After decades of disappointment in efforts to develop a malaria vaccine, researchers are starting to see promise in a new approach.
While most vaccines trigger the body's defenses to produce antibodies against a disease-causing germ, the new approach recruits an entirely different branch of the immune system.
If it works, it could open up a new route to attack other diseases, including hepatitis and possibly HIV, the virus that causes AIDS.
Nearly 450,000 people die of malaria each year, according to the World Health Organization. The parasites that cause the disease are increasingly becoming drug-resistant.
One successful vaccine has been developed so far, but it prevented only about a third of cases in a clinical study.
Experts have decided that's better than nothing. The vaccine is being piloted in Ghana, Kenya and Malawi.
Other scientists are trying a different angle of attack.
There are basically two ways to prevent germs from causing infections. "You either prevent them from getting into cells with antibodies, or you kill them inside the cells with T-cells," said Stephen Hoffman, chief executive officer of Sanaria, a company working on one vaccine.
Most vaccines target the infection by building up antibodies. "If you need to kill them inside the cells with T-cells, we haven't been overwhelmingly successful," Hoffman said.
But Sanaria is one group seeing success by targeting malaria parasites inside infected liver cells, the first stop in the complex life cycle of the disease.
One key difference is how the vaccine is delivered. Hoffman's group tried a typical route: injecting radiation-weakened parasites into patients' skin or muscle. That didn't work.
But it did work when injected directly into veins.
The weakened parasites traveled to the liver, where they set off an immune reaction. Defensive cells killed liver cells that were infected with malaria parasites.
And the liver's defenses were ready when faced with the real thing months later.
Most of that early work has been done in mice and macaques. When Hoffman and colleagues did something similar with a handful of human patients, most were protected against infection.
Recruiting immune cells in the liver is especially effective because "we don't need to wait until the immune system figures out that the parasite is in the liver and starts mounting an immune response, which can take days and sometimes weeks," said Adrian Hill, director of the Jenner Institute at Oxford University.
"By then, the malaria's gone. It only spends a week in the liver, and then it's out in your blood causing disease."
Hill's group just published a study in the journal Science Translational Medicine in which immune cells in the liver were triggered by using a protein from the parasite, rather than the entire organism.
Scientists hope to get a better grasp on the system these vaccines employ, known as cellular immunity. Harnessing this system could help tackle hepatitis and HIV infection.
Drugs can control HIV infection but can't eliminate it from the body.
"If somebody could get cellular immunity to work really well for vaccination, that would be transformative for a whole range of diseases," Hill said. "Not just for infectious diseases that we want to prevent, but ones that we want to treat and we can't treat today."