BioWorld International Correspondent
LONDON - Cautious optimism again surrounds the development of a vaccine to protect against Alzheimer's disease.
A team of researchers in Switzerland analyzed the immune response of patients who took part in a trial of a candidate vaccine against the disease, which was halted earlier this year because of safety concerns. They were delighted to find that the immunized patients had produced antibodies that selectively attacked beta-amyloid, the abnormal brain protein that is thought to cause the symptoms of the neurodegenerative disease.
Roger Nitsch, director of the division of psychiatry research at the University of Zurich in Switzerland, told BioWorld International, "This is a remarkable finding. The antibodies reacted precisely and specifically with the intended pathogenic target structures, without any detectable cross-reactivity against normal brain cells. This makes the characteristics of these antibodies very exciting."
Elan Corp. plc, of Dublin, Ireland, and Wyeth-Ayerst Laboratories, of Madison, N.J., the pharmaceutical division of the former American Home Products Corp., started trial AN1792 in late 2001. It involved injecting patients who had mild to moderate Alzheimer's disease with a preparation of synthetic beta-amyloid called amyloid-beta 42, or with placebo. Earlier tests on transgenic mice that displayed abnormalities typical of Alzheimer's disease, such as amyloid plaques in the brain, had shown that the candidate vaccine could reduce the extent of the plaques, and that clearance of beta-amyloid from the brain was associated with restored brain functions in the mice.
AN-1792, which involved 360 patients in the U.S. and four European countries, was suspended in January after four patients in France who had received the candidate vaccine were found to have clinical signs associated with inflammation of the central nervous system. Subsequently, a further 11 patients were reported to have such symptoms.
Nitsch and his colleagues at the University of Zurich carried out an independent adjunct study of the immune response of a subgroup of the participants. They report their results in a paper in the Oct. 13, 2002, issue of Nature Medicine titled "Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer's disease."
"The high degree of specificity of the antibodies observed in our present study, together with the absence of unwanted cross-reactions with normal brain cells, argues in favor of the vaccination against beta-amyloid," Nitsch said.
"We are carefully observing the vaccinated patients to determine how long antibodies are present in blood after the last vaccination. We are also testing the patients to determine whether high blood concentrations of antibodies are associated with prevention of further cognitive decline or the slowing of the progression of dementia," he told BioWorld International. Brains scans would, he said, show whether shrinkage of the brains was slowed in the presence of the antibodies.
Nitsch and his team are planning further basic research studies to try to identify the precise nature of the immune response to the vaccine and to better understand the immunological mechanisms that caused the risk of brain inflammation.
The study in Nature Medicine reports the results of a series of immunohistochemical investigations on sera and cerebrospinal fluid obtained from 30 patients from the Zurich cohort within the trial. Of them, 24 had received a primary and a booster intramuscular injection of the active vaccine, separated by a period of four weeks, and six had received placebo.
Their experiments demonstrated that sera obtained before immunization did not stain any specific areas of the brains of transgenic mice that had brain abnormalities typical of Alzheimer's disease, whereas sera obtained from patients after the booster injection stained both beta-amyloid plaques and brain blood vessels in the brains of the mice. Both plaques and brain blood vessels are major sites of beta-amyloid deposition in the brains of patients with Alzheimer's disease.
Further tests suggested that the antibodies generated by the vaccination did not cross-react with full-length human amyloid precursor protein or its normal physiological derivatives. The team also showed that antibodies in the sera from immunized patients could bind to amyloid deposits in post-mortem brain sections taken from patients with Alzheimer's disease.
The Zurich group also is focusing on alternative vaccination strategies that may avoid brain inflammation. "The two principal options that we have discussed to date are passive immunization with infusions of antibodies only, and vaccination under temporary anti-inflammatory protection," Nitsch said.