Malaria vaccine at least eight years away, conference told

Veteran Melbourne malaria researcher Prof Robin Anders believes a malaria vaccine is still at least eight to 15 years away -- but he is optimistic that a vaccine is feasible, and will be effective, despite the phenomenal capacity of the parasite, Plasmodium falciparum, to take evasive action against drugs and vaccines.

The La Trobe University researcher, who began studying malaria in the mid-1960s in New Guinea, reviewed progress towards a malaria vaccine during his 18th Leach Lecture at the annual Lorne Conference on Protein Structure in Lorne on Sunday night.

Anders focused on two particular parasite antigens that he and his former co-workers at the Walter and Eliza Hall Institute for Medical Research identified as candidates for a vaccine in the mid-1980s.

They are called AMA1 (apical membrane antigen 1), and MSP2 (merozoite surface protein 2) - the latter appears to be unique to the most deadly Plasmodium species, P. falciparum.

Anders said research had confirmed that both are highly immunogenic -- that is, they are targets for a strongly protective immune responses in individuals who have survived malaria in infancy and developed immunity to the parasite.

Moreover, both antigens have been shown to be essential to the in vitro survival of P. falciparum.

Anders said that in regions where parasite transmission is intense, children under the age of four would be the primary beneficiaries of a malaria vaccine -- most mortality occurs in this age group.

Women who have developed immunity become more susceptible during pregnancy, so they would also benefit from a vaccine.

"It would also be good for immigrants and tourists entering malarious areas," Anders said. "Malaria is not just a health or humanitarian problem, it's an economic problem -- it has been estimated that malaria reduces economic activity in African countries where it is endemic by around 1.3 per cent a year."

Anders said the eventual vaccine will probably target both the sexual and asexual stages of the parasite's life cycle -- because it is split between the Anopheles mosquito and human beings, it offers many potential points of attack.

Anders' own work has focused on the parasite's asexual, blood stages, because of clear evidence that victims' natural immune response is directed mainly at these stages.

AMA1 is an integral membrane protein, which the parasite secretes from its apex -- the 'sharp end' just before it invades a red blood cell. The protein spreads over the parasite's surface, and presumably facilitates its passage through the cell membrane.

It is antigenically diverse -- in New Guinea, researchers found 168 different variants in a sampling of malaria parasites from villages just a few kilometres apart.

But the antigenic diversity of the AMA1 protein is constrained to particular regions of the molecule, and has minimal effects on its overall shape -- otherwise, the vital protein would not function properly, said Anders.

An 'average antigen' should still elicit a useful, generalised antibody response - and here, the parasite's natural diversity should actually work to boost immunity, said Anders.

People in malarious regions of PNG are constantly re-infected by different strains of the parasite, but only about 1 in 20 episodes results in severe infection -- mild episodes gradually build immunity.

Anders said he believed that the additive effects of this immunity, combined with the vaccine, should produce a strongly protective response.

Similarly, the parasite's MSP2 antigen, also a membrane protein, is antigenically diverse, exhibiting variations between different strains in the same locality.

But MSP2's diversity is also constrained -- within all the variation, the molecule has two basic forms, and incorporating both forms in the vaccine should elicit a strong immune response

Both AMA1 and MSP2 both inhibit development of the parasite in vitro, and elicit strongly protective antibody responses when tested individually in animals. Pre-clinical trials in humans have yielded strong antibody responses.

Anders said a vaccine combining the two antigens, perhaps with a third antigen from the parasite's sexual stage, would have a "very significant impact on morbidity and mortality" in areas where malaria is endemic.

He described the completion of the Plasmodium genome project last October as a "fantastic development", and one which is already revealing many new potential targets for antimalarial drugs.

But paradoxically, it could actually slow progress towards an effective vaccine. "Unless there is a dramatic increase in resources, it may slow development by stretching existing resources over too many candidate antigens," he said.

-- Graeme O'Neill will continue to bring you the latest reports from the Lorne Protein conference all this week