First successful vaccination against 'mad cow'-like wasting disease in deer

Researchers at NYU Langone Medical Center and elsewhere say that a vaccination they have developed to fight a brain-based, wasting syndrome among deer and other animals may hold promise on two additional fronts: Protecting U.S. livestock from contracting the disease, and preventing similar brain infections in humans.



The study, to be published in Vaccine online Dec. 21, documents a scientific milestone: The first successful vaccination of deer against chronic wasting disease (CWD), a fatal brain disorder caused by unusual infectious proteins known as prions. Prions propagate by converting otherwise healthy proteins into a disease state.


Equally important, the researchers say, this study may hold promise against human diseases suspected to be caused by prion infections, such as Creutzfeldt-Jakob disease, kuru, familial insomnia, and variably protease-sensitive prionopathy. Some studies also have associated prion-like infections with Alzheimer's disease.


"Now that we have found that preventing prion infection is possible in animals, it's likely feasible in humans as well," says senior study investigator and neurologist Thomas Wisniewski, MD, a professor at NYU Langone.


CWD afflicts as much as 100 percent of North America's captive deer population, as well as large numbers of other cervids that populate the plains and forests of the Northern Hemisphere, including wild deer, elk, caribou and moose. There is growing concern among scientists that CWD could possibly spread to livestock in the same regions, especially cattle, a major life stream for the U.S. economy, in much the same manner that bovine spongiform encephalopathy, or Mad Cow Disease, another prion-based infection, spread through the United Kingdom almost two decades ago.


According to Dr. Wisniewski and his research team, if further vaccine experiments prove successful, a relatively small number of animals (as few as 10 percent) could be inoculated to induce herd immunity, in which disease transmission is essentially stopped in a much larger group.


For the study, five deer were given the vaccine; another six were given a placebo. All of the deer were exposed to prion-infected brain tissue; they also were housed together, engaging in group activities similar to those in the wild. Scientists say this kept them in constant exposure to the infectious prions. The animals receiving the vaccine were given eight boosters over 11 months until key immune antibodies were detectable in blood, saliva, and feces. The deer also were monitored daily for signs of illness, and investigators performed biopsies of the animals' tonsils and gut tissue every three months to search for signs of CWD infection.


Within two years, all of the deer given the placebo developed CWD. Four deer given the real vaccine took significantly longer to develop infection -- and the fifth one continues to remain infection free.


Wisniewski and his team made the vaccine using Salmonella bacteria, which easily enters the gut, to mirror the most common mode of natural infection -- ingestion of prion-contaminated food or feces. To prepare the vaccine, the team inserted a prion-like protein into the genome of an attenuated, or no longer dangerous, Salmonella bacterium. This engineered the Salmonella to induce an immune response in the gut, producing anti-prion antibodies.


"Although our anti-prion vaccine experiments have so far been successful on mice and deer, we predict that the method and concept could become a widespread technique for not only preventing, but potentially treating many prion diseases," says lead study investigator Fernando Goni, PhD, an associate professor at NYU Langone.



'Hairclip' protein mechanism explained

Research led by the Teichmann group on the Wellcome Genome Campus has identified a fundamental mechanism for controlling protein function. Published in the journal Science, the discovery has wide-ranging implications for biotechnology and medicine. The shape of a protein determines its function, for example whether it is able to interact with another protein or with a drug. But a protein's shape is not constant -- it may change in response to different conditions, or simply as a matter of course.



Understanding how this process works is key to figuring out how to manipulate proteins, for example in order to disrupt a disease. Today's finding provides important clues that will help focus future research.


The team looked at a family of bacterial RNA-binding proteins that control a basic process in metabolism: one type of bacteria lives in very high temperatures, and the other likes things colder. The goal was to determine how a protein morphs from an active configuration (one that lets it bind to RNA) to an inactive one in two very different environments.


"The process is controlled by mutations, but these mutations aren't in an obvious place, where the binding happens," explains Sarah Teichmann, research group leader at the European Bioinformatics Institute (EMBL-EBI) and the Wellcome Trust Sanger Institute. "They're actually working from a distance, indirectly, to change the shape of those sites. We wanted to know how that works at an atomic level."


Undertaken initially as a purely computational study, lead author Tina Perica stepped away from her laptop and into the lab, where she worked with others to fill in the picture with experiments in biophysics, and integrated structural biology to detail how these mutations work.


"Any stable protein will have a lot of constraints on its mutational pathways," says Tina. "These mutations have very few options -- just like a person walking along a cliff will need to keep to a narrow path. But at the same time, proteins need enough wiggle room to be able to bind to things, like another protein or a drug. To find where the protein could provide that wiggle room, we retraced its steps millions of years into the past, and used a lot of different approaches to figure out what was happening."


"If you know how a species of bacteria has evolved, you can reconstruct proteins that it may have had in the past, but which don't exist today," says Yasushi Kondo from MRC Laboratory of Molecular Biology. "We made a couple of these proteins, and used X-ray crystallography to solve their structures. That let us see details we would never have seen if we'd only studied proteins from the bacteria that live today. When we put that new information together with computational work and simulations, we started to see a clear picture of how these proteins change."


"We were really pleased to do the elastic network modelling for this study, because it helps you see the dynamics of how the protein goes from one configuration to another," says Nathalie Reuters of the University of Bergen, Norway. "It also shows that these fluctuations are the same for natural mutations between the thermophilic and mesophilic organism, for allosteric ligands, for small molecules binding, or for engineered mutations."


"These proteins provide a very good example of a fundamental biophysical phenomenon that we think can happen in many proteins, regardless of which organism," says Sarah. "We believe our findings will help future research into manipulating proteins, which has potential applications across the life sciences."




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The above story is based on materials provided by European Molecular Biology Laboratory . Note: Materials may be edited for content and length.