NEW YORK (Reuters Health) - A genetically attenuated Plasmodium parasite is unable to establish blood-stage infections but does generate complete sterile protection within host organisms, offering new hope for an effective malaria vaccine, scientists in Germany and the U.S. report in the November 29thissue of Nature.
Through expression profiling, Dr. Kai Matuschewski’s team identified the uis3 gene (“upregulated in infective sporozoites gene 3") as one that is essential for Plasmodium early liver-stage development. Sporozoites lacking this gene can infect hepatocytes but cannot establish blood-stage infections or cause disease.
Using as a model Plasmodium berghei, a rodent parasite similar to the human parasite P. falciparum, Dr. Matuschewski, of the Heidelberg University School of Medicine, Germany, and his associates generated uis3-negative organisms.
The uis-negative sporozoite was defective in its ability to complete transformation into liver trophozoites and mature liver schizonts. When injected into young rats, uis3-negative sporozoites failed to induce blood-stage parasitemia.
After intravenous and subcutaneous vaccination followed by two booster doses of the altered parasite, the animals were completely protected against a challenge with wild-type sporozoites 1 to 4 weeks and 2 months later.
Previous attempts to develop effective malaria vaccines have failed, Dr. Matuschewski told Reuters Health. For a while, efforts using recombinant subunit vaccines had raised hopes, but the complexity of the Plasmodium parasite rendered vaccines ineffective against the organism.
“The parasite has more than 5000 genes, so it is hard to come up with a good collection of protective antigens” to use in a subunit vaccine, he said. “No matter which subunits you look at, these recombinant subunit vaccines don’t seem to work.”
There have also been efforts to produce irradiation-attenuated parasites, which turned out to be impractical, he added. Their own study is the first to produce a genetically modified strain. Moreover, “we designed the genetic disruption so the organism cannot revert to the wild type,” Dr. Matuschewski added.
Their lab is now using the same principles to develop a “double-knockout” P. falciparum that they hope to test in a clinical setting.
Source: Nature 2004.www.nature.com [ Google search on this article ]
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