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Valley fever hit epidemic proportions last year and experts are wondering if 2002 will be a repeat.

If the disease infects anywhere near the same number of Kern County residents as it did in the early 1990s, the cost could be staggering. During the epidemic years of 1991-93, valley fever costs mounted to more than $56 million. A similar outbreak now could mean even greater costs.

Researchers are making progress toward a vaccine, but the going has been slow. The Californian examines the impact of the disease and the efforts of those ìFighting the Fever.î

Vaccine years away

The making of a vaccine graphic

By MICHELLE TERWILLEGER Californian staff writer e-mail: mterwilleger@bakersfield.com

Sunday June 23, 2002, 12:00:00 AM

Dan Ocampo / The Californian A long-tailed macaque peers through its outdoor cage at the California Regional Primate Research Center at UC Davis. Scientists used macaques as test subjects in valley fever research.

Dr. Demosthenes Pappagianis remembers the excitement surrounding the valley fever vaccine trials of the early 1980s.

Scientists thought they had found a way to prevent the fungal disease.

"I gave it to my wife," recalls Pappagianis, a longtime valley fever researcher at the University of California at Davis. "She got a sore arm out of it."

She wasn't the only one.

While it didn't make volunteers seriously ill, they complained so much about the pain and redness researchers reduced the doses until they were no longer effective.

Fast-forward two decades.

The failure of the 1980s vaccine trial behind them, scientists at five major institutions are getting closer to developing a new valley fever vaccine without painful side effects.

Researchers say they foresee human trials within the next few years and a commercial valley fever vaccine available to patients in the next decade.

But even as scientists gear up for the final push in their research, there are still business difficulties like finding a drug maker to manufacture the vaccine.

Science behind the vaccine

Dan Ocampo / The Californian In a high-level laboratory at the Southern Arizona VA Health Care System in Tucson, researchers grow Coccidioides immitis, the fungus that causes valley fever.

The idea behind vaccines is fairly simple: give people a bit of a disease in a form that won't make them sick. Their bodies are tricked into creating protection against the disease.

Then, when an immunized person is exposed, he won't get sick.

Vaccines only work, however, for diseases that don't reoccur after the initial infection.

Early on, scientists discovered that nearly everyone who had valley fever and fully recovered didn't get it again.

From 1980 to 1984, people rolled up their sleeves in Bakersfield, Visalia, Lemoore and Tucson, Ariz., and received a killed form of the valley fever fungus.

Then came the complaints of sore arms. Scientists aren't sure what caused the painful reactions, but they have a few ideas.

Dan Ocampo / The Californian Dr. Demosthenes Pappagianis steps inside a temperature- and pressure-controlled laboratory at UC Davis where he tries potential valley fever vaccines out on mice.

Pappagianis, a professor of medical microbiology, also called "the Godfather of valley fever" due to his half-century of work with the disease, believes one of the problems was a hard substance called chitin.

Chitin, which is contained in the fungus that causes the disease, is also found in the exoskeletons of insects and sea animals like crabs and lobsters.

That could have made the old valley fever vaccine feel like an injection of sawdust, he said.

"We had to make a more tolerable vaccine," Pappagianis said. "Our approach has been to try to break down the organism."

Vaccine researchers no longer consider using the entire fungus for the vaccine. They can separate it into individual proteins and use those to create inoculations.

The proteins are most effective in vaccines because they appear to be the parts that carry foreign information. That information can trigger an immune response in the body, said Dr. John Galgiani, an infectious disease specialist and researcher at the Southern Arizona VA Health Care System in Tucson.

Under the umbrella of the Valley Fever Vaccine Project, which has its financial assets handled by the Cal State Bakersfield Foundation, researchers in laboratories in Ohio, Texas, Arizona and Davis are identifying those proteins, called antigens, that they hope will inoculate people against valley fever.

Likely candidates

Dan Ocampo / The Californian Dr. John Galgiani, an infectious disease specialist at the Southern Arizona VA Health Care System in Tucson, holds a dish of Coccidioides immitis, the fungus that causes valley fever.

Galgiani and Rebecca Cox, a researcher at the University of Texas Health Science Center at San Antonio, identified the same protein independently at almost the same time. That protein, Antigen 2, or Proline Rich Antigen, may be one of those used in vaccine testing.

Two other proteins also are likely candidates and the Valley Fever Vaccine Project is seeking patents for all three.

The vaccine may contain one, two, all or none of those proteins, depending on laboratory results.

"Most of us think it will have to be more than a single protein," Pappagianis said. "All of us are cautious of thinking there will be one remarkable protein."

To obtain Antigen 2, Galgiani grows the valley fever fungus in a level-three biohazard laboratory at the VA hospital in Tucson.

In petri dishes and test tubes the white fuzzy fungus looks a lot like the gunk on food left too long in the fridge.

Galgiani and his lab workers get the genetic material they need from the fungus and put it in yeast to grow a specific protein. The protein is used in creating test vaccines.

So far, all three proteins look promising in tests on mice.

"It's doing pretty well," Galgiani said of Antigen 2. "It's showing evidence of some type of protection."

Pappagianis takes a different approach in his lab at Davis.

He and fellow researchers break the fungus down into different parts, or fractions, and test them on mice.

The scientists make the fractions smaller and smaller to get more specific parts that may work in a vaccine. The fractions may contain up to 30 proteins. The researchers hope to reduce that number as they shrink the fractions.

Before allowing vaccine testing on humans, the U.S. Food and Drug Administration requires extensive data and research, which usually includes animal testing.

The first animal is almost always some type of rodent.

If the vaccine doesn't work in rodents, it usually doesn't move forward.

Pappagianis' team at UC Davis is testing its fractions in mice laboratories on campus, which is a time- and labor-intensive process.

The mice are kept in cages in rooms specially pressurized and kept at certain temperatures to maintain an ideal environment.

Typically, a group of mice will be inoculated with a potential vaccine and then exposed to Coccidioides immitis. Then the researchers see what happens.

Up the evolutionary chain

Dan Ocampo / The Californian Dr. Nicholas Lerche, a veterinary researcher at the California Regional Primate Research Center at UC Davis, conducted a study on long-tailed macaques for the Valley Fever Vaccine Project.

Just down the road from Pappagianis' lab, monkeys are similarly exposed to valley fever spores at the California Regional Primate Research Center.

Dr. Nicholas Lerche, a veterinary researcher at the primate center and an adjunct professor of epidemiology and infectious disease, has been hired by the research team to run tests on monkeys there.

The researchers prefer testing on primates before trying out vaccines on humans because they are so physiologically close to humans, he said.

The monkeys must be cared for with even more diligence than test mice. No one sets foot in the primate area without certain inoculations and tuberculosis tests.

Rooms full of monkeys in large cages line a hallway. When a visitor steps inside, the monkeys almost immediately turn their mirrors to get a better view.

To create a baseline for future vaccine tests, last year Lerche had lab workers expose 20 long-tailed macaques to Coccidioides immitis. Long-tailed macaques are tropical monkeys, native to Southeast Asia.

Half the monkeys were vaccinated using the old vaccine from the 1980s. Half were not.

All the monkeys -- immunized or not -- developed pneumonia after exposure to the spores. But the monkeys who were immunized fared worse than their nonimmunized counterparts.

This was a surprise to Lerche and other researchers.

After being exposed to the spores, five of the immunized monkeys received a severe enough infection that veterinarians decided they should be euthanized.

They had severe respiratory problems and stopped eating. In a few monkeys, the disease spread to other parts of the body.

"One animal looked like the fungus had spread to the spine and to the skull," Lerche said.

All of the monkeys who were unvaccinated lived.

In addition, the unvaccinated animals had a stronger immune response to the disease than the vaccinated ones.

Lerche and others are puzzled by the study's results.

"There's some things that we really didn't expect to find," he said.

In the future, Lerche will probably test the monkeys' immune responses to experimental vaccines that Pappagianis, Galgiani and others are creating in their labs.

If the monkeys respond favorably, the next test subject could be humans.