A novel approach to attenuating the malaria parasite could herald a whole-organism vaccine for humans, according to research published this week in
A research collaboration between Stefan H.I. Kappe, assistant member of the Seattle Biomedical Research Institute's Malaria Antigen Discovery Program, and Kai Matuschewski's group at Heidelberg University School of Medicine induced complete protection against malaria by infecting mice with living
Kappe's group had previously identified UIS3 as being essential for early liver-stage development of the parasite.
On injecting these infectious sporozoites into animals, the team discovered to their "great surprise" that the parasites were never able to fully develop through the liver cycle and induce blood-stage infection. This suggested the use of those parasites as a whole-organism vaccine, because repeated injections with them could never result in the animals developing malaria, Kappe said.
"By just deleting a single gene in a parasite that has over 5000 genes, you can completely block development to the liver stages—a kind of Achilles heel, I'd call it, of the parasite," Kappe said.
Whole-organism vaccination using X-ray irradiation-attenuated
But the results relate to a species of malaria markedly different from any human malaria, since
Kappe said his team is "doing this right now by actually complementing the knockout in the rodent parasite with the
Still, W. Ripley Ballou, vice president of Clinical Development at GlaxoSmithKline Biologicals, was less than enthusiastic about the findings. "There are concerns about an organism's ability to cross over and replace a single gene, therefore [it would be better] to have multiple attenuations," he told The Scientist.
"They are haploid organisms—there is no possibility that the gene function would be restored, and we have not seen any compensatory mechanism that would allow the parasite to overcome the block in liver-stage development," said Kappe. But he added that they were working to create parasites that are disrupted in multiple genes affecting liver-stage development, "so that we have an additional level of safety for these parasites."
Kappe said that culturing sporozoites in mosquitoes or insect cell lines was now possible, although Ballou described this as "a fantasy." Ballou added that in order to induce an immune response, massive infection at the red blood cell stage would be necessary, resulting in anemia and other effects associated with red blood cell destruction. However, the organisms do not make it to the blood cell stage, and the mice were immune based on what was present in the liver, according to the authors.
Correction (posted December 7, 2004): When originally posted, this article misstated Stefan Kappe's affiliation.