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

Abstract

BackgroundImmunotherapy 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.MethodsA 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.ResultsTwenty-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.ConclusionsABvac40 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.Trial registrationClinicalTrials.gov, NCT03113812. Retrospectively registered on 14 April 2017.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0340-8) contains supplementary material, which is available to authorized users.

Rationale for the development of an Alzheimer’s disease vaccine

“…47,48 ADvac40 did not significantly change levels of plasma Aβ 1-40 . 40 The median concentration of plasma Aβ 1-40 in phase IIa trials of CAD106 reached a maximum of approximately two to three-fold of the baseline level (at 57 weeks, 1 week after the fourth injection), and maintained nearly that level through week 122. 41 In a phase IIb trial of CAD106, median concentration of plasma Aβ 1-40 reached a maximum of approximately 3 times the baseline level (at 38 weeks, 2 weeks after the fifth injection), and maintained a level about double the baseline through week 90, 30 weeks after the last injection.…”

“…38 Median Aβ antibody titers in human trials of ADvac40 reached 810 after the third vaccination (given at week eight). 40 Median Aβ antibody titers in phase IIa trials of CAD106 reached a maximum (at 8 weeks, 2 weeks after the third injection) of about 40-50 units (in reference to rhesus monkey reference serum), and a sustained level (at 122 weeks, 30 weeks after the last injection) of 23-24 units. 41 In a phase IIb trial of CAD106, mean Aβ antibody titers reached a maximum (at 8 weeks, 2 weeks after the second injection) of about 40-90 units, and remained between about 20 and 120 units for the rest of trial.…”

Analysis of the Consolidation Phase of Immunological Memory within the IgG Response to a B Cell Epitope Displayed on a Filamentous Bacteriophage

“…Interindividual variability may prove a particularly serious problem for vaccines that focus the antibody response on a precise target, for instance, a short B cell epitope, as in the case of many second generation anti-Aβ vaccines for the prevention of Alzheimer's Disease. Since a clinical trial of immunization of Alzheimer's Disease patients with the full-length Aβ peptide 1-42 caused aseptic meningoencephalitis in some individuals [17], with evidence of a T cell infiltrate in the brain, several anti-Aβ vaccines have been generated that do not contain T cell epitopes of β-amyloid and combine a defined B cell epitope with a carrier [18][19][20][21][22][23][24].…”

Blood Markers in Healthy-Aged Nonagenarians: A Combination of High Telomere Length and Low Amyloidβ Are Strongly Associated With Healthy Aging in the Oldest Old

“…The free fraction in plasma (FP) of Aβ was quantified by direct analysis of plasma samples, whereas total Aβ in plasma (TP) levels were determined in diluted samples, as previously described (Perez-Grijalba et al, 2015 , 2016 ). Detection of anti-A β 40 and A β 42 antibodies in plasma (Experiment 2): Plasma anti-Aβ40 antibody levels were measured at the Araclon Biotech laboratory with ELISAs as previously reported (Lacosta et al, 2018 ). These assays yielded an estimate of the net adsorbed signal (NAS) defined as the difference between the absorbance observed without pre-adsorption and that observed in the pre-adsorbed sample with the C-terminal peptide of Aβ1-40 or Aβ1-42.…”

“…Detection of anti-A β 40 and A β 42 antibodies in plasma (Experiment 2): Plasma anti-Aβ40 antibody levels were measured at the Araclon Biotech laboratory with ELISAs as previously reported (Lacosta et al, 2018 ). These assays yielded an estimate of the net adsorbed signal (NAS) defined as the difference between the absorbance observed without pre-adsorption and that observed in the pre-adsorbed sample with the C-terminal peptide of Aβ1-40 or Aβ1-42.…”