A vaccine developed by a Harvard researcher appears to have partly reversed Alzheimer’s-like signs, including cognitive impairments, in aged vervet monkeys in a nine-month trial. The research, sponsored by the biotech company Elan and its partner Wyeth Pharmaceuticals, could lead to human trials of the vaccine.
“I’m really enthusiastic to see how this pans out,” says Samuel Gandy, a clinician at the Mount Sinai School of Medicine who also chairs the Alzheimer’s Association’s Medical and Scientific Advisory Council.
The vaccine was developed by Cynthia Lemere, an associate professor of neurology at Harvard Medical School and Brigham & Women’s Hospital. It is designed to stimulate the production of antibodies to a small protein, or peptide, called beta-amyloid. In its insoluble form beta-amyloid accumulates in the brains of most people as they age, but clumps of amyloid fibrils, called amyloid plaques, are particularly evident in areas of brain tissue destroyed by Alzheimer’s disease.
Since the 1980s the “amyloid hypothesis”—that accumulations of the plaques are the cause of the disease—has been popular among Alzheimer’s researchers. There is evidence that amyloid plaques through one or more mechanisms can damage brain cells, and this has led to various efforts to remove it from the brain or to prevent its accumulation. But to date no anti-amyloid drug has emerged successfully from full-scale clinical trials.
In the late 1990s a vaccine against amyloid developed by Elan and Wyeth was tested successfully in mice that had been engineered to develop an Alzheimer’s-like condition in their brains. But an early human trial of this amyloid vaccine ended in 2002 when 18 of 298 volunteers receiving the vaccine developed meningoencephalitis.
The life-threatening inflammation apparently resulted from an invasion of the brain by powerful, vaccine-provoked T cells, some of which attacked amyloid peptide sequences in healthy nerve tissue.
To get around this problem, Lemere developed a vaccine based on a shortened fragment of beta-amyloid. The fragment, which includes approximately one-third of the full beta-amyloid peptide, lacks the sequences that seem to provoke a strong T-cell reaction. It provokes instead a less hazardous reaction by immune B cells, which produce antibodies.
The amyloid fragments in Lemere’s vaccine are also combined into a multi-copy structure she calls a dendrimeric tree. “We think we’ve created something that should not be recognized as a ‘self’ protein in humans or monkeys,” she says.
But Lemere’s dendrimeric vaccine apparently does provoke a robust immune response against the harmful forms of amyloid. As Lemere reported in the Journal of Neuroscience in 2006, the vaccine cleared amyloid plaques from the brains of genetically engineered “Alzheimer’s mice.”
A Monkey Model for Alzheimer’s?
Testing in mice would normally have been the last step before testing the vaccine in humans. It is commonly thought that there is no good animal model for Alzheimer’s other than mice specifically engineered to get an Alzheimer’s-like disease. But the Elan vaccine—along with a number of other prospective Alzheimer’s therapies—had seemed safe and effective in mice but then were shown to be otherwise in human trials. Among Alzheimer’s researchers, the worry had grown that, as Gandy puts it, “mouse models may be misleading.”
Neither chimps nor rhesus monkeys appear to suffer from an Alzheimer’s-like disease. But Lemere, even before the disappointing outcome of the Elan trial, had happened upon a group of monkeys, the Caribbean vervets, that seemed unusually promising as an Alzheimer’s model.
The vervets are descendants of African green monkeys brought to the islands of St. Kitts, Nevis and Barbados in the 1600s from West Africa. With their propensity to chew sugar cane and even to make off with the pricey beachside cocktails of tourists, they are generally considered a nuisance. But their new and relatively benign environment also means that they seem to live considerably longer than their African cousins—apparently long enough to show signs of age-related neurodegeneration.
McGill University psychiatrist Frank Ervin set up a vervet research colony on St. Kitts in the 1970s and by the early part of this decade had noticed Alzheimer’s-like changes in some of the monkeys. “We have a subset that begin, as they get older, to look a little demented—socially inadequate, impaired on formal cognitive tests, and so on,” he says. “When we go to look at their brains, sure enough the pathology looks very much like the human condition.”
Testing the Vaccine
Lemere began working with Ervin to study the vervets as a possible disease model for Alzheimer’s in 2001. She reported in the American Journal of Pathology in 2004 that a simple amyloid vaccine, similar to the one tested by Elan and Wyeth, significantly reduced the amount of amyloid plaques in the animals’ brains.
When that study was published, Lemere received backing from Elan and Wyeth for a larger trial using her new dendrimeric vaccine, this time in 20 aged St. Kitts–born vervets at a primate facility Ervin had established at UCLA.
During a nine-month period last year, in a series of seven inoculations, Lemere and her colleagues gave seven of the monkeys her dendrimeric vaccine, another seven a version of Elan and Wyeth’s original full-length vaccine, and six a control mixture, or “vehicle,” that included the same elements as the vaccine minus the amyloid component. In addition to the usual pathology analyses, the monkeys were given computer-based cognitive tests before their first immunization and at the end of the trial.
All but one of the vaccine-immunized animals made antibodies to beta-amyloid, and those that did showed a significant clearance of amyloid plaques in their brains, in the tissue samples Lemere has tested so far. None of the monkeys developed meningoencephalitis or any other inflammatory side effect–although their numbers might have been too few to show such a side-effect.
Cognitive testing provided the most interesting result: “The vehicle controls declined in cognitive testing,” says Lemere. But for the vervets that received the Elan/Wyeth full-length amyloid vaccine, she adds, “cognition was stabilized. And those who were immunized with the dendrimeric beta-amyloid actually showed improvement.”
The monkeys were sacrificed at the end of the nine-month period so that their brains could be examined in detail, a process that will take months to finish. “We have 9,000 [monkey brain] sections that we’re still working on,” Lemere says.
But clinician Gandy, who heard a presentation by Lemere at a recent scientific meeting, already regards the cognitive results as much-needed good news for the Alzheimer’s research community: “It’s a small group [of monkeys], but no one else has shown improvement in a non-genetically engineered system in primates that looked like Alzheimer’s, so that’s where most of my enthusiasm is at the moment, seeing how that work evolves.”
A promising anti-amyloid drug, Neurochem's Alzhemed, failed in clinical trials last year, and another anti-amyloid candidate, Myriad's Flurizan, performed less well than expected in a phase 2 study. Other companies have amyloid vaccines in early clinical trials, but all have tested them first only on engineered mice. Elan and Wyeth also are developing a “passive” immunotherapy against amyloid using a monoclonal antibody they call bapineuzumab but haven’t yet released the results from their phase 2 trial in volunteers with mild to moderate Alzheimer’s.