Study may lead to CWD vaccine

"Knowing this structure should help us understand how CWD pathogens grow and spread, and what might be done to stop them in deer, elk and moose," said Byron Caughey, chief of TSE/prion biochemistry at the National Institute of Allergy and Infectious Disease Rocky Mountain Laboratories in Hamilton. "The structure has also suggested a possible molecular basis for the apparent human resistance to CWD infections."

The scientists were able to map a CWD prion, the misfolded protein that causes the deadly brain disease, to the near-atomic level. The prion was collected from a naturally infected whitetail deer.

The detailed analysis indicated the cervid version of CWD has "striking diff erences" in its structures from human prions that may help protect against infections.

"Prion pathogens are abnormal thread-like clumps of a protein called PrP that grow by incorporating normal PrP molecules onto their ends," Caughey explained. "This new CWD structure should help researchers search more rationally for eff ective CWD drugs and vaccines that block the growing ends of CWD prions. Researchers have already noticed features of the CWD prion that may make it difficult for a CWD prion from a deer to grow using human PrP molecules if it infected a human host.

However, further testing is needed to substantiate these preliminary ideas and to better understand human vulnerabilities to the multiple strains of CWD pathogens that afflict cervid species of North America, Europe and Asia."

Malfunctioning prions are also the infectious proteins that caused a mad cow disease outbreak in Great Britain in 1985. It's believed the disease led to the deaths of more than 170 people who suffered from the human form of mad cow, variant Creutzfeldt-Jakob Disease. CWD is also similar to scrapie, which can infect sheep.

CWD in cervids

Chronic wasting disease was first found in a wild deer killed near Bridger in south-central Montana in 2017. Since then, it has spread to more than 33 of the state's 139 hunting districts, with detections "geographically distributed across much of Montana," according to a 2023 CWD report from Fish, Wildlife & Parks.

"Between 2017-2023, we estimated that CWD has had a maximum annual epidemic growth rate of 38% among white-tailed deer and 35% among mule deer in Montana," the report said.

Hunting districts with the highest prevalence of CWD are "600, 640, 555 and 670 for mule deer and HDs 340, 555 and 322 for white-tailed deer." Male whitetails and mule deer are more likely to be infected than female deer in Montana.

In Wyoming, CWD has been detected across most of the state with the exception of a few counties in the far west.

In both Montana and Wyoming, wildlife agencies will test hunter-killed deer, elk and moose for CWD at no charge to protect humans from possible infection, as well as to track the disease's spread. Hunters are also encouraged to dump carcasses only at approved landfills and to take extra precautions disinfecting any cutting boards, knives or grinders they use to process wild game.

CWD spread

The always fatal neurological disease was first found in captive deer in Colorado in 1960 before spreading to wildlife.

"Has it always been there at some level, and now the surveillance programs are picking it up?" Caughey questioned. "Or is it really spreading anew from some localized source, like northern Colorado, southern Wyoming, to other places?"

CWD was detected in wild deer in southeastern Wyoming as early as 1985, spreading to elk a year later. It may have migrated into Montana from infected animals in Wyoming and Saskatchewan, Canada.

The disease is now found in 35 states and five Canadian provinces as well as Norway, Finland, Sweden and South Korea.

"European cases of CWD in the reindeer and the moose there seems to be clearly a distinct origin of CWD because the strain looks so different," Caughey said.

There are also rare examples of spontaneous disease, which is what happens in people with sporadic Creutzfeld-Jakob disease, especially in older people, he added. Such an outbreak in wildlife could create a new strain.

'Really potent'

CWD is highly infectious and spreads from contact with a sick animal's bodily fluids. The infectious proteins can live in the soil even after the host dies, making the disease extremely difficult to kill and contain.

"These CWD prion preparations that we purified from this Montana deer had, by our estimates, about a billion lethal doses per milligram of protein," Caughey said. "So these things are really potent."

Of the protein-based neurodegenerative diseases — which includes Alzheimer's, ALS and Parkinson's — CWD seems to be the "most obviously contagious of all of the proteins," he added.

According to a 2011 study, "Some models show that environmental transmission plays a larger role in CWD spread as the epidemic progresses, likely causing management through hunting and culling to become less effective."

Although no case of CWD spreading to hunters after consuming an infected animal has ever been documented, the Centers for Disease Control and Prevention advise against eating an infected cervid.

Yet Caughey also stated, "At this point in time, all the indications so far is that humans are quite resistant, as far as we can tell, at least to the strains that we know people are being exposed to."

He also encouraged hunters to continue to have their animals tested for CWD.

Atomic level

To map the CWD prion, the Hamilton scientists "isolated the prions and froze them in glasslike ice," according to a post on the NIAID Now website. "Then, using electron microscopy techniques, they developed a 3-D electron density map that indicated the detailed shapes of the protein molecules within the prion structure. This involved taking nearly 80,000 video clips of the sample, magnified 105,000 times the original size, at various orientations. They marked prion filaments in the video clips and collected more than 500,000 overlapping sub-images. They isolated about 7,300 of the highest quality sub-images and then used supercomputers to generate a 3-D density map and a molecular model to fit the map."

Caughey cautioned this analysis is of one of what may be several CWD strains, each of which could have different structures and abilities.

"So we are only scratching the surface now," he said.

However, the detailed information "could guide the rational design of vaccines and therapeutics, as well as identify mechanisms that protect humans from CWD pathogens in deer, elk, moose and reindeer," the website post said.

"The study authors note that previous attempts to develop vaccines against CWD in cervids failed to be protective, and, at least in one case, had the opposite effect," the post added. "They speculate that one explanation for adverse vaccine effects could be that antibody binding to the sides, rather than the ends of prion fibril surfaces, promotes fragmentation — creating infectious particles rather destroying them."

Previous study

In May, scientists at the Hamilton lab published results of an experiment showing that even with prolonged exposure to CWD, cerebral organoids were not infected. It was the first study to use human cells to study transmission of the disease.

"Human cerebral organoids are small spheres of human brain cells ranging in size from a poppy seed to a pea," the lab explained. "Scientists grow organoids in dishes from human skin cells. The organization, structure and electrical signaling of cerebral organoids are similar to brain tissue."

Despite the results, the scientists cautioned that some people may be more genetically predisposed to infection, as seems the case with the mad cow disease outbreak, and that cerebral organoids do "not reproduce all aspects of the human brain," which might make it more susceptible to CWD infection.

Caughey said scientists are also concerned CWD could someday infect livestock and that by passing through another species gain the ability to infect humans.

"There's certainly precedent that there can be changes in species tropism, as we call it, when going through an intermediate species," he said. "And so that's something that's being studied, and we don't really understand very well."

For now, however, the scientists will be looking at ways to use the new information they've acquired to conduct future studies that can add to their understanding of CWD, Caughey said. That could include analysis of other prions like those found in infected sheep and cattle.

"We'd love to solve all of these," he said, but resources are limited.