Malaria, ‘Mother of Fevers’

Rip Ballou’s world began to blur around the edges as he stood among the croquet wickets, sipping home-brewed beer at a friend’s lawn party. He should have expected it. Two weeks earlier, he’d agreed to let infected mosquitoes land on his arm and fill their bellies with his blood.

The five other volunteers were already sick, but the 34-year-old physician still hoped he would be protected. Ballou and a team of Army scientists had devoted years to making a vaccine against malaria, and the young officer had eagerly volunteered to serve as one of the first guinea pigs.

Maybe it was the beer, he told his wife, as she drove them home that day in 1987. Maybe it was too much sun. Then a tremor shook his body, and he resigned himself to the truth. The vaccine had failed. Instead of defeating one of man’s oldest foes, Ballou knew the organism had beaten him.

Malaria is a ferocious predator, each year claiming more than 1.1 million lives. In Africa, it kills enough children every day to fill 100 kindergarten classes. Once subdued in much of the world, malaria has rebounded and today infects up to half a billion people a year.

Rich nations and the pharmaceutical industry pay little attention to the disease, which mainly strikes poor countries. But for nearly a century, a few scientists have dreamed of vanquishing malaria with a vaccine.

The more they discovered about the organism, though, the more it seemed to mock them.

Finally, last year, they could claim some success. For a short time, they protected hundreds of people from malaria in Africa, proving that a vaccine was at least possible.

The ancient Hindus crowned malaria “King of Diseases.” The Chinese called it “Mother of Fevers.” After evolving more than a million years ago in Africa, it arrived in the Americas shortly after Columbus.

For centuries, physicians blamed malaria on vapors drifting off rotting vegetation. (Malaria comes from the Italian for “bad air.”) Then in 1880, a French army doctor in Algiers put the blood of a feverish soldier under his microscope and saw a wiggling form. Soon after, British and Italian scientists discovered that malaria was spread by female Anopheles mosquitoes, found all over the world.

The hunt for a vaccine began.

Traditionally, vaccines are aimed at viruses or bacteria. Malaria is a more complicated organism, commonly called a parasite, that acts more like a cunning predator than a brainless microbe. There has never been a successful vaccine against any parasite.

Because human malaria can’t infect animals, there was no safe way to test vaccines. Researchers tried making vaccines against animal malarias, but that didn’t work. In the mid-1940s, a New York City health department scientist developed a monkey vaccine, but it was toxic. After World War II, scientists abandoned malaria vaccine research in favor of public health measures. Searching for a malaria vaccine demanded discipline and perseverance. It was a role, it seemed, that Rip Ballou had prepared for all his life.

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Born in Fort Campbell, Ky., Ballou is descended from Army officers. Ballou Sr., a colonel, had nine sons, and he imposed a quasi-military discipline on them.

After studying biology at Georgia Tech, Ballou accepted a military scholarship that committed him to four years of service. As a resident at the Walter Reed hospital in 1981, Ballou was required to spend a year in the lab. At the Army Institute of Research, one of the world’s leading centers for tropical medicine, he analyzed blood from rodents. He hated it.

The lab chief offered him another job. Would Ballou like to make a vaccine against malaria?

Infectious disease was considered a backwater of research; few scientists back then realized that malaria was resurging.

Pharmaceutical companies were more interested in drugs for heart disease and cancer, the ailments of industrial nations.

Even the military neglected malaria, though it can be as lethal as an enemy’s bullet. In recent years the Pentagon spent only about $5 million annually on malaria vaccine research--a tenth of what it spent last year on Viagra, the anti-impotence drug, for troops.

Ballou and his colleagues at Walter Reed, named after the Army scientist who established that mosquitoes spread yellow fever, labored in decrepit labs.

The researchers didn’t care. They felt they were nearing a goal of generations of scientists.

The Army hoped to attack the parasite right after it entered its victim. The vaccine would have to wipe out all dozen or so invading parasites in the few minutes before they reached the liver. If even one slipped by, it would multiply and cause full-blown illness.

Crafting a vaccine in the lab was only a start. It would have to be tested by exposing people to the parasite. Scientists call this a “challenge,” and Ballou was put in charge.

As they solved one problem after another, the Army scientists grew confident. In those heady days, Ballou recalled, Army brass visited the researchers regularly and drug company executives courted the Walter Reed team.

In April 1987, Ballou and the other volunteers--all military scientists--were inoculated. Weeks later, they let infected mosquitoes bite them. Ten days later, two fell ill. A third followed. Soon, Ballou was thrashing in his bed. The next day, a fifth volunteer fell ill.

A Washington Post headline summed it up: “Malaria Vaccine Bites Dust.”

But one volunteer--Dr. Daniel M. Gordon--did not. Gordon might have been a fluke, but later tests showed the vaccine pushed his antibody levels higher than anyone else’s. If the vaccine could protect one person, the Army scientists asked, why couldn’t it be made to protect everyone else?

By the mid-1990s, Pentagon officials began to question whether the vaccine effort was worthwhile. SmithKline Beecham, Walter Reed’s only real drug-industry ally, also wavered, researchers said.

SmithKline describes its efforts as an act of charity.

But some scientists say there is another reason the drug maker is involved: an AIDS vaccine, which could find a lucrative market in Western nations. The key to preventing AIDS might be adjuvants--compounds that boost the immune system. Because volunteers can’t be deliberately exposed to AIDS, malaria vaccines are a surrogate for testing adjuvants.

One new adjuvant, derived from the bark of a South American tree, was added to yet another version of the vaccine.

Walter Reed rounded up six volunteers.

Two weeks later, one volunteer developed chills and a fever and was treated. The others waited, but none fell ill.

The Army researchers were elated. When the New England Journal of Medicine published the paper in January 1997, reporters clamored for interviews.

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In the banks of the Gambia River in West Africa, doctors working with Walter Reed and SmithKline bounced down dirt roads in a Land Rover. In the fall of 1998, they inoculated 306 men in villages near the dusty port city of Basse. Half received a placebo, half the Army vaccine .

For the first eight weeks, the vaccine had reduced cases of malaria by almost two-thirds. And among those who got sick, there were significantly fewer cases--40%--of severe infection.

To many of malaria’s victims, Ballou knew, that could mean the difference between life and death.

Everyone understood that the vaccine needed more tinkering and testing. Its effect faded far too quickly. But it had worked. Eleven years earlier, the Walter Reed doctors had protected a single scientist in Washington. Now, they had for a time protected scores of men in the African bush.

“It was a landmark that broke through the skepticism,” said Dr. Philip Russell, a Johns Hopkins vaccine expert. Until Walter Reed’s work, many scientists believed a malaria vaccine was an illusory goal, said Dr. Adrian Hill of Oxford University, a leading malaria researcher. The Gambia trial, he said, “has provided proof the whole thing is doable.”

Western governments and public health groups are taking up the cause. Perhaps it is the fear that malaria might return to the developed world. Whatever the reason, the pursuit of a malaria vaccine is no longer a lonely one.

In the last year, the National Institutes of Health and the U.S. Centers for Disease Control and Prevention have raised spending significantly on malaria research. The Gates Foundation, funded by Microsoft billionaire Bill Gates, pledged $50 million last year to create malaria vaccines. Other labs are planning trials of Walter Reed’s vaccine in the coming months; SmithKline plans to test it in children in Gambia this fall.