A TRIAL in which volunteers were made immune to malaria by injecting them with just a few of the parasites has revealed a new way to create a vaccine. This may be important if the vaccines now being tested don鈥檛 live up to their promise.
The body tackles infectious diseases in two main ways: it produces antibodies that latch onto invaders or infected cells and neutralise them, or T cells that tell other cells to destroy intruders. Most potential malaria vaccines have been designed to stimulate production of antibodies, but it is very difficult to sustain high levels of the different types needed to fight various malaria strains.
In the latest study, however, the volunteers gained protection from the disease through T cells alone. 鈥淭here was no antibody at all. It was almost unbelievable,鈥� says Michael Good, director of the Queensland Institute of Medical Research in Brisbane, who led the study.
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Other groups have been able to produce a T cell-mediated response against the liver stage of the disease
(see Graphic). For instance, a DNA-based vaccine that stimulates this response, created by a team led by Adrian Hill of Oxford University, has just begun the second stage of trials in Gambia. But the Australian study is the first to show that T cells can attack the blood stage of the disease too. 鈥淚t鈥檚 really nice evidence that cell-mediated immunity against the blood stage can protect people,鈥� Hill says.
The cell-mediated response doesn鈥檛 occur normally, probably because the huge numbers of parasites overwhelm the T cells before they can do their job. Although some people do naturally develop partial immunity to malaria, it is antibody-based.
In the Australian trial, three men and two women were injected every five weeks with red blood cells containing the most deadly species of malaria parasite, Plasmodium falciparum. On each occasion, the volunteers received around 30 parasites, a tiny number compared with the tens of thousands that invade blood cells after bursting out of liver cells. On the first three occasions, the parasites were allowed to multiply for one week before the volunteers received drugs to clear the infection. The fourth time around, drug treatment was delayed for two weeks鈥� long enough for symptoms to have appeared. One volunteer had dropped out, but the other four appeared to be protected from the disease (The Lancet, vol 360, p 610).
鈥淚n three of the volunteers we could not detect parasites. The fourth person was interesting. His parasites grew, but he didn鈥檛 get ill,鈥� says team member David Pombo of the LDS Hospital in Salt Lake City.
None of the volunteers produced antibodies. Instead, they had an up to tenfold increase in the production of T cells. 鈥淸Good鈥檚 team] has found a completely unexpected route by which you may be able to gain immunity,鈥� says malaria researcher Louis Schofield of the Walter and Eliza Hall Institute in Melbourne. The challenge now is to identify the parts of the parasite that produce this immunity, he says, to create a vaccine.
The complex life cycle of the malaria parasite has long eluded efforts to develop effective vaccines, but there are now some promising candidates, including the Oxford vaccine created by Hill鈥檚 team, the 鈥淩TS,S鈥� vaccine developed by GlaxoSmithKline and another developed by the Papua New Guinea Institute of Medical Research. The RTS,S vaccine provokes both an antibody and cell-mediated response, so it targets both the sporozoites injected by the mosquito and the liver stage.
In preliminary tests in Africa, the RTS,S vaccine protected 71 per cent of people, better than any vaccine so far. But just two months after vaccination, the level of protection fell rapidly. Nonetheless, the team hopes that the vaccine will reduce the severity of the disease even if it can鈥檛 prevent it, says Joe Cohen of GlaxoSmithKline. A safety trial on children is already under way in Mozambique, and a larger trial is due to begin in October. And in tests on 120 children, the Papua New Guinea vaccine reduced parasite numbers by 60 per cent on average.
The team is now trying to improve it further. An effective vaccine may have to combine many approaches. The ideal vaccine would target the parasite at every stage of its cycle, producing high levels of antibodies to prevent the sporozoites reaching the liver in the first place, a cell-mediated response against the liver stage and, now, both against the blood stage. Antibodies against the sexual form of the parasite could also prevent it being picked up by mosquitoes that bite infected people, while those against a malarial toxin recently identified by Schofield could help reduce the severity of symptoms.