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AB1601

Long-term safety and immunogenicity of ABvac40 active immunotherapy in mild cognitive impairment and very mild Alzheimer's disease: Results from AB1601 phase 2 extension study

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Year of Publication: 2026

Authors: María Pascual-Lucas, Ana María Lacosta, María Montañés, ..., Mercè Boada

Journal: Alzheimer's & Dementia

Citation: Alzheimers Dement. 2026 Aug 12;22(8):e71746. doi: 10.1002/alz.71746

Link: https://doi.org/10.1002/alz.71746

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PMC13469337/

Clinical Question

Is the anti-Aβ40 vaccine ABvac40 safe over the long term, and does it produce durable, boostable immunological memory in early Alzheimer's disease?

Bottom Line

ABvac40 showed a favorable long-term safety profile over up to 42 months in amnestic MCI and very mild AD, with no ARIA-E or aseptic meningoencephalomyelitis and only a single asymptomatic ARIA-H event in the extension, and elicited durable, boostable anti-Aβ40 antibody responses detectable in CSF — supporting continued clinical development but not yet establishing clinical efficacy.

        Major Points
        Of 108 Part A completers, 77 entered the 18-month extension (Part B): 40 in the placebo + booster group (ABvac40 in Part A) and 37 in the ABvac40 group (placebo in Part A); 95% and 89% completed the extension, respectively
TEAEs occurred in 75.0% (placebo + booster) and 81.1% (ABvac40) of participants in Part B; serious TEAEs in 5.0% vs 16.2%; no deaths and no TEAEs leading to treatment discontinuation in Part B
No cases of ARIA-E or aseptic meningoencephalomyelitis were reported in either part of the study; ARIA-H occurred in only one Part B participant (2.7%, ABvac40 group) — asymptomatic, not treatment-related, and not leading to discontinuation
Only one treatment-related serious TEAE occurred in Part B (lacunar infarction, placebo + booster group)
ABvac40 induced robust anti-Aβ40 antibody responses following the delayed booster, consistent with sustained immunological memory over up to 42 months
Anti-Aβ40 antibodies were detectable in CSF at month 12 of Part B and correlated with plasma antibody levels
Most common non-serious TEAEs in Part B were COVID-19 infection (22.5% and 16.2%) and urinary tract infection (10.0% and 13.5%)

      

Design

Study Type: Phase 2, multicenter, randomized, double-blind, placebo-controlled trial conducted in two sequential parts: a 24-month confirmatory phase (Part A) followed by an 18-month double-blind crossover-style extension (Part B)

Randomization: 1

Blinding: Double-blind; treatment assignments remained blinded to investigators and participants throughout Part A and Part B

Allocation: 1:1 (ABvac40 vs placebo in Part A); Part B treatment determined by Part A assignment (crossover sequence)

Enrollment Period: Part B conducted between November 18, 2020, and March 23, 2023

Follow-up Duration: 18-month extension (Part B); up to 42 months total exposure across Part A and Part B

Centers: 19

Countries: Spain, France, Sweden

Sample Size: 77

Analyzed: 77

Analysis: All Part B endpoints exploratory; no formal hypothesis testing. Safety summarized by treatment received (safety population); immunogenicity analyzed descriptively by treatment assigned (ITT population). Spearman's rho used for correlation analyses.

Registration: ClinicalTrials.gov NCT03461276 (registered March 2, 2018); EudraCT 2016-004352-30 (registered March 10, 2017)

Inclusion Criteria

Age 55-80 years (Part A)
Diagnosis of amnestic MCI per NIA-AA criteria or very mild AD per NINCDS-ADRDA criteria
MMSE score 24-30
CDR global score 0.5
RBANS total score ≤85
Enrollment independent of amyloid PET status
For Part B eligibility: completion of at least the 18-month visit of Part A
Written informed consent from participants and caregivers

Exclusion Criteria

Presence or history of immunodeficiency
Significant kidney and/or liver disease
Major uncontrolled systemic condition
History or signs of cerebrovascular disease (including vascular dementia)
Relevant pattern of microvascular disease on MRI or >1 lacunar or territorial infarcts (up to 3 microhemorrhages acceptable)
Treatment with anticoagulants or antiaggregant therapy
Suicidal behavior or ideation

Baseline Characteristics

Characteristic	Placebo + booster (ABvac40 in Part A)	ABvac40 (Placebo in Part A)
N	40	37
Age, years, mean (SD)	72.2 (5.7)	72.2 (5.4)
Female, n (%)	21 (52.5)	20 (54.1)
Caucasian, n (%)	36 (90.0)	37 (100.0)
University degree, n (%)	13 (32.5)	14 (37.9)
APOE e4 non-carriers, n (%)	18 (45.0)	12 (32.4)
APOE e4 heterozygous, n (%)	15 (37.5)	21 (56.8)
APOE e4 homozygous, n (%)	7 (17.5)	4 (10.8)

Arms

Field	Placebo + Booster (ABvac40 in Part A)	ABvac40 (Placebo in Part A)
N	40	37
Intervention	Placebo subcutaneous injections on the Part B schedule, except a single ABvac40 delayed booster injection at month 4 of Part B	Five monthly subcutaneous immunizations with ABvac40 (0.2 mg immunogenic peptide) at months 0-4 of Part B, followed by a booster dose at month 10
Duration	18 months (Part B)	18 months (Part B)

Outcomes

Outcome	Type	Control	Intervention
All Part B endpoints were exploratory: long-term safety and tolerability (TEAEs, TESAEs, TESAEs of special interest including ARIA-E, ARIA-H, and aseptic meningoencephalomyelitis) and immunogenicity (anti-Aβ40 antibody response in plasma and CSF)	Primary	Placebo + booster: any TEAE 75.0%; serious TEAE 5.0%; TESAESI 0.0%; ARIA-H 0.0%	ABvac40: any TEAE 81.1%; serious TEAE 16.2%; TESAESI 2.7%; ARIA-H 2.7% (1 participant, asymptomatic, not treatment-related)
Immunogenicity: ABvac40 induced robust anti-Aβ40 antibody responses following the delayed booster in previously vaccinated participants, indicating sustained immunological memory over up to 42 months	Secondary
First-time vaccinees (placebo in Part A) mounted antibody responses to the 5-dose + booster regimen in Part B	Secondary
Anti-Aβ40 antibodies were detectable in CSF (lumbar puncture at month 12 of Part B) and correlated with plasma antibody levels (Spearman correlation)	Secondary
Plasma Aβ40 and Aβ42 concentrations were quantified longitudinally by mass spectrometry (ABtest-MS) to characterize Aβ40 trajectories during vaccination and follow-up	Secondary
Any TEAE (Part B): 30/40 (75.0%) placebo + booster vs 30/37 (81.1%) ABvac40	Safety
Treatment-related TEAE: 12/40 (30.0%) vs 13/37 (35.1%)	Safety
TEAE leading to treatment discontinuation: 0 in both groups	Safety
TEAE leading to death: 0 in both groups	Safety
Serious TEAE (TESAE): 2/40 (5.0%) vs 6/37 (16.2%)	Safety
Treatment-related TESAE: 1/40 (2.5%, lacunar infarction) vs 0/37 (0.0%)	Safety
TESAE of special interest: 0/40 (0.0%) vs 1/37 (2.7%)	Safety
Aseptic meningoencephalomyelitis: 0 in both groups and in both study parts	Safety
ARIA-E: 0 in both groups and in both study parts	Safety
ARIA-H: 0/40 (0.0%) vs 1/37 (2.7%); the single event was asymptomatic, not treatment-related, and did not lead to discontinuation	Safety
ARIA-H by APOE ε4 status (Part B): only event occurred in a heterozygous carrier in the ABvac40 group (1/21, 4.8%)	Safety
Corona virus infection	Adverse	9 (22.5%) placebo + booster vs 6 (16.2%) ABvac40
Urinary tract infection	Adverse	4 (10.0%) vs 5 (13.5%)
Injection site reaction	Adverse	3 (7.5%) vs 4 (10.8%)
Peripheral swelling	Adverse	1 (2.5%) vs 4 (10.8%)
Fall	Adverse	4 (10.0%) vs 0 (0.0%)
Headache	Adverse	3 (7.5%) vs 3 (8.1%)
Erythema	Adverse	0 (0.0%) vs 3 (8.1%)
Injection site erythema	Adverse	1 (2.5%) vs 3 (8.1%)
Pruritus	Adverse	0 (0.0%) vs 3 (8.1%)
Depression	Adverse	0 (0.0%) vs 3 (8.1%)
Injection site pain	Adverse	3 (7.5%) vs 1 (2.7%)
Injection site induration	Adverse	3 (7.5%) vs 1 (2.7%)
Injection site swelling	Adverse	1 (2.5%) vs 2 (5.4%)
Fatigue	Adverse	2 (5.0%) vs 2 (5.4%)
Insomnia	Adverse	1 (2.5%) vs 2 (5.4%)
Bronchitis	Adverse	0 (0.0%) vs 2 (5.4%)
Constipation	Adverse	0 (0.0%) vs 2 (5.4%)
Toothache	Adverse	0 (0.0%) vs 2 (5.4%)
Anemia	Adverse	0 (0.0%) vs 2 (5.4%)
Atrial fibrillation	Adverse	0 (0.0%) vs 2 (5.4%)
Musculoskeletal pain	Adverse	2 (5.0%) vs 2 (5.4%)
Inflammation	Adverse	2 (5.0%) vs 1 (2.7%)
Dizziness	Adverse	2 (5.0%) vs 0 (0.0%)
Irritability	Adverse	2 (5.0%) vs 0 (0.0%)
Iron deficiency	Adverse	2 (5.0%) vs 1 (2.7%)
Hyperglycemia	Adverse	2 (5.0%) vs 0 (0.0%)
Loss of consciousness	Adverse	2 (5.0%) vs 0 (0.0%)
Periodontitis	Adverse	2 (5.0%) vs 0 (0.0%)
Platelet count decreased	Adverse	2 (5.0%) vs 0 (0.0%)
Back pain	Adverse	2 (5.0%) vs 0 (0.0%)

Subgroup Analysis

ARIA-H by APOE ε4 carrier status: in Part B, no events in non-carriers or homozygous carriers; 1 event among heterozygous carriers in the ABvac40 group (1/21, 4.8%). Spearman correlations assessed: interval from last Part A dose to Part B booster vs antibody fold increase; age at treatment initiation vs maximum plasma antibody concentrations; plasma vs CSF anti-Aβ40 antibody levels.

Criticisms

All Part B endpoints were exploratory with no formal hypothesis testing; no efficacy conclusions can be drawn
Small extension sample (77 participants) limits detection of uncommon adverse events such as ARIA
Variable timing of Part B entry (after 18-month or 24-month Part A visits) due to protocol amendment introduces heterogeneity
No standardized neuropsychological or clinical assessments were conducted at the start of Part B
Two placebo-randomized participants inadvertently received one ABvac40 dose in Part A, complicating analysis populations
Crossover design leaves no untreated control group in the extension phase
Predominantly Caucasian population limits generalizability

Funding

This study was funded by Araclon Biotech-Grifols (per the Acknowledgments). Authors are affiliated with Araclon Biotech-Grifols and Grifols.

Based on: AB1601 (Alzheimer's & Dementia, 2026)