Breaking the Cycle

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Breaking the Cycle
Though often overshadowed by the specter of AIDS, malaria remains a deadly menace in Africa. The U.S. Army and its partners have been trying to develop a vaccine for decades, but is this a battle they can win?

Okoth did not have even the cheap anti-malarials. She carried Bibianca, as she tells the story, to a nearby government dispensary, which had no effective antimalarials on hand and whose attendants could tell Okoth nothing more than that Bibianca appeared to have malaria. They referred her daughter to another government health facility, where Okoth paid 20 shillings as a registration fee and was told that Bibianca, who by then was lapsing into a coma, needed a blood transfusion. But the facility didn't have the equipment or blood to do the procedure. Okoth was referred yet again, this time to a health facility up the chain of Kenya's medical bureaucracy, Kisumu District Hospital, 30 kilometers away and reachable only by a public bus that would cost Okoth a considerable sum, about 100 shillings.

She needed to go home for the money, but by that time it was too late to catch a bus to Kisumu. When Okoth arrived at the hospital the next afternoon, her daughter had already been in an untreated coma for a full day. Unable to breathe, Bibianca was given oxygen for two days. Now, as Ogutu and Heppner study the girl, she is breathing on her own, and her vital signs look stable. She is receiving an intravenous quinine drip to fight the parasites, but her coma has shown no signs of breaking, and both Ogutu and Heppner worry about what they cannot see in Bibianca. "There's just no way of knowing," a frustrated Ogutu says. "Not here."

Heppner sighs, shakes his head.

"They don't have the right tools here to measure the glucose [in her blood]," Ogutu says softly to Heppner, alarmed because a low glucose level can itself cause a coma. "There's no glucose meter."

"I think I'd be giving her glucose every eight hours," Heppner says. "But there's a danger in giving someone too much glucose. You need that meter."

"Yes," Ogutu says, touching Bibianca's forehead. "You ask, Why isn't there a meter?"

Part of the reason that Heppner sees a vaccine-based solution as a medical and moral imperative is that he views the health-care infrastructure of African countries as woefully inadequate to the task of treating malaria. And Bibianca's case is just one more reminder. Heppner and Ogutu say that the technical equipment used at the Kisumu hospital to look for microscopic parasites is substandard, meaning that some malaria cases will be missed. And there are no first-line antimalarial drugs yet at the hospital; they are caught up in a Kenyan bureaucratic tangle that has them sitting in a distant warehouse.

"What good are treatments for malaria if they're not in a hospital?" Heppner says. "That's why you need something like a vaccine that reduces the need for treatments. But look: Obviously, you still need equipment, you still need drugs -- people are getting sick. I think it's just not possible to [address] malaria without looking at all of it -- poverty, infrastructure, lack of hospitals, bad [health care] delivery. And there will be challenges, too, for anyone who develops a vaccine. If we have a vaccine, we'll need to get it to people, and so you need to start thinking about all that now."

From the corner of the bed, Benta Okoth clears her throat. She rubs at her eyes; she jerks her head away from the window and mumbles something in Luo.

"She is saying that she won't be able to sleep, really, until her daughter comes out of the coma," Ogutu whispers. "Too nervous."

Okoth is still mumbling. Ogutu leans closer.

"It makes her very scared," Ogutu adds. "It has happened before, she says."

Happened to Bibianca?

Okoth morosely shakes her head. No. For a while, she can't speak. Then her words come in a torrent. Her head drops. Ogutu takes a deep breath: "She says she's already lost two children. One at age 10 to a heart condition. Another at age 7 to malaria or typhoid fever or meningitis. It is that way with malaria quite often. No one around is sure what it is. No doctor was present for the second child, it seems. The child just died."

Okoth turns back to the window. Ogutu whispers to her that he will return, assuring her that he thinks her daughter is improving. But all those hours her comatose brain was without treatment -- almost no one recovers from that kind of malaria without paying a severe price, he will say later. "It can't be good," he mutters in English. He walks on to the next bed, where another mother, bending over another closed-eyed child, tells him her story.

DONALD GRAY HEPPNER JR. DOES NOT GIVE UP EASILY ON A DREAM. Raised in Lynchburg, Va., and inspired by the intellect and stature of physicians in his town, he set his sights on becoming a doctor, only to be rejected by every medical school to which he applied. Rather than surrender, he started knocking on doors at the University of Virginia, where he had graduated with an undergraduate degree. He got a job there as a technician in an endocrinologist's research laboratory, hoping to impress his superiors enough that their recommendations would help him gain entry to U-Va.'s medical school.

Admitted into the medical program a year later, he became intrigued by the work of faculty members who had a passion for infectious diseases -- "the dominant tribe" of the med school, he says. He was particularly fascinated by their work with the deadly, resilient malaria parasite.

After graduating from medical school, he did his internship and a residency at the University of Minnesota, where, in the late '80s, he went looking in his spare time for another lab to advance himself, offering his services for free. He assisted a malaria researcher who, among other things, was growing falciparum parasites. While in Minnesota, he joined the Army Reserves after hearing from an involved Army doctor about the armed forces' work in tropical disease research. But Heppner didn't sign on for active duty in the Army until 1990, when he accepted a position as an infectious disease officer in Walter Reed's malaria program, which had first tested a malaria vaccine in 1986.

Most researchers in the program, wanting to assist their colleagues in the study of promising vaccines, volunteered to serve as subjects in at least one clinical trial. Heppner volunteered for the trial of a vaccine called RLF, which was a complete bust, just one in a long series of failures during the '90s. Heppner spent four years in Thailand, running a lengthy clinical trial of a greatly anticipated vaccine invented by a prominent Colombian researcher. That one flopped, too, but by then Heppner was convinced that the research community was on the right path. And besides, it was Heppner's nature. "I'm not a morose guy," he says. "Every time we had a disappointment, I saw a benefit."

David Lanar has admired Heppner's resolve and optimism. "He's very supportive, and a [researcher] always appreciates support in a [field] so . . ." -- Lanar pauses, searching for the tactful word -- "uncertain." Heppner became chief of the Walter Reed malaria program in 1999. Many members of the department had more glittering aca-demic backgrounds than Heppner's. But, at 50, Heppner is about nothing so much as tenacity. His license plate spells MALARIA. A few weeks after his trip to Kenya, he will head to Paris to speak about RTS,S to a symposium of immunologists. He says his speech will note that the development of RTS,S has been "a study of perseverance."

THE ARMY'S PURSUIT OF A VACCINE, any vaccine, is never rooted in altruism. Other scientists in the malaria research community might be chiefly focused on saving foreign children, but the Defense Department has its own agenda. "The Army's goal above all else is to protect American soldiers," Heppner says.

To keep soldiers alive and fit for duty, the Army has been attacking cruel diseases in its ranks for three centuries. Its immunization efforts flourished as early as the Revolutionary War, when Gen. George Washington, responding to a lethal smallpox outbreak among his troops, agreed to recommendations from his medical corps that soldiers be inoculated with an application of live smallpox virus to the skin, a painful procedure that nonetheless protected against the disease.

During World War II, the Army recorded more than a half-million cases of malaria among its troops in the Pacific theater. "This will be a long war," Gen. Douglas MacArthur reportedly said, "if for every division I have facing the enemy, I must count on a second division in the hospital with malaria, and a third division convalescing from this debilitating disease."

Intravenous quinine helped to treat the disease by neutralizing the parasites in the infected. It got soldiers back on their feet, though in many cases recoveries took weeks. In 1965, while fighting in Vietnam, more than 10 percent of American troops contracted malaria, the beginning of a six-year wave that resulted in 80,000 cases of the disease among GIs there, according to an Army study. In some Army units deployed to Vietnamese jungles, malaria rates were as high as 60 percent. Only effective drugs kept deaths from the disease low (less than one in every 500 troops who fought in Vietnam).

Regulations prohibit Heppner from lobbying Congress for funding, and his discussions with military brass have had at best a negligible impact in recent years: The funding that his program receives from the Defense Department has increased little. Heppner and his Army colleagues remain serious players in the vaccine research field only because of the largess of other groups. His department received $2.7 million last year from the U.S. Agency for International Development and $1 million from its vaccine collaborator GlaxoSmithKline. But his most critical source of funding in recent years has been the private nonprofit Malaria Vaccine Initiative, created with a grant from the Gates Foundation in 1999.

Worldwide funding for malaria, last calculated by the research group Malaria R&D in 2004, stood at $323.4 million. Columbia University economist Jeffrey Sachs estimates it would take $3 billion to vaccinate every African child who needs it.

Last year, the White House announced a five-year plan and pledged $1.2 billion to fight the disease with drugs, bed nets and pesticides. Publicly, the pledge has drawn praise from malaria activists. But, privately, several of the same activists observe that the commitment is less than one-tenth of the funding in the White House's AIDS initiative -- and assert that much of the money is merely making up for the Bush administration's previous cuts to malaria programs. And they note that what's missing is specific funding for malaria vaccine research. Administration spokesmen, noting that the president plans to convene a malaria "summit" in December, say that Bush's plan to fight the disease reflects a preference for spending any new money on techniques already yielding benefits.

IN ANY WAR, AS HEPPNER KNOWS, the longer a man chases a resilient enemy, the more likely he will acquire a grudging respect for it. "The parasite has survived everything meant to eradicate it to this point," Heppner says. "You can't say that about many things under attack this long. It's been a battle."

A few drugs have had an upper hand temporarily against the parasite, most notably an antimalarial called chloroquine, which was developed in 1934 and proved effective in Africa, off and on, for several decades. But by the 1970s, adaptive parasites began showing signs of resistance to chloroquine. By the late '80s, resistance to the drug was fierce, as evidenced by increasing deaths among children who used it. Africa's new front-line antimalarial became sulfadoxine-pyrimethamine, commonly called SP. But the parasites' resistance to SP took a frightening leap within five years, and by 2004, the drug's rate of protection was so low, and so many kids were dying, that the Kenyan Ministry of Health concluded that SP ought to be phased out, too.

That hasn't stopped African parents from buying SP for their ill children. The drug costs just pennies. Nowadays, a new antimalarial in Kenya receiving international subsidies is Coartem, a so-called combination therapy. There are high hopes for Coartem, not least because it contains several components, which means the parasite will need to become resistant not to only one element in the drug but several. Still, Heppner sees the same fate awaiting Coartem as every other drug: obsolescence and failure.

But Heppner and his allies at GlaxoSmithKline face their own stiff challenge: Never has anyone created a successful vaccine against a parasitic disease affecting a human being. Their chief weapon for the moment is RTS,S, whose goal is to destroy the parasite before it leaves the liver and enters the blood. The vaccine contains a part of the same protein present on the surface of the parasite as it attempts to invade the liver. Researchers believe that the protein will be recognized by the body as a foreign invader, triggering the body's immune system to attack the proteins wherever it can find them, including the proteins of incoming malaria parasites.

Heppner knows that, scientifically speaking, this is a bold combat plan, complicated by the number of invading parasites that accompany a bite from an infected mosquito, sometimes as many as 100. Heppner uses a combat metaphor: "The idea is that RTS,S will work like a Patriot missile system," he says. "All these parasites will be coming in like missiles, and RTS,S will be shooting them down. And even if a couple of the parasites get through sometimes, the vaccine will have been successful -- because it will have already significantly reduced the number of missiles that we have to get [later]."

RTS,S he says, "takes aim at the parasite twice. It tries to get the parasite with antibodies before it enters the liver, and then it will surveil the liver with special white blood cells that will attack the [parasites that make it in] . . . If we have a combination vaccine made up of several vaccines, RTS,S will be the first attacker. The other vaccines will get the remaining parasites at the next stages."

At the time of the Silver Spring trials. the plan was to test David Lanar's vaccine in the bodies of those 22 volunteers. The goal was to train the body's immune system to recognize a protein on the parasite that protects it inside the liver, at its most vulnerable developmental stage.

Just as some skeptics don't believe an antimissile system can be foolproof, there are those who see serious flaws to the Walter Reed-GlaxoSmithKline approach. One of Heppner's rivals, Louis Miller of the National Institute of Allergy and Infectious Diseases, questions the idea of trying to fight off malaria infection altogether. Miller has devoted himself to creating a vaccine whose principal aim is simply to slash the number of parasites, so as to reduce the severity of the disease. Something like RTS,S hasn't yet shown in clinical trials that it can stop most or all parasites, Miller says. "And an important thing to remember is that malaria isn't like measles or mumps; it isn't something that people, young or old, necessarily get just once in their lives and it never comes back. This is more like flu; many people are likely to get malaria several times in a lifetime . . . So how long is the [RTS,S] vaccine or any other vaccine going to protect people? How often will they need to be [re-vaccinated] if the [goal] is to stop all the parasites?"

With his vaccine, Miller aims to keep children alive long enough for their bodies to build immunity against severe disease. But that alone isn't enough for Heppner, who needs to keep soldiers and Western travelers from falling ill at all.

Heppner says that the Army and GlaxoSmithKline can't be sure how long protection will last beyond the duration of the RTS,S clinical trials. Like the critics, he wonders whether the parasite might one day mutate in the face of a vaccine and render it less effective, if not impotent. "What we're doing here -- trying to stop the parasite altogether and prevent infection -- may be more complicated," Heppner says. "But that doesn't mean it's not the best way."

ON A SATURDAY MORNING, the 10th day after being bitten by the infected mosquitoes, a small group of volunteers in the clinical trial of Lanar's vaccine say they feel great. The nursing student Samantha Nolte and her fiance, John Davis, tease each other over who between them will be safe from malaria the longest, knowing the longer that parasites don't show up in their blood draws, the more money they'll take home.

Meanwhile, the volunteers feel as if they are on a mini-vacation, though most are still going to their jobs. Walter Reed has put them all up at the Courtyard by Marriott in Silver Spring, where they eat breakfast and then go about their normal routines. The doctors, researchers and support staff also have rooms at the hotel, where they study the volunteers' blood, looking for parasites. "If anyone does get sick, we'll know it right away, and we can quickly treat them right here," Heppner says. "All they'll have to do afterward is walk down a hallway, go into their room and rest."

Nolte goes shopping at a mall with Davis. At about 1:30 that afternoon, her cellphone rings; she receives news from a Walter Reed nurse: Parasites have been detected in her blood; the vaccine has failed to protect her. Nolte is stunned. She feels great, she tells herself. Well, maybe not exactly great. Actually, she's feeling a tad lethargic, listless. But for now she still can't quite believe this news.

In the next hour, Nolte is back at the hotel. A researcher pulls out a glass slide with the thinnest smear of Nolte's blood, sticks it under a microscope and shows a parasite to Nolte. It looks like a round dot with a crescent moon surrounding it. While the nursing student in her understands the ruinous wonder of this thing, another part of her is still grappling with a question: How can anything this tiny make you so sick?

The 57-year-old Lanar has reminded himself that one positive test will not amount to failure. If most of the volunteers are protected by his vaccine, it will be dubbed a success. If, say, 18 of the 22 are protected, it will be declared a stunning achievement, with profound implications for malaria and vaccines. He might still make it onto the cover of Science.

But over the weekend, many more of the trial subjects test positive, including all six volunteers who did not receive the vaccine. Several of the inoculated volunteers have gotten sick, experiencing the first wave of malaria and receiving treatment that will cure them within a couple of days. John Davis tests positive the next day, and within a day he is racked by fever and the shakes. Brian Kiragu is positive, too.

However, the Georgetown grad student Matt Randall continues to show no parasites. "I'm feeling good," he says. "I've still got some confidence in the vaccine because nothing has happened to me."

The next day, Lanar comes to the hotel to receive disappointing numbers: More than half of the volunteers have tested positive. While he digests that information, the numbers are updated to include more positive tests.

"Well, sometimes something works, and sometimes it doesn't," he says, then reminisces about the vaccine's high moments, when it tested so well in mice. "This is a [vaccine] that the worldwide vaccine community wanted to evaluate for many years, and now we have done that. Sure, I'd like to have been the inventor of the malaria vaccine. But people who get awards must stand on the shoulders of those before them."

A few seconds later, a strange sound comes from the suite's bathroom. Lanar walks over to investigate. A woman in sweats, a trial subject, is bent over a toilet, vomiting.

"Are you all right?" Lanar asks.

She retches again.

"Obviously not," he says.

"Ohhhh," the woman groans, face down in that toilet bowl.

"Oh, no," Lanar says. "Do you want to see a doctor?"

It takes a while for her to get the next words out. "I just saw one."

She finishes vomiting and trudges out of the room. Lanar turns back and falls into his chair. It has been a long day.

"Yeah," he says, allowing himself a little smile, "that could have gone better."

IN WASHINGTON, THE TRIAL SUBJECT MATT RANDALL, whose confidence in the vaccine has remained unshakable, receives a call early in the afternoon on the 12th day of the trial. Parasites have been found in his latest blood test.

He rides the Metro back to the hotel in Silver Spring. Within a few minutes, he is experiencing terrible chills and is huddled up on a back seat, with a scorching headache. He has a fever, too, which will peak at 102.5 degrees that night.

Now all 22 trial subjects who took the vaccine have tested positive for the parasite. The vaccine is a failure. Lanar would like to figure out, if possible, where it went wrong. "Either immunity was not developed with the way we designed the vaccine, or our basic idea was off the wall," he says. "But am I fatalistic now about vaccines? No, not at all. We will still have a malaria vaccine someday. It's bigger than me; it's bigger than any of us."

Heppner is also resolute. He says he has a promising vaccine to be tested in the fall and that Lanar is helping to develop a new one, too. And he is more confident than ever in RTS,S, whose latest clinical trial appeared to protect against severe malaria for 18 months in about half the children tested. "There have never been numbers like that in the history of malaria research," he says. "We are getting closer all the time to what we all want . . . But I don't have a date, a year, for anybody. I don't think anyone honestly does. We've never faced anything like the parasite."

Michael Leahy is a staff writer for the Magazine. He will be fielding questions and comments about this article Monday at noon at washingtonpost.com/liveonline.