The first big clinical trial of a malaria vaccine is about to start in Africa. After more than 20 years in research and development, the RTS,S vaccine will be given to some 14,000 babies and children in seven countries over the next two or three years.

RTS,S is the grandaddy of malaria vaccines and the only one so far to have received sufficient funding to begin a Phase III clinical trial. It has received an estimated $400m so far from GlaxoSmithKline, the Bill & Melinda Gates Foundation and other sources.

But academic and industry researchers are working on dozens of other candidate vaccines in earlier stages of development, which may be more effective than RTS,S at preventing infection by plasmodium parasites.

For example Oxford University’s malaria vaccines programme, run by Adrian Hill, has carried out about 30 small clinical trials on volunteers in Britain and Africa.

RTS,S originated in work during the mid-1980s at the US Walter Reed Army Institute of Research, a hotbed of discoveries in tropical medicine in general and malaria in particular. It was soon taken up by GSK Biologicals in Rixensart, Belgium, in a long-term collaboration that later extended to a public-private partnership with the PATH Malaria Vaccine Initiative (MVI) funded by the Gates Foundation.

The vaccine’s strange name is a historical legacy that reflects its complex construction (though GSK will market it under the trade name Mosquirix). RTS,S contains surface proteins – antigens – from the so-called sporozoite stage of plasmodium development, when the parasite enters the human bloodstream after a mosquito bite and heads toward the liver where it will mature and multiply. Added to this is a component of GSK’s hepatitis B vaccine, Engerix-B, intended to boost the immune response.

Even so, RTS,S is far from a perfect vaccine. Results of smaller clinical trials suggest that its efficacy is 35 to 55 per cent. But even this relatively low level of protection would bring a significant reduction in the toll of 800,000 African children under the age of five who die every year from malaria.

“We expect to get the first set of data from the Phase III trial within a year and a half,” says Christian Loucq, MVI director. “That would allow GSK to submit the vaccine for licensing in 2011 and we could introduce it [for widespread use] in 2013.”

At the same time MVI and other organisations are pushing towards much more effective vaccines. “Our target is to have vaccines with a minimum of 80 per cent efficacy available by 2020- 25,” says Dr Loucq.

Prof Hill at Oxford points out that researchers will be able to demonstrate the effectiveness of vaccines that offer 80 per cent protection through much smaller and less expensive trials than the huge one being organised for RTS,S. “We would like to think we could hold a Phase III trial with about 1,000 people,” he says.

He is keen for GSK to test RTS,S in combination with other candidate vaccines, on the ground that this will produce a better immune response. Joe Cohen, GSK project leader, says the company is open to such combinations but has not yet found one that is more effective than RTS,S alone.

Of the several candidates in development at Oxford, Prof Hill thinks the first to reach Phase III will be a vaccine based on a virus that normally affects chimpanzees but not people. This adenovirus has been genetically modified to make a plasmodium protein called ME-TRAP. It is being developed with a Swiss-Italian vaccine company, Okairos.

Several other specialist vaccine companies are active in malaria research. Mymetics of Switzerland focuses on vaccines that contain proteins from both life stages of plasmodium in people: the sporozoites transmitted by mosquito bites and the merozoites that emerge from the liver to infect red blood cells.

Other vaccines target only one stage – Sylvain Fleury, Mymetics chief scientist, says that this limits their effectiveness.

Mymetics’s latest candidate vaccine contains five peptides (protein fragments) selected from sporozoites and merozoites to stimulate the immune system. Its carrier is a “virosome”, a microscopic fat-filled sphere made from the membrane of the influenza virus – essentially an empty viral shell.

Dr Fleury says Mymetics is carrying out the research in the knowledge that its vaccine is likely to take 15 to 20 years to reach the market. Predicted sales then would be €200m-€300m ($259m-$388m) a year.

Sanaria, a US company, is taking a different tack. Stephen Hoffman, its chief executive, advocates a vaccine based on live plasmodium sporozoites that have been weakened by irradiation to stop them replicating.

This is similar to traditional “live attenuated” vaccines that protect against viruses and bacteria – and contrasts with the high-tech “component” vaccines, containing parts of the parasite designed to stimulate the human immune system, being developed by others.

Which approach will work best in the long run may not become clear for several years.

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