4 Reactivity of ABvac40-induced anti-amyloid-β (anti-Aβ) antibodies: a Post-immune plasma samples (week 10) from an ABvac40-treated patient (S013) recognised different forms of synthetic Aβ40 peptide (lane 1). In contrast, they did not label any form of synthetic Aβ42 (lane 2). Pre-immune plasma (week 0) did not show reactivity with Aβ40 or Aβ42. b and c Binding of plasma samples from the same patient (S013; week 10) to amyloid plaques in paraffin-embedded brain sections from APP/PS1-transgenic mice (b) and patients with AD (c). Pre-adsorption of plasma with Aβ33–40 peptide prevented plaque staining. Specific anti-Aβ40 polyclonal antibody was used as a positive control. Scale bar = 100 μm
Fig. 4 Reactivity of ABvac40-induced anti-amyloid-β (anti-Aβ) antibodies: a Post-immune plasma samples (week 10) from an ABvac40-treated patient (S013) recognised different forms of synthetic Aβ40 peptide (lane 1). In contrast, they did not label any form of synthetic Aβ42 (lane 2). Pre-immune plasma (week 0) did not show reactivity with Aβ40 or Aβ42. b and c Binding of plasma samples from the same patient (S013; week 10) to amyloid plaques in paraffin-embedded brain sections from APP/PS1-transgenic mice (b) and patients with AD (c). Pre-adsorption of plasma with Aβ33–40 peptide prevented plaque staining. Specific anti-Aβ40 polyclonal antibody was used as a positive control. Scale bar = 100 μmCC BY · PubMed Central

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Authors
Lacosta, A.-M., Pascual-Lucas, M., Pesini, P., Casabona, D., Pérez-Grijalba, V., Marcos-Campos, I., Sarasa, L., Canudas, J., Badi, H., Monleón, I., San-José, I., Munuera, J., Rodríguez-Gómez, O., Abdelnour, C., Lafuente, A., Buendía, M., Boada, M., Tárraga, L., Ruiz, A., & Sarasa, M.
Affiliations
  • Hospital Universitari Germans Trias i Pujol (ES)
  • Fundació ACE (ES)
Corresponding author
Pesini, Pedro
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2018-01-29
Volume
10
Issue
1
Pages
12-12
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-018-0340-8
PMC
PMC5789644
OpenAlex
W2789484532
Cited by
111
References
61
Citations by year
2026: 9 · 2025: 20 · 2024: 14 · 2023: 19 · 2022: 16 · 2021: 14 · 2020: 9 · 2019: 6 · 2018: 3
FWCI
5.50
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Araclon Biotech
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, Aβ40, active immunotherapy, vaccine safety and tolerability, immunogenicity, anti-amyloid antibodies, amyloid-related imaging abnormalities, vasogenic edema, microhemorrhages, mild to moderate Alzheimer's disease, dose escalation, subcutaneous immunization
MeSH terms
Immunogenicity, Vaccine, Protein Domains, Aged, Aged, 80 and over, Alzheimer Disease, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Peptide Fragments, Severity of Illness Index, Amyloid beta-Peptides, Treatment Outcome, Alzheimer Vaccines

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