MALARIA

What is malaria?

Malaria is a disease caused by one of four species of the parasite Plasmodium. It is spread by the bite of infected mosquitoes and is endemic in tropical and sub-tropical parts of the world (Figure 2). The Plasmodium parasite has a complicated life-cycle with several different stages, some found in the mosquito host and some in the liver and red blood cells of infected humans (Figure 1). Of the four Plasmodium species (P. falciparum, P. vivax, P. ovale and P. malariae), P. falciparum is the most dangerous and may cause coma, severe anaemia, kidney failure, convulsions and pulmonary oedema, in addition to a high fever. Untreated P. falciparum malaria has a high death rate. Fluctuating fevers, chills, malaise, nausea, muscle pains and headache are the most frequent symptoms of malaria, often accompanied by anaemia and jaundice, but may initially be mistaken for influenza. However, parasites can be seen in the blood through a microscope, confirming diagnosis.

Who does malaria affect?

The World Health Organisation has estimated that 300-500 million people worldwide are infected by malaria each year, and that the disease causes more than 1 million deaths a year. More than 85 per cent of these deaths are estimated to occur in Africa, and children under five years old account for the majority of cases. Malaria is not endemic in the UK, but approximately 2,000 cases occur every year in those returning from malaria-endemic countries. In 2005 there were 1,754 recorded cases in the UK (76 per cent of them due to P. falciparum) and 11 deaths.

Present treatments and shortcomings

Prophylaxis (prevention) is the most important consideration for travellers visiting areas where malaria is endemic, and a variety of physical measures are recommended (for example, use of impregnated mosquito nets, insect-repellent sprays, etc). However, preventive medicines are also necessary and several are available. Which one is chosen will depend on the types of malaria most often encountered in the area to be visited and their resistance to anti-malarial medicines. The parasite has become resistant to chloroquine (Avloclor, AstraZeneca) in many countries and other medicines will often be chosen, such as mefloquine (Lariam, Roche), doxycycline (Vibramycin-D, Pfizer) or atovaquone + proguanil (Malarone, GSK). The most common side-effects of these medications when used for prevention of malaria are gastrointestinal upsets (pain, nausea, vomiting, diarrhoea) and headache. Sensitivity to light may occur with doxycycline and dizziness or blurring of vision have been reported with chloroquine and mefloquine. Rarely, serious side-effects have been associated with mefloquine, such as seizures, mood changes or psychoses.

Treatment of malaria has in the past often been with quinine, and this may still be used in certain situations, but the WHO now recommends the use of combination therapies with two or more medications that act in different ways, in order to avoid the resistance which may develop if a single agent is used. In particular, combinations based on artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin) such as artemether + lumefantrine (Riamet, Novartis) are recommended. While low blood sugar levels are a common side-effect of quinine treatment, artemisinin derivatives are generally well tolerated.

What's in the development pipeline?

The growing problem of resistance means that development of new anti-malarial treatments is a continuing need. In addition, while current treatments are effective, they are generally too expensive for widespread use in the main malarial areas. Moreover, there is a pressing need for a preventive vaccine that could reduce the huge number of deaths caused by malaria in sub-Saharan Africa.

Several new malaria treatments are in development to counter the problem of resistance. At the Phase 3 stage, GlaxoSmithKline is developing a combination of chlorproguanil, dapsone and artesunate (CDA), while Sigma-Tau is studying a combination of dihydroartemisinin and piperaquine, an antimalarial medicine that has already been used successfully in China against resistant malaria. Pfizer has a combination of chloroquine and the antibiotic azithromycin also in Phase 3 trial.

New compounds in Phase 2 research include GSK’s tafenoquine, an 8-aminoguinoline active against P. vivax malaria, Immtech’s pafuramidine (DB 289), HE-2000 (Immunitin, Hollis- Eden) sanofi-aventis's ferroquine (SSR 97193), which has been shown to be active against chloroquine-resistant strains of P. falciparum, and RBx11160, from Ranbaxy. This last compound is intended as a replacement for artemisinin, which must be harvested from plants and which is consequently in limited supply. It will be used in combination with the long-acting compound piperaquine phosphate. Lastly, at Phase 1, Immtech has AQ13.

An effective malaria vaccine is the ultimate goal of research into prevention. This goal is still a long way from being achieved, but positive results have been reported in Phase 2 trials of a vaccine called RTS,S/AS02A (Mosquirix, GSK) directed against the stage of the malarial parasite that is injected when a mosquito bites. In an 18-month follow-up of children in Mozambique who had been given three doses of the vaccine, there was a 35 per cent reduction in malaria episodes.

Other companies are also developing vaccines that act against various stages of the disease. Pevion Biotech has a vaccine (PEV3A) in Phase 2 trial and Oxxon Therapeutics is collaborating with the Malaria Vaccine Initiative and the Wellcome Trust on two vaccine projects. In addition, Crucell has a malaria vaccine based that is about to start Phase 1 trials. Vaccines directed against the blood-borne stages of the disease have also been extensively researched, but none has yet shown sufficient protective efficacy to merit full development.

All of the vaccines mentioned above are directed against the P. falciparum form of malaria, which is the most widespread and difficult to treat, but the Malaria Vaccine Development Branch of the National Institutes of Health in the United States has carried out Phase 1 studies on a vaccine (Pvs25H) against P. vivax malaria, which is the next most common form.