A genetically engineered parasite could offer new hope to researchers and patients desperate for a safe and effective malaria vaccine.

The mosquito-borne malaria parasite Plasmodium falciparum poses a major health threat in many parts of the world, with studies indicating that it kills more children under 5 years of age than any other infectious agent. Sadly, no proven and reliable vaccine is currently available.

There are a number of obstacles to the development of 'subunit-specific' vaccines for malaria and other parasites. First, parasites typically have larger genomes than bacteria or viruses; P. falciparum has more than 5,300 genes, many of which exhibit considerable variability. In addition, parasites typically undergo multiple life stages, each with unique gene expression patterns and tropisms. Finally, genomic data for these organisms are generally limited, slowing the identification of target proteins.

As such, many investigators have focused their attention on whole-organism vaccines for malaria, such as the use of irradiated P. falciparum. Now, a new article from Nature (online 5 December 2004, doi: 10.1038/nature03188) presents a promising new approach, using the first genetically modified attenuated malarial parasite. This work, a collaborative effort between investigators at the Heidelburg University School of Medicine (Heidelburg, Germany) and the Seattle Biomedical Research Institute (Seattle, WA), benefited from the recent assembly of complete genomic sequences for several Plasmodium species. Working with these data, the researchers selected a gene, UIS3, expressed in the late stages of liver infection that precede blood cell infection; by targeting this stage, the researchers hoped to attenuate the liver-stage parasite without affecting the stage at which the parasite is mosquito-transmissible.

The group worked with P. berghei, the rodent malaria parasite, to engineer a UIS3-deficient strain. These modified parasites showed partial ability to progress through their life cycle, including the mosquito-borne stage, but were incapable of full maturation, suggesting that pathology should be blocked. Indeed, mice showed no ill effects after immunization and a pair of boost injections—they did, however, exhibit full protection against wild-type parasites introduced either intravenously or by mosquito. These mice remained fully protected against large doses of parasite (50,000 sporozoites—roughly 500 times the number in a mosquito bite) even two months after immunization.

Data obtained since publication have continued to support their strategy. “We have just challenged another set of immunized animals after 3 months,” says author Stefan Kappe, “and we still get complete protection [against] mosquito bite and i.v. inoculation with sporozoites. The bite experiments are important, because that's really the natural mode of transmission.” Buoyed by this success, Kappe and his colleagues are awaiting approval to begin human clinical trials. “We are collaborating with the Walter Reed Army Institute of Research to do those trials,” he tells Lab Animal, “[and] I would say if everything works and funding comes in, we hope [to] conduct some trials by the end of next year.”