Anti-tau vaccine for AD shows ‘exceptional immunogenicity’
medwireNews: A first-in-human clinical trial of an active vaccine targeting pathologic tau protein in patients with Alzheimer’s disease (AD) has shown the vaccine elicits a well-tolerated, strong, and specific immune response.
“These results provide an encouraging precedent to the nascent field of tau-targeted immunotherapy in Alzheimer’s disease and non-Alzheimer’s disease tauopathies,” say Petr Novak (AXON Neuroscience SE, Bratislava, Slovakia) and co-researchers.
The vaccine, AADvac1, is a synthetic 12-amino acid peptide that is designed to target N-terminally truncated tau151-391/4R, which is common to many pathologic tau species in AD, and differentiate from physiologic tau.
The phase I study involved 30 patients aged 50–85 years with mild-to-moderate AD, of whom 24 were randomly assigned to receive monthly injections of AADvac1 (40 µg) for 12 weeks whereas six were assigned to placebo. After 12 weeks, the patients entered an extension phase and either received a further three doses of the vaccine or, in the case of placebo-treated patients, an initial three doses and a further three in a follow-up study.
The only adverse event linked to treatment was local injection-site reactions, occurring in 53% of patients. For almost all patients, these were reversible.
Two patients withdrew from the trial after three doses due to serious adverse events. For one patient, the events – viral infection followed by epileptic seizure – were considered possibly related to treatment.
Three other serious adverse events – troponin-T elevation, breast cancer, syncope – were deemed unrelated.
The researchers note in The Lancet Neurology that “[a] distinct advantage of immunotherapy targeted against neurofibrillary pathology is the absence of pathological tau protein deposits in the walls of brain blood vessels.”
This limits the potential for dose-limiting toxic effects that are seen with anti-amyloid monoclonal antibodies, they explain. Indeed, no safety issues previously reported with therapies targeting beta amyloid, such as edematous brain changes or meningoencephalitis, were detected on magnetic resonance imaging, and just one patient with pre-existing microhemorrhages had newly occurring ones.
The vaccine was highly immunogenic, with high titers of the desired immunoglobulin (IgG) antibodies seen in 29 of 30 patients within the first three doses. Each further dose contributed to the immune response, with 56% of 27 responder patients achieving the highest titer after six doses.
Immunoblotting of serum samples from 25 of the patients showed that the antibodies raised by the AADvac1 vaccine specifically targeted the pathologic forms of tau proteins, both monomeric and oligomeric forms, including the A68 tau triplet, which is “a characteristic and reliable biomarker for the neurofibrillary pathology in Alzheimer’s disease,” the researchers comment.
They add that the serum antibodies preferentially recognized the desired tau target with about six times higher affinity that the naturally occurring tau isoform.
These data, together with the fact that there was no precipitous cognitive decline, “confirm that AADvac1 can induce a selective, pathological, tau-specific antibody response in elderly patients,” say the researchers.
But Francesco Panza and Giancarlo Logroscino, both from University of Bari Aldo Moro in Italy, point out in a related comment that the use of just one dose of the vaccine meant dose-dependent effects could not be determined. And not enough samples were provided to study the effects of the vaccine on concentrations of tau in cerebrospinal fluid.
“These limitations might partly undermine the interpretation of the results in terms of safety and, particularly, that of a possible biological effect of the vaccine on tau pathology in the brain,” they say.
By Lucy Piper
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