Trial and error: Malaria's shape shifting makes vaccine development tough. Credit: © WHO/A.Crump

The vast knowledge of Proteus, Greek mythology's Old Man of the Sea, was matched by his reluctance to share it. He knew all things, past, present and future, but would always decline to be interviewed, or claim to be out when you called. The only way to catch him would be when he was off guard - while he was enjoying his afternoon nap. Startled, he would try to escape, by assuming a variety of different shapes.

If there is anything in the modern world that deserves to be dubbed protean, it is the malaria parasite Plasmodium falciparum. The life cycle of this creature is so complex that it is as if at least four different organisms draw from the same genome.

The sporozoites on their way to the liver are different from the merozoites that invade red blood cells. Different again are the trophozoites, which feed vampire-like on haemoglobin, and the gametocytes, the germs of the sexual stage, which lie dormant in red blood cells until and unless they are sucked up by another mosquito.

The molecular characteristics of each of these stages are poorly understood - trying to keep tabs on malaria's feverish shape-shifting is as hard as getting Proteus to tell all. As a result, experimental vaccines have targeted just a few of these stages so far, one at a time.

Now an analysis of the P. falciparum genome reveals what proteins the parasite makes. Because proteins are what our immune system recognizes, this proteome should make rich pickings for vaccine hunters looking to target all stages at once.

Stage play

Laurence Florens of the Scripps Research Institute in La Jolla, California, and colleagues have discovered that the parasite switches on a completely different subset of genes in each stage of its life cycle1.

Sporozoites, for example, use different genes from merozoites, say. In fact, almost half of the proteins in sporozoites are unique to that stage. Of the 2,415 malaria proteins that Florens' team studied - 46% of all of the parasite's gene products - only 152 are common to the entire cycle. These are the kinds of basic housekeeping proteins that you would expect in any cell, such as those for cell support.

Natural immunity is our greatest ally. Credit: © WHO/A.Crump

Another team, led by Edwin Lasonder of the University of Southern Denmark in Odense, finds that a vast number of proteins encoded by the Plasmodium genome are associated with its reproductive, gametocyte stages.

This detailed picture of the molecular make-up of each stage provides an opportunity to develop a vaccine or group of vaccines that targets every stage. In particular the sexual stage, so key to the transmission of the parasite.

Such a multipotent vaccine will hope to mimic the strange, ill-defined kind of immunity seen in malaria survivors. They appear to acquire resistance to a cocktail of malaria proteins.