The Search For Solutions

In medicine there are three kinds of good ideas: the obvious ones, the not-so-obvious ones and the sort that Dr. Edward Jenner came up with in 1796. He had heard from his neighbors in rural Gloucestershire, England, that people who caught cowpox didn't get the more-lethal smallpox very often, and he suspected the first disease was triggering the body's defenses against the second. The notion must have sounded preposterous to his colleagues. At the time they didn't have words for the "immune system" and "germs" because they hadn't figured out either concept. Nonetheless, Jenner believed in his idea, and so did a mother who let him test it on her 8-year-old son, James Phipps, when cowpox broke out on her farm in the spring of that year. The doctor collected pus from an infected milkmaid, shot it into the boy, and waited. After six weeks he injected the boy with smallpox. He waited some more until he was sure James wouldn't get sick. Then he announced the dawn of an era. He had invented the vaccine. No doubt Jenner sounded crazy when he proposed his idea. Revolutionaries often do.

Vaccines have transformed the entire world by eradicating smallpox, and they have largely rid the developed world of polio and measles. If vaccination is one of the most important medical innovations of the past two centuries, it is also one of the most cost-effective. Vaccines do not cure disease; they prevent it, which is better. Immunize 100 people and you not only keep them healthy, you stop them from infecting thousands more. Each year, vaccines save uncountable numbers of lives, uncountable because in the West it is impossible to imagine life as we know it without them—which makes it all the more confounding that millions of people still can't get them. When it comes to immunization, much of the developing world is still stuck in the 18th century. In vast parts of rural Africa, Asia and Latin America, kids don't get any of the basic vaccines available in developed countries; they die because of that fact. And no one anywhere gets routinely and effectively immunized against the big global killers—HIV, tuberculosis and malaria, which together take 6 million lives each year—because, even with all the technological prowess of modern medicine, good vaccines for those diseases do not exist.

Why this grim reality? There are challenges at every level. The science is hard: doctors struggle to run clinical trials in the shambles of the developing world, and biologists can't always outsmart bacteria and viruses. The logistics are hard: the path a vaccine takes from the lab to the patient is fraught with difficulty. The financing is hard: cost-effective though they are, vaccines are still too expensive for most poor countries to afford, and experience has shown that it doesn't work when rich countries just throw money at the problem. Considering the obstacles, it's kind of amazing that people get immunized at all.

And yet, 211 years after Jenner treated his first patient, those obstacles are starting to look a little more surmountable. The basic idea behind vaccines hasn't changed much; they work the same way, and the goal is still to use them to wipe out the world's worst diseases. But something else has changed: Jenner has a large new group of heirs, and they share his doggedly optimistic attitude. They include a doctor who's making it easier to do high-tech science in low-tech environments; a biologist who has spent 23 years failing to defeat HIV and trying, trying again; an engineer who thinks patients can ward off disease with a cheap inhalable powder, and a banker who has improved the health of poor people by getting rich people to invest in bonds. All four are given to unorthodox thinking. Put more bluntly, sometimes they sound a little crazy. But if they're crazy like Jenner, that's probably a good thing.

Dr. Fred Binka, 54, was standing at a hospital bed one day two weeks ago, looking down on a sleeping 4-month-old girl. Her name was Jennifer Mansua, and she had spent most of this day in the Kintampo Health Research Centre, in central Ghana, in the dark—the power kept going out. The nurses gave her blood transfusions by candlelight and tried as best they could to keep mosquitoes away from her. The mosquitoes, however, had already won. Jennifer had malaria. Her mother, Cecilia Nakabu, had tried to cure her with methods that didn't involve a costly hospital visit—over-the-counter meds, TLC, prayer. Now Jennifer was soothed and on her way back to health, but Nakabu still hovered near Binka, looking worried. Binka, meanwhile, was thinking about saving not just Jennifer but millions of other kids. "Imagine the stress on the whole system," he said. "If you could just develop a vaccine to prevent this disease, malaria, then, well, it would be fantastic."

That is precisely what Binka is trying to do. But he is not a guy who spends a lot of time hunched over a microscope. He's the executive director of INDEPTH, a network of 37 research centers across Africa, Asia and Central America. INDEPTH is creating a huge database on virtually every aspect of the lives of patients at these sites: their medical histories, their marriages, even their religions. At Kintampo alone it is tracking 140,000 people. The data, in many cases, are the only official record of their existence. Few Ghanaians register births or deaths with the government; fewer still have ID cards; some don't know how old they are. "Thousands of people are born here, grow up, live their life, retire and die, and no one outside their village even knows they existed," says Binka. "There simply is no information available."

Clinical trials are all about information. Without basic data, high-quality research will never come out of developing countries. Yet trials of vaccines for these countries must be conducted there, so doctors can see if their study subjects will catch whatever disease it is they're trying to prevent. Databases like Binka's can ensure that trials in the developing world live up to the standards set by the developed world. For any vaccine to be accepted worldwide, the trial behind it has to be perfect.

GlaxoSmithKline is currently testing a malaria vaccine in children across Africa. The early results look good. A lot of the credit goes to GSK scientists. But Binka's work—the databases, and also his efforts to improve infrastructure at the trial centers—has strengthened the operation. "This trial is getting the same scrutiny as it would if it were done in the U.S.," says Ripley Ballou, a GSK researcher who helped develop the trial vaccine. "Hiring staff, training them, improving blood cultures, and transportation and infrastructure—it's all being done."

The improvements to the Ghanaian health-care system will last long after the GSK team has gone home. They'll help all patients, not just the ones who take part in this trial or future ones. At least that's what Binka is hoping. He wants consistency—a health-care system that works even when there's no drug company in town. "You want to develop these people into laboratory scientists," he says. "Can you imagine that you'd do a trial in Ghana that brings about a good result, and then it's over and you say, 'OK, now the government can take over everything'?" Binka has allies at the PATH Malaria Vaccine Initiative, a nonprofit that supports promising vaccine candidates. "You can't just parachute into the middle of Africa and then leave," says John McNeil, the group's scientific director: it's not fair to the African people and it also means you lose the infrastructure you've just built. Next year, when GSK begins to announce results from its trial, Binka will probably still be hard at work. That's how he wants it.

Emilio Emini, who oversees vaccine development at Wyeth Pharmaceuticals, is big in every way. He's 6 feet 4 and broad-shouldered, he thinks big and his scientific reputation is one of the biggest in Big Pharma. Still, even he can be humbled by the challenge of getting vaccines to the developing world. It has a way of making people feel small.

Emini, 53, met his lifelong nemesis for the first time in 1983, when he was a vaccine developer at Merck. He's a guy who doesn't so much speak as release a flood of arguments, facts and intimidating technical terms. Most people would not want to be his enemy. But then, his enemy isn't a person. It is a virus: HIV, which was discovered the same year Emini went to Merck.

At the time, Emini didn't expect to spend the next 24 years fighting the virus. No one else did, either. Yes, AIDS was bad, but Margaret Heckler, the secretary of Health and Human Services, predicted that an HIV vaccine would go into trials within two years. It did, then it flopped, and so has every other attempt since then. The problem, which scientists still don't fully understand, is that HIV thrives on immune-system activity—and nothing boosts immune activity as effectively as a vaccine. "The objective for those of us who make vaccines," says Emini, "is to kill the bastard before it has the chance" to exploit the body's response to it.

Until last Friday, Emini thought he might be able to kill the bastard, or at least cripple it. At Merck, in the mid-'90s, he worked on a vaccine, adding HIV genes to the "adenovirus" that causes the common cold. Tests on monkeys looked promising. Before human trials started, Emini left Merck, in 2003, to head the International AIDS Vaccine Initiative. In 2005, he moved to Wyeth Pharmaceuticals and launched more HIV vaccines there. But he kept track of his old vaccine. Many people did: it was probably the most promising candidate around. "Was," because last Friday, Merck pulled it. The vaccine was brilliantly designed and apparently safe, but like the string of failures that preceded it, it simply didn't work.

This is the biggest disappointment HIV researchers have had in years. A few scientists have even begun to suggest that the virus is vaccine-proof. Emini is not one of them. "This is not the time to give up," he says. His Wyeth team is now pursuing several approaches, and there are dozens more, based on every tactic scientists can think of. Most are percolating in petri dishes, but one, from SanofiPasteur, has gone slightly farther in clinical trials than Merck. Those who continue to do this kind of work have extraordinary faith that they'll succeed. If any of the new vaccines is even a little helpful, "we'll be happy, really happy," says Dr. Jose Esparza, an HIV expert at the Bill and Melinda Gates Foundation. "If we get one that's 40 percent effective we'll open a bottle of champagne."

In the meantime, Emini has plenty else to do. He's working on other vaccines at Wyeth, most notably "Prevnar 13," which he calls "the most complex biological product ever made." Its chemistry is remarkable: it is essentially 13 vaccines in one. A new variation on an existing shot, it targets 13 strains of the pneumonia-causing pneumococcus bacterium, some of which are found mainly in the developing world. It's currently in latestage trials.

There's a carrot on a stick for firms that work on pneumococcal vaccines: a unique type of funding called an "advance market commitment." Last year several wealthy countries, mostly in Europe, announced that they wanted a vaccine for pneumococcal disease. Make a good one that developing countries will want, the donors said, and we'll buy it from you and give it to them. You'll recoup your investment, they'll get their medicine, and we'll know our money made a difference. Future AMCs may target vaccines for malaria, TB and yes, AIDS. There's already plenty of incentive to develop an HIV vaccine: there's a Nobel Prize out there. But an extra push couldn't hurt. As Emini knows too well, defeating HIV may take every weapon the world has to offer.

As it happens, David Edwards, 46, is working on a new one, though it's not intended for HIV—yet. A biomedical engineer at Harvard University, he speaks softly and quickly, like a man who needs to finish talking because there are a thousand more important things he should be doing. His research, translated into action, could save millions of lives. But he is modest about it; praise him and he'll shrug, saying what he does is simply "a combination of art and science." His colleague, Barry Bloom, the dean of Harvard's School of Public Health, is more effusive: he calls Edwards's biggest innovation "way out."

Edwards's work is like his conversations: precise and economical. It's also, well, kind of technical. Basically, what he's done is taken a process that didn't work for making vaccines, stripped it to its essence and thus made it feasible. The process, "spray-drying," is the same one used to make pasteurized milk. It's usually done with chemicals that protect what's being dried from excessive heat. But when applied to live bacteria, those chemicals aren't protective—they're lethal. This was Edwards's insight. He and his graduate student Yun-Ling Wong took out the chemicals and spray-dried bacteria in a simpler solution of mostly water. The result, published in February, was a powdered version of Mycobacterium tuberculosis. It could replace the current TB vaccine. All a patient would have to do is breathe it in.

In theory, this could be huge. The spray-drying technology could make vaccines against any disease, not just TB. The powder is easy, fast and cheap to make, and it's stable at room temperature, unlike most traditional vaccines, which have to be kept cold—obviously a tricky task in the hot, shifting climates of tropical countries. It could also replace the unwieldy, if iconic, mechanism used to deliver most vaccines in the developing world today. "Getting rid of the needle would be great," says Edwards. "Getting a better vaccine would be even greater." He might get that, too. The powder contains 10 times as many live, replicating bacteria as the traditional vaccine. It's probably very potent.

That's the catch. Some people find the idea of voluntarily inhaling a giant cluster of TB germs a little discomfiting. The organisms in the powder are weakened, but they still might cause reactions in an organ as delicate as the lung, says Jerald Sadoff of the Aeras Global TB Vaccine Foundation. "There's a risk, and that risk has to be examined thoroughly," he says. So far, it's been examined only in guinea pigs. They did fine. But like Jenner, Edwards needs to test his idea on people.

That may happen soon. Last week, the Gates Foundation, which funds an enormous amount of vaccine research—it is impossible to write about the field without mentioning its name—expanded its reach even further. It announced a $200 million grant to Aeras for trials of six new TB vaccines, including the powder. Edwards also is moving ahead with plans to make the stuff on a large scale. Last year South African scientists visited his lab to learn how to build their own spray-drying facility. Someday, Edwards says, they could produce the world's annual supply of TB vaccine, an effort that would take about 50 days. Think he's just dreaming? Take a deep breath and think again.

Christopher Egerton-Warburton studied biochemistry at Oxford University. But he's not a scientist or a doctor or an engineer; academia is too precarious and ill-paid for him. He's a banker, and, at first glance, a pretty stereotypical one. Until recently, he worked in the London offices of Goldman Sachs, which he calls "the big bad bank." He goes by "Edge," wears cuff links with crests on them and is the picture of worldly success: there's a sharp-suited photo of him in the company's 2003 annual report. He knows you probably think Goldman Sachs types "eat babies for breakfast." It's unclear whether he cares. He's charming but ruthless; he says, for example, that doing charity work makes it "sometimes hard to meet your colleagues in the eye."

But Edge knows charity. When the British government needed advice on a decidedly unglamorous vaccine project, the task fell to him. His job was to transform the business of immunization into an investment opportunity glittery (and secure) enough to attract billions in risk-averse international capital. He did it, and how: among his investors were Bono, British Prime Minister Gordon Brown and the pope.

The project that Edge helped put together is called IFFIm, the International Finance Facility for Immunisation. It started with a phone call. In 2002, Brown was the chancellor of the exchequer, in charge of the Treasury. His officials called up Goldman Sachs wanting a favor: could the bank help out with an innovative scheme for raising money on the bond markets? And could it do so in the next two months? Free of charge? Goldman Sachs said yes and handed over the responsibility to Edge. He was barely out of his 20s, but he had the right résumé for the job. He'd already done some similar bond work for post-apartheid South Africa.

Later, Edge would start wondering why someone hadn't done this sort of thing already for vaccines. The answer: it was hard. The project called for banking skills, but it also required some mediation. The money he raised was earmarked for the Global Alliance for Vaccines and Immunization (GAVI). The agency is market-oriented and famous for getting results fast. But it's still a nonprofit, and it wants to help people—not exactly the kind of value that always shows up on a balance sheet.

At one point, negotiations hit a bit of a snag. Several European governments had agreed to back IFFIm's first bond offering, but the tricky rules of budgeting stopped them from offering megabucks upfront. Edge offered what seemed to him like a reasonable solution: make the aid dollars conditional on financial good behavior. Legally, that would allow the governments to offer money in big lump sums. But to GAVI, Edge's clause was heresy. Failing states with messy finances were the ones who needed help the most; the agency didn't want to abandon poor people there. Edge scratched his head. Then he saw a loophole: GAVI could take care of the most chaotic countries with the part of its budget that didn't come from IFFIm. From that point things started to move.

IFFIM finally launched last November. Since then, it has sponsored efforts against measles, polio, tetanus and yellow fever. Edge is still a moneyman, now at RMB International. He looks back fondly on his vaccination project, and he says (maybe jokingly) that it helps him sleep at night. It was also a rare opportunity to do good while also doing well. No matter what his cuff links look like, that shouldn't tarnish them too much.

This week many of the world's smartest humanitarians will be in New York City for the Clinton Global Initiative, a gathering that is half policy briefing and half drum circle. On Wednesday, a panel will consider the problems that people like Binka, Emini, Edwards and Edge are facing. No one can say exactly when, or even if, these problems will be solved. What's clear, though, is that solutions are more likely now that people around the world are working together on them. The guest list includes several people mentioned in this article and many more who share their goals. It also includes Dr. Tachi Yamada, president of the Gates Foundation's Global Health Program. He'll be roaming the halls, listening for "ideas so novel that people might try to shoot them down." In other words, he'll be looking for Jenners.

Meetings like this happen all the time. Even as the Clinton conference gets underway, another, more scientific group of innovators will be assembling at the Massachusetts Institute of Technology for a different conference. But most of us won't be at either meeting and, for that matter, most of us don't work in global health.

What Yamada would like to get across is that it makes no difference. He will look for good ideas anywhere. If he hears one from, say, a banker, he'll take it, even if that banker hasn't thought much about vaccines before. He has a big idea of his own: to bring people together who don't usually talk about health and don't usually talk to each other. That, he says, is how you get a revolution. Hey, if a country doctor, a farm woman and an 8-year-old boy can start one, maybe we all can.