Combatting an Ancient Enemy

By Claudia Wallis

A major step is taken toward producing a malaria vaccine

In the heady days of the 1960s, international health authorities thought they had it licked. The enervating fevers, the trembling chills, the splitting headaches and the appalling child-mortality rates were on their way out. Malaria, exulted the World Health Organization in Geneva, was defeated in Europe, banished from Sri Lanka (then Ceylon) and on the run in India and Pakistan, thanks to the effectiveness of drugs and insecticides. Even in Africa, it stood to go the way of smallpox. They could not have been more wrong. Today more than half the world's people live under the threat of malaria. By some estimates, 250 million--more than the population of the U.S.-- fall ill each year; a million die in Africa alone. Says Dr. Adetokunbo Lucas, director of Tropical Disease Research at WHO: "We have moved from despondency to euphoria and back again."

Last week a ray of hope pierced the gloom surrounding and one of the world's biggest health problems. Two groups scientists, one at New York University Medical Center, the other at the National Institutes of Health and Walter Reed Army Institute of Research in Washington, announced they had taken a major step toward creating the first malaria vaccine. The teams reported in the journal Science that they had synthesized a constituent of the malaria parasite that could trigger immunity to the disease. "This is the protein that is important in developing protective antibodies against the initial stage of the malaria parasite," explained Colonel Franklin Top of Walter Reed. "For the first time, we have the possibility of making enough of it to test its use as a vaccine."

Both groups predict that animal tests will begin within a year, and if all goes well, human trials could start a year later.

The breakthrough represents a new stage in the ancient battle against malaria and the insect that carries it, the female Anopheles mosquito. Peruvian Indians discovered the first important weapon: the bark of the Cinchona tree. For centuries the bark and its derivative, quinine, were the only means of preventing and treating malaria's waves of fever, which can recur erratically and weaken victims for years. Gin and tonic, originally made with quinine, is said to have been developed by British colonialists as a way of making their daily doses more palatable.

During World War II, when quinine became scarce, hundreds of thousands of Allied troops in Africa, Sicily and the South Pacific fell victim to the disease. The U.S. Army responded with what has been called "a biological Manhattan Project." It led to development of chloroquine. More effective than quinine, it was hailed as a wonder drug. Wartime research also yielded a wonder pesticide: DDT. It was the potent combination of chloroquine and massive DDT spraying in Asia, South America and Africa (and even in the U.S., where there were pockets of malaria as recently as 1950) that fostered WHO's rosy vision of conquering malaria once and for all.

Man and nature fought back, however. War in Southeast Asia and political instability in countries like Idi Amin's Uganda interfered with eradication efforts. Premature reports of success against malaria led some health authorities to relax their vigilance. Then came the worst blows of all: in the mid-1960s, Plasmodium falciparum, the most lethal of the four species of parasite that cause human malaria, showed signs of becoming resistant to chloroquine. Soon there were resistant strains on three continents. About the same time, health officials around the Mediterranean began to find mosquitoes that were immune to DDT. It was a classic illustration of Darwinian evolution: a handful of mosquitoes that were DDT-resistant and a tiny number of parasites that were drug-resistant had survived, multiplied and defeated the best efforts of modern science. Malaria returned with a vengeance. In just four years, the incidence in Sri Lanka rose from 18 cases to more than a million. The entire eradication program backfired, says Dr. Kenneth Warren, director of Health Sciences at the Rockefeller Foundation. "It's the worst mess in medicine."

Malaria research had largely come to a halt during the years that chloroquine and DDT seemed all conquering. But Dr. Ruth Nussenzweig of N.Y.U. continued to pursue a malaria vaccine, a goal many viewed as impossible. The malaria bug presented unique obstacles. The first was the complex life cycle of the Plasmodium parasite, which is in a sense three bugs in one (see diagram): the sporozoite, which enters the human bloodstream when an infected mosquito bites; the merozoite, which invades the red blood cells and causes the disease's chills and fever; and the gametocyte, which, when ingested by a biting mosquito, reproduces inside the insect and yields a new generation of sporozoites.

All vaccines work by teaching the immune system to recognize the face of the enemy. Once the body knows the chemical features, or antigens, of an infectious agent, it can produce specific weapons, or antibodies, against it. With malaria, however, there are three faces to recognize. Each stage is marked by different antigens, and antibodies against one stage will not provide protection against another. Nussenzweig and her immunologist husband Victor decided to focus their efforts on a sporozoite vaccine. In 1967 she showed that it was possible to protect mice against malaria by injecting them with sporozoites that had been rendered harmless by irradiation. The same result was achieved in a small number of human subjects. But there was no way to mass-produce a vaccine, because the only method of obtaining sporozoites was to dissect the salivary glands of infected mosquitoes.

The advent of genetic engineering in the 1970s made such tedious work obsolete. Using methods for dissecting molecules, the two groups of researchers reporting in Science were able to identify the specific antigen, found on the surface of the sporozoite, that is responsible for producing immunity to this stage of the parasite, and they were able to unravel part of the chemical structure of the antigen. To their surprise, it was quite simple. So simple, says Victor Nussenzweig, "that it can be very easily synthesized using plain, old-fashioned chemistry." Nonetheless, a vaccine based on the antigen still faces "a lot of pitfalls," warns Top of Walter Reed. Indeed, many scientists question whether any vaccine can prompt the immune system to react fast enough to catch sporozoites after they have been injected into the body by a mosquito: each sporozoite takes only a few minutes to find sanctuary in the liver, where it is safe from the marauding antibodies. Even if only a handful of sporozoites get through to the liver, malaria will result.

Most malariologists agree that the ideal way to prevent the disease would be with a "cocktail" of vaccines for all three stages. Progress toward that end is now moving swiftly. Researchers in Geneva and Melbourne have been so successful in identifying antigens of the merozoite that they plan to begin animal tests of the vaccine by the end of the year. A gametocyte vaccine is being developed by Dr. Richard Carter at NIH, but much work remains to be done. An experimental vaccine for all three stages may be only a decade away, according to Pathologist Sydney Cohen of Guy's Hospital medical school in London. "If it is very effective," he says, "malaria eventually will be eradicated like smallpox."

But if history holds one lesson for the malariologist, it is modesty in the face of nature. Scientists admit that vaccines alone will not defeat this resilient organism. "Controlling malaria will take all the resources we have: insecticides and drugs, as well as vaccines," says Top. Drug research is continuing at Walter Reed and elsewhere. Mefloquine, discovered by the Army in 1974, remains about 98% effective against the deadly falciparum strain, but signs of resistance are already appearing. Quinghaosu, a Chinese drug derived from the wormwood plant, is "extremely promising," according to Lucas of WHO. But because drug resistance develops quickly, the search cannot stop. Says Top: "If we don't put out a good malaria control drug every five to seven years, we will be in trouble."

New methods of mosquito control are also vital. The challenge is to produce insecticides that are environmentally safe and that can overcome the problem of resistance. Entomologist Brian Federici, a WHO consultant at the University of California, Riverside, may have found a way of solving these two problems by spraying breeding grounds with a naturally occurring bacterium that kills mosquito larvae. But the method is costly, and Federici asks, "Who is going to pay for it?" That is the ultimate question in controlling malaria. According to one estimate, the cost of producing a malaria vaccine and distributing it to Third World children would be $200 million. In countries where less than $5 per capita is spent on annual health care, even a mosquito net is a luxury. --By Claudia Wallis. Reported by Mary Carpenter/New York and Patricia Delaney/Washington

With reporting by Mary Carpenter, Patricia Delaney