Mud-brick, thatch-roofed school houses in small villages that cling to rugged mountainsides in Papua New Guinea - this was the topic of conversation between two malaria researchers at a Philadelphia restaurant during a break in the action at the 2003 American Society of Tropical Hygiene meeting. Well, not the school houses themselves, but what was in them: A group of children who appear to be immune to the Plasmodium vivax parasite, despite their constant exposure. Why?
Christopher King of Case Western University's Center for Global Health and Diseases and Ivo Mueller of the Papua New Guinea Institute for Medical Research wanted to design a study to find out. Sitting at the restaurant, they both agreed: "We need to do this study," King says. In the end, it provided evidence that antibodies can protect people from vivax malaria.
Papua New Guinea is a nation beset by malaria, the single most common cause of illness and death in the country. Vivax malaria - a less virulent but more common cousin to the deadly P. falciparum variety - alone infects tens of thousands of Papua New Guineans every year. Worldwide, the disease strikes about 100 million people a year.
After monitoring 200 children from whom vivax parasites had been cleared following antimalarial therapy for six months, the researchers found that about 10% of the kids developed high levels of so-called blocking antibody. This antibody cuts off the parasite's access to a key receptor - the Duffy antigen - on the surface of erythrocytes, preventing it from infecting the blood cells. The children with high levels of blocking antibody were approximately 50% less likely to contract vivax malaria. Children who developed lower levels of antibodies had correspondingly lower protection from vivax. The findings were published in the Proceedings of the National Academy of Sciences earlier this year (105:8363-8, 2008).
Conducting vaccine research in a country like Papua New Guinea can seem impossible. Even arriving safely at study sites can be a harrowing ordeal, according to James Kazura, a Case Western University parasitologist who has worked frequently in Papua New Guinea. Everything from lighting systems to centrifuges is run off generators in remote study sites. "The infrastructure for research is much greater in politically stable areas of Sub-Saharan Africa than it is in [Papua New Guinea]," says Kazura.
King says that even the photovoltaic cells that powered his telephones at study sites in Papua New Guinea would sometimes disappear in the hands of thieves. "This happens all the time," he says. Still, the children in King's study "were so excited to participate; we had [something along the order of] 99% follow-up."
King likens the Duffy antigen to "a single key that the parasite has to get through to get into the cell." The "lock-and-key" arrangement makes blood-stage vivax infection more tractable than falciparum infection, which employs a suite of entry mechanisms to invade cells.
It's that Achilles heel that makes a vaccine against vivax so promising, according to John Adams, a molecular parasitologist at the University of South Florida who was not involved with King's study. "This is a prelude to a vaccine test," he says. The hope is that vaccines could target the portion of the vivax parasite that binds to the Duffy antigen receptor, and thus mimic the natural immunity developed by the Papua New Guinean school children with high levels of blocking antibody.
The study also provides a quantifiable method to measure protection from infection based on antibody levels, a crucial tool for vaccine trials. The next step is to see if antibodies correlate in any way to a reduction in clinical presentation of the disease.
King's research represents a crucial advance in the wider battle against all types of malaria, says Lou Miller, the head of the National Institute of Allergy and Infectious Diseases' malaria cell biology section, who was the first to clone and express the Duffy antigen in the mid-1990s. "If we're going to eliminate malaria from the world, we have to go after vivax and falciparum."