Whole-organism malaria vaccine?

Genetically modified parasite induces immunity in rodents, but some doubt use in humans

By | December 6, 2004

A novel approach to attenuating the malaria parasite could herald a whole-organism vaccine for humans, according to research published this week in Nature.

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 Plasmodium berghei lacking a single gene, known as UIS3 for "upregulated in infectious sporozoites gene 3." The results, Kappe told The Scientist, are "very exciting." But safety and production issues could prevent the development of the vaccine for humans, say other scientists.

Kappe's group had previously identified UIS3 as being essential for early liver-stage development of the parasite. Plasmodium knockout technologies allowed the team to disrupt the gene without affecting the red cell cycle, meaning that the parasites could be maintained as asexual stages in the red blood cells of the host with no detrimental effects to the parasite. This was crucial, as the organism has to infect the host liver to induce a full immune response, Kappe said.

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 Plasmodium falciparum parasites has been known for many years to protect humans from blood-stage P. falciparum malaria infection and disease, said Filip Dubovsky of the Malaria Vaccine Initiative (MIV). "[However] this paper demonstrates in an elegant way that, rather than relying on X-rays to attenuate parasites, it is possible to use gene knockout mutation of the newly identified gene, UIS3, to attenuate parasites, in a verifiable manner, as to render them protective," he told The Scientist in an E-mail.

But the results relate to a species of malaria markedly different from any human malaria, since P. berghei cannot infect humans, Dubovsky said. "It will be crucial to determine whether this gene deletion attenuation is similarly effective in the most important human parasite—P. falciparum."

Kappe said his team is "doing this right now by actually complementing the knockout in the rodent parasite with the P. falciparum gene, which would be proof that the gene has the same function."

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. The Scientist regrets the error.

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