Using a harmless form of the herpes virus, scientists at the University of Rochester Medical Center put into mice a payload of genetic information that created a carefully crafted immune response, one that muted the type of toxic side effects seen in a previous study in people of a vaccine against Alzheimer's. The work was published on-line June 25 in Neurobiology of Aging.
Though the current study was not in people but in mice, researchers are excited because it demonstrates a level of control over an Alzheimer's vaccine that was previously unattainable.
"This work provides a platform to shuffle the immune response, a flexibility to modify the approach to create a vaccine that is safe and efficacious," says Howard Federoff, M.D., Ph.D., professor of neurology and director of the Center for Aging and Developmental Biology. "This points the way toward shaping and modulating the exact immune response needed to fight or prevent Alzheimer's disease."
In a previous study, other researchers showed that a potential vaccine designed to protect against Alzheimer's was apparently effective in some people – but the vaccine caused severe inflammation in the brains of several participants, and the study was halted last year because of the danger.
With funding from the National Institutes of Health, Federoff and William Bowers, Ph.D., assistant professor of Neurology, set out to create a vaccine without the harmful side effects, by boosting part of the immune system not responsible for the side effects. And they succeeded: While a vaccine most like the previous form proved lethal to four out of six mice, a modified form of the vaccine, additionally equipped with a tetanus toxin to alter the immune response, proved much safer while still causing a 20-percent decline in the amount of amyloid plaque in the brain. The additional antigen tweaked the immune response in a way that muted the original vaccine's harmful side effects.
"From our studies and those of others, it appears that you need to induce specific immune activity to clear existing plaque or prevent the formation of new plaque deposits," says Bowers. "In essence, we want the beneficial effects of the vaccine without the toxicity. The herpes vector system gives us the flexibility to fine-tune the nature of the immune response so we can possibly create an effective vaccine that has a more optimal safety profile."
The immune system's versatility is what makes such experiments possible at all. The body has many players collaborating to keep the body safe from intruders, even rivaling in complexity the maze of law enforcement agencies that keep citizens safe. For the fight against terrorism, for instance, the nation relies on the CIA, FBI, Homeland Security, other federal agencies – not to mention village and city police, county sheriffs, state police, security guards at airports, Federal marshals on airplanes, and so on. If a known terrorist is known to be on board a jet over the Pacific, asking police in thousands of towns around the nation to set up roadblocks to find the culprit would be a waste of resources and would cause unnecessary "side effects" such as widespread confusion and costs mounting to billions of dollars.
Likewise, the body's immune system has an assortment of resources at its disposal, each geared to thwart a particular type of intruder, but using them wisely through a vaccine is challenging. Cytotoxic T-cells, monocytes, macrophages, B-lymphocytes--the list goes on and on. The system developed by Bowers and Federoff allows them to recruit just the immune resources necessary for a well-coordinated attack to protect the body, minimizing the side effects that would be caused by unnecessary and potentially lethal "personnel" from the immune system's array of forces.
The team is conducting several more studies designed to contribute toward a custom vaccine against Alzheimer's. In addition, Bowers has just been awarded a five-year, $1 million grant from the National Institutes of Health to study a closely related topic, the role of inflammation in the disease. Understanding how inflammation contributes to Alzheimer's will help Bowers and others create a vaccine best suited to treat or prevent it.
Central to their efforts is the herpes virus, best known for causing painful cold sores or genital lesions. Federoff has pioneered use of the virus as a potential tool to fight Parkinson's disease, Alzheimer's disease, stroke, cancer, and AIDS. The virus is adept at infecting a variety of cells, and scientists are using that ability to introduce into cells DNA that helps fight disease.
In addition to Bowers and Federoff, other authors include technicians Michael Mastrangelo, Hilary A. Stanley, and Ann E. Casey, and student Lawrence J. Milo, Jr.
Journal
Neurobiology of Aging