In Izmir, Turkey this past weekend, the International Congress ofParasitology heard of a multi-component, naked-DNA vaccine thatprotected 100 percent of mice from infection by malarial parasites.That result is so recent that it was not in the presenter's abstract.Denise Doolan, a parasitologist in the Malaria Program of the U.S.Naval Medical Research Institute in Bethesda, Md., told the Izmirmeeting that combining the genes encoding both circumsporozoiteand liver-stage antigens in a single vaccine produced the total anti-malarial protection.The director of the Malarial Program, and co-organizer of the Izmircongress, is tropical-disease specialist Stephen Hoffman.The paper Doolan presented bears the title: "A DNA Vaccine ofPlasmodium Yoelii Hep 17, a New Antigen Found in Both theLiver and Blood Stages, Protects Against P. yoelii sporozoitechallenge." In other words, the vaccine cuts off the liver-exitingparasites at the pass, before they can invade the blood.P. yoelii is to mice what P. falciparum is to humans _ the principalmalarial parasite. Its sporozoite stage is injected through the skin bythe sharp probosces of Anopheles mosquitoes.These sporozoites make a beeline for the liver, where they multiplymightily, and pump thousands of second-stage parasites, livermerozoites, into the bloodstream. These in turn invade red bloodcells, causing the symptoms of malaria.Not only is this vaccine the first use of naked DNA to immunizeagainst a non-viral pathogen, but it demonstrates the power ofmulti-gene immunization. Explaining the strategy, RichardHedstrom, second author on Doolan's paper, told BioWorld Today:"Anything that escaped the sporozoite immunity would be trappedin the liver stage, and if it escaped that too, at the red-blood-cellstage."Hedstrom is the Navy malaria program's senior molecular biologist."Experts agree," he added, "that it will require multi-componentvaccines to get complete protection."A total-protection vaccine already exists, based on sporozoiteskilled by irradiation. "But it's not a feasible vaccine," Hedstromsaid; "it would require too large an insectary to produce it."Parasitologists harvest their sporozoites by infecting mosquitoes,then dissecting their glands by hand. So the irradiation-basedvaccine, however efficient in the laboratory, Hedstrom explained,"is not practical to prevent the 200 to 500 million new infections,and one to two million deaths caused annually by malaria."Multi-Component Vaccine's One-Two PunchTwo genes are better than one, but even a single-barreled vaccine,aimed only at that first-stage, liver-seeking sporozoite, provedstrikingly effective in mice. Hedstrom is also co-author of a paperin the current Proceedings of the National Academy of Sciences(PNAS), dated Oct. 11. It reports that this earlier mono-componentconstruct "induces high levels of specific antibodies and killer Tcells, and protects against malaria in an extremely rigorouschallenge model system."Its bottom line is that the one-shot vaccine protected 68 percent ofmice challenged with the live parasite. But last week at the ColdSpring Harbor 1994 meeting on Molecular Approaches to theControl of Infectious Diseases, Hedstrom was able to update thatfigure to 83 percent.A sentence in the PNAS paper describes how, "After establishmentthat immunization with P. yoelii circumsporozoite protein inducesprotective immune responses, all work was switched to a vectorproduced by Vical Inc. [of San Diego] to facilitate the practicaldevelopment of human malaria plasmid DNA vaccines."That switch occurred in early 1993, recalls Robert Zaugg, Vical'svice-president for business development, when the company put theNavy-isolated clone into its naked-DNA vector. This, he toldBioWorld Today, led in November 1993 to a cooperative researchand development agreement between Vical and the Naval malarialprogram."Since Vical invented the technology," Hedstrom commented, "andare devoted to producing these vectors, we decided that the bestthing was to get with the professionals. We incorporated theirvector in our study at that point."Zaugg expects that this joint project will move from mice tomonkeys, from P. yoelii to P. falciparum, "sometime in the first halfof 1995."Vical, now teamed with France's Pasteur-Merieux, has two othernon-viral vaccines on its drawing board: Lyme disease andHelicobacter pylori. (See BioWorld Today, Sept. 30, 1994, p. 1.)Mosquitoes breed on stagnant bodies of fresh water, not salt water.Why, then, has the Navy taken a lead in developing this cutting-edge malaria vaccine?"Malaria," Hedstrom explains, "is one of the biggest infectious-disease threats to our forces. In fact," he added, "in 1994, it was thenumber-one infection research topic in the armed forces."Most Vicious Killer Wears Two HatsIn most of its victims, malaria is a lingering ailment, with recurrentbouts of chills and fever, that waxes and wanes. In most of the twomillion who die of malaria every year, mainly children, the parasitewaxes and waxes until it reaches the brain.At this point in the disease, a patient's fever may suddenly climbfrom 104o F to 110o F or even 112o F, temperatures that can kill.The parasites hyperinfect more than 5 percent of red blood cells,each of which may harbor not one but six to 30 merozoites.Delirium, mania, convulsions and coma often follow.Cerebral malaria is the infection at its most pitiless, yetparadoxically it kills only about 20 percent of those who get it.A specific gene may account for this paradox. It encodes tumornecrosis factor (TNF), which is responsible for cerebral malaria,according to a report in the current Nature, dated Oct. 6. Its title:"Variation in the TNF-a promoter region associated withsusceptibility to cerebral malaria."Pediatric immunologist William McGuire and his co-authors at theJohn Radcliffe Hospital in Oxford, U.K., conducted a case-controlstudy of 1,144 children in The Gambia, a West African malarialhot-spot. They found that high levels of one highly active form ofthe TNF cytokine, encoded by the TNF2 variant gene, correlatedwith severity and fatality of cerebral malaria.Yet, they also found that this same TNF2 gene allele is morecommon in the Gambian population than its pathogenicity couldexplain. Their alternative explanation: "This implies that theincreased risk of cerebral malaria in TNF2 homozygotes, [i.e., withboth parents carrying the gene], is counterbalanced by somebiological advantage . . . protection against life-threateningconditions other than cerebral malaria." n
-- David N. Leff Science Editor
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