Malaria vaccine breakthrough for WEHI

Groundbreaking research on a malaria toxin could lead to the development of an effective vaccine for the deadly disease according to a paper published in the August 15 issue of Nature.

The research, a collaboration between Walter and Eliza Hall Institute (WEHI) scientist Dr Louis Schofield and Massachusetts Institute of Technology (MIT) scientist Peter Seeberger, demonstrated that a synthetic version of malarial toxin glycosylphosphatidylinositol (GPI) induced immunity in a mouse model of the disease, and significantly protected the immunised animals from the effects of the parasitic infection.

"What the study shows for the first time is that there is a malaria toxin that underlies the pathology and fatalities of the disease," said Schofield.

Schofield explained that, while the idea of a toxin underlying the pathogenesis of the disease was first suggested in 1886 by Camillo Golgi, this study is the first to actually prove that malarial GPI has that role.

GPI is a molecule consisting of an oligosaccharide domain, also known as a glycan, linked to three lipids. Removal of the three lipids makes the glycan non-toxic.

According to Schofield, the native toxin is very difficult to purify, so the researchers decided to try to synthesise it.

"We were very fortunate to persuade Peter Seeberger at MIT to take on the project," he said.

The synthetic version of the toxin is a precise mimic of the GPI glycan, Schofield said. He said that for the vaccine, the synthetic GPI glycan was coupled to a protein carrier to help the host recognise it as foreign.

When the synthetic GPI glycan was used to immunise mice, the scientists observed that the mice made antibodies that could neutralise the native toxin.

But the real clincher was seen when the mice were challenged with the malaria parasite, Plasmodium berghei, which models severe human disease in the rodent model.

"In mice, the symptoms are a pretty good model of what we see in humans," said Schofield. "These pathologies were alleviated in the vaccines."

The vaccinated mice had significantly reduced fatalities, and a reduction in the development of acidosis, pulmonary oedema and cerebral malaria, the leading pathologies associated with severe disease.

Schofield said that while they are reasonably sure that the GPI glycan vaccine would have a similar effect in humans, there are still questions to be answered, such as whether the vaccine would provide a sufficiently protective immune response.

He noted that in regions with endemic malaria, children are initially susceptible to severe disease, but then appear to develop acquired immunity, which protects them against the life threatening pathologies despite repeated infections.

"We're cautiously optimistic that it will be of benefit to humans," Schofield said.

Now the researchers plan to continue their studies to develop the vaccine for human use. Schofield said that a lot of attention would be paid to safety and toxicological studies, which will be required by regulatory bodies like the TGA in Australia and the US FDA.

His team will also examine the human response to the toxin, a project he has a student already working on. Improvements to the immunogenicity of the vaccine and to the synthesis are other goals.

The intellectual property associated with the project is entirely owned by WEHI, according to Schofield.

"We own the world rights in developing vaccines for malaria and other diseases around these GPI molecules," he said.

While Schofield said that the potential vaccine was commercialisable to a degree, he noted that big pharmaceutical companies did not invest a lot of money into malarial vaccines, in part because of the difficulty in designing a vaccine for the continuously changing pathogen.

In contrast to the surface antigens of the malaria parasite, the GPI toxin appears to be highly conserved, and is identical between the four species of Plasmodium that infect humans.

"Once we achieve some kind of efficacy in human trials, then I believe big pharma will come forward," Schofield said.

He said that human trials of the vaccine were still five years away.