Vaccination delays onset of prion brain disease in mice

July 02, 2002

Immunization with a non-toxic genetically engineered prion, a protein that causes a group of fatal brain diseases, including mad cow disease, delayed the onset of brain disease in mice, according to a preliminary study by NYU School of Medicine researchers and colleagues.

Other studies have shown it may be feasible to recruit the immune system to fight prion-related disease. But the new study, published in the July issue of the American Journal of Pathology, is the first to show a vaccine can delay symptoms in a natural model of prion disease in mice, according to the NYU researchers.

Mad cow disease belongs to a group of fatal diseases called transmissible spongiform encephalopathies. These diseases are characterized by progressive dementia and abnormal limb movements and affect people as well as animals. Prions cause mad cow disease in cattle and scrapie in sheep. Humans can get a number of different prion diseases, including variant Creutzfeldt-Jakob disease (vCJD).

The vaccine approach presented in the new study may be more easily applied to animals, such as cattle, at risk for developing prion disease, than to humans, according to the NYU researchers.

The vaccine in the study is based on the normal sequence of amino acids for the prion protein, which could potentially be toxic if used in humans, explains Einar Sigurdsson, Ph.D., Assistant Professor of Psychiatry and Pathology, an author of the paper. "We are currently making alterations in the prion protein to reduce the likelihood of toxicity while maintaining a therapeutic effect," says Dr. Sigurdsson.

Many scientists believe that the transmissible spongiform encephalopathies are caused by prions, unusual infectious proteins, but it isn't known exactly how the deadly particles kill brain tissue, producing sponge-like holes in the brain. It is known that prions turn deadly by changing their shape. Normal prion protein is present throughout the body, especially in the brain.

Although the experimental vaccine did not prevent brain disease, the new study shows that it could break the body's tolerance to prion protein by inducing an immune response in the form of antibodies in mice. Most importantly, higher antibody levels were found in the animals who resisted the disease for the longest period of time, bolstering the evidence that these antibodies can potentially shield the body from the disease.

"In effect, there was a therapeutic response in the animals who received the vaccine. They took longer to get sick," says Thomas Wisniewski, M.D., Associate Professor of Neurology, Pathology, and Psychiatry at NYU School of Medicine, an author of the study. "This is a step in the right direction, and we are really encouraged because the experiments suggest that the production of antibodies is critical to a therapeutic response. Obviously, we would prefer to prevent infection altogether."

"Prion is an infectious agent," says Blas Frangione, M.D., Ph.D., Professor of Pathology and Psychiatry at NYU School of Medicine and an author of the paper. "This study shows that it is possible to block prion infection by active or passive immunization," he says.

There are no treatments for prion-related brain diseases, and prion infection does not elicit an immune response - antibodies are not normally produced to fight infection. In England more than 100 people have died of variant Creutzfeldt-Jakob disease in recent years because they allegedly ate scrapie-contaminated beef (cattle that had eaten infected sheep meat), and it is feared that millions of people could be vulnerable to the disease because they ate tainted beef in the past. Consequently, many researchers are looking for ways to prevent the development of the disease.

The idea for the new study stemmed from recent research showing immunization can prevent another neurodegenerative disease, Alzheimer's, in mice. In Alzheimer's, the prion diseases, Parkinson's, and a handful of other conditions, certain proteins fold into abnormal forms, or conformations, in the brain. These misfolded proteins tend to aggregate in toxic, cell-killing clumps.

Last year, Drs. Sigurdsson, Wisniewski, and Frangione, and colleagues reported that they had devised a vaccine modeled on one of these proteins to prevent the development of Alzheimer's in mice. "We wanted to extend this immunological approach to prion disease, and our results suggest that it may be applied to all members of the extended category of conformational diseases," says Dr. Wisniewski.

Set up of the experiments

In the study, female mice were divided into four groups. The first group was immunized with a genetically engineered prion made of 209 amino acids. They were subsequently vaccinated every two weeks. Fourteen weeks after the first immunization, the researchers measured blood levels of prion antibodies in the animals. Then the mice were divided into two groups and injected with brain tissue containing a scrapie strain that causes disease in mice. The animals received a 10-fold or a 1000-fold dilution of this tissue. The control group of mice was divided into two groups; one received the 10-fold dilution and the other the more dilute mixture.

Then the researchers watched the mice. Prion disease usually takes 120 days to develop in mice, and the onset of disease is determined by the animals' behavior. In the lab, the mice walked around on a series of small parallel bars in their cages. Normal mice have no problem walking on the bars, but sick mice get their fore and hind paws stuck between the bars and trip. Diseased animals also become lethargic.

The onset of symptoms was delayed, on average, 16 days in the vaccinated animals receiving the 10-fold dilution, and 12 days in immunized mice receiving the more dilute mixture, compared to the animals who weren't immunized. In about one-third of all vaccinated animals, the delay was 40 days, and the highest blood levels of prion antibodies were found in these animals.

In the second set of experiments, the process was reversed, and mice were exposed to the scrapie protein first and given the vaccine a day later. The researchers expected less of a response in these animals because it takes several weeks to generate high levels of antibodies. In the meantime the disease progresses and becomes more difficult to fight. The delay to the onset of symptoms was eight days in the group receiving the 1000-fold dilution.

In ongoing experiments, the NYU researchers will evaluate whether the prion antibody by itself can protect against the onset of disease in mice and analyze the region of the genetically engineered prion protein that is eliciting an immune reaction.
The authors of the study are: Einar Sigurdsson, Blas Frangione, and Thomas Wisniewski from NYU School of Medicine; David Brown and Maki Daniels from the University of Bath, United Kingdom; and Regina Kascsak, Harry Meeker, Richard Carp, and Richard Kascsak from the New York State Institute for Basic Research in Development Disability, New York City.

The study was supported by grants from the National Institutes of Health.

NYU Langone Medical Center / New York University School of Medicine

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