Valley fever dog vaccine research could help humans, too

Randy Ford had never heard of valley fever when he moved to Tucson from Salinas, Calif., with his dog, a reddish brown vizsla named Tyler.

"A few days before Tyler died he was raising hell — chasing toys in the pool. Then all of a sudden he quit eating, and he'd stand outside his doggie door and shake like it was cold," Ford said.

That was in 2005. Tyler had breathed in spores from the fungus that causes valley fever, a disease that starts in the lungs and then can spread. Tyler’s valley fever infection  had spread into his bloodstream and his kidneys started to shut down. Ford spent more than $5,000 trying to save his beloved dog, but Tyler was too sick. He died within days of first getting ill.

An annual “Howliday Party” in Tyler’s memory has been held every year since his death at   Tucson’s Sit!Stay!Play! Doggie daycare, where Tyler was a client.

The event raises $2,000 to $4,000  annually for efforts at the the University of Arizona to develop a valley fever vaccine. Contributions like these from dog lovers over the past 20 years, plus the support of a California pharmaceutical startup, have buoyed researchers at the university. They say a canine vaccine against valley fever could be available within the next 10 years, and the work to save dogs from the disease could also advance efforts to create a viable vaccine for people.

"I really think a dog vaccine is a realistic goal unless we run into a scientific problem in the lab work that we didn't anticipate," said Dr. Lisa Shubitz, a veterinarian and associate research professor in the UA's School of Animal and Comparative Biomedical Sciences, and part of the team working on the vaccine. "We think the dog is the path to the human."

Mutant spore

The live vaccine, a mutant spore invented by UA fungal geneticist Marc Orbach, is called delta-CPS1. It has already protected mice from valley fever. Proving that it works in dogs is the next step.

Orbach invented delta-CPS1 after reviewing work by a researcher at Cornell University. That researcher, who studies a fungus that causes disease in corn, had identified a gene that was needed by that fungus to be pathogenic.

Orbach found a very similar gene in the coccidioides posadasii strain of valley fever fungus. By splicing out the gene, he created a mutant spore strain that doesn’t make animals sick.

Using that mutant strain, the Orbach lab was able to create a live, attenuated vaccine. The risk of using a live vaccine is that the recipient — human or animal —  gets sick with the disease the vaccine is trying to prevent. That was a concern for the researchers. The safety data so far are impressive but it has only been tested in mice.

The UA holds the intellectual property on the vaccine.

Over 20 years, a total of $400,000 earmarked for the University of Arizona's canine vaccine has been raised, all of it from dog lovers like Sit!Stay!Play! owner Janet Galante who have seen the heartbreaking toll the disease can take on dogs.

"Many of my clients’ dogs have valley fever. The emotional and economic costs are enormous," Galante said.

"What they are doing over there is remarkable,” she said of the UA researchers. "If they do this for valley fever they are going to open the door for other fungal diseases. It's really important research."

The donations frequently come in amounts of $20 or $30, from concerned and grieving pet owners. Larger donations have come in from kennel clubs and owners of dog-related businesses.

"These add up, and I am endlessly grateful for the support, big and small, of those who have given to this project over the years, giving to a hope that we could accomplish this," Shubitz said.

USDA not FDA

Part of the reason a dog vaccine is likely to hit the market sooner than a human one is the different regulatory pathways it would follow. Vaccines for animals go through the U.S. Department of Agriculture (USDA) Center for Veterinary Biologics to get to market, while a human vaccine would need to go through the U.S. Food and Drug Administration (FDA) for approval.

"The regulatory process is very similar to humans, but it is a lot more condensed for animals," said Kwansun Ahn, CEO of Anivive Lifesciences, a veterinary pharmaceutical startup based in Irvine, Calif.

The UA has made some progress in moving delta-CPS1 past the development stage by partnering with Anivive Lifesciences.

There is no sure-fire way to prevent valley fever, and, once a person is infected, there is no cure. The disease, also known as coccidioidomycosis, makes about 50,000 people sick per year nationally, including an estimated 30,000 Arizonans. Twice as many dogs as people in Arizona — about 60,000 — get sick with valley fever each year, Shubitz estimates.

Researchers are mindful of past attempts to create a vaccine for humans. At least two previous attempts at creating a valley fever vaccine have failed.

The first resulted in sore arms but no conclusive proof that it worked. The second attempt, a laboratory-created hybrid protein vaccine, looked promising, but stalled due to costs.

Politics and funding are problems for getting any valley fever vaccine to market because the disease is focused in one region, the southwest. And because it affects fewer than 200,000 people per year, it is considered an orphan disease.

Unlike efforts to develop a human vaccine, the current vaccine effort for dogs begins with an actual spore. This eliminates the need for the expensive protein purification step that bogged down the last human vaccine attempts.

“I think it has a lot of promise and potential,” said Dr. George R. Thompson, a valley fever expert who is an associate professor of medicine in the division of infectious diseases at the University of California at Davis.

NIH support

The delta-CPS1 researchers are hopeful about applications for grants they've submitted  to further the vaccine development — $6 million over five years from the National Institutes of Health (NIH) and $250,000 from the Arizona Biomedical Research Commission. They expect to hear about both this year.

The UA team was heartened to see the request for proposals on the NIH grant specifically encouraged vaccines with small market potential and called out valley fever as an example, along with Lyme disease and Zika virus. Federal officials say they expect to make funding decisions by late spring at the earliest.

University of Arizona Valley Fever Center for Excellence Director Dr. John Galgiani believes the explicit mention of valley fever reflects what he sees as keen interest in valley fever from U.S. Rep. and House Majority Leader Kevin McCarthy, a Republican from Bakersfield, Calif., who co-chairs a congressional valley fever task force with U.S. Rep. David Schweikert, a Republican from Phoenix.

McCarthy and Schweikert have been working together on improving awareness and research into valley fever since 2013, when McCarthy hosted a symposium on the disease in Bakersfield, spurred in part by the Center for Health Journalism Collaborative’s year-long reporting project on valley fever.

If researchers don't get the money, it doesn't mean the canine vaccine won't move forward, but it will be a hurdle to overcome, Galgiani said.

The UA research team does not have an exact estimate of how much it will cost to get a delta-CPS1 vaccine to market.

“We don't have enough money to develop the vaccine, but the grant will push it along," Galgiani said. "I don't think it will be $40 million to get into dogs. It might be in the order of $20 million, maybe as low as $10 million."

Trials to include local dogs

Anivive officials say they are aiming to get a canine vaccine to market in three to five years, though others say it could take as long as seven years.

The vaccine has not been injected into any dogs yet. The research team, which includes Orbach, Shubitz and Galgiani, says it was advised to get more regulatory input from the U.S. Food and Drug Administration before starting introductory safety and immunology studies in dogs.

"We don’t want to hurt our position to license the vaccine by being premature," Shubitz said.

Still, a timeline of three to five years is possible, USDA spokeswoman Donna L. Karlsons wrote in an email.

Shubitz anticipates clinical trials for the vaccine will include dogs from both Arizona and  highly endemic parts of California — specifically the Central Valley around Bakersfield.

Shubitz said she's never been as optimistic as she is now. But she knows there is a lot more work ahead.

"The reality is we need to seize this moment in time," Shubitz said. "No one is going to pay for this twice. We need to be right."

Image

Dr. Marc Orbach, right, examines a culture plate for single bacterial colonies as student researcher Jesse Lewis, left, watches in Orbah's lab at the University of Arizona in Tucson. Orbach has developed a vaccine that has already protected mice from valley fever and will next test it in dogs. 

[Photo by Ron Medvescek/Arizona Daily Star.]

Vaccine fundraising

Some dogs with valley fever end up getting euthanized because their owners cannot afford to treat them.

The anti-fungal medication that is often necessary to keep the valley fever at bay for the rest of their pet’s life costs $4 to $6  per day, and blood tests and associated veterinary costs can run into the thousands. Also, blood tests can give false negatives and require additional testing and money.

Dogs will often lose large amounts of weight and if the infection moves into the bones it will affect their ability to move. This is what happened with Tyler.

"A vaccine sure would save a lot of people a lot of heartache," said the dog’s owner, Randy Ford, an aircraft mechanic. "Tyler was beautiful. The fungus is bad stuff."

Dogs at high risk

A 2005 UA study found that dogs in Pima and Maricopa counties had a 28 percent chance of becoming infected with valley fever in the first two years of life. During that time, the chance of a dog becoming ill was 6 percent.

The risk of infection was nearly five times greater for dogs that spent more than 80 percent of their time outdoors compared with predominantly indoor dogs, the study found. Dogs with more than an acre of land to roam were found to have a risk of infection 6.2 times greater than dogs with a smaller roaming area.

Company officials would not divulge a price point for the vaccine, but said the intent is to create a vaccine that is affordable.

Shubitz said that even if the vaccine costs $100 per animal, that would be a bargain compared to what many people spend on treating the disease in their dogs, not to mention the emotional toll of watching one’s pet get seriously ill. It's still unclear whether the vaccine would work with one dose or have to be repeatedly given.

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