Vaccines against Alzheimer’s disease: Clinical trial evidence, safety and endpoint design

Alzheimer's disease remains without a widely available disease-modifying treatment.Passive immunization with monoclonal antibodies has entered clinical practice for early disease; however, it is costly, requires repeated infusions, and is associated with an increased risk of amyloid-related imaging abnormalities.Active immunization represents a less expensive alternative with a more sustained immune response.This review discusses eleven such preparations that have entered clinical trials, describing their design, the current evidence on clinical efficacy, and their safety profiles.Separation of the B-cell epitope from T-cell epitopes, shortening the antigen below the length required for presentation by major histocompatibility complex class II molecules, and the selection of adjuvants favoring a Th2type immune response were intended to avoid the meningoencephalitis that led to the discontinuation of the first trial, and no further cases have been reported, although the causal role of the T-cell epitope was never established.Vasogenic edema occurred rarely or not at all, while microhemorrhages in several trials were at least as frequent in control as in vaccinated arms, although control arms were small.Antibody concentrations in cerebrospinal fluid reached only about 0.1% of serum concentrations.Clinical efficacy was a prespecified primary endpoint in three trials only; one was halted, one did not reach its planned duration, and one was completed and proved negative.Each study used its own threshold for the serological response and its own assay, while cognitive and volumetric outcomes were predominantly exploratory.Active immunization is therefore better described as unproven than as ineffective. Keywords: immunotherapy, Alzheimer disease, tau proteins, amyloid beta-peptidesThe terms used were Alzheimer's disease, dementia, vaccine, vaccination, active immunization, amyloid-β, tau, clinical trial, immunogenicity and safety, combined in varying configurations and supplemented by searches for each preparation by name.Reference lists of the retrieved articles were screened for further sources.Clinical evidence on efficacy and safety was restricted to trials conducted in humans, of any phase.Preclinical and in vitro studies were cited only to illustrate mechanisms, principally in the section on the pathophysiological basis for vaccine development.Articles were selected by the authors jointly and disagreements were resolved by discussion.Because the selection was not exhaustive and no formal risk-of-bias assessment was performed, the findings are presented descriptively and no pooled estimates are reported.