A Fresh Shot At Malaria?

New research may spur drugmakers to action

Dr. Stephen L. Hoffman is determined to conquer malaria, a scourge many public-health experts call the world's most grievous disease. How determined? On a spring day in 1987, following in the tradition of scientists who put their own health on the line, the Naval Medical Research Institute captain pressed an open carton with five malaria-laden mosquitoes against his arm and waited until they feasted on his blood, infecting him with the parasite. For two weeks, it appeared that an experimental vaccine had protected him from the disease. But then, while giving a presentation at a San Diego conference, Hoffman began to shiver with the uncontrollable shaking chills of malaria. "Unfortunately," he says, "the vaccine failed."

Now, Hoffman is scrambling to get funding for an innovative idea dubbed MustDo (for multi-stage DNA vaccine operation). In papers submitted for publication, he and his colleagues describe promising new vaccine results and report, for the first time, the complete DNA sequence of a malaria chromosome. It's all part of an explosion of new science that could revolutionize "not just malaria vaccine development but the way the biomedical research is done," he enthuses.

Standing in Hoffman's way, however, is the daunting scientific task--along with the West's longstanding apathy toward malaria. The disease's toll is staggering. The parasite slays an estimated 2.7 million people a year worldwide--nearly all in developing countries--and infects some 500 million. Yet spending for malaria research and control totals about $100 million--a pittance compared with, say, the $2.5 billion the National Institutes of Health spend on cancer research.

What's more, the pharmaceutical industry's pipeline is nearly empty of new drugs and vaccines. Mosquito-control efforts are also faltering, and malaria is developing resistance to drugs, meaning they won't be effective much longer.

Now, however, officials are getting more serious about tackling malaria. In May, Gro Harlem Brundtland, the new director-general of the World Health Organization, launched a $20 million plan for cutting deaths in half by 2010. Meanwhile, WHO and industry representatives and others will meet at New York's Rockefeller Foundation on Sept. 17 to consider a plan for foundations and health agencies to fund academic-industry partnerships to develop new drugs.

COMPLEX CYCLE. The growing will to fight the disease couldn't come at a more opportune time. "Malaria has come back with a vengeance," says infectious-disease specialist Philip K. Russell of Johns Hopkins University School of Public Health. Cases have soared across Africa and Asia. Malaria was the top cause of casualties among U.S. troops in Somalia, despite the military's extensive use of malaria medications. And it has recently struck Americans in New York and tidewater Virginia.

The ideal solution would be a vaccine that prods the immune system to wipe out the parasite. It's a difficult task, partly because the life cycle of the malaria parasite is so complex. The dance of parasite and host begins when an infected mosquito injects a few dozen pointy malaria cells, called sporozoites, into the blood (diagram, page 70). The sporozoites rush to the liver and multiply like mad. By the time the immune system mounts a response, sporozoites in the liver have changed into a new, rounder form called a merozoite. Bursting out of liver cells, the merozoites infect and destroy red blood cells, causing fever, chills, and anemia. Some of these merozoites then become gametocytes--sex cells--which, after being sucked back into another mosquito, eventually give rise to sporozoites that begin the cycle all over again.

Back in 1987, Hoffman and other researchers hoped that a vaccine based on a key sporozoite protein would prod the body to make antibodies against the sporozoite, thus wiping out the parasite. The vaccine's failure taught them that fighting the parasite with antibodies alone is like trying to stop an elephant with a handgun: The antibodies need help from the other part of the immune system--so-called cellular immunity. Hoffman and others have been working with vaccines made of DNA strands that when injected into muscle, help generate an immune response involving killer T-cells. In his forthcoming scientific paper, he and colleagues will report that such a vaccine is safe and does stimulate a T-cell response in humans. Even with that improvement, however, scientists predict that no sporozoite-based vaccine will ever be better than 85% to 90% protective. That's woefully inadequate for Africa and other places where malaria-carrying mosquito bites occur many times a day.

STRUGGLING. In another approach, Louis H. Miller and colleagues at the NIH are fashioning a vaccine using proteins made during the parasite's blood stage. Such a vaccine can't prevent the disease but could lessen its severity. And by including both sporozoite and blood-stage proteins, Hoffman's MustDo vaccine promises to reduce infection rates and to temper any disease that does appear. "I'd like to think that in my career we will develop an effective vaccine," he says. Until that happens, drugs, used for treatment and prevention, are the best way to tame malaria.

With companies having shut down most of their malaria efforts, military and academic labs struggle to fill the void. At the Walter Reed Army Institute of Research, Colonel Wilbur Milhous heads a team that has devised a new drug now in human trials in Africa and Thailand. "It may be the most significant thing that's happened at this institute in 20 years," Milhous says. At Johns Hopkins, chemist Gary H. Posner has a drug that cures animals. Unfortunately, he can't find a drug company willing to take on its development. And at Harvard University's School of Medicine, tropical medicine specialist Dyann F. Wirth is searching for chemicals that can block a key mechanism the parasite uses to elude chloroquine and other drugs. That way, "we can regain the use of chloroquine," she says.

Malaria research is also about to get a boost from the deciphering of the parasite's DNA. J. Craig Venter, head of The Institute for Genomic Research (TIGR), will soon publish, with Hoffman and his colleagues, the first sequence of one of malaria's 14 chromosomes. It contains more than 200 genes. And the genes code for proteins that contain numerous repeats of the same building blocks, or amino acids--a pattern seen in no other species. Having the full genome will not only offer many more targets for drugs or vaccine possibilities, researchers say, it will also catapult malaria from a backwater area of science to center stage.

But all of this progress will amount to nothing unless industry steps in to carry drug and vaccine candidates from labs to pharmacies. And with a few exceptions, such as SmithKline Beecham PLC's collaborations with Walter Reed, companies aren't willing to spend the bucks.

That's why scientists are desperately seeking strategies to solicit more industry involvement. At a recent meeting of drug CEOs, NIH chief and Nobel laureate Harold E. Varmus challenged them to set aside profits from blockbuster drugs to tackle diseases such as malaria. At Harvard, Wirth is setting up a consortium to get public-sector and industry donations. And Dr. Alain B. Schreiber, CEO of biotech company Vical, which holds key patents on DNA vaccine technology, surprised his staff by agreeing to supply Hoffman with enough of his MustDo DNA vaccine for clinical trials. "Malaria is a wonderful setting to test the technology," explains Schreiber.

The most ambitious effort, however, is being led by Trevor M. Jones, director general of the Association of the British Pharmaceutical Industry, and Winston E. Gutteridge of the WHO. They've devised a plan for companies to collaborate with academic labs on projects funded with $15 million to $30 million a year from foundations and agencies. "I've felt a sense of despair as to whether we could find the right mechanism," says Jones. "But I now feel this will lead to actual drug hunting." If the cash does materialize at the Sept. 17 meeting, then there's a glimmer of hope that malaria can finally be conquered.