Malaria vaccine trials move forward

EXETER — For decades, malaria vaccines have proved frustratingly difficult to develop. So scientists have been quick to welcome the recent news (December 2001) that a candidate vaccine tested in West Africa provided partial protection against the parasite Plasmodium falciparum, which causes the disease. The vaccine, given the less-than-catchy name of RTS,S/AS02, is the first of its kind to show convincing effects against the parasite. But the protection is incomplete and shortlived, at least in adults, and the vaccine's developers are already modifying it to try to improve its efficacy. Meanwhile, the existing form of the vaccine is already being tested in children, because the team have sufficient confidence in it to believe that it may benefit children more than adults.Malaria kills about one million people each year, most of them children in Sub-Saharan Africa, according to the World Health Organization (WHO). Each year, about 300 million people are infected by the causative parasite. Recent studies suggest that malaria can slow economic development and might even cause stunting and affect cognitive development in some of those who survive it.RTS,S has been under development since the mid-1990s by scientists at the Walter Reed Army Institute of Research near Washington, DC and GlaxoSmithKline (GSK). In 1997, the team found that the vaccine protected about 80% of a group of volunteers who were deliberately exposed to 'challenge' with malaria parasites after vaccination. Field trials of the vaccine began the same year in The Gambia, West Africa, in adult men, headed by Kalifa Bojang of the Medical Research Council Laboratories in Banjul, with a large international team of collaborators. The final results of the Gambian trials, published in 8 December 2001 The Lancet, showed that, overall, three doses of RTS,S provided 34% protection against infection over a 15-week period. In the first nine weeks, 71% of the subjects were protected, but protection fell to zero in the last six weeks. A subgroup of the men received a fourth 'booster' dose in the next year's malaria season, and for this group the vaccine provided 47% protection in the first nine weeks. "This is the first vaccine of its kind to show clear and unequivocal evidence of protection," said Adrian Hill, a member of the international team, from the University of Oxford. "No one is arguing about that." The bad news, however, is the short duration of protection, he warned. A vaccine for use in developing countries would need to protect people for longer to be practical and cost-effective. "It's definitely progress, but not enough to sell a vaccine yet," suggested Hill.There was one further piece of good news from the Gambian trial. The vaccine appeared to offer protection against different strains of P. falciparum. This was unexpected; in the artificially controlled conditions of the laboratory challenge experiments, volunteers had been exposed only to the same strain as that used to make the vaccine.Malaria poses a tough problem for vaccine developers, not least because each stage of the parasite's complex life cycle looks different to the immune system. It reproduces sexually in the gut of certain species of mosquito, such as Anopheles gambiae, and is transmitted to humans when the insects bites and takes a blood meal. The sporozoite stage is present in the saliva of the mosquito and is injected during the feed, circulating in the blood until it reaches the liver where it invades hepatocytes and develops into a merozoite. The merozite leaves the liver cells and invades red blood cells, often in massive numbers, which is the cause of the characteristic malarial fever. Some merozoites develop into gametocytes that can then return to mosquitoes through a subsequent bite, to begin sexual reproduction, and the life cycle starts all over again.Efforts have long focused on the sporozoite stage as the target of vaccines designed for malaria-endemic areas, because by interrupting the life cycle in its earliest phase in the human they hope to arm the immune system against infection, rather than simply reducing the symptoms of disease. RTS,S is made from a surface protein of the sporozoite. This is fused to the surface antigen of the hepatitis B virus, and combined with a new adjuvant — a substance that stimulates the immune system — called AS02. Although its protection is modest, the vaccine is believed to show enough potential to have received backing from the Malaria Vaccines Initiative (MVI), funded by the Gates Foundation and based at the Program for Appropriate Technology in Health, Seattle. In April 2001, the MVI and GSK began Phase 1 trials — to test the vaccine's safety and immunogenicity — in Gambian children aged between six and twelve years. On 5 December 2001, the MVI announced that the Phase II trials to test the vaccine's efficacy would be conducted in younger children in Mozambique where malaria is transmitted throughout the year, unlike in The Gambia where it is seasonal. The trials will begin in 2002 with the collaboration of the Centro de Investigacao em Saude de Manhica in Mozambique. Phase 1 trials are continuing in The Gambia.The hope is that the vaccine might be more useful in children, who account for 90% of all malaria deaths in Sub-Saharan Africa. It is also young children who suffer the vast majority of severe cases of malaria illness, in part because their immune systems are relatively naïve to the parasite, whereas an older child or adult has developed partial immunity from repeated infections. The team hope that, even if the vaccine provides only partial protection, it might reduce the severity of each episode by limiting and slowing the number of parasites that escape from the liver and enter the bloodstream. In this way, a child would experience milder episodes while the immune system builds up some natural immunity. The only other candidate malaria vaccine triggering interest over the past decade has been Spf66, developed by Manuel Patarroyo of the Institute of Immunology in Bogota, Colombia. Hopes for the vaccine ran high in the late 1980s and early 1990s when it appeared to provide protection against malaria in Latin America. Then in a trial in Tanzania in the mid-1990s, the vaccine seemed to show only partial efficacy, at levels comparable with RTS,S. But, further trials showed no effect for the vaccine.GSK and its collaborators are already experimenting with different formulations of the vaccine that might increase its protection. In one approach being pursued by Hill's group at Oxford University, two different pox viruses, harmless to humans and modified, are being used as vectors. The first virus is used to carry a first "priming" dose of sporozoite protein into the body, followed by a second "boosting" dose carried by the second virus. This approach also has the backing of the MVI.Howard Engers at the Tropical Disease Research programme at WHO, which is supported by the UN Development Program, the World Bank and others as well as WHO, said that further trials of partially effective malaria vaccines were to be welcomed because of their potential to benefit children. But, he warned that even if a perfect vaccine were to be developed, other tools such as insecticide-impregnated bednets and chemotherapy regimes would continue to be needed to control malaria.Some researchers have raised questions about partially effective vaccines, arguing that they are worse than useless because of the evolutionary pressure they might put on the parasite, resulting in the emergence of more dangerous strains. But, others argue that this theory does not apply to vaccines directed at the sporozoite stage.

Malaria vaccine trials move forward

New malaria vaccine that reacts to the parasite as it is injected by the mosquito shows promise.

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