Alzheimer's Vaccine Trial Gets Second Life

A clinical trial of a vaccine for Alzheimer's disease that was killed three years ago when a few participants suffered from meningoencephalitis is being resurrected.

The decision to undertake a new 27-month, double-blind trial, which will be conducted at 31 sites nationwide, was prompted by favorable results in participants in the interrupted trial who were followed for up to a year after their last injection. The trial is based on the assumption that protecting the body's immune system against beta amyloid that builds up in Alzheimer's disease victims could slow or even prevent a disorder affecting 4.5 million Americans.

The beta-amyloid hypothesis was formulated in the late 1990s after mice bred to develop Alzheimer's-like disease were found to be protected from mental decline after they had been vaccinated at birth against beta amyloid. Older mice receiving the vaccine appeared to regain cognitive function.

The favorable results that prompted the new trial are reported in two papers in the May 10 Neurology, along with a summary of the results from hundreds of Alzheimer's patients from the previous trial.

On the whole, participants whose immune systems mounted a response against beta amyloid performed significantly better on a series of memory tests than did those who received a placebo injection.

Although the study showed no statistical difference between the placebo and beta-amyloid groups in results on five tests often used in patients with Alzheimer's disease and other dementias, there were significant differences on a battery of other tests that measure memory, executive function, and verbal ability. The differences reached statistical significance in immune responders compared with patients who received placebo.

In spinal-fluid samples taken from 21 of the participants, 11 immune responders had a significant decline in levels of the tau protein, a structural protein considered a hallmark of cell death in the brain, when compared with 10 participants who received placebo.

Also encouraging, but not conclusive, is evidence from autopsies conducted on phase I and II trial participants who died in the years since the studies were completed or stopped. Three participants died of causes unrelated to the vaccination, two of whom had developed encephalitis. All had large patches of their brains in which beta amyloid had apparently been cleared out, though the tangles of tau protein were still visible.

The new trial builds on the interrupted study's design and includes MRI and electrocardiogram exams, blood and urine tests, regular vital-sign exams, and tests of memory and thinking ability. All of the injections will be in the first year, with the second year for follow-up exams.

In a new twist, rather than injecting participants with beta amyloid itself, the new trial will employ injections of humanized antibodies against part of the beta-amyloid molecule. The antibodies could help trigger the immune system to attack beta amyloid, but will be cleared by the body soon after injection. A series of six injections will help prompt the body to attack beta amyloid, according to investigators.

All of the trials have been funded by Elan Corporation and Wyeth Pharmaceuticals.

“The idea of inducing the immune system to view beta amyloid as a foreign protein, and to attack it, holds great promise,” said Sid Gilman, M.D., the first author on one of the new papers and the head of the Data Safety Monitoring Board for both clinical trials.

“We now need to see whether we can create an immune response safely and in a way that slows the progression of Alzheimer's disease and preserves cognition.”

Gilman is the William Herdman Professor of Neurology at the University of Michigan Medical School and director of the Michigan Alzheimer's Disease Research Center, one of 32 centers in the country funded by the National Institute on Aging.

An abstract of the the report “Clinical Effects of Aß Immunization in Patients With AD in an Interrupted Trial” is posted online at<www.neurology.org/cgi/content/abstract/64/9/1553>. An abstract of “Effects of Aß Immunization (AN1792) on MRI Measures of Cerebral Volume in Alzheimer Disease” is posted at<www.neurology.org/cgi/content/abstract/64/9/1563>.▪

Neurology 2005 64 1553

Neurology 2005 64 1563