UA Researchers Closer Than Ever to Valley Fever Vaccine

After another long day at the office, Adam Buntzman, PhD, a University of Arizona assistant professor and pulmonary research investigator in the lab of renowned UA asthma physician-scientist Monica Kraft, MD, at the UA's BIO5 Institute, headed out to his car.

On his way, he paused for a few moments to breathe in the evening air and take in the outdoors, something he hadn't been able to do for weeks. Dr. Buntzman had been working under deadline on a grant proposal, so his movements had been limited to his commute from home to the university and back again.

Dr. Adam Buntzman (right), a research assistant professor in the UA College of Medicine – Tucson, has firsthand experience with Valley Fever and is part of a team at work on a vaccine. (Photo: Bob Demers/UANews)

Weeks later, his back began to hurt. He had difficulty drawing a full breath. He ran a fever and sweated profusely, especially at night. He was fatigued, too, but it was a fatigue unlike any he had known before. An X-ray showed pneumonia in his right lung. Antibiotics were prescribed, but they didn't help.

Eventually, Dr. Buntzman and UA infectious disease specialist John N. Galgiani, MD, had a good idea of what was ailing the researcher: He had contracted Valley Fever.

But with so little time spent outdoors, and no exposure in the lab, how in the world did he end up with the disease?

Dr. John Galgiani (being interviewed by a local TV station at left in his BIO5 lab), who established the UA Valley Fever Center for Excellence in 1996, has been working on the disease since his arrival at the UA 38 years ago.

Five months on, it's a question Dr. Buntzman often asks himself, and not just because he still struggles with the effects. Valley Fever is the focus of some of his research.

Dr. Buntzman is a research assistant professor in the UA College of Medicine – Tucson. He is a member of a team led by Dr. Galgiani that’s working to come up with a vaccine for Valley Fever, which is caused by the fungus Coccidioides and is known formally as coccidioidomycosis

A Fungus with a History
Coccidioides is no stranger to Dr. Galgiani, a professor in the UA College of Medicine – Tucson and the BIO5 Institute. He has been working on it in the lab since his arrival at the UA 38 years ago — and in the Valley Fever Center Clinic at Banner – University Medical Center Tucson each Friday, where he treats patients with Valley Fever.

Coccidioides is endemic to soils in many parts of the southwestern United States, northern Mexico, Central America and South America. Dr. Galgiani says there also are scattered locations where the fungus has taken a toehold, such as Dinosaur National Park, located on the border of Colorado and Utah, as well as southeastern Washington state.

Meanwhile, Arizona's population has risen dramatically and so have the state's cases of Valley Fever. "Only relatively recently has there been this big population explosion in Arizona, which now puts the population where the fungus is," Dr. Galgiani says.

Yet, despite Valley Fever's prevalence in Arizona, it takes an average of 2.3 visits to the doctor for someone to be diagnosed with the disease, according to a study by the Arizona Department of Health Services.

"It's seldom diagnosed on the first trip to the doctor," says Lisa Shubitz, DVM, a veterinarian and research scientist with the Valley Fever Center for Excellence.

Valley fever is common among dogs, including one owned by veterinarian Lisa Shubitz (right) that contracted the disease. 

With that in mind, Dr. Galgiani established the UA Valley Fever Center for Excellence in 1996. The UA-based center focuses on the latest research, treatment and outreach on Valley Fever.

Marc Orbach, PhD, is a professor in the UA College of Agriculture and Life Sciences — and most importantly, a fungal geneticist.

"I'm interested in what it is that makes a fungus a pathogen," Orbach says. "There are 100,000 or more described fungi and probably 5 million fungi out there overall, but only a very small percentage of them are pathogens."

Professor Marc Orbach (left): "We don't yet know how the gene works, but what we do know is that without it Coccidioides won't cause the animal to get sick."

Pathogens are micro-organisms that can cause disease. Most of them break down dead matter, Dr. Orbach says. But others, such as Coccidioides, live on living tissue rather than waiting for the organism to die.

Although Valley Fever is not often fatal in humans, it can be debilitating and even disfiguring for those whose immune systems react to it in a particular way. And yet, others have no idea they have been exposed to the disease.

"Most people can clear Valley Fever on their own," says Dr. Buntzman, who was trained as a virologist but now works on high throughput immunological research, an experimental method used in diagnostic testing of the immune system. "But a small number cannot, and they get pneumonia. In a very small proportion of cases, the infection will travel throughout the body, including the brain."

Which is why Dr. Galgiani contacted Dr. Orbach to enlist his help. "The fungal geneticist knows so much more about genetics than I do," Dr. Galgiani says. "And the immunologists know so much more about immunology than I do, but I don't know if they would have pursued this research on their own."

Dr. Orbach recalls how he became involved.

"Dr. Galgiani contacted me and said, 'We've got this very interesting fungus. It's endemic here. It's a big problem. And we want to look at the genetics and the molecular biology.' So, that's how he and I started working together."

As fortune would have it, a colleague of Dr. Orbach's, B. Gillian Turgeon, PhD, of Cornell University, had been studying the fungus Cochliobolus heterostrophus, a pathogen of maize. Dr. Turgeon, another fungal geneticist, was looking for mutated strains of the pathogen to identify strains with reduced virulence. She ended up identifying a gene known as CPS1 that, when deleted from the corn pathogen, significantly reduced its virulence.

With that in mind, Dr. Orbach began to focus on CPS1 and its possible importance in Valley Fever.

The Not-So-Secret Life of Coccidioides
Coccidioides has two different phases to its life cycle. In the first, while in the dirt, it makes tiny spores, which are 2 to 4 microns long. To give you an idea of how small this is, the width of the average human hair is about 75 microns. These spores can become airborne by way of even mild breezes, and if they land somewhere else, they can grow as bread-mold-like hyphae. The hyphae mature and then differentiate into more spores without involving humans or other mammals.

But if the soil is disturbed and a mammal inhales a spore, Coccidioides go through a very different developmental stage in the lung. Instead of growing in a polar manner, as hyphae do, the fungi round out and form spherules, ranging from 80 to 100 microns in diameter — and inside generate a hundred or more cells, known as endospores. Eventually the spherules rupture, and all of the endospores are released into the lung to cause pneumonia or to spread through the blood and lymph system to other parts of the body.

"You end up with this quiescent but viable fungus in your lung," Dr. Orbach says. "But once you've been infected, you're supposed to be immune to a secondary infection, and that could be because your immune system is constantly responding."

In fact, about 60 percent of people and dogs who breathe in the spores don't get sick, Dr. Shubitz says. "They become immune. And they never know they had it."

Dr. Shubitz works in the clinic treating dogs with severe cases of Valley Fever, but she also is working with Drs. Orbach, Galgiani, Buntzman and the rest of the team to develop a vaccine for the disease.  Two of her dogs are currently being treated for the disease, as is her mother's dog. Dr. Orbach, too, says two of his four dogs had contracted Valley Fever.

"Valley Fever is hugely common (among dogs)," Dr. Shubitz says.

In fact, Coccidioides can cause disease in almost all mammals, including cattle, horses, coyotes, goats, cats, sea lions, nonhuman primates and others, Dr. Shubitz says. But they don't seem to die of the disease. However, llamas and alpacas are especially sensitive to the fungus and often do succumb to it.

The most common treatment for both humans and animals is an anti-fungal drug, fluconazole. Arizonans spend an estimated $60 million per year treating their dogs for Valley Fever, Dr. Shubitz says. Although fluconazole doesn't kill the fungus, it does slow it down. And people whose central nervous system is infected with the fungus often end up taking the drug for the rest of their life.

A Shot at a Vaccine
"A vaccine could protect you from getting sick with a pneumonia that you usually get over," Dr. Galgiani says. "But it can also protect a small percentage of people, maybe half a percent, who don't get over it but have a more progressive form of the disease."

The idea behind the vaccine is to reach into the genes of the fungus and delete the one that makes the fungus healthy, Dr. Buntzman says.

"You want your immune system to generate a response to it, but you don't want the bug to kill the host," he says. "You want a really, really gentle version of the bug that creates an immune response."

Intriguingly, such a vaccine would be live, Dr. Galgiani says, meaning that it would use a weakened form of the fungus.

"As a clinician, I couldn't get my head around a live vaccine," he says. "It sounded weird, and for this disease, it sounded even weirder."

But so far, an experimental version of the vaccine has worked well in a mouse model. A paper co-authored by Drs. Orbach, Galgiani, Shubitz and Buntzman appeared in the August 2016 issue of the journal Infection & Immunity and underscored the importance of the breakthrough for a vaccine for pets as well as humans.

"When we cut out the CPS1 gene from Coccidioides, it still grew well in a dish, so we could produce it," Dr. Orbach says. "But when you put it into an animal, it seems to fall apart during the first attempt to become a spherule. That's the perfect scenario. We don't yet know how the gene works, but what we do know is that without it Coccidioides won't cause the animal to get sick."

Dr. Galgiani says the next steps are creating a formulation that is consistent, stable, safe and can be administered first to dogs and eventually to humans. But to ensure safety, the researchers must first understand the molecular mechanisms underlying the vaccine's effectiveness. That is, they need to figure out what role the excised gene plays in the immune process and how it affects the fungus' other genes.

"We want to ask what happens if you take out that gene and how the rest of the genes express themselves," Dr. Buntzman says. "That's the part that I do. I handle the computational analysis so we can understand how the Valley Fever genes are regulated."

Says Dr. Shubitz: "We really hope to drive this forward to a vaccine. I've been working on this for almost 20 years. And this is the best thing that we've come up with so far. It's highly protective, and it looks to be affordable. Affordability is an extremely important issue when you're making a vaccine for a regional problem. It meets many criteria for a vaccine to be successful."

Dr. Buntzman says he knows it's natural to wonder how he got Valley Fever, but he also knows the answer is elusive.

"When spores, little fungi, are on the wind, blowing through the air, and all you have to do is merely walk into that little pocket of wind and inhale it, it's a very difficult thing to answer: How and where did you get it?" he says. "So, the presumption is that I just walked into the wrong pocket of wind and breathed it in."

According to the Centers for Disease Control and Prevention, Valley Fever is not contagious. Instead, people acquire Valley Fever by breathing in microscopic fungal spores. Symptoms of the disease include:

  • Fatigue
  • Cough
  • Fever
  • Shortness of breath
  • Headache
  • Night sweats
  • Muscle aches or joint pain
  • Rash on upper body or legs

As part of Valley Fever Awareness Week, which is Nov. 12-20, Janis E. Blair, MD, professor of medicine and director of the internal medicine residency program at Mayo Clinic in Scottsdale, will deliver the 21st Annual Farness Lecture. The topic of her talk is "Coccidioidomycosis in Transplantation." The lecture will take place at noon on Nov. 16 and will be held at the UA Health Sciences Center, Room 5403, 1295 N. Martine Ave., Tucson.

The annual Farness Lecture is named for Orin J. Farness, a Tucson physician who in 1938 was the first to report a postive culture for coccidioidomycosis, or Valley Fever.

"Valley Fever Research, Vaccine Gain Congressional Attention in Phoenix" | Posted: Oct. 18, 2016

Release Date: 
10/27/2016 - 3:45pm