CAMBRIDGE, Mass.--By mimicking a toxin produced by the most lethal malaria parasite, researchers at the Massachusetts Institute of Technology and in Melbourne, Australia, report in the Aug. 15 issue of Nature that they have created a vaccine that is extremely effective in mice.
The researchers hope their work may lead to a human vaccine against the tropical disease that infects 5 to 10 percent of the world's population and kills more than 2 million people each year.
"After much tenacious searching, Louis Schofield of the Walter & Eliza Hall Institute (WEHI) of Medical Research in Melbourne identified the complex sugar within the toxin that causes the fatal forms of the disease," said Peter H. Seeberger, the Firmenich Assistant Professor of Chemistry at MIT. "He provided us chemists with a target to work toward to turn the synthetic molecule into a vaccine."
At MIT, Seeberger had created an oligosaccharide synthesizer, which cuts the time required to produce extremely complex carbohydrate molecules by a factor of 100. The device has opened the door to a flood of potential new research and disease treatments.
Armed with a kind of blueprint from Schofield, Seeberger and MIT chemistry graduate student Michael C. Hewitt built a complex oligosaccharide that is structurally similar to the toxic carbohydrate found in the single-celled parasites that cause malaria.
The parasite Plasmodium falciparum accounts for the majority of malaria infections and is the most lethal of the four different parasites. As part of its life cycle inside the human host, it releases glycosylphosphatidylinositol (GPI). This toxin may be the culprit behind the fever, convulsions and deaths associated with severe malaria.
AN EFFECTIVE VACCINE
Schofield, a Howard Hughes International Research Scholar at WEHI, first zeroed in on this toxin several years ago. He isolated a tiny amount from the parasite and used it to immunize healthy mice. He found that most of them did not die when later given fatal malaria.
The synthetic toxin created by Seeberger produced exactly the same immune response as the natural product. "We found very good protection--over 65 percent--and we believe the level of protection can be brought up to almost 100 percent by changing the formulation of the vaccine," he said.
Hooking the carbohydrate to a protein makes it a red flag to the body's immune system. By injecting just tiny amounts of the toxin-protein combination into the body, the immune system learns to recognize the toxin as an invader and destroys it the next time it shows up.
The carbohydrate vaccine may confer immunity against the life-threatening forms of the disease, which individuals in malaria-ridden regions are exposed to during childhood.
A GLOBAL KILLER
Malaria is a tropical disease transmitted by mosquitoes. Fossils of mosquitoes up to 30 million years old show that the vector for malaria was present well before Homo sapiens came along.
Called by the World Health Organization the world's most important tropical parasitic disease, malaria kills more people than any other communicable disease except tuberculosis. In many developing countries, particularly in Africa, malaria exacts an enormous toll in lives and medical costs. UNICEF recognizes malaria as one of the five major causes of death in children under five worldwide.
Antimalarial drugs are available, but variants of P. falciparum have developed resistance to the drugs. There is currently no malaria vaccine.
PUMPING OUT COMPLEX CARBOHYDRATES
Thanks to Seeberger's oligosaccharide synthesizer, biologically significant structures involved in cancers and a whole host of diseases are readily available for researchers to probe, analyze and manipulate. Researchers can use the tabletop device--a modified peptide synthesizer--to design and synthesize large numbers of different sugars and test their effect on cells.
Seeberger, Hewitt and graduate student Dan Snyder, in collaboration with Schofield, are starting to make large quantities of the carbohydrate for primate studies. They also are synthesizing related structures to understand exactly how the vaccine works.
This work is supported by the UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases, the National Institutes of Health, an NIH Biotechnology Training Grant, the Human Frontiers of Science Program, the Howard Hughes Medical Institute, and the Australian National Health and Medical Research Council.
