The animal that kills the most humans worldwide isn't the shark, lion, or grizzly bear: It's the mosquito. In 2012, about 200 million people developed malaria after being bitten by the insect; some 600,000 died, 90% of them in Africa and most of them children under 5. The slippery parasite that causes the disease has long defied efforts to develop a vaccine. But a study of malaria-resistant children in Tanzania has turned up an antibody that helps stop the infection in its tracks. Based on this antibody's actions, scientists have developed a preliminary vaccine that shows promise in mice.
The parasite that causes malaria is a single-celled organism called Plasmodium. It might as well have been designed by a diabolical mad scientist, says Jonathan Kurtis, an immunologist at Brown University and senior author of the new study. When an infected female mosquito bites a human, the microbe enters the victim's bloodstream and makes for the liver, where it multiplies by the tens of thousands. From the liver it goes back into the bloodstream, infecting and multiplying inside red blood cells. Eventually it bursts out again, in a form called a schizont -- infecting more blood cells and re-entering the bloodstream to infect the next hungry mosquito, in whose body it goes through a cycle even more complex. The bursting-out stage, which occurs about every 24 hours, produces the fever, chills, and aches that make the patient so miserable. "It's like the worst flu you've ever had," Kurtis says.
Because different proteins are produced in each stage of the microbe's cycle, Plasmodium presents a shifting target for potential vaccines. So far, the most promising candidate is one dubbed RTS,S. In a phase III clinical trial reported in late 2012, this vaccine, which works by reducing the amount of infected liver cells, led to a 50% decrease in the number of severe symptoms and blood levels of the parasite in children aged 5 months to 17 months.
But even in malaria-stricken areas, some people have only mild symptoms or none at all, and they may show only minimal levels of the parasite in blood samples. To find out why, Kurtis and colleagues compared the blood of people who are resistant to those who aren't. With colleagues at the National Institutes of Health, Harvard Medical School, and the University of Washington, the team examined a group of children in Tanzania who had been studied since shortly before their birth. First researchers took blood samples of 23 2-year-old children (the age at which resistance to malaria typically develops); 12 were resistant to the disease, as evidenced by the small number of parasites in their blood. To see whether these 12 had unique, protective antibodies, the team checked the blood plasma—the clear, antibody-containing fluid from all children—against a set of Plasmodium genes known to be turned on when the parasite infects the blood.
Of the proteins produced by about 3 million possible genes, antibodies in the symptom-free children's blood latched on to just three, the team reports online today in Science. One gene produces a protein known to help the parasite infect red blood cells and is already under study as a target for a vaccine. Another, previously unknown gene—when the investigators worked out its protein's structure and studied it in tissue culture—proved to do just the opposite: The protein helped the schizont leave the infected blood cell.
"At first, this didn't make sense. We checked the results three times," Kurtis says. Apparently, antibodies to this protein protected against malaria by trapping the schizont inside the red blood cell -- not by preventing it from infecting new ones. The researchers checked the larger group of study participants. Of about 450 children, about 6% had antibodies to the protein; none of these children developed severe malaria (defined as difficulty breathing, convulsions, high fever, low blood sugar, or severe anemia). When the researchers checked blood samples drawn from a group of teenagers in an unrelated study in Kenya, they found that blood containing the antibody had only about half as many parasites as did samples without it.
Finally, Kurtis and colleagues used the antibody to develop a vaccine candidate that they gave to mice infected with a particularly lethal form of malaria. The vaccinated animals lived almost twice as long, and, in one trial, had about one-fourth as many parasites as untreated mice. Kurtis says a vaccine that exploits the antibody's ability to imprison Plasmodium within blood cells would have more time to work with than one that tries to block reinfection. "The parasite infects a new cell within about 15 seconds, so a vaccine to prevent that action would have to work immediately," he says. Infected blood cells are removed by the immune system, he explains.
"It's a very elegant approach," says David Lanar, a parasitologist at the Walter Reed Army Institute of Research in Silver Spring, Maryland. After the few seconds that Plasmodium takes to invade a previously uninfected red blood cell, it's hidden from any antibody, he explains. When the new cell is infected, however, the membrane becomes leaky for several hours before the schizonts burst out again, giving larger molecules like an antibody or vaccine a chance to get in. A vaccine that keeps the schizonts trapped would shift the timeline in the patient's favor, he says.
A vaccine based on this approach would need to work in tandem with others aimed at different parts of the cycle, Kurtis cautions. The strategy wouldn't eliminate the parasite, only reduce it to levels that can ease the symptoms, he explains.
"At this stage of the game, that's a good thing," Lanar says. No treatment breaks the cycle of infection between humans and mosquitos, he says. The next best thing is to reduce the number of clinical symptoms. "The number of parasites in your blood determines how sick you will be."
A vaccine would be especially effective in people who have never been exposed to the disease before, or who lost their childhood immunity by leaving malaria-stricken areas, Lanar says, because these groups are more vulnerable to very severe forms of the illness than those who are partially immune. As a next step, Kurtis's group is conducting a study of the vaccine in nonhuman primates. If it's successful, the team will begin clinical trials in humans.
*Update, 23 May, 12:12 p.m.: This article has been updated to clarify that as the red blood cell membrane grows leaky to allow the schizonts to escape, it provides an opportunity for treatments to enter.
*Correction, 27 May, 4:57 p.m.: An earlier version of the caption for this article inaccurately described the image. The malaria parasite takes up almost the whole red blood cell; the dark, rodlike shapes are bits of hemoglobin that it has digested.