T H E   N I H    C A T A L Y S T      M A R C H  –   A P R I L  1999



by Doug Loftus


Louis Miller

The quest for a malaria vaccine is expanding its clinical dimension in the form of a new initiative headed by Louis Miller, chief of NIAID’s Laboratory of Parasitic Diseases (LPD), the home of NIH’s core program of malaria research. Now added to the LPD research agenda—which includes the parasite-host interaction, the genetics of pathogenesis and drug resistance, and immunological strategies for prevention and intervention—is the highly specific task of producing a blood-stage vaccine that would elicit an immune response—primarily antibodies—capable of intervening at the critical disease-producing phase in the life cycle of the parasite Plasmodium falciparum (see "Mosquitoes, Parasites, and Malaria").

Vaccine Development

The vaccine, says Miller, who is also chief of the Malaria Cell Biology Section, would target the parasite proteins that mediate merozoite entry into red blood cells (RBCs) and the binding of RBCs to endothelium (the endothelial-RBC interaction prevents RBC transit through the spleen and subsequent destruction, providing a "safe haven" for merozoite proliferation).

In close collaboration with Stephanie James, deputy director of NIAID’s extramural Division of Microbiology and Infectious Diseases, Miller will oversee the activities of a research program designed, he says, to operate "like a small company." He calls it "a major undertaking," pointing out the myriad logistical hurdles involved in making products that will be used in people. Expression systems, production methods, formulation, and testing must each be carefully evaluated and controlled, with a relentless attention to procedural details.

Miller believes that NIH’s unique brand of long-term, committed support has brought the intramural malaria program to where it is today, poised to advance to the next round of discovery and development. He admits, however, that stepping into the clinical realm was not his natural inclination. "I would have never considered it," he says, but did so at the urging of David Kaslow, who has been chief of the Malaria Vaccines Section (see The NIH Catalyst, November–December 1997). "It was a turning point in the lab," Miller says, noting that Kaslow "single-handedly ran against the grain" in advocating a bench-to-clinical approach. "Unfortunately," he adds, "David is leaving so I’ve taken over the group. We’re trying to recruit people to fill in all the different aspects of vaccine development."

Although the vaccine program is just beginning to take shape, portions of the molecular strategy are already being developed. Miller believes that, given the number of variables associated with producing an effective clinical-grade reagent, initial efforts should be tightly focused on a single target molecule. They will start with the merozoite surface protein MSP-1 because high antibody titers against MSP-1 have been correlated with protective immunity in animal studies, and among Africans, resistance to disease also is correlated with serum antibodies against parasite surface proteins. For help with handling the scientific details of vaccine design and development, Miller feels fortunate to have an advisory panel of colleagues from NIAID’s Laboratory of Infectious Diseases, whose experience in developing vaccines for rotavirus (see "More than Two Decades of Research Culminates in Rotavirus Vaccine") and other viruses is a valuable asset.

With all the pieces about to fall in place, Miller acknowledges that the development path will be long and challenging. He envisions taking a product through Phase II clinical trials—which could take "5–15 years"—and then handing it to industry for final testing phases and bringing it to market. According to Miller, even the ultimate consumers of the anticipated vaccine recognize the need for persistence and patience. "They’re pretty sophisticated," he said, recounting discussions he’d had with village elders during a visit to Mali.

Drug Resistance

Proceeding apace in the LPD is research aimed at understanding the mechanisms of parasite resistance to drugs that, at least for a time, had triumphed over malaria. Drug resistance is now widely acknowledged as a critical problem in treating and reducing the spread of the disease. Thomas Wellems, chief of the LPD Malaria Genetics Section, observes that chloroquine, an inexpensive, easily administered first-line antimalarial agent, had been a boon to the public health comparable to penicillin until the emergence of chloroquine-resistant strains of P. falciparum over the last 30 years or so.

Wellems and his group have been trying to identify genes responsible for chloroquine resistance, and he now believes they are narrowing in on a candidate, which could make efforts to overcome resistance through drug design feasible. Citing the apparent reluctance of big drug companies to invest effort in developing antimalaria therapeutics, he suggests that they simply haven’t known "where to start." The lack of molecular targets and simple in vitro culture methods mitigates against the high-throughput methods of drug discovery typically used in industry, he explains. "What we’re missing in P. falciparum is a model system—we don’t have one," he says. He explains that mice, for instance, which aren’t susceptible to P. falciparum, can be infected with another Plasmodium species, but disease takes a significantly different course from that in humans.

LPD clinical research efforts also extend overseas, particularly to Africa. LPD Assistant Chief Robert Gwadz heads a three-pronged collaborative initiative with researchers at the National School of Medicine in Mali that encompasses molecular epidemiology, natural protective factors against severe malaria, and candidate vaccine strategies. Wellems observes that when projects are based in malaria-endemic regions, the "most relevant questions" tend to surface, helping to focus research directions.

Mosquitoes, Parasites, and Malaria

According to the World Health Organization, the female Anopheles mosquito transmits malaria to about 500 million people a year in more than 90 countries of Africa, Asia, and South America. The parasite Plasmodium falciparum causes the most severe form of malaria in humans, leading to the death each year of about two million people, mostly children.

Anopheline mosquitoes inject Plasmodium sporozoites into the human bloodstream while feeding. These sporozoites find their way to the liver, where they mature into merozoites and again are released into the blood. Merozoites infect red blood cells (RBCs), where they obtain the hemoglobin they need to proliferate. The RBC eventually bursts, releasing more merozoites into circulation; these cycles of infection and cell rupture produce disease. Occasionally, a merozoite within a red cell switches to a sexual form called the gametocyte. A feeding mosquito can take up RBCs harboring gametocytes, which further develop in the mosquito gut and eventually give rise to sporozoites that infect the mosquito salivary gland, ready to be injected into the next human host.

Discoveries near the end of the last century led to a better understanding of malaria’s cause and mode of transmission. The use of pesticides and the development of synthetic derivatives of quinine, a component of cinchona bark long known for its antimalarial properties, were instrumental in bringing malaria under control in the first half of this century. However, the effectiveness of these methods has waned progressively over the past 30–40 years, resulting in a resurgence of malaria as a major public health concern in many parts of the world.



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