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Biomedicine

Sweet Hope for a Malaria Vaccine

Malaria claims more than a million lives each year. One firm is betting that a sugar molecule can help.

Each year, malaria parasites infect up to half a billion people and kill at least one million, most of them in sub-Saharan Africa, most of them children under the age of five. Nearly 3,000 children die each day. Before dying, they suffer severe anemia and recurring bouts of high fever, as the microbes invade red blood cells, reproduce, and escape, exploding the cells and releasing a devastating toxin. Fluid accumulates in the lungs, the blood turns acidic, the kidneys fail, and the brain can become inflamed, causing dizziness, seizures, and even personality changes.

And that doesn’t even fully describe the horror of the disease. “It’s not just the deaths,” says Filip Dubovsky, the scientific director of the Malaria Vaccine Initiative, a program funded by the Bill and Melinda Gates Foundation. “It’s the farmer who’s too sick to get to his work, to feed his family. It’s the loss of a fetus to a mother who’s expecting a baby. The thing is, people are used to it-and that’s one of the biggest tragedies.”

For decades, public-health groups have combatted malaria by trying to control infective-mosquito populations with insecticides and treating as many of the ill as possible with antimalarial drugs. But problems with parasite resistance to the drugs and mosquito resistance to the poisons-not to mention distribution costs and logistics-mean that far too often these strategies fail. Essential to the battle is finding a way to prevent the disease despite infective bites. “A vaccine is really badly needed,” says Marcel Tanner, director of the Swiss Tropical Institute in Basel. An effective vaccine could be cheaply and easily integrated into existing programs to immunize infants in malaria-infested regions against common childhood diseases. And in fact, researchers are working on almost 90 different versions of a malaria vaccine, 17 of which have started human testing (see “Sampling of Malaria Vaccines in Human Testing,” below).

Sampling of Malaria Vaccines in Human Testing
GROUPS VACCINE/STATUS
GlaxoSmithKline Biologicals (Rixensart, Belgium) Protein vaccines; the most advanced is in phase II clinical trials in children in Africa
Queensland Institute of Medical Research (Brisbane, Australia);
Cooperative Research Centre for Vaccine Technology (Brisbane, Australia)
Protein vaccine; phase I trials
University of Oxford (Oxford, England); Oxxon Pharmaccines (Oxford, England); Impfstoffwerk Dessau-Tornau (Rosslau and Dessau, Germany) DNA vaccine; phase II clinical trials in Africa
Walter Reed Army Institute of Research (Forest Glen, MD) Protein vaccines; the most advanced is in phase II trials in Africa

Despite decades of effort, however, scientists have yet to produce a vaccine that works. “There has been a lot of technical failure,” says Marie-Paule Kieny, who coordinates the World Health Organization’s funding of malaria vaccine research. The main reason is that the parasites make slippery targets, routinely changing their appearance as they mature and spending much of their lives inside human blood cells, where the immune system has a hard time tracking them down. Since most vaccines work by training the immune system to fight invaders directly, the malaria microbes’ exceptional elusiveness has made vaccine development maddeningly frustrating.

But new hope is emerging from an unlikely source: the sugar responsible for the disease’s devastation. Instead of prompting the immune system to find and kill the malaria parasites, a new vaccine seeks to prime the immune system to attack the toxin that causes the most lethal aspects of the disease. The result of a collaboration between immunologist Louis Schofield of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, and chemist Peter Seeberger of the Swiss Federal Institute of Technology in Zrich, the vaccine consists of a synthetic version of the malaria toxin-a sugar molecule that Schofield first identified in the late 1980s. So far, tests of the vaccine have yielded promising results in animals.

To commercialize the vaccine, Seeberger and Schofield have helped start up a company, Ancora Pharmaceuticals in Cambridge, MA. With the right funding, Seeberger says, the team could be ready to start human tests by the end of the year; but that funding has yet to materialize. The problem is in many ways endemic to malaria research. And the cause is simple: the disease afflicts mainly poor countries that have little political or financial clout. “One of the toughest things with malaria is going to be getting a way to finance the work,” says biotech entrepreneur Carmichael Roberts, Ancora’s cofounder. Seeberger is blunter. “Hell would break loose if 40,000 people died in the U.S. in a month,” he says, as has happened in some malaria-ridden regions of Africa.

Many experts doubt that the sugar-based vaccine will be the sole answer to malaria, but if it works, it could be a vital piece of the strategy for combatting the disease. Because the vaccine comprises a sugar, it has advantages over other vaccines being tested: it does not require refrigeration, and it could be more robust against parasite resistance. And that could help it save lives and ultimately boost the economies in many developing nations. “If we could reduce malaria by 10 percent, that would be enough for me,” Seeberger says. “You’re talking about millions of people.”

Target: Toxin

You can excuse Louis Schofield’s impatience to begin human testing. His search for an effective malaria vaccine is now in its third decade. His quest began in the late 1980s, when as a postdoc at New York University, he went hunting for the malaria toxin. His idea, even then, was that vaccinating against the toxin rather than the parasites could prevent the actual disease-the fever and uncontrolled inflammation that are the deadly hallmarks of malaria. Unlike the parasites, Schofield reasoned, the toxin exists outside the blood cells and should be readily accessible to the immune system.

In general, vaccines work by inciting the immune system to produce proteins called antibodies; each antibody specifically reacts with one particular molecule-say, a protein on the surface of a parasite. This interaction typically focuses the killing effects of the immune system on the invader. But the antibodies recruited by an antitoxin vaccine like the one Schofield has in mind simply bind to the toxin, neutralizing it. The concept is not unique: two of the world’s most successful vaccines, against diphtheria and tetanus, are such antitoxin vaccines.

But to create an antitoxin vaccine, you first have to find the toxin. Much of malaria research has focused on proteins, but Schofield took a different tack, going after a suspicious molecule, a carbohydrate studded with fats, found on the parasite’s cell surface. He thought that this molecule could be the villain causing the inflammation problems characteristic of malaria. “That turned out to be a good guess,” he says. Over 18 months, at the National Institute for Medical Research in London, he painstakingly extracted the toxin from malaria parasites. Once he had enough of it in hand, he injected it into mice; the rodents grew sick, experiencing a slew of symptoms-“pretty much those that you see in people sick and dying of malaria,” he recalls. He had found the malaria toxin.

But a tremendous hurdle still remained. Without a way to make a completely pure version of the toxin’s carbohydrate backbone-and do it relatively quickly-Schofield could not prove it would make an effective vaccine, much less produce it commercially.

The technological breakthrough came several years later from research being done in Cambridge, MA. Then at MIT, chemist Seeberger, working with graduate student Obadiah Plante, had invented a machine that automated the laborious and time-consuming synthesis of sugars. Seeberger’s machine tantalized Schofield: it could churn out large quantities of a pure version of the basis for a vaccine cheaply and quickly, possibly within weeks or days.

Optimistic and determined, Seeberger took on the project-and a partnership was born. “He undertook to do the synthesis on the strength of my conviction,” Schofield says. Seeberger first made a stripped-down version of the toxin. Though the process initially took 10 months, he soon had it down to a matter of hours. Then, in Schofield’s lab, researchers infected mice with malaria parasites. Normally, almost all of the animals would have died within a week. But injection with a prototype vaccine based on Seeberger’s molecule apparently negated the effects of the toxin, raising the rodents’ survival rate to between 65 and 75 percent. “The results were very clear,” Seeberger says.

Ancora’s Answer

Based on these results, Seeberger and Schofield decided to make malaria an early target for the type of sugar-based vaccines and drug treatments they planned to develop at their new company, Ancora Pharmaceuticals. On a recent visit to Ancora’s lab in Beverly, MA, Seeberger-who flies in from Switzerland every four to six weeks-showed off the technology that he hopes will help make the malaria vaccine a reality.

Tucked into a corner of a large, nondescript office park, Ancora sublets its space from another startup: one long, narrow room that serves as an office area and a couple of work counters in a lab. It could be any other fledgling company short on money-except for the pair of boxy, automated sugar synthesizers that sit sequestered behind a closed door. While not quite the heart and soul of the tiny firm-those would be its founders-you might call these machines the company’s backbone.

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