Despite long-running efforts by UC researchers, there is still no vaccine for valley fever.
Sherry D. Martinez thought she had the flu. The then-45-year-old had all the usual symptoms—fever, fatigue, sore joints—and then some. When it became difficult to breathe, a doctor diagnosed her with pneumonia and sent her home with antibiotics. A few days later, bumps appeared on Martinez’s skin. When she scratched at them, they oozed. Her doctor put her on stronger antibiotics, but still her condition worsened. She developed a rash and severe eye pain. Finally, an eye specialist asked if she’d been tested for a fungal infection called coccidioidomycosis—known colloquially as cocci or valley fever.
She’d been sick for more than a month before being correctly diagnosed.
Valley fever is named for the San Joaquin Valley where the fungus that causes it, Coccidioides immitis, is endemic. In the namesake valley and large swaths of the Southwest, cocci spores reside in the soil, where they can be churned up in dust and carried on the wind, to be breathed in by unsuspecting victims.
Three weeks before she developed symptoms, Martinez had been doing yard work with her husband on their 10-acre property in Santa Margarita, a rural community in the Santa Lucia Mountains. Dust churned as they worked, but Martinez paid little mind.
“I took a shower and didn’t think twice about it,” she said.
Once inhaled, the spores lodge deep in the lungs. Then, like something out of a horror film, the spherules that make up the fungus begin dividing internally, ballooning with dozens of smaller endospores. Eventually, the spherules burst, releasing the endospores into the blood and lymphatic system where they, in turn, become spherules, and the cycle continues.
A single inhalation is all it takes to get sick, but not everyone does. Most people who are infected show little or no symptoms and gain lifelong resistance to the disease. (Valley fever is not contagious.) Others, like Martinez, experience a cascade of influenza-like symptoms that can advance to lesions, pneumonia, even fungal meningitis, a dangerous swelling of the membranes lining the brain and spinal cord. For reasons that remain unclear, certain ethnic groups, including African Americans and Filipinos, are especially susceptible to severe cases. For the elderly and otherwise immunocompromised, infection can be deadly, but even in non-life-threatening cases, recovery can take months.
When former Cal baseball player and Arizona Diamondbacks star Conor Jackson contracted the disease in 2009, it forced him to sit out 129 games. He said in a Chronicle Live interview at the time, “I’m tired. I’m fatigued. Some days I feel like I’m able to do stuff, and I do stuff. I sleep 12, 13 hours and I’m exhausted.”
It’s estimated there are about 150,000 cases of cocci annually, and infections are on the rise—according to California Department of Public Health records, up more than 200 percent from 2014.
There is currently no known cure for coccidioidomycosis, and no vaccine either, despite the long-running efforts of UC researchers to develop one.
THE UNDISPUTED LEADER in the field of cocci research was Charles E. Smith, who served for many years as dean of Berkeley’s School of Public Health. Smith was the first to determine that the disease was contracted by inhaling Coccidioides spores and the first to develop a test for exposure to the disease.
In 1937, the bespectacled epidemiologist, known to friends variously as Chuck, Charlie, and Uncle Snuffy—after the cartoon Barney Google and Snuffy Smith—began boarding the train from San Francisco to Bakersfield. He went to conduct field research on valley fever and found quite a lot of it among Dust Bowl refugees from the central plains who came to the San Joaquin Valley to live and work in the fields as migrant labor.
They had traded dust for dust. Thousands of the new arrivals succumbed to valley fever.
Smith would become a common sight in the San Joaquin Valley, roaring down country roads in his battered ’37 Ford, kicking up clouds of dirt. His colleagues dubbed his ride the Flying Chlamydospore after the thick-walled fungal spores adapted for survival in extreme environmental conditions—and perhaps also for Smith’s propensity for infecting other people.
“Many are the stories, some humorous, some tragic that followed Charlie in his pursuit of that protean fungus,” a fellow cocci researcher wrote of him. “One concerns the infection of a large number of his students while attending a lecture in the old public health building at Stanford. His laboratory and animals were in the basement of this building. The fungus spores were wafted thru the heating ducts from the laboratory to the classroom.”
It wasn’t just his students. Smith’s wife fell ill after washing his dusty clothes, his older son developed pneumonia after Smith unwittingly brought back infected cotton balls as a gift, and his younger son became sick from playing in the lab. (Researching this story, I was surprised to find the Flying Chlamydospore’s license plate in a file folder at the Bancroft Library. It was rusted, bent, dingy. I held my breath as I turned it in my hands.)
Each new wave of outsiders to the San Joaquin Valley, susceptible as they were, brought renewed awareness to the disease and kept Smith on the frontlines of public health in the state. At the onset of World War II, the Army began training pilots in the valley. To cut down on troops’ exposure to spores, Smith proposed that the army plant lawns, pave roads, and surface airfields. He suggested spraying refined oil on outdoor exercise areas and constructing pools so recruits could exercise by swimming instead, measures that drastically reduced infections.
Then came the German prisoners of war who were brought to the valley in WWII. In the summer of 1945, 10 percent of those POWs were hospitalized with valley fever. When the German government complained that the conditions were a violation of the Geneva Conventions, Smith investigated, and the prisoners were relocated. No such measures were afforded Japanese-American prisoners in the Gila River internment camp near Phoenix, where serious outbreaks of cocci also occurred. Even now, prisoners in state correctional facilities are disproportionately affected by the disease.
After the war, Smith set his sights on a new tool for fighting cocci: a vaccine. His team at Cal, which included cocci researchers H.B. Levine and Demosthenes Pappagianis, worked diligently toward finding a formula, and in 1962 the Oakland Tribune reported on their progress. “Scientists at Berkeley are on the trail of a vaccine that may end the threat of San Joaquin Valley fever. An experimental form of the vaccine has eased symptoms of the disease and prevented deaths in mice and monkeys…. Tried for the first time on a handful of human volunteers, the vaccine has induced what may be true immunity.”
That “handful of human volunteers” included the researchers themselves. “Dr. Smith and I decided to take the first step: we injected it into the deltoid muscle of each other,” Levine would later write. “Swelling developed at the site of vaccination but, after three and four doses, we felt that the vaccine was reasonably well-tolerated.”
Six others from the lab offered up their arms for the cause as well, and Pappagianis vaccinated some non-lab volunteers, too. “Some of these volunteers were inmates at a Correctional Facility in Vacaville, California,” Levine wrote. “Dr. Pappagianis enjoys reminding me that one of the volunteers later escaped; an unusual property of the vaccine.”
Home Movie: Medical Research, Coccidioidomycosis, Valley Fever, San Joaquin Valley, CA, Spring 1938, Charles Smith
Smith died from a heart attack in 1967 but his team forged on, publishing the bulk of their research in the mid-’80s. Unfortunately, the first public vaccination trials in Bakersfield, from 1980 to 1985, failed to prevent the serious symptoms of the infection and a subsequent formula developed by the Valley Fever Vaccine Project did not meet FDA standards. “The vaccine caused too many local side effects, like pain and swelling, and it just wasn’t usable,” said Dr. George Rutherford, director of the Prevention and Public Health Group at UC San Francisco, who worked on that project.
Still, a consortium of labs in California, Texas, and Arizona carried on. They identified candidate antigens, developed mutant forms of the fungus, and discovered a defect in cocci’s life cycle that could potentially be exploited with a vaccine. And then, funding stalled out.
Though progress had been made, the vaccine still seemed elusive, and pouring more money into a vaccine for an orphan disease—a condition that impacts fewer than 200,000 people nationwide each year—didn’t pencil out for the drug companies. As Dr. John Galgiani, director of the Valley Fever Center for Excellence at the University of Arizona, puts it, “The flu vaccine? That’s a vaccine market. Tetanus or polio? That’s a market. The idea that we would be able to make a boutique protein for this orphan disease didn’t compute as a business concept.”
WHEN ERICK VICARME WOKE UP in intensive care at Community Regional Medical Center in Fresno, he had no idea where he was. The Caltrans engineer had arrived at the hospital on a Friday in September 2018, complaining of breathing problems. He assumed he’d be back to work on Monday. Ten days later, he awakened from an induced coma with no memory of what had transpired.
The 38-year-old Vicarme, whose job involves “jumping from construction site to construction site,” had contracted valley fever, which had advanced to severe infection. He spent more than 20 days on life support, followed by three weeks in ICU step-down and a long period of rehabilitative therapy. “It helped me do daily tasks like brushing my teeth, putting on my clothes, bathing myself, breathing exercises, and whatnot,” he says.
By the time he was released, he’d been out of work for five months—a fact that underscores another, less obvious consequence of the disease. As Galgiani points out, “The inpatient and outpatient costs, as well as the economic impact of work days lost, makes [the disease] roughly a half billion dollar annual problem.” The per capita impacts of the disease in places like Bakersfield and Phoenix, he stresses, are comparable to those of polio and chickenpox—before the advent of vaccines.
Now, it seems, valley fever is spreading. A map of coccidioidomycosis at the website of the Centers for Disease Control and Prevention shows known and emerging endemic areas covering the entire Southwest and northern Mexico, with newly formed satellite regions in Utah, far northern California, and southeast Washington. Even Sherry Martinez’s case is indicative of the disease’s slow creep. Her town, Santa Margarita, is in San Luis Obispo County, outside the San Joaquin Valley. Health officials in the county report a sharp increase in cases there, from 82 in 2013 to 460 in 2018.
Some of the increase may be explained by improved diagnosis, but other factors are also at work; for example, increased migration and visitation to areas where C. immitis is endemic. Think of all the snowbirds who flock to desert every winter, the kids descending annually on Coachella, and the hordes of retirees settling in Phoenix. Each new construction project brings its own risks as long-undisturbed soil is suddenly lofted into the air as dust. Indeed, outbreaks can occur whenever there are large-scale disturbances of the soil. In the wake of the so-called Tempest of Tehachapi, a massive 1977 dust storm, cases of cocci spiked as far north as the Bay Area and Sacramento. The fungus also infected firefighters and others exposed to smoke from recent California wildfires.
Climate change is another factor, as dust storms have increased and intensified under recent drought conditions. Unfortunately, wet winters like the one the state just experienced only exacerbate the problem.
Berkeley’s John Taylor, a professor of plant and microbial biology, has a theory for why this is so: Cocci is carnivorous. He notes that Coccidioides frequently infects small, short-lived mammals, such as pocket mice and ground squirrels. When those animals die, says Taylor, “the fungus goes from making spherule structures to growing as little threads or filaments.” His lab has found that those filaments excrete enzymes that break down proteins. Cocci “gets access to a wet bag of protein in a very dry, harsh environment which has very little organic soil matter,” he says. The fungus consumes the dead animal, then returns to the soil where it can be dispersed over long distances by wind—a cycle cocci researchers call “grow and blow.”
“To me, the obvious explanation [for the increase of valley fever after wet years] is more rain, more grass, more small mammals, more hosts,” Taylor says.
Evolutionarily speaking, infecting modern-day humans is a “dead end” for Coccidioides, according to Taylor. If antifungals don’t end the fungus’s life cycle, modern burial practices will. On the other hand, “If you really want to get a case of cocci, go to a Native American site and start excavating.” His theory is that cocci have persisted there for hundreds, even thousands, of years, particularly in middens, which are filled with protein waste.
Much like Smith before him, Taylor takes monthly trips to the San Joaquin Valley to sample the soil and air for the presence of Coccidioides spores—albeit more carefully than his predecessor did. Taylor, who has tested positive for valley fever, doesn’t allow his students to do the sampling. “I couldn’t live with myself if somebody got sick trying to do this,” he says.
I told Taylor about holding my breath while examining the Flying Chlamydospore’s license plate, then chastising myself for overreacting. He was quick to respond. “I’m telling you, not necessarily.” He says that even the researchers who handle Native American skeletons in the Hearst Museum of Anthropology are “very nervous when they work with them, because they might have cocci.”
THERE’S A VERY PARTICULAR FLAVOR of humor at a conference for a niche fungal infection. Think dad jokes meet biology textbook. At April’s 63rd Annual Coccidioidomycosis Study Group held at the UC Davis School of Medicine, a quip involving the Bob Dylan song “Blowin’ in the Wind” gets gut-busting laughs.
Cocci researchers are a tight-knit community and even now, a half-century after his death, the friendly specter of Charles Smith hangs over the event. During breaks, his name comes up frequently in conversations and one UC Davis group uses Smith’s data sets to show how cocci spread in the body before the development of modern antifungal drugs. There’s even a living connection; Smith’s former collaborator Demosthenes Pappagianis is in attendance. A small, congenial man now in his 90s, Pappagianis still heads up a cocci lab at UC Davis.
The good news from the meeting is that money for valley fever research is starting to flow again. Last year, before he left office, Governor Jerry Brown signed legislation allocating $2 million to educate health departments, doctors, and the public about valley fever, plus $6 million for cocci research, to be split between the Valley Fever Institute in Kern County and UC-led efforts. Taylor’s lab gets a piece of that grant. He’ll use the funds to identify the genomes in more than a hundred cocci strains. The data could help us understand what makes some strains drug resistant and how they interact with host immune cells.
For all the researchers assembled here, an effective vaccine remains the Holy Grail. Cocci is one of several types of fungi that can infect and cause fatal disease in otherwise healthy humans. Currently, there are no licensed vaccines for any fungal infections, including for cryptococcal meningitis (which kills 181,000 people each year, many in Sub-Saharan Africa) and Histoplasma capsulatum, which causes symptoms similar to valley fever (and which famously infected Bob Dylan in the late 1990s).
The money now flowing won’t be enough. UCSF’s Rutherford says vaccine development for valley fever would require “$100 million, minimum.” Galgiani estimates it would cost $40–50 million just to produce enough vaccine for clinical studies. For now, his lab in Arizona is forging ahead with a different idea: a vaccine for dogs.
Yes, canines get valley fever, too. This is promising for researchers, as clinical trials on pets are less strictly regulated than they are on people. The National Institutes of Health has funded Galgiani’s research with matching donations from Anivive Lifesciences, a veterinary company based in Southern California, for a combined $10 million. “We have a pretty good chance of getting it tested and released for field trials,” he says. He thinks the dog vaccine could be available within four years and hopes some of the research will lend itself to developing a vaccine for humans, as well.
If a valley fever vaccine had been available, Erick Vicarme, who still takes antifungal drugs daily, says he would definitely have gotten it as a precaution for his job.
As for Sherry Martinez, she now works to raise awareness of valley fever and runs social media groups for fungal disease survivors. In her view, educational outreach—about early diagnosis, treatment, and living with the infection—is most important of all.
“So many people have no clue about it until it’s too late.”
Lexi Pandell, M.J. ’13, is a freelance journalist from Oakland. Her work has been published by The Atlantic, The New York Times, WIRED, Condé Nast Traveler, GQ, and others.
From the Summer 2019 issue of California.