Protein chemist Dr Robin Anders confesses a grudging respect for one of our deadliest enemies, even as he tries to develop a vaccine to defeat it. 'One can get so fascinated with the beautiful biology of the malaria parasite that one could forget it is such a devastating pathogen,' said Dr Anders. The malaria parasite of the Plasmodium genus is a molecular chameleon that can change its guise to deceive even the wondrously adaptable weaponry of its host's immune system. Australian scientists are working on vaccine Dr Anders' research group is working on a vaccine against Plasmodium falciparum, deadliest of the four human malaria parasites. Ideally, he says, the vaccine will also protect against Plasmodium vivax. Genetic diversity of the parasite presents difficulties Relentless selection pressure from the human immune system has seen some of the parasite's genes become extremely polymorphic. This means that new strains are constantly emerging as meiosis reassorts the various alleles of these genes. In a single village in Papua New Guinea, for instance, individuals may have antibodies to many different parasite strains. This genetic diversity presents a formidable obstacle to a vaccine, says Dr Anders. Targeting specific antigens is not the answer Any vaccine that targets a narrow spectrum of antigens is unlikely to be protective, because at different times and in different populations the immune system may be targeting quite different antigens. Moreover, immunising against specific antigens may only impose pressure on the parasite to change its identity. Dr Anders says monkeys immunised against a malaria antigen of low variability in nature became immune, but the parasite broke through by deleting the gene for that antigen. Parasite can change its spots Most protozoan parasites have a remarkable ability to 'change their spots', by switching between forms of a highly variable protein antigen. In malaria, this antigen is expressed on the surface of infected red blood cells. The immune system limits the initial parasitaemia by directing its antibody attack at this antigen. But the parasite then switches off the gene for that antigen and begins expressing another variant. Why does the parasite betray its presence? The parasite itself is safely hidden inside a red blood cell, where it feeds and multiplies. So why does it express its antigen on the surface of the cell where it is visible to the immune system? Dr Anders says it cannot avoid doing so. During the latter half of its 48-hour asexual phase, the different forms of the variant antigen serve to anchor the parasitised red cells to the lining of blood vessels in a range of different tissues. This means the parasite can avoid passing through the spleen, which swarms with hostile phagocytes and antibody-secreting B-cells. After rupturing, the infected cells release a new flush of parasites into the bloodstream, triggering the recurrent waves of fever typical of malaria. Will scientists be able to produce an effective vaccine? So what is the prospect for an effective vaccine, when the very idea of a vaccine is to elicit a protective immune response against specific, constant antigens? 'Several things make us very optimistic,' says Dr Anders. 'First, immunity does develop naturally – most human deaths from malaria are in children under the age of four. After that, symptoms become less severe and people develop significant immunity and suffer less severe, briefer episodes of parasitaemia than non-exposed individuals. 'Those who have acquired immunity may be making antibodies against secreted toxins that cause the classic symptoms of malaria, rather than against structural antigens, which opens another promising avenue for vaccine development.' By comparing antibodies from villagers in Papua New Guinea, monkeys and mice, the Australian researchers have identified shared features in several antigens from the blood stages of each parasite species. Vaccine could reduce the incidence of malaria 'Our evidence suggests that the protective immune response is against the asexual blood stage, which is the major cause of illness and death in humans. A vaccine against this phase alone could have a dramatic impact on death rates,' Dr Anders said. But the researchers are exploring multi-component vaccines, combining several antigens from the blood-stage with antigens from other stages of the malaria parasite's life cycle. These blood-stage antigens could be combined with a vaccine such as that being developed by Glaxo Smith Kline, to improve the effectiveness of the vaccine. Related sites
Other boxes Box 1. Life cycle of malarial parasite
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