United Press International - August 14, 2002
Lidia Wasowicz, UPI Senior Science Writer

Incorporating a novel approach to target the main toxin produced by parasites that spread the world's deadliest tropical disease, the vaccine alleviated three severe complications of malaria in infected mice -- high acidity in the blood, fluid in the lungs and clogging of the brain arteries -- and spared the rodents' lives, investigators report in the Aug. 15 issue of the British journal Nature.

If such a vaccine can be fashioned for use in humans, it may provide much-needed protection against a disease that infects up to 500 million people annually, the researchers said.

"Malaria ranks with AIDS and tuberculosis as one of the three greatest infections of humanity," lead study author Louis Schofield, a Howard Hughes Medical Institute international research scholar at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, told United Press International in a telephone interview. "Recent research shows it's a major cause of poverty in developing countries. You get rid of malaria, and you ease poverty in many countries where it's endemic."

Much work remains before the true-life benefits of the research can be known, other scientists said.

"This is still at a very early stage in terms of a vaccine of this type for human use. What is seen in mice may not be true in humans," Xinzhuan Su of the Laboratory of Malaria and Vector Research at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., told UPI. "Combinations of this (vaccine) with other vaccine candidates may provide better protection. This has to be tested."

Development of an effective vaccine is viewed as critical to subduing the malaria epidemic. Increasingly resistant to the standard drug therapies chloroquine and mefloquine, malarial parasites have eluded worldwide efforts to rein in their reach. Years of intensive work have netted no vaccine to prevent the spread of the plague, which runs rampant in sub-Saharan Africa and other tropical and sub-tropical parts of the globe, primarily among children under age 5.

Schofield and his team decided to take a different approach to attacking the complex malaria problem. Whereas current malarial vaccine candidates are aimed at specific proteins in the various life stages of the deadliest of the malarial microorganisms, Plasmodium falciparum, their strategy targets a toxin released by the parasite. The toxin glycosylphosphatidylinositol, or GPI, contributes to the virulence of malaria in mice, and likely in humans, the study's authors said.

"This is first formal demonstration that the toxin does promote serious pathogenesis," Schofield said.

The team showed mice inoculated with a chemically synthesized fragment of GPI were protected against several of the signs of malaria, and against death, including:

-- Blood acidosis, an overflow of acid in the blood that can disturb numerous bodily functions, resulting in such complications as renal tubular acidosis, a disease that occurs when the kidneys fail to excrete acids into the urine, ultimately leading to growth retardation, kidney stones, bone disease and progressive renal failure, if left untreated;

-- Pulmonary edema, or abnormal accumulation of fluid in the lungs; and

-- Cerebral syndrome, in which the parasite causes clogging of the brain arteries.

"The primary conclusion of the authors is ... GPI is responsible for inducing the manifestation of disease and that immunization with a synthetic product can neutralize these effects," Anthony Holder, head of the Division of Parasitology at the National Institute for Medical Research in London, told UPI.

"This novel approach adds another useful tool to the development of a malaria vaccine. As the authors point out, bacterial toxins have been a successful target for preventive vaccines against tetanus and diphtheria," Dr. Joerg Schneider, vice president and director of research at Oxxon Pharmaccines Ltd. in Oxford, England, told UPI. "An anti-toxin vaccine might not eliminate the parasite, but sufficiently suppress parasite pathology to create a time window to allow the immune system of the host to mount an effective immune response," he said.

The findings support a theory postulated more than a century ago.

"In 1886, it was proposed by Camillo Golgi that malaria produces a toxin that appears to be associated with the intense periodic fevers caused by the infection," Schofield said. "In 1993, we published findings on the properties of GPI, showing that it was a toxin that produces a potent inflammatory response both in cell culture and in mice. That work proposed GPI to be the toxin that Golgi hypothesized more than 100 years earlier. Our work also led us to believe that GPI constituted an excellent target for a vaccine."

GPI is a glycolipid, a molecule consisting of sugar and fat that comprises cell membranes. Schofield and his colleagues found that a glycan chain -- a core component of GPI -- was necessary for the molecule to trigger symptoms. Glycan, then, would be a good candidate for use in a vaccine, they reasoned.

"These findings not only show the efficacy of the anti-GPI vaccine in the best available animal model of the disease, but also that GPI is central to the initiation of all these effects," Schofield said.

Even if the findings hold up in humans, however, it could take years to develop a safe and affordable vaccine, scientists cautioned.

"The exciting aspect is that the acquisition of 'antitoxic immunity' does happen naturally. But there is a tremendous amount of work required before knowing even that this was a safe strategy to develop in man," said Nick White, professor and director at Wellcome Trust-Mahidol University in Oxford and the Tropical Medicine Research Program at Mahidol University in Bankok, Thailand.

"Malaria is complicated," White told UPI. "Over the past 30 years (research results) have not yielded the benefits anticipated at the time. This has often been because the underlying assumptions, that the laboratory model or experiment (conducted in a wealthy temperate country) reflected well the human condition in the malarious tropics, proved incorrect."

Over the next few years, Schofield and team will work to create a variety of anti-GPI vaccines and test them in other animal models of malaria.

"This paper represents only a proof of principle," Schofield said. "We are aiming for a cheap, synthetic molecule that can be conjugated to a carrier protein that is approved for use in humans," he said. "Ninety percent of malaria fatalities are in young children, and the long-term hope is that such a vaccine could become a part of standard childhood immunization."

The vaccine is one of several candidates, he said. Years in the making, several other vaccines are being tested in Africa, a nation that accounts for some 90 percent of the estimated 2.7 million malaria deaths each year.

One vaccine, developed to protect the U.S. military stationed in parasite-infested countries, is being tried on adult volunteers in western Kenya, a malaria hotspot. The vaccine focuses on the "blood stage" of the infection, when the parasite rapidly reproduces and relentlessly attacks red blood cells, causing disease.

In July, safety trials began in 60 Mozambique children, ages 1 to 4, of a vaccine candidate called RTS,S/AS02 that has been shown to protect adults from infection temporarily. Its effects in adults begin to wane after two months, but researchers hope that due to differences in their immune system, children either could withstand infection longer or be spared from severe disease.

"Obviously (the anti-toxic vaccine) is early work and really cannot be compared with more developed approaches such as RTS,S/AS02 which have been developed intensively by large (pharmaceutical companies) for many years," Schneider told UPI. "However, I think the approach has significant potential in complementing existing vaccine developments, particularly blood stage-specific approaches. Malaria is characterized by soaring fever, chills, headache, sweating and, in the most severe cases, organ failure, coma and death.

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