Malaria

(Published: 14 January 2005)

For fifty years scientists have been trying – and failing – to develop a vaccine against malaria, but last October the Lancet (see news item) published details of the most effective candidate yet, which could be licensed in 2010. The research team (see news item) tested the vaccine on 2,022 children aged between 1 and 4 in Mozambique, where each person receives an estimated 38 bites each year from malarial mosquitos. At the end of the trial the vaccine had reduced a child's risk of developing one episode of malaria by 30% and the risk of developing severe malaria by 58%, while extending the time to first infection by 45%.

The need for a malaria vaccine is acute and statistics about the disease make grim reading. Some 40% of the world's population is at risk – see the map here – because it is endemic in over 100 countries and territories. Some 300 million to 500 million new cases occur each year, leading to between 1.5 million and 2.7 million deaths. Its impact is greatest in developing countries; more than 90% of all new infections are in sub-Saharan Africa.

Four species of the one-celled protozoan parasite Plasmodium are responsible for malaria: P. vivax, P. ovale, P. malariae and P. falciparum. All are transmitted by the female Anopheles mosquito, the male being a harmless vegetarian. When the insect bites its victim, the sporozoite form of the parasite (for a small photograph click here) is transferred from the mosquito's salivary glands to the human bloodstream, and passes to the liver. Here it reproduces asexually to form merozoites – this photograph shows a liver cell full of them. The merozoites enter the bloodstream and infect red blood cells, where they grow and multiply further, eventually causing the cells to rupture. The most dangerous species is P. falciparum because it is capable of colonising red blood cells of all ages; P. malariae can only attack older cells, while P. ovale and P. vivax only enter younger cells. P. falciparum can thus produce enormous parasitic loads, the proportion of circulating red cells with severe disease sometimes exceeding 20%. This often results in the host's death from multiple organ failure.

Some of the newly released merozoites go on to infect other red blood cells, but others develop into sex cells; male and female gametocytes. When a female mosquito subsequently bites the host, these gametocytes are ingested and mature in the insect's stomach. Male and female gametocytes then undergo sexual reproduction, uniting to form zygotes that subsequently multiply to produce sporozoites. These, in turn, migrate to the insect's salivary glands, ready to infect a future human host. A diagram and brief account of the parasite's life cycle can be found on Encarta, but this is somewhat simplified. For example, as merozoites mature within the red blood cells they pass through a number of intermediate stages (ring, trophozoite and schizont). The intracellular lifestyle of the malarial parasite is unique, and if you are interested in the mechanisms by which it enters host cells and modifies them, the Tulane University site has a highly detailed description.

Symptoms of malaria vary with the type of plasmodium causing the infection, but sufferers generally experience headache, nausea, fever, vomiting and flu-like symptoms within 9 – 14 days of being bitten. The severity may fluctuate in a cyclical fashion, corresponding to the development and release of merozoites into the bloodstream. The pathophysiology section of this eMedicine page explains briefly how symptoms are caused by the activities of the parasite; for example, merozoites metabolise glucose 70 times faster than the red blood cells they inhabit, leading to hypoglycaemia and lactic acidosis. There is also comprehensive coverage of anti-malarial medications.

For travellers visiting a malarial area, prevention is absolutely vital. Firstly, they should minimise the chances of being bitten by such measures as limiting outdoor activities between dusk and dawn, wearing long-sleeved shirts and long trousers, applying insect repellent containing DEET, applying aerosol insecticides in living and sleeping areas at dusk, and using a mosquito bed net, preferably one impregnated with permethrin. Chemoprophylaxis is equally important. As Plasmodium's pattern of drug resistance is constantly evolving, the latest information regarding anti-malarial agents for a particular region should be obtained before departure, from such organisations as the WHO or CDC. Artemesinin combination treatment (ACT) has proved to be highly effective in south east Asia, but a question mark remains over whether this should be introduced as first-line therapy in Africa, where the intensity of transmission is much higher.

In fact, the impact of malaria on the African continent has greatly increased over the past two decades; the average number of cases between 1982 and 1997 was four times that between 1962 and 1981, there has been a striking increase in the number of severe malaria epidemics, and the annual mortality rate has jumped dramatically. Medicins Sans Frontieres argues that ACT therapy must be widely implemented in sub-Saharan Africa as it is the best treatment for malaria today. However, the Roll Back Malaria programme, established by UNDP, UNICEF, WHO and the World Bank, and which aims to halve the burden of malaria by 2010, takes the view that a combination of different strategies is required. It cites the facts that treating an African child with ACT costs 20 times as much as with chloroquine (now largely ineffective in the region), making universal introduction impractical, and that insecticide-treated mosquito nets contributed significantly to a 98% reduction in the incidence of the disease in Vietnam. However, everyone is agreed that an enormous amount of work is required, and the scale of the challenge is monumental.

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A Tour around Malaria

A Tour around Malaria