Toxin Trumped: New malaria vaccine protects mice

If you can’t kill a deadly enemy, disarming it is your next best option. That’s the rationale behind an experimental vaccine that neutralizes a toxic molecule made by malaria-causing parasites. The vaccine protects mice from the most dangerous symptoms of the disease, Louis Schofield of the Royal Melbourne Hospital in Australia and his colleagues report in the Aug. 15 Nature.

Investigators have long struggled to develop a vaccine that can prevent people from becoming infected with the malaria-causing parasite Plasmodium falciparum. The new vaccine, however, doesn’t confer immunity to the mosquitoborne parasite.

The vaccine consists of a harmless piece of a natural molecule, called glycosylphosphatidylinositol or GPI, that’s formed from sugars and lipids.

Schofield contends that the full-length GPI made by P. falciparum acts as a toxin and is responsible for most of the deadly aspects of malaria.

The notion that malaria symptoms stem from a parasite toxin dates back more than a century, but doubts remained because no one had ever identified the toxin. About a decade ago, Schofield and his colleagues began presenting the case that GPI is the culprit. For example, they showed that the parasite’s GPI stimulates immune cells and blood vessel walls to release inflammatory chemicals. In severe cases of malaria, it’s these chemicals that cause acid buildup in blood, lung problems, brain dysfunction, and ultimately death.

Adding to the case against GPI, a research team led by D. Channe Gowda of Pennsylvania State University in State College reported several years ago that healthy people living in malaria-plagued regions make large amounts of antibodies to the parasite’s GPI, but young children in those areas and people never exposed to P. falciparum don’t produce such antibodies. “There is a clear correlation” between GPI-binding antibody concentration in blood and disease protection, says Gowda.

For several bacterial diseases, such as diphtheria and tetanus, physicians can prevent the illness by immunizing people against the microbes’ toxins. Schofield decided to pursue the same strategy with GPI.

The challenge, however, was to synthesize the molecule, which is difficult to isolate from the parasite. Schofield turned to Peter Seeberger, a chemist at Massachusetts Institute of Technology, who recently developed a new method for creating complex sugar-based molecules (SN: 4/13/02, p. 232: The True Sweet Science).

After Seeberger’s group synthesized a GPI fragment, Schofield’s team injected it into mice and later infected them with a parasite that’s a close relative of P. falciparum and causes malaria-like disease in the animals. The immunization generated GPI-binding antibodies, inhibiting the release of inflammatory chemicals in the bloodstream of the mice. The immunized mice didn’t develop the fatal brain damage suffered by unprotected mice. Moreover, the treated mice maintained stable blood acidity and didn’t suffer lung problems.

While the immunized mice survived much longer than unprotected mice, they did eventually die. The parasite had continued to replicate and ultimately burst the majority of the animals’ red blood cells. Schofield notes that this rarely happens in people because the human body normally checks the growth of P. falciparum if the GPI-triggered aspects of the disease haven’t weakened the person too much.

Tony Holder of the National Institute of Medical Research in London says that the new work vindicates Schofield’s contention that GPI is an important malaria toxin.

“If it was combined with another [vaccine] component that kills the parasite, that would be a very good combination,” he says.

Schofield agrees, although he notes that immunizing children with just a GPI vaccine may keep them healthy enough to develop natural immunity to the parasite.

Investigators will probably next test the GPI vaccine in monkeys and begin investigating its safety in people.

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