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Friday, June 13, 2008 - Page updated at 12:04 PM

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Gates Foundation tackles a giant that preys on Africa's children

Seattle Times science reporter

Reporting from Tanzania and Zambia

On vaccination days, pharmacist Abel Mdemu unsnaps the padlock on the old Bagamoyo Hospital morgue after lunch.

The squat structure was built from coral and stone in the late 1800s, the waning years of a slave trade that funneled more than half a million Africans through this port town on Tanzania's coast. But when Mdemu swings back the weathered doors, he could be stepping into a research lab on Seattle's South Lake Union.

Four high-tech refrigerators hum where corpses once lay. Their digital displays read 5 degrees C.

Their contents: Tiny glass vials that hold the first promising vaccine for malaria, an ancient scourge that helped nudge the Roman Empire into a tailspin and still kills more than a million people a year. Most victims are African children, their bodies ravaged by the mosquito-borne parasites.

Scientists have been chasing a vaccine for nearly four decades, only to watch it slip away time and again, like a genie who beckons but never delivers. This time their wish may finally be granted.

With an unprecedented infusion of cash and a businesslike approach, the Bill & Melinda Gates Foundation has kicked the quest for a malaria vaccine into high gear. Since 1999, no single government agency or organization has spent more on the effort. Of all the diseases the foundation has tackled, only AIDS gets more money than the $1.14 billion committed to malaria so far — and Bill Gates vows to keep the funds flowing.

"This is the time period where malaria can be largely conquered," he said in an interview. "Whatever it takes, we're just going to stay at it."

The Gates Foundation has almost single-handedly revitalized malaria research, says retired Maj. Gen. Philip K. Russell, a medical doctor who oversaw the Army's malaria research for more than 15 years. "It was not on anybody's agenda until Gates put it there."

The vaccine project embodies the Gateses' conviction that science and technology hold the best solutions to the health problems of the world's poor. A malaria vaccine would be the ultimate technological fix for a disease so entrenched in Africa that health crusaders once abandoned it as a lost cause.

A malaria vaccine would also represent the young Gates Foundation's first grand-slam: a breakthrough treatment for one of the world's great killers.

"Malaria is a disease where they're determined to win," says Melinda Moree, former director of the Gates-funded Malaria Vaccine Initiative.

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If a final round of field trials goes well, the drug being tested in Tanzania could be ready as early as 2012. But Gates may find that mountains of money and brilliant minds aren't enough to ensure a vaccine will get to the children who need it most.

The scientific hurdles are still formidable. No one has ever developed a vaccine against a human parasite. The current version is the most advanced in the world, but in early trials it kept only about a third of children from getting sick.

Even if the drug works perfectly, Africa's poverty and feeble infrastructure could undermine the foundation's best intentions.

Bagamoyo is only 45 miles north of Tanzania's capital, yet the power supply is so spotty the retrofitted morgue is wired separately and equipped with two backup generators and an alarm to ensure the vaccine stays cold.

Many clinics in Africa don't have refrigerators. Roads are often no more than rutted tracks. Villagers who travel days to visit a doctor may find no one there because health workers are fleeing for better-paying jobs. And while Gates has committed nearly $350 million to develop a vaccine, it will cost billions to manufacture and distribute it in countries where most people live on less than $2 a day.

Critics who fault the Gates Foundation for its faith in technological solutions say the shelves are already groaning with drugs and devices that never reach poor Africans because of these "downstream issues."

Dr. Regina Rabinovitch, leader of the foundation's infectious-disease programs, is well aware of the stakes. "We know our job is not finished when the vaccine is done," she says. "It doesn't do any good if it doesn't get out there."

MDEMU is running late.

Sixteen mothers and babies are waiting for the vaccine in Bagamoyo District Hospital's new pediatric clinic, built with Gates Foundation money. Nearby is a new children's ward paid for by the foundation, and a laboratory stocked with equipment most African researchers see only in catalogs. Foundation funding has boosted the staff of four doctors to 11, more than any other local hospital in the country.

Mdemu slides racks of vaccine out of a refrigerator in the old morgue and loads them into a cooler for the short trip across the compound in heat that steams like a sauna.

Slave traders favored Bagamoyo's harbor because of its proximity to the island of Zanzibar, hub of the human trade with Asia and Arabia. Today the town of 20,000 has reverted to its fishing roots. Each morning a fleet of dhows raises sail and disappears over the horizon of the Indian Ocean, one man in each boat bailing.

Lush rains nourish palm plantations, cassava plots — and Anopheles gambiae, the mosquitoes that transmit the malaria parasite.

The disease was eradicated from the Western world so long ago many Americans consider it no more than a historical footnote — an annoyance British bwanas warded off with a stiff gin and tonic.

But for the young Tanzanian women lined up on a hospital bench, malaria is as constant a presence as the centuries-old baobab tree that shades the courtyard. Most have shivered through the chills and sweats and have watched the sickness overwhelm friends or relatives. Some have carried comatose children to this hospital. All are here because they want better odds for the youngsters bouncing on their laps.

"He's always been healthy," said Asia Bundela, fanning her 3-month-old son, Benedicto. She doesn't quite understand the project but is clear on her reasons for making the two-hour trip to have her son inoculated: "I hope this medicine will keep him from getting sick."

Mdemu signals that the vaccine is ready, and the mothers file into an examination room. A nurse claps her hands to distract the unsuspecting infants, then delivers a jab to the thigh. The babies' eyes widen; wails pour out.

About 90 percent of those who die from malaria are African children under the age of 5. The World Health Organization estimates malaria kills a child every 30 seconds. At that rate, Seattle's 46,000 public schoolchildren would be wiped out in about two weeks, and the outrage would reverberate to the highest levels.

In Africa, many of the deaths aren't even recorded. Babies are buried quietly, mourned only by their families.

Children who survive can be left with brain damage. Those who make it to adulthood usually develop enough immunity to avoid being killed by the disease, but not enough to fend off repeated bouts.

DR. SALIM ABDULLA has seen enough malaria in his life. He wishes his fellow Africans were equally fed up.

"Too many people say: 'This is just the way it is. Everybody has to deal with malaria.' "

The Tanzanian physician, who leads the vaccine trials in Bagamoyo, started at a small hospital where malaria dominated the daily roll call of misery. HIV/AIDS may garner most of the headlines, but malaria is the biggest burden on African health systems. A typical village of 1,000 can suffer 600 to 700 cases a year. The World Health Organization estimates half a billion people worldwide are sickened annually, more than 60 percent of them in Africa.

In countries where the average person earns less than $400 a year, it's not unusual for families to spend a quarter of their income on malaria drugs. Harvard economist Jeffrey Sachs estimates the disease costs Africa $12 billion a year in medical expenses and lost productivity.

Abdulla is a genial man, but his smile vanishes when he talks about malaria.

"We can do better than this," he says, pointing to the packed clinic where more than 120 children are treated every day.

It's particularly frustrating because malaria is preventable and curable.

Bed nets infused with insecticide protect against female mosquitoes, which bite mostly at night. Though many malaria drugs have lost their effectiveness, good alternatives exist. But poverty and neglect have kept these simple tools from most Africans. Only 3 percent of young children in sub-Saharan Africa sleep under treated nets.

Diligence doesn't always guarantee protection. A university professor and a doctor say they get the disease at least once a year despite sleeping under nets. Mosquitoes are so thick in some parts of Tanzania that people average 1,000 infected bites a year — the highest rate in the world. New drugs still work, but history shows resistance is inevitable.

"This is why we need a vaccine," Abdulla says, spreading his arms to emphasize a point he considers obvious.

But until recently, a succession of letdowns and meager funding made many scientists question whether a malaria vaccine was possible. Few pharmaceutical companies were interested in a disease whose victims are too poor to buy shoes.

The Gates Foundation money transformed the landscape. Its Malaria Vaccine Initiative, managed by the Seattle-based nonprofit PATH, supports 10 vaccine projects. As in a business bent on quick results, promising candidates get fast-tracked and losers weeded out.

The foundation is putting up nearly $110 million for field trials.

Abdulla and researchers at nine other sites across Africa will track more than 16,000 children to see how well the leading vaccine candidate works. The answers should be in by early 2011.

One analysis says an effective vaccine could reduce malaria deaths by nearly 70 percent. But the study cautions that without significant improvements in Africa's health systems — from refrigeration to staffing to distribution networks — only a quarter of those lives will be saved.

RIPLEY BALLOU thought he had malaria beaten 20 years ago.

Then a researcher at the Walter Reed Army Institute of Research, Ballou and his colleagues were so optimistic about their first vaccine candidate they used themselves as guinea pigs.

"You put five infected mosquitoes in an ice-cream cup and hold it against your arm," Ballou recalls. "Then you wait to see if the vaccine works."

Within a week, the other subjects were sick. Ballou felt so good he went for a seven-mile run.

Two hours later his head was splitting and his body wracked with fever and chills. He didn't feel good for six weeks.

"It was the worst illness I ever had," he says. "You can just imagine what a little kid goes through."

Ballou keeps a vial of that early failure in his office at GlaxoSmithKline's vaccine division in a suburb of Brussels, Belgium. Under an agreement with the Gates Foundation, GSK manufactures the vaccine being tested in Africa.

The company also recently retooled a production plant at its own expense to crank out doses for the clinical trials — and, Ballou hopes, initial sales.

The new drug is descended from the dozens of disappointments Ballou worked on in the Army and in collaboration with GSK scientists. Scientific obsession drove him on, coupled with the hope of making a difference.

Ballou joined GSK four years ago to shepherd the vaccine through field trials.

"My whole life has been chasing this project," he says.

The fact that few people ever become fully immune to malaria is a red flag for vaccine makers.

With diseases such as mumps and measles, if you survive one infection you're safe for life. Vaccines against those bugs are relatively simple: Inject a killed or synthetic version of the virus, and the body is tricked into mounting an immune response that fends off future assaults.

But if a virus is a Lincoln Log, the malaria parasite is a log cabin.

Viruses have only a handful of genes. Plasmodium falciparum, the single-celled malaria parasite most common in Africa, has 3,000. Its life cycle includes more than 10 distinct stages, each expert at evading human or mosquito immune systems.

The wormlike version a female Anopheles injects with her bite lingers only a few minutes in the bloodstream before racing to the liver, where it's hidden from antibodies. There it burrows into cells and morphs into a kind of sack that fills with progeny as the parasite divides.

By the time it bursts out of the liver, a single parasite will have multiplied into 10,000 to 30,000 organisms. Each invades a red blood cell, multiplying, feasting on hemoglobin, then exploding from the cells — and destroying them in the process. Some children lose half their red cells to the voracious invaders.

Scientists don't fully understand how the parasite shifts its shape, but most stages seem to be triggered by chemical signals from the host's body. Fever, for example, may actually assist the parasites by spurring them to synchronize their cycles.

The classic symptoms of chills, fever and drenching sweats occur as parasites annihilate blood cells and release toxins. The body heats itself up in an attempt to cook the attackers to death. Parasites can also stick to capillaries, disrupting blood flow to the brain, lungs and placenta.

By the time immune cells are mobilized, the parasite is shifting shape again. Like a con artist with a suitcase of wigs, plasmodium can rearrange its outer surface in more than a thousand combinations.

Early vaccines didn't stand a chance.

"Malaria is the toughest we've ever seen, with the exception of HIV," says Russell, the former Army research chief.

WHEN MUCH of the developed world lost interest in malaria, the military kept up the fight because the disease historically killed almost as many troops as bullets did. More than 60,000 died of malaria in the Pacific Theater during World War II and more than half a million fell ill. Entire units in Vietnam were laid low.

Malaria has shaped military and human history since before the time of Alexander the Great, whose death is blamed on the parasite.

Malaria nearly obliterated America's first permanent settlement at Jamestown and sickened several presidents. The U.S. Centers for Disease Control and Prevention was established in Atlanta to fight the disease, which was rampant in Southern states at the end of World War II. Armed with window screens, DDT and a mandate to drain swamps, health officials banished the disease from the United States by the early 1950s.

A Global Malaria Eradication Campaign was launched in 1955, the year Bill Gates was born.

The U.N.-sponsored program was a success in temperate zones such as Europe, where mosquitoes flourish seasonally. Rich nations backed control programs in India and Sri Lanka, and malaria cases plummeted. But when the money went away, the disease came back full force.

In Africa, wide-scale malaria control was never even attempted.

By the 1970s, worldwide malaria deaths started to soar as the parasites developed resistance to chloroquine, a workhorse drug that costs only pennies a dose. Development and deforestation expanded mosquito-breeding grounds, and the use of DDT dribbled to a halt after the U.S. banned the insecticide. AIDS and malaria began a cycle of amplification, with one disease leaving people more vulnerable to the other.

Today, health officials say, malaria in Africa is worse than it was 40 years ago.

ABOUT THE TIME global malaria-control programs were unraveling, vaccine researchers thought the silver bullet was in their sights. Advances had allowed them to sequence and clone a key gene from the malaria parasite.

"There was a feeling that a vaccine would be a slam-dunk," Ballou says with a rueful laugh.

Then one after another, the drugs they developed proved worthless.

The turning point came with the addition to the team in 1987 of a soft-spoken researcher born in Egypt, educated in France and once employed in Pennsylvania. Joe Cohen left academia for the drug industry so his discoveries would have more impact.

The problem with the early vaccines was that the main ingredient — small proteins from the parasite's outer membrane — evoked only a weak immune response. Not nearly enough to disable the parasites, which Ballou likens to stealth battleships. "You have to have a lot of hits on them," he says.

Revving up the immune response is Cohen's specialty. His breakthroughs have earned patents and helped revitalize GSK's vaccine division.

He started his upgrade of the malaria vaccine by hooking the small parasite proteins to much larger particles — the shell of the virus that causes hepatitis B. The combination forms a ball studded with malaria proteins and big enough to set off all the immune system's warning lights.

Cohen and his colleagues boosted the vaccine's potency even more by adding a mixture that includes an oily emulsion, bits of bacteria and soapy molecules derived from tree bark. Vaccine makers call such substances adjuvants and aren't sure exactly how they work. But the results are clear: Like the crew of the Starship Enterprise shifting to warp speed, they jolt the immune system into high gear.

Many outside scientists were skeptical. If even one parasite escaped the dragnet, they argued, the vaccine would be worthless.

The team persisted. In 1995, the vaccine protected six out of seven volunteers.

"We had a lot of champagne," Cohen recalls. "There was a light at the end of the tunnel, though we were naive about how long that tunnel was going to be."

PHARMACEUTICAL companies are often cast as the villains in global health. Impoverished people don't buy drugs, so few corporations invest in diseases of the developing world. GSK, Europe's biggest drug maker, earned special scorn when it sued South Africa to block distribution of generic AIDS medications.

In 1999, GSK was on the verge of a reorganization that would have shuffled the malaria-vaccine project into obscurity. Cohen was despondent. He spent a worried weekend, then called his boss at home with a proposal: Create a division to focus on malaria and other neglected diseases, and let Cohen scrounge the money from outside sources.

Today, "Joe's Division" and the malaria vaccine are a source of pride for the entire company.

"People I don't know e-mail me and say: We're so glad you're doing this," Cohen says.

Gates Foundation money was the lifeline.

To many nonprofits, an alliance with the drug industry is akin to a pact with the devil. But Bill Gates didn't become the world's richest man by disdaining capitalism. His foundation takes the view that industry's expertise is vital to push products through to market and accomplish goals where others have fallen short.

The foundation put up $6 million, matched by $2 million from GSK, for a study in 2,000 children in Mozambique. The vaccine prevented malaria in 35 percent. Nearly 50 percent of children were protected from the severe form of the disease most likely to kill.

Those results weren't good enough for the Army, which is seeking almost perfect protection for soldiers. But malaria's sweep in Africa means even partial protection could have a big impact.

"We may not have the perfect vaccine here, but we think we have something that could actually save lives," says the foundation's Rabinovitch.

The Malaria Vaccine Initiative's contract with GSK sets a ceiling on the price that can be charged for the vaccine, but it also guarantees a profit. Otherwise, the company would have no incentive to keep producing a drug that has no market in the wealthy world, Rabinovitch says. GSK estimates it has invested $300 million of its own money in the vaccine project.

But it's still unclear who will pay for the finished product. The vaccines that African children get now cost a few cents to a few dollars. The price of the more complex malaria vaccine will depend on how many countries use it, but it could be as high as $9. Up to 25 million children a year would need three doses, pushing the potential annual cost to nearly $700 million.

The hope is that rich nations will pay through international groups like the Global Fund to Fight AIDS, Tuberculosis and Malaria and a vaccine program called the GAVI Alliance — both of which get major grants from the Gates Foundation.

THE GSK VACCINE gets the most attention, because it's so far ahead of the pack.

"This is going to sound cocky and immodest," Cohen says, "but there is nothing else out there today that is even close."

The Gates Foundation rarely bets on a single horse, though. Several other possibilities are in the pipeline.

Patrick Duffy, of Seattle Biomedical Research Institute (SBRI), is tracking 5,000 Tanzanian children to understand and tap the partial immunity that develops naturally by age 5. SBRI is also exploring a vaccine to protect pregnant women from a form of malaria that attacks the placenta and can kill both mother and fetus.

The Gates Foundation has license to bet on even longer shots, such as the project run by Duffy's SBRI colleague Stefan Kappe. In an insectary near Lake Union, Kappe isolates parasites from malaria-infected mosquitoes. He's looking for a way to genetically cripple the parasites so they aren't able to make people sick. The harmless parasites could then be used in a vaccine.

Another Gates-funded scientist is using radiation to neuter parasites. Others are exploring ways to prevent the parasite from destroying blood cells or block reproduction inside the mosquito. The ultimate goal is a vaccine that is at least 80 percent effective. That will probably mean a combination drug that attacks the parasite on several fronts, Rabinovitch says.

"We're looking under every rock we have."

THE LONG RAINS are starting in Morogoro, a city nestled at the base of a mountain range 100 miles inland from Bagamoyo.

Duffy does much of his research here, in a lab stuffed with some of the most advanced equipment in Africa. But the regional hospital, which serves nearly 2 million people, is typical of a country where annual per capita health spending is less than the cost of a grande mocha.

Mothers squeeze onto wooden benches and spill onto the concrete floor of the waiting area. Their boldly patterned wraparounds paint a colorful picture. The coughs, cries and feverish stares of the children they hold are a portrait of misery.

Malaria is the number-one complaint, says head nurse Tatu Kasuku. More than 200 children are treated here every day, she says, reaching down to tickle youngsters as she passes through the crowd. Diagnosis is not always reliable. Today, the power is down, so microscopes don't work.

The hospital has three general practitioners but needs eight. Kasuku's nursing staff is half the size it should be. Ambulances don't work, and supplies of malaria medications sometimes run out.

In the children's ward, 5-month-old Mkude Mwishehe lies motionless on a narrow bed. His mother mops sweat from his body. Quinine drips into a vein through an IV needle.

On average, 10 children die here every month. Early treatment matters in malaria, but by the time Mkude's mother got him to the hospital, a single drop of his blood seethed with more than 200,000 parasites.

Kasuku waves away Anopheles mosquitoes resting on his IV bag. "The mosquitoes are so bad," she says, proceeding down the line to the next sick child.

When malaria season is at its peak, 60 patients often crowd into the ward's 30 beds. "They have to share," she says with a shrug.

THESE ARE the realities of health care in Africa that many Westerners fail to factor into their optimistic plans, says Dr. Theonest Mutabingwa, who has studied malaria nearly 30 years. Through decades when the world seemed to have forgotten the disease, he kept offering blunt reminders.

Today, he collaborates with Duffy in Morogoro, leads several malaria-drug studies — and is still wrestling with the logistical challenges his country poses. A load of scientific equipment has been stranded in customs for six months, and he's heading to the capital to plead for its release.

Mutabingwa, who holds appointments with the Seattle Biomedical Research Institute and the Tanzanian government, likes to say he's not "anti-vaccine." But he is concerned about the emphasis on a one-shot solution.

A vaccine that protects less than half the time could be worse in the long run than nothing at all, he fears. "Everyone will say: This didn't work. And then they will have lost trust in vaccines." African nations may decide a vaccine that isn't very effective isn't worth adopting.

Vaccines have to be kept cold, but Mutabingwa ticks off the many things that go wrong in Africa: Shipments sit in the airport for hours; the power blinks out at storage depots; kerosene-powered refrigerators break down.

The Gates Foundation hopes to piggyback the new malaria vaccine on Africa's most successful public-health program: childhood immunizations. It's taken 20 years to establish that program, Mutabingwa points out, and nearly a third of kids still don't get the shots. Several other new vaccines, including pneumonia and childhood diarrhea, are expected to come on line before malaria, taking up what little extra capacity exists in the system.

Few in the field of global health criticize the powerful Gates Foundation openly. Those who do say new drugs and technology will not solve the health problems of the developing world. Instead, they argue, Gates' vast wealth would be better spent hiring and training medical workers, improving basic sanitation and water quality and strengthening the public-health networks that were largely responsible for reducing disease in the developed world.

"The Gates Foundation wants a big, showy breakthrough that saves lives," says William Muraskin, a health historian at City University of New York. "Who wouldn't want that?" But, he asks, where's the benefit in saving a child from malaria, only to have her die from drinking dirty water?

Programs paid for by outsiders and narrowly focused on specific diseases could actually undermine public health in Africa, warns Laurie Garrett, senior fellow at the Council on Foreign Relations. Cash-strapped health ministries cater to rich donors' interests, leaving basic health programs to suffer.

"The years ahead could witness spectacular improvements in the health of billions of people ... ," Garrett writes, "or they could see poor societies pushed into even deeper trouble, in yet another tale of well-intentioned foreign meddling gone awry."

Rabinovitch says the foundation has taken such criticism to heart. But one of the early lessons learned is that even the world's richest foundation can't do everything.

"Our malaria work is driven by a belief in the power of innovation to improve health," she says. Vaccines get the most money, but the foundation also funds research on malaria drugs, better bed nets, new insecticides and ways to combat drug resistance. A program in Zambia aims to cut malaria deaths 75 percent with low-tech approaches, such as bed nets and mosquito spraying.

The vaccine program is working with African nations to find out what it will take to get the drug to those who need it, and looking for ways to streamline the approval process. And if the vaccine doesn't make sense in areas where malaria can be controlled more cheaply with nets and sprays, that's fine, Rabinovitch says.

"While I am a proponent of vaccines, I will do whatever works in malaria."

AT THE BAGAMOYO hospital, the babies have forgotten the trauma of their inoculations and are suckling quietly. A van pulls up outside the hospital to shuttle the families back to their villages.

Dr. Abdulla moves on to another of the day's tasks.

It's a trial run to see if frozen blood samples from the children can be shipped to Belgium for analysis at GSK without thawing or getting damaged in transit. A courier idles his truck outside the lab while white-coated technicians extract the vials from the minus 70 C freezers in a cloud of frozen smoke, pack them in liquid nitrogen and Styrofoam, and tape the box shut.

The mood is tense. If the package arrives intact the next morning, the Bagamoyo team members can start regular shipments of the experimental blood samples. If not, they have to keep repeating the drill.

Abdulla laughs dryly.

"Things that are routine anywhere else can't be taken for granted here."

Seattle Times reporter Kristi Heim contributed to this report.

Sandi Doughton: 206-464-2491 or sdoughton@seattletimes.com

Copyright © 2007 The Seattle Times Company


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