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Published On April 13, 2017

CLINICAL RESEARCH

On the Desert Wind

A new vaccine may prevent valley fever and break a long-standing impasse on fungal research.

Most people with valley fever don’t know they have it. The infection causes coughing, chills and fever, symptoms that are easy to confuse with the flu or common cold. Left untreated, the disease can lead to pneumonia or meningitis, which can be fatal. But valley fever is different in one significant way from most other infectious disorders: It is caused by a fungus rather than by bacteria or a virus.

Fungi don’t generally pose a serious risk to healthy adults, which is one reason there is so much concern about the wide spread of valley fever. (While fewer than 200 deaths are attributed to it each year, there were 11,000 confirmed cases in 2015, and as many as 150,000 people may be infected annually.) Research into fungal infections lags significantly behind research on other infectious agents, and only a few classes of drugs are used to fight fungi in the human body. Just one of those was developed in the past 30 years.

No test can rapidly and accurately diagnose valley fever, and there’s no vaccine to prevent it. In fact, no vaccine for fungal diseases has ever been approved for human use. But researchers have long suspected that valley fever might be a good candidate to break that impasse.

The disease is caused by fungi of the genus Coccidioides, which mostly live in the dry, warm desert soil of the southwestern states and northern Mexico. Dust Bowl settlers and military outposts arrived in the region in the 1930s and 1940s, and many people were infected, giving physicians their first chance to study the disease in depth. Those who recovered tended not to get valley fever again, suggesting that immune system exposure to the fungus produced a lasting protective response. To create a vaccine, researchers needed to stimulate that response without causing the disease.

A team from the University of Arizona’s Valley Fever Center for Excellence show early evidence that they have done just that. John Galgiani, director of the center, in collaboration with fungal geneticist Marc Orbach, created a vaccine by removing a single gene, CPS1, from the fungus. They targeted CPS1 because a related fungus that preyed on corn had an analogous gene that seemed to control the pathogen’s ability to spread. “Without that gene, it looks like the fungus can’t propagate in mammals,” Galgiani says. But the neutered valley fever fungi still provoked the immune response, which was what the team was seeking. “The enormous implication was that it might make a safe vaccine,” says Galgiani.

In October 2016, the team published a study in Infection and Immunity showing that their vaccine did prevent infection in mice. Even after being bombarded with spores, mice that had been treated with their gene-altered version of Coccidioides showed no sign of serious infection. The researchers have now applied to the National Institutes of Health for a grant to fund a laboratory-based vaccine trial in dogs. Every year, the infection affects an estimated 6% to 10% of dogs living in the valley fever corridor.

Galgiani says there’s no timeline for a human trial, and he expects the Food and Drug Administration to need extensive proof of safety in animal models before approving studies in people. Because there has never been a live vaccine based on a fungus, regulators “are going to be slow and careful, and rightly so,” he says.

Stuart Levitz, an infectious disease specialist at the University of Massachusetts Medical School, calls the new vaccine study a “huge step.” He says that identifying and eliminating the CSP1 gene was an important accomplishment that could inspire creation of other live-organism vaccines. But he notes that promising results from other vaccine studies—including his own work on vaccines against the fungi of the genus Cryptococcus, which can harm patients with compromised immune systems—have yet to lead to products.

Market forces, which also hinder the development of antibiotics and other anti-infectives, have slowed the push to create vaccines that fight more serious fungal infections. Clinical trials for such products are expensive and logistically difficult, and potential profits may be relatively small. “A lot of good fungal candidate vaccines sit on the shelves,” says Levitz. “It’s hard to get companies excited about it.”

“But if you were going to pick one disease to try a fungal vaccine, this would be the one,” Levitz says. Unlike most other invasive fungal infections, valley fever affects people with healthy immune systems that could be goaded into attacking the fungus. And because valley fever affects a wide range of people in a distinct region, the impact of an approved vaccine could be easy to measure.

In the meantime, Janis Blair, an infectious disease specialist with the Mayo Clinic in Phoenix, says that physicians in the affected areas need to learn more about valley fever, which may be the underlying cause of patients’ flu-like symptoms or pneumonia. “Some doctors don’t even think about valley fever,” she says. “We have to get over that hurdle.”