Vaccination against Alzheimer’s disease is one of the most promising treatment strategies. But safety concerns arising after initial human trials have slowed clinical development of such vaccines. Now new research that aims to bring the benefits of vaccines without the harmful side effects are raising hopes once again for this largely untreatable disease.

“There is tremendous interest in this approach,” says Neil Buckholtz, chief of the dementias of aging branch at the National Institute on Aging (NIA), in Bethesda, MD. “People believe this could be a promising therapeutic, but they are proceeding slowly because of safety concerns.”

Alzheimer’s vaccines work by preventing or clearing the buildup of a protein, known as beta-amyloid, which clogs the brains of Alzheimer’s patients. A patient can be injected with either an active or passive vaccine. Active vaccines contain the protein itself, triggering the body’s immune response to produce protein-specific antibodies that tag the protein for clearance. Passive vaccines, on the other hand, contain antibodies to the protein and therefore may not require an active immune response.

Animal tests of both approaches have been promising: animals given the vaccines showed less buildup of the toxic protein and better performance on cognitive tests. But an early clinical trial of an active vaccine, sponsored by the Ireland-based Elan Corporation, was stopped in 2002 after four patients developed encephalitis, an inflammation of the brain. Later, autopsies of these patients’ brains showed that despite the inflammation, the vaccine did clear the toxic protein from the brain.

“The challenge now is, are there other ways to use the immunotherapy approach to get the benefits without the adverse effects?” says Richard J. Hodes, director of the NIA.

The NIA is sponsoring a new trial, announced earlier this week at the Society for Neurosciences conference, in Atlanta, of a different type of antibody therapy: intravenous immunoglobulin (IVIg), a blood product used to treat immune disorders. IVIg contains a mix of different antibodies, including one against amyloid. Because the product has already been used to treat thousands of people with immune disease, scientists say it is unlikely to cause the inflammatory problems seen in the first Elan trial. “We have a good understanding of the side effects and how to avoid them,” says Hodes.

Elan is also testing a passive vaccine, currently in clinical trials.

Scientists still aren’t sure exactly what part of the complex immune response is necessary to successfully clear amyloid protein or what part triggers excessive inflammation, as seen in the first Elan trial. But second-generation vaccines that create more-targeted responses might soon answer that question.

William Bowers and Howard Federoff of the University of Rochester Medical Center, in New York, are working on a gene-therapy vaccine delivered via a stripped-down herpes-simplex virus. Their vaccine carries both the code for the toxic protein and the code for genes involved in different aspects of the immune response. “We can shape the response and evoke different kinds of antibodies and different immune responses,” says Bowers, who presented his findings at the neuroscience meeting. In addition, the researchers can use different genetic “promoters”–genetic sequences that control where and when a gene is expressed–to target the vaccine to specific cell types. By testing different varieties of the vaccines, they hope to tease apart each component’s effects.

“This is an example of how to deal with a promising pre-clinical therapy that didn’t work in the clinic,” says Marcelle Morrison-Bogorad, associate director of NIA’s neuroscience and neuropsychology of aging program. “Don’t give up–just go back to the bench.”