WASHINGTON, DC—Preliminary results from the first human study with an experimental Alzheimer's disease vaccine suggest that it can be safely administered; however, it is far too soon to tell if the vaccine will actually reduce disease pathology and clinical symptoms. Although the phase I clinical trials are not yet completed, researchers discussed their initial observations at the World Alzheimer Conference 2000. "We have started clinical studies; and at this point, all systems are go and it looks good," said Dale B. Schenk, PhD, Vice President of Neurobiology at Elan Pharmaceuticals, South San Francisco, California.

OF MICE AND MEN

Just over a year ago, researchers had developed a vaccine against amyloid peptide A坆 that prevented plaque deposition and decreased the concentration of existing plaques in mice. Six-week old PDAPP mice (transgenic mice that overexpress mutant human amyloid precursor protein) that were immunized with the vaccine, Dr. Schenk explained, had a profound reduction in amyloid deposition. "In fact, if you looked at the amount of amyloid deposition in these animals that have been immunized from a young age onward and sacrificed at 13 months, [amyloid] was essentially absent in all but one of the animals."

Furthermore, astrocytosis and neuritic dystrophy were reduced when older mice with advanced pathology were immunized with Aß vaccine. "At 12, 15, and 18 months of age, there was a clear rise in amyloid deposition if the animal was left untreated," he said. In the immunized animals, however, "there was a dramatic reduction, even below where they had started at 12 months."

Early safety trials with the PDAPP mouse model indicated that the vaccine was safe and well tolerated, Dr. Schenk continued. The animals did not experience any complications after immunization. There were no alterations in simple behavioral markers such as grip strength. There was no B cell or T cell infiltration, he said, and he added that the mice showed no evidence of glomerular toxicity.

Additional studies with Swiss Webster mice, guinea pigs, rabbits, and monkeys have confirmed the safety of Aß vaccine. All these species have Aß sequences that are homologous to humans so "Aß is a self antigen in them also," Dr. Schenk noted. Although it is possible that immunization may lead to an autoimmune response, Dr. Schenk pointed out that the Aß vaccine is extracellular—and that the immune response "will be in the extracellular space and is less likely to do damage."

BOOSTING THE IMMUNE SYSTEM

Vaccination with Aß is believed to work by activating an immune response to clear the peptide from the brain. A series of experiments have demonstrated that the vaccine is capable of producing a B cell-mediated response. "Peripheral administration of [Aß-specific monoclonal and polyclonal antibodies] reduced amyloid burden in the complete absence of the T cell response," Dr. Schenk said. Epitope and IgG class may determine antibody efficacy, he pointed out, adding that IgG reactivity was seen in some plaques in the immunized animals but not seen in the non-immunized control animals.

An ex vivo assay with sections of PDAPP or Alzheimer's disease brain tissue has demonstrated that the Aß-specific antibodies were capable of clearing amyloid plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation, Dr. Schenk explained. These findings "bridged the gap between mouse and human," he commented. Antisera from primates, he added, produced the same results, which "bridged the gap even further beyond mouse antibodies," he said.

Clinical trials have begun to test whether the Aß vaccine can be safely administered to patients with Alzheimer's disease. Although the researchers hesitate to predict the outcome of the ongoing clinical trials, "true prevention is, of course, a possibility based on animal data," said Dr. Schenk.

WILL CLINICAL TRIALS PAN OUT?

A group of 24 Americans with mild to moderate Alzheimer's disease were enrolled in the initial safety trial. None of the patients who were immunized with a single dose of the Aß vaccine reported side effects, Dr. Schenk said. A second trial with 80 patients is currently under way in the UK, he said. Patients will be given multiple doses of the Aß vaccine at two- to three-month intervals. The patients will be assessed to see if the vaccine was sufficient to mount an immune response.

"What we have been working on for the past decade or longer is trying to get rid of this ugly lesion, which is the amyloid plaque in the brain tissue of Alzheimer's patients," said Dr. Schenk. However, it remains to be seen whether a vaccine that eliminates amyloid in the tissue of Alzheimer's patients will indeed help the clinical picture of the disease.

—Kimberly C.G. Jones

Suggested Reading
Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of alzheimer disease. Nat Med. 2000;6:916-919.
Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease--like pathology in the PDAPP mouse. Nature. 1999;400:173-177.
Schenk DB, Seubert P, Lieberburg I, Wallace J. Beta-peptide immunization: a possible new treatment for Alzheimer disease. Arch Neurol. 2000;57:934-936.

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