Malaria vaccine waylays parasite in liver.

By triggering an attack on the parasite that causes malaria as it passes through the liver, a new vaccine intercepts the single-celled organism before it can enter the bloodstream and do damage.

The vaccine imparted partial or full protection to eight of nine chimpanzees that researchers infected with Plasmodium falciparum, the protozoan that causes the most lethal form of malaria in people, researchers in France report in the November NATURE MEDICINE.

The scientists used synthetically produced versions of a protein called liver stage antigen-3, or LSA-3. The original form is found in P falciparum when it's a schizont. Mosquitoes carry the protozoan in an immature stage in their saliva and inject it into people. As a schizont, P falciparum passes through the liver in only 5 days--but still represents an ideal vaccine target, says study coauthor Pierre Druilhe, a parasitologist at the Pasteur Institute in Paris.

The parasite's stay in the liver precedes the onset of malaria symptoms, which include chills, fever, and anemia. Liver cells infected with malaria display certain telltale parasite proteins, including LSA-3, that the immune system might target, Druilhe says.

LSA-3 is common to several strains of malaria. "Our results establish the concept that a carefully chosen single molecule can induce strain-transcending protection against malaria," Druilhe says.

"This is an important contribution" to malaria vaccine work, says Philip K. Russell, a vaccine specialist at Johns Hopkins Medical Institutions in Baltimore.

Proteins have proved handy in vaccine development for other diseases. For example, in making the influenza vaccine, researchers mass-produce an innocuous version of the virus, complete with viral surface proteins. In a flu shot, this noninfectious virus primes the body to recognize these proteins later and attack live viruses displaying them.

Experiments 3 decades ago hinted that the proteins of sporozoites disabled by radiation treatment could also induce immunity. But the liver stage of malaria has represented a "black box" to scientists, says Druilhe.

Until recently, researchers were unsure which malaria proteins an infected liver cell might display and which would therefore make good vaccine candidates, he says. Unlike viruses and bacteria, P. falciparum can't be cultured in a laboratory.

To get around that problem, Druilhe and his colleagues isolated the gene that encodes LSA-3 and then made a version of the protein. They then injected it into the chimpanzees.

The researchers don't know precisely how the chimpanzees' immune systems mustered protection against the subsequent challenge with P falciparum--whether they formed antibodies against malaria schizonts or unleashed specialized immune cells called T cells. He says there is evidence that T cells called CD4 cells play a role and that interferon, an immune protein known to stymie viruses, is present as well.

Not knowing the details is common in the early stages of work on a novel vaccine technology, says Mark E Wiser, a parasitologist at Tulane University School of Public Health in New Orleans. "You determine protection first and worry about the mechanism later," he says.

Scientists' views differ on how effective a liver-stage vaccine would need to be. Wiser says that permitting even one infected liver cell to escape immune surveillance could lead to full-blown malaria. On the other hand, Russell suggests that killing off 90 percent of the infected liver cells "gives the host a better chance of handling the subsequent blood-stage infection."