8 minutes reading time (1623 words)

    Malaria - A Growing Threat

    Graeme O'Neill

    Australia is certified free of malaria by the World Health Organisation, but elsewhere it is a killer. Australian researchers are currently working on a vaccine against malaria.

    Malaria is one of the leading causes of illness and death in the world. According to the World Health Organization, between 300 to 500 million people contract malaria every year and up to 2.7 million die from it. Nine out of ten of these deaths occur in Africa. The rest occur in Asia and Latin America. People suffering from malaria are often anaemic and have enlarged spleens. They are also susceptible to other infections.

    Cycle of malarial parasite

    Malaria is caused by a parasite (Plasmodium) that lives in red blood cells and cells of the liver. The parasite is transmitted from person to person by the female Anopheles mosquito. When an uninfected female Anopheles mosquito bites an infected person, the mosquito takes up parasites in her meal of blood. Once they are safely inside the mosquito, some of these parasites reproduce sexually in the mosquito's gut. The parasites then travel to the salivary glands of the mosquito where they mature into sporozoites. At the next meal, the mosquito injects a small amount of saliva into her victim to stop the blood clotting, and the sporozoites are passed into a new host. The sporozoites are carried along in the blood of the new host until they reach the liver.In the host's liver cells the parasite multiplies repeatedly. After about 5 days there are in the order of 40,000 new parasites, called merozoites. At this stage, the liver cell bursts and the merozoites attack red blood cells. In the red blood cells, the parasite divides again, forming about 16 new merozoites. Infected red blood cells rupture and release the toxins that cause fever and chills and the new merozoites, which invade new red cells. From time to time, some merozoites form gametocytes. A mosquito with a blood meal can take these up.

    What has been done to control malaria?

    During the 1950s the World Health Organization carried out a program to eradicate malaria from some parts of the world. Insecticides, mainly DDT, were used to control mosquito populations. At first this program was successful, and malaria was eradicated from southern Europe, the United States and the former Soviet Union. But it soon became clear that, in hotter and more humid climates where mosquitoes are present all year long, they had become resistant to the insecticides being used.

    Other methods to control malaria were attempted, including drug treatment of whole populations, but the malarial parasites became resistant to the drugs. By 1970, with the number of cases of malaria increasing, it became obvious that the program had failed.

    Today, the battle against malaria is continuing on two fronts:

    • Fighting mosquitoes. A range of methods is used to deal with mosquitoes. A simple but effective method is for people to sleep under nets that have been soaked in insecticide. This is being tried in Vietnam and parts of Africa and has been found to reduce the incidence of the disease.
    • Fighting the disease. Good health care, with early detection and full treatment with drugs, is essential. Unfortunately, most cases of malaria occur in countries that cannot afford such programs.

    Controlling malaria

    By far the most effective control for malaria has nothing to do with mosquitoes. The risk of getting malaria is related to the number of people who have malaria. (Mosquitoes only carry malaria from one person to another.) In countries that have eradicated or greatly reduced malaria, better treatment has been of paramount importance.

    A little thought will show why better treatment of malaria is more important than mosquito control. A single malaria infection, if untreated, can last in a human for more than a year. Adult mosquitoes only live a very short time (on average 3-4 days), so it's unlikely that malaria can persist in the mosquito population for more than about 3 weeks. If you kill the mosquitoes but don't treat the people, you have to eradicate all the mosquitoes for more than a year. Total eradication is basically impossible at an acceptable environmental cost. On the other hand, you could eradicate malaria by treating all the people for about a month.

    We have had outbreaks of malaria in Australia in the past, and we still have plenty of mosquitoes that can transmit malaria. An increased population density and a trend towards more outdoor living are factors that ought to make malaria more prevalent, and yet we have been officially malaria-free since 1981. The reason we no longer have malaria in northern Australia is an example of the effectiveness of prompt treatment. It takes about 10 days after you get sick from malaria before the gametocytes mature enough to infect mosquitoes. So if a person is treated in the first 10 days after getting sick, there is no chance of that person giving malaria to mosquitoes. In Australia, it is now highly unlikely that someone will be sick with malaria for 10 days and not be treated. Hence no malaria.

    Widespread spraying programs have rarely been used as a control program for malaria. They are costly and ineffective. By far the most common form of spraying has been to spray houses with a contact insecticide. This kills mosquitoes when they rest on the walls. Selective spraying like this has a relatively minor impact on the environment.

    Malaria can be treated successfully with a variety of drugs if it is caught early enough. Until recent years, quinine was the most effective drug given for cases of cerebral malaria. But some forms of the malarial parasite have become resistant to quinine. New and more expensive drugs have to be administered in these cases.

    Fortunately, two recent studies have shown that an old Chinese herbal remedy made from the shrub. Artemisia annua, can effectively treat quinine-resistant malaria. The active compound - artemisinin - derived from this plant has been shown to clear the parasite from the blood more quickly and with fewer side effects than quinine-based drugs. This is good news for Africa, where the majority of malaria cases occur. The recent discovery of exactly how artemisinin kills the malarial parasite may lead to a series of new anti-malarial drugs.

    Progress towards a malaria vaccine
    The malaria parasite of the Plasmodium genus is a molecular chameleon that can change its guise to deceive the host's immune system. Protein chemist Dr Robin Anders (from Melbourne's Walter and Eliza Hall Medical Research institute) 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.

    Dr Anders' research group is working with Dr Allan Saul's team at the Queensland Institute of Medical Research on a vaccine against Plasmodium falciparum, deadliest of the four human malaria parasites. Ideally, he says, the vaccine will also protect against Plasmodium vivax. By targeting the parasite at each stage of its life cycle, the vaccine will at least reduce the rate of transmission of malaria in affected communities.

    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. 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. In malaria, the 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.

    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.

    "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 partners from the two institutes are exploring multi-component vaccines, combining several antigens from the blood stage with antigens from other stages of the malaria parasite's life cycle. Forcing the parasite through a series of bottlenecks during its life cycle could limit the transmission of malaria within populations.

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