Malaria – a growing threat
Box 3 | Anti-malaria vaccine
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, the 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.
The RTS,S vaccine
Vaccines work by exposing the body to a little harmless piece of a particular virus or parasite, which the body then learns to recognise and destroy. In the case of a malaria vaccine called RTS,S, developed by British pharmaceutical company GlaxoSmithKline, it is a piece of the malaria virus called circumsporozoite. But the body doesn’t ‘see’ circumsporozoite strongly enough for it to be a good vaccine. So, in RTS,S, scientists have stuck the circumsporozoite to a piece of Hepatitis B virus that the body ‘sees’ very well. When the body reacts to the Hepatitis B virus it will also react to the circumsporozoite stuck to it and in this way develop immunity to the whole malaria parasite.
Results announced in 2011 from trials of the RTS,S in Africa were very encouraging, with a reported drop of around 50% of both clinical and severe malaria in infants. However, how long the children will remain protected is still unknown, and further tests are yet to be conducted on younger babies. While this vaccine will not provide a ‘silver bullet’ to defeat malaria, it will certainly play a role.
Boxes
Box 1. Life cycle of malarial parasite
Box 2. Controlling malaria
Box 4. Australian research
Related sites
The hunt for a malaria vaccine (The Science Show, Australian Broadcasting Corporation (transcripts), 27 July 2002)
Sequencing the malaria genome (The Science Show, Australian Broadcasting Corporation (transcripts), 2 March 2002)
RTS,S malaria vaccine factsheet
Australian Army Malaria Institute
OzEMalaR - Australia - Europe Malaria Research Cooperation
Related articles
The RTS,S malaria vaccine (British Medical Journal, Editorial, 27 October 2011, by Christopher J. M. Whitty) Malaria not swatted yet (The Economist, 22 October 2011)
Important step toward malaria vaccine (Cosmos, 19 October 2011, by Kerry Sheridan)
Malaria vaccine results face scrutiny (Nature, 26 October 2011, by Declan Butler)
Malaria vaccine one step closer to approval (Nature,18 October 2011, by Daniel Cressey)
Malaria vaccine warrants more support (Australasian Science, September 2008)
Page updated January 2012.