Sep. 6, 2002 A vaccine that interferes with inflammation inside blood vessels greatly reduces the frequency and severity of strokes in spontaneously hypertensive, genetically stroke-prone rats, according to a new study from the NIH's National Institute of Neurological Disorders and Stroke (NINDS). If the vaccine works in humans, it could prevent many of the strokes that occur each year.
In the study, researchers used a nasal spray to deliver a protein that, under normal circumstances, contributes to inflammation of the cells that line the inner walls of blood vessels. Exposing rats to this substance, called E-selectin, programs blood cells called lymphocytes to monitor the blood vessel lining for the inflammatory protein. When these lymphocytes detect E-selectin, they produce substances that suppress inflammation.
The vaccine is the first treatment to target inflammation in blood vessels as a possible means of preventing stroke, says senior author John M. Hallenbeck, M.D., chief of the Stroke Branch at NINDS. "Clinically, stroke is hard to treat. If we can prevent it from happening, that's clearly the way to go," he adds. The study appears in the September 2002 issue of the journal Stroke.
Stroke is the third leading cause of death in the United States and the most common cause of disability in adults. Each year more than 500,000 Americans have a stroke, and about 150,000 die from stroke-related causes. A stroke occurs when the blood supply to the brain is suddenly interrupted, as with a blood clot (ischemic stroke), or when a blood vessel in the brain bursts, spilling blood into the spaces surrounding brain cells (hemorrhagic stroke). Current stroke prevention strategies include reducing risk factors, such as high blood pressure (hypertension), or blocking the formation of blood clots using drugs such as aspirin and warfarin.
Animal studies have shown that blood vessels undergo periodic cycles of inflammation. These cycles are more frequent and intense in stroke-prone animals. In rats with stroke risk factors, such as hypertension, diabetes, or advanced age, a single dose of a substance found in bacteria can provoke inflammation that leads to a blood clot or a blood vessel hemorrhage. Researchers believe inflammation also contributes to stroke in humans.
In the new study, Dr. Hallenbeck and colleagues tested human E-selectin and two other substances (used as controls) in a total of 113 stroke-prone rats with genetically induced hypertension. Some of the rats received a single course of E-selectin every other day for 10 days, while others received the 10-day course of treatment every 3 weeks until they died or until the study was complete.
The results of the investigation were dramatic. During more than a year of study, the rats that received repeated E-selectin vaccine treatment had 16 times fewer ischemic strokes than those given repeated treatment with a control substance. Furthermore, none of the rats given repeated vaccine treatment had a hemorrhagic stroke, while the other groups had two to three hemorrhagic strokes on average during the study period. Strokes that did occur in the rats with repeated vaccine treatment caused much less brain damage than strokes in the control rats. The researchers also found that lymphocytes from rats treated with the E-selectin vaccine produced a type of chemical called a cytokine that blocked inflammation in blood vessels.
The single course of vaccine treatment did not maintain the animals' resistance to stroke; repeated treatment with the vaccine was required for long-term stroke prevention, the researchers say.
The vaccine did not have any effect on the rats' blood pressure. This shows that its beneficial effects are not linked to reduction of high blood pressure, a proven means of reducing the risk of stroke, Dr. Hallenbeck notes. If the vaccine proves effective in people, it would be used in conjunction with control of high blood pressure and other risk factors, he adds.
"We think the E-selectin vaccine works by reducing immune and inflammatory reactions in vessels that threaten either to become blocked or to rupture and bleed," Dr. Hallenbeck says. This contrasts with many other vaccines, such as flu shots, which work by increasing the immune system's reactions to specific viruses or bacteria.
The researchers are now planning a Phase I clinical trial to test the effects of human and bovine E-selectin vaccines in people at high risk for stroke. That trial will study whether the vaccines are safe to use in people and what the side effects may be. The bovine E-selectin will be tested in addition to the human protein because there is a chance it may produce a stronger response, Dr. Hallenbeck says. The two vaccines are being produced by Novavax, Inc., of Columbia, Maryland, under a Cooperative Research and Development Agreement (CRADA) with NINDS.
The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system.
Reference: Takeda H, Spatz M, Ruetzler C, McCarron R, Becker K, Hallenbeck J. "Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats." Stroke: Journal of the American Heart Association, Vol. 33, No. 9, September 2002, pp. 2156-2164.
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