The ancient war between the human immune system and the malaria parasite, Plasmodium falciparum, is fought daily, on a million individual fronts. Every individual’s private battle with the parasite is unique. Infected siblings in an African village will make different antibodies against different P. falciparum antigens.

The parasite’s ability to frustrate the immune response by switching antigenic guise has defied efforts to identify fixed antigenic targets that could be combined in a general purpose vaccine. Three decades of intense scientific effort have yielded promising candidate antigens, but a viable vaccine may be years away.

Resistant strains have left the cupboard almost bare of antimalarial drugs. DDT, for decades the frontline weapon against malaria, is gone, leaving millions of children exposed to mosquitoes that transmit the parasite. Malaria is resurgent, and killing as many as three million people a year - 90 per cent of them under the age of five.

But as so often happens in research, hope has recently sprung from an unexpected quarter: Professor Alan Cowman’s research group at the Walter and Eliza Hall Institute for Medical Research has made a discovery that raises the possibility of designing new drugs to uncloak the parasite and transform it into a personalised, live vaccine for its human host.

Cowman and co have pinpointed a potentially fatal weakness in one of the parasite’s key defensive strategies: its ability to find safe haven from prowling immune-system cells in the quiet backwaters of the bloodstream.

It does so by inducing infected red blood cells to stick to the endothelium of tiny blood vessels in major organs like the liver, intestine, placenta and, most lethally, the brain. Riding at anchor, away from the powerful currents of the bloodstream, it avoids being swept through the spleen with its hostile hordes of antibody-secreting B cells.

“It all started with our paper in Science in 2004 in which Marti et al identified a sequence required for the export of parasite proteins to the red blood cell,” Cowman says. “It allowed us to identify the P. falciparum exportome [the full complement of exported proteins]. Having identified the exportome, we wanted to work out what the important ones were doing.

Exportome proteins are identified by two unique motifs: a pentameric PEXEL (P. falciparum Export Element), and a hydrophobic element. But in many cases, time and mutation’s tides have obscured the DNA sequences specifying these elements by “static”, making them very difficult to identify by the standard approach of aligning and comparing selected DNA sequences from candidate exportome genes with model PEXEL sequences.

Toby Sargeant, a PhD student in Professor Terry Speed’s bioinformatics group at WEHI, has developed powerful new search tools that can peer through the clutter to detect PEXEL and hydrophibic elements embedded in candidate genes, considerably expanding the exportome catalogue.

“One of the interesting findings from Toby Sargeant’s PhD is that the falciparum exportome is much larger than in other Plasmodium species,” Cowman says.

The parasite re-engineers its human host’s red blood cells to express a sticky protein, P. falciparum erythrocyte membrane protein 1 (PfEMP1). Knobs projecting from the surface of the infected cell are tipped with the adhesin protein. In the process, the parasite remodels the normally flexible cells into misshapen, rigid sacs that stick to the microvascular endothelmium

The transformation requires the parasite to export PfEMP1 and a supporting cast of exportome proteins through its own outer membrane, then through the erythrocyte’s membrane.

On the surface of the cell, they assemble into knob complexes, with PfEMP1 outermost. PfEMP1 anchors the infected erythrocyte to the microvasculature of the target organ.