A randomized, placebo-controlled, double blind Phase 1 trial of the Aβ vaccine, AV-1959R, in non-clinically impaired participants: prelude for secondary preventive therapy in preclinical AD

Abstract Background Active immunotherapy targeting amyloid-β (Aβ) represents a promising strategy for preventing Alzheimer’s disease (AD) in cognitively normal individuals at risk, referred to as the preclinical AD population. However, all Aβ vaccines tested so far in people with disease have faced significant challenges, primarily due to inadequate immunogenicity and insufficient antibody titers required to clear, reduce, or slow amyloid pathology. AV-1959R is a new generation MultiTEP-based Aβ vaccine specifically designed to overcome self-tolerance, provide broad T helper cell support, avoid the activation of Aβ-specific T cells, and elicit high levels of antibodies that selectively target pathological Aβ species in 100% of vaccinated individuals. Methods We conducted a randomized, double-blind, placebo-controlled Phase 1 trial in 16 healthy adults aged 40–60 years. Participants received three intramuscular immunizations of AV-1959R (100–300 µg) or placebo formulated with Advax-CpG55.2 adjuvant (Day 1, Week 4, Week 14). Primary endpoints were safety and tolerability; secondary endpoints included humoral immunogenicity, antibody specificity, and isotype profiling. Antibody responses were assessed using validated ELISA and conformational Aβ microarray assays, and antibody kinetics were modeled to estimate durability. Results AV-1959R was safe and well-tolerated, with no serious adverse events or ARIA observed. Adverse events were predominantly mild, transient injection-site reactions typical of adjuvanted vaccines. After receiving only two immunizations (priming), all vaccinated participants (12/12) developed antibody titers exceeding those reported for other Aβ vaccines in clinical trials. Induced antibodies selectively targeted pathological Aβ 42 protofibrils and fibrils, with weaker binding to oligomers and minimal reactivity to monomers. Modeling based on priming and a single booster immunization predicts that antibody titers will remain 5 times above the baseline for approximately 1 year after priming, supporting an annual booster strategy. Vaccine-induced antibodies were of the IgG isotype and bound to amyloid plaques in human AD brain tissue. Conclusions AV-1959R combines a favorable safety profile with potent, selective, and durable anti-Aβ immunity. Its 100% responder rate, induction of high antibody titers, selective targeting of pathogenic Aβ species, and dosing regimen distinguish AV-1959R from all previously discontinued Aβ vaccines and several AD vaccines tested in Phase 1/2 trial with Alzheimer’s and/or Down Syndrome individuals. These features classified AV-1959R as the top-tier, scalable immunogenic Aβ vaccine that can be safely used in the preclinical AD population with the evidence of amyloid pathology, with or without tau pathology, aiming to clear, reduce, prevent, or at least slow Aβ accumulation and the onset of Alzheimer’s. The protocol for a planned Phase 2 preventive trial of AV-1959R under IND 30925-0004, has received IRB approval. Once initiated, the study will evaluate the vaccine’s biological efficacy using established AD brain and blood biomarkers. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12624000737538; ClinicalTrials.gov NCT06831812.