Companies Halt First Alzheimer Vaccine Trial

One cutting-edge neuroscience issue is whether a vaccine can cure Alzheimer disease (AD). A much-ballyhooed clinical trial recently sought an answer. But a mistrial was soon declared, and scientific sleuths now face a fresh mystery: Why did 15 trial subjects get sick? The vaccine, developed by Elan Corp., contained Ab, the peptide widely believed to trigger AD by forming brain-clogging amyloid plaques. When Elan researchers vaccinated transgenic mice that had developed AD-like pathology, plaques melted away. Two-and-a-half years of animal experiments yielded further encouraging results. The vaccine prevented and possibly reversed cognitive deficits.1 Last September, Dublin-based Elan and its partner, Wyeth Pharmaceuticals, began a Phase II trial of the vaccine, AN-1792, injecting 375 mildly to moderately afflicted AD patients. In mid-January, the companies suspended further dosing because four patients showed signs of central nervous system inflammation. On March 1, the companies halted the study after 11 more troubling cases turned up. The complaints—low-grade fevers, headaches, stiff necks—varied among the 15 patients. Two suffered ischemic strokes. "The one common denominator," recalls Ivan Lieberburg, Elan's chief scientific and medical officer, "was that there was an acute worsening of the Alzheimer symptoms, which manifest as confusion and inability to perform activities of daily living." Spinal taps revealed elevated protein and lymphocyte levels, but no bacteria or viruses were found. Lieberburg says that when the caseload hit double digits, "I felt that, as always, the primary concern is for the safety of our patients and that I simply had to stop the study permanently." The 15 afflicted patients have recovered, or their conditions have stabilized, he reports. AD researchers were disappointed, but not shocked, at the trial's demise. Because the vaccine targeted a peptide naturally present in the human body, "there were a group of people who said this will never work because you're going to get a generalized immune response in the brain," according to Bill Thies, vice president for medical and scientific affairs at the Chicago-based Alzheimer's Association. The Elan/Wyeth trial appears to have followed all the rules. Christopher M. Clark, an associate neurology professor who directed clinical aspects of the Phase I trial at the University of Pennsylvania Medical Center, describes the protocol as "very conservative." Consequently, no one is predicting a witch-hunt or a chilling effect on future studies. Some observers even foresee a boon. "If the vaccine looked like a slam-dunk in December or January before this bad news, that might have tempered enthusiasm for other vaccines because people would say, 'Well, gee whiz, we're almost there,'" observes John Q. Trojanowski, professor of pathology and laboratory medicine at University of Pennsylvania School of Medicine. "The fact that there are problems, I think, will reinvigorate the field to look at other vaccines and other strategies." Analogous Mouse Study Lieberburg remains puzzled why 5% of the 300 Ab-vaccinated subjects (the rest were controls) took ill after one to three inoculations. Antibody titers did not correlate with the presence or severity of symptoms. The Phase II trial was virtually identical to the Phase I trials, where the only complaint was soreness at the injection site. Lieberburg suggests that those studies might have treated too few patients to yield an adverse reaction, if a 5% rate applied. He speculates that, in afflicted subjects, activated T cells might have entered the brain, as is thought to occur in multiple sclerosis, or that particular tissue or HLA types could have sent the immune system into overdrive. A study reported last November by Dave Morgan, a pharmacology professor at the University of South Florida in Tampa, could shed some light on the mystery. He and colleagues administered a monthly Ab vaccine to mice bearing two AD-linked transgenes. After five months, the mice's hippocampi showed increased CD45, a transmembrane protein tyrosine phosphatase found in immune-system cells. Four months later, the experimental group's CD45 levels dropped to control levels.2 How is this study relevant to the Elan/Wyeth trial? CD45 upregulation indicates activation of microglia, the brain cells that phagocytose, or eat up, antibody-bound tissue. Microglial activation, in turn, is a sign of inflammation. Consequently, these mice might have reacted to the Ab vaccine as did the trial's 15 patients. To explain the drop in CD45 levels after nine months, Morgan suggests that the mice became tolerant to the vaccine, much as older people often can tolerate substances that once triggered allergies. In two respects, however, his mice are not good models for AD patients. The animals were middle-aged, not old, and their inflammatory reactions were probably mild, given that their memory never faltered. Morgan's study also does not address the crucial issue of whether microglial activation can cause disease-related autotoxic inflammations. "There are certainly papers that show that activated microglia in vitro are associated with neurotoxicity," says Samuel C. Silverstein, who chairs the physiology and cellular biophysics department at Columbia University College of Physicians and Surgeons in New York. "As far as I know, there is no clear in vivo evidence." Microglial activation is basically impossible to measure in living animals. Fixing the Vaccine In the wake of the terminated clinical trial, AD researchers are testing alternatives to the Ab vaccine. One strategy is to inoculate animal models with antigens besides the full 42-amino acid peptide. Another experimental approach is passive immunization with monoclonal antibodies, which sidesteps the weakened immune systems of many AD patients and promises a more targeted attack. Elan's Frédérique Bard and New York University's Einar M. Sigurdsson discussed these strategies March 13 at an IPSEN Foundation conference in Paris that attracted 120 researchers. Dennis J. Selkoe, a professor of neurologic diseases at Harvard Medical School and an Elan consultant, proposes screening patients before vaccination: "You would draw blood, culture the lymphocytes, and stimulate them with the amyloid-beta peptide or whatever vaccine you chose to use." People whose cells reacted too strongly would not be vaccinated. Some biologists worry, however, that the Ab vaccine strategy might be irreparably flawed. Ashley I. Bush, an associate psychiatry professor at Harvard Medical School, argues that by eliminating Ab from tissues, the vaccine might expose its possible normal function. (Many researchers doubt the peptide has any function.) He hypothesizes that the peptide is involved in copper metabolism and fights oxidative stress. Noting that plaques "entomb" Ab, Bush also says that an amyloid-dissolving vaccine would release the peptide, which then could react with copper to form destructive hydrogen peroxide. This problem could be alleviated, he adds, "if the epitope of the antibody blocks the active site of Ab, the site that produces hydrogen peroxide." Trojanowski has another qualm about Ab vaccines. AD is characterized not only by plaques but also by intracellular tangles composed of the protein tau. "It isn't clear to me," he says, "that removing Ab with the magic vacuum cleaner will vacuum out the tangles as well." He foresees that if a vaccine fails to remove tangles, it might leave many AD patients with movement and cognitive disorders known as tauopathies. Selkoe questions this analysis, contending that AD-related tauopathies follow Ab accumulation and should not arise when plaques are absent. Research Will Continue Despite these ongoing scientific disputes, no one advocates abandoning AD vaccine research—least of all Elan. "We have not been deterred in any way," Lieberburg vows. Besides pursuing new vaccines, the company will monitor the patients vaccinated in its aborted Phase II trial, looking for signs of both cognitive improvement and a halt to AD-associated brain atrophy. "We have to keep pursuing all the leads that are available to us at the moment because we don't know what's going to pan out," states Marcelle Morrison-Bogorad, associate director of the National Institute on Aging's neuroscience and neuropsychology of aging program. NIA and the National Institute of Neurological Disorders and Stroke are accordingly spending $22.5 million over the next five years to fund 13 nonclinical AD vaccine studies. During that period, NIA will devote an additional $5.7 million to such research. Morrison-Bogorad traces the institute's involvement with AD vaccines back to 1999, when a speech by leading Elan researcher Dale B. Schenk at a Washington conference piqued White House interest. The wild card is the Food and Drug Administration's response to the Elan/Wyeth trial. Howard L. Weiner, a neurology professor at Harvard Medical School, says he has no idea what to expect when he meets with agency officials this month to discuss an anticipated nasal Ab vaccine trial. But he acknowledges that the terminated trial could heighten FDA scrutiny. "Anytime a drug has a side effect, it's a setback," Weiner observes. "Sometimes, you get around them." Douglas Steinberg (dougste@attglobal.net) is a freelance writer in New York. References 1. D. Steinberg, "Testing potential Alzheimer vaccines," The Scientist, 16[2]:23, Jan. 21, 2002. 2. D.M. Wilcock et al., "Number of Ab inoculations in APP+PS1 transgenic mice influences antibody titers, microglial activation, and congophilic plaque levels," DNA and Cell Biology, 20:731-6, November 2001.

Companies Halt First Alzheimer Vaccine Trial

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