Background

ACI-35 is a liposome-based vaccine. The rationale behind it is that the vaccine will treat tauopathy in Alzheimer’s disease by eliciting an immune response targeted to certain pathological conformers of phosphorylated tau without also mounting autoimmune B cell or T cell responses against physiological forms of this ubiquitous intracellular protein. The vaccine contains 16 copies of a synthetic tau fragment phosphorylated at the protein’s pathological phosphorylation residues S396 and S404 and is anchored into a lipid bilayer. It uses the adjuvant MPLA (Hickman et al., 2011; Jun 2012 conference news).

In both wild-type C57BL/6 and P301L mutant tau transgenic mice, a three-month regimen of subcutaneous ACI-35 injection rapidly generated high titers of polyclonal IgG antibodies specifically directed against phosphorylated tau, rather than non-phosphorylated tau. The resulting antibodies were reported to bind neurofibrillary tangles in mouse brain tissue sections and to reduce soluble tau as well as insoluble, aggregated tau in brain extracts. ACI-35 also reportedly improved three of four tested clinical parameters: It increased retention of body weight, delayed onset of a clasping motor phenotype, and extended lifespan, but it did not improve endurance on a rotarod test. This preclinical study also reported that tests of gliosis, T cell activation and other inflammatory markers were negative (Theunis et al., 2013). Similar data in nonhuman primates were presented at the 2013 Society for Neuroscience conference. In 2015, ACI-35 was licensed to Janssen.

Findings

In December 2013, AC Immune began the first human trial of a phospho-tau-specific vaccine. This Phase 1b study compared a six-month course of undisclosed low, medium, and high doses of ACI-35 to placebo in 24 people with mild to moderate AD. The initial dosing regimen was followed by a subsequent booster shot, and a further six-month safety observation period. This was a safety, tolerability, immunogenicity study with secondary outcomes to take an initial look at biomarkers and clinical/functional outcomes, according to the company (Aug 2014 news). Besides routine safety measures, primary outcomes included MRI scans taken five times, biochemistry measures from CSF collected twice, as well as antibody titer measurements from blood collected throughout the study. Secondary outcomes included ADAS-cog, MMSE, trail-making and fluency tests, Clinical Global Impression of Change Disability Assessment in Dementia, and Neuropsychiatric Inventory Scale. This trial was registered in May 2015, ran at sites in Finland and the U.K., and was completed in June 2017 (see ISRCTN registry).

Results were presented at the virtual AAT-AD/PD Focus Meeting (Apr 2020 conference news). ACI-35 raised no safety concerns, but elicited a weak immune response. Booster shots had little effect. A redesigned version, ACI-35.030, includes a second adjuvant and an epitope to activate helper T cells. According to the presentation, the second-generation vaccine produced a stronger immune response in rhesus monkeys than the original, and booster shots increased antibody titers. The antibodies were specific for phosphorylated tau, and recognized paired helical filaments extracted from AD brain.

In July 2019 AC Immune and Janssen initiated a small Phase 1b/2a trial to test safety and immunogenicity of ACI-35.030 in people with early AD. The trial enrolls 24 people for sequential testing of up to three dose levels of the vaccine versus placebo, administered multiple times over 48 weeks. Primary outcomes are adverse events and other safety measures, plus anti-phosphoTau IgG titers in blood up to 74 weeks after baseline. This trial will also evaluate the presence of anti-tau antibodies, and monitor cognition and behavior changes using the CDR-SB, RBANS, and NPI. 

In July 2020, AC Immune announced that the lowest-dose cohort was complete, that ACI-35.030 had generated positive safety, tolerability, and immunogenicity data, and that the trial was recruiting into the next-highest dose (press release). Subsequently, the company added to this trial, evaluating two doses of a second vaccine, JACI-35.054, and raising the number of participants to 56. Running at nine centers in Finland, Sweden, the Netherlands, and the U.K., the trial is slated to end in 2023.

In February 2021, AC Immune reported completion of the middle dose of ACI-35.030 with no safety problems. The company stated in a press release that all participants in the first two dose groups developed anti-Tau IgG and IgM antibodies preferentially against phosphorylated tau, with high IgG titers.

At the 2022 CTAD conference, AC Immune showed data on all three dose groups (Dec 2022 news). All participants were reported to have mounted an antibody response to phosphorylated tau two weeks after injection. Most also had antibodies to paired helical filaments and non-phosphorylated tau, although titers against phosphorylated tau were highest. Antibodies to phosphorylated tau and paired helical filaments were sustained for more than a year, while those recognizing unphosphorylated tau waned. JACI-35.054, a protein conjugate of the same tau peptide, performed less well. It required more shots and generated antibodies not specific for pathological tau. The company said it will move forward with ACI-35.030.

On December 15, 2023, the company announced it had started a Phase 2/3 registration trial of ACI-35-030 (press release). Called ReTain, it will enroll 500 people with preclinical AD ascertained by amyloid and tau biomarker positivity. They will receive up to four years of vaccinations, against a primary outcome of decline on the Preclinical AD Cognitive Composite 5 (PACC-5). Tau PET, measured annually, will serve as a key secondary endpoint. The study does not appear in registries yet.

For details on ACI-35 trials in Alzheimer's, see clinicaltrials.gov. For ACI-35.030, see clinicaltrials.gov.