Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria

Louis Schofield (), Michael C. Hewitt, Krystal Evans, Mary-Anne Siomos and Peter H. Seeberger
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Louis Schofield: Royal Melbourne Hospital
Michael C. Hewitt: Massachusetts Institute of Technology
Krystal Evans: Royal Melbourne Hospital
Mary-Anne Siomos: Royal Melbourne Hospital
Peter H. Seeberger: Massachusetts Institute of Technology

Nature, 2002, vol. 418, issue 6899, 785-789

Abstract: Abstract The malaria parasite Plasmodium falciparum infects 5–10% of the world's population and kills two million people annually1. Fatalities are thought to result in part from pathological reactions initiated by a malarial toxin. Glycosylphosphatidylinositol (GPI) originating from the parasite has the properties predicted of a toxin2,3,4,5,6; however, a requirement for toxins in general and GPI in particular in malarial pathogenesis and fatality remains unproven. As anti-toxic vaccines can be highly effective public health tools, we sought to determine whether anti-GPI vaccination could prevent pathology and fatalities in the Plasmodium berghei/rodent model of severe malaria. The P. falciparum GPI glycan of the sequence NH2-CH2-CH2-PO4-(Manα1-2)6Manα1-2Manα1-6Manα1-4GlcNH2α1-6myo-inositol-1,2-cyclic-phosphate was chemically synthesized, conjugated to carriers, and used to immunize mice. Recipients were substantially protected against malarial acidosis, pulmonary oedema, cerebral syndrome and fatality. Anti-GPI antibodies neutralized pro-inflammatory activity by P. falciparum in vitro. Thus, we show that GPI is a significant pro-inflammatory endotoxin of parasitic origin, and that several disease parameters in malarious mice are toxin-dependent. GPI may contribute to pathogenesis and fatalities in humans. Synthetic GPI is therefore a prototype carbohydrate anti-toxic vaccine against malaria.

Date: 2002
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DOI: 10.1038/nature00937

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