Every 20 seconds a child somewhere in the world dies of malaria. Last week the governments of South Africa, Mozambique and Swaziland joined forces in an ambitious anti-malaria drive. Mark Honigsbaum reports on the race by scientists to find a vaccine
Every six months Dr Stephen Hoffman, a captain in the United States navy, enters an insectary swarming with irradiated mosquitoes and allows himself to be bitten repeatedly on the arm.
A few days later he repeats the torture until he is sure he has received more than 1 000 bites. Then, and only then, is it safe for him to travel to the front zone of the navy’s war against malaria – countries such as Kenya and Ghana where Plasmodium falciparum, the deadliest form of the disease, is rampant.
Hoffman’s behaviour may appear bizarre, but as the malaria parasite has become resistant to conventional drugs such as chloroquine and mefloquine (Larium), the treatment is the surest protection against the disease – and one scientists believe holds the clue to the holy grail of malaria research: development of a vaccine.
Next month the World Health Organisation (WHO)launches a major initiative to encourage pharmaceutical companies and scientific institutions to plough more money and resources into an effective anti-malarial agent for the 21 century.
Bill Gates, Microsoft software mogul, has donated $50-million to help develop a vaccine for malaria, and the World Bank is expected to follow suit. The concern is driven by the fact that, because of global warming and the collapse of public health programmes in developing countries, malaria is again becoming a scourge. In the past 15 years it has killed nearly 50 million people worldwide (Aids has killed five million). This year malaria will account for two million deaths, most of them children in sub- Saharan Africa.
In addition, mosquitoes are plaguing Florida and, more recently, New York, and the World Wide Fund for Nature predicts the falciparum strain could soon be in southern Europe. One of the reasons malaria is such a killer is that children who survive a first bout often do not survive a second. Even those who grow into adulthood will develop only partial protection against the disease.
But if the prognosis for natives of malarial regions is grim, it is even worse for tourists and troops visiting the tropics. Chloroquine, the prophylactic of choice since the war, is now only 30% effective in many regions, while mefloquine-resistance, first noticed on the Thai-Cambodian border, is spreading to other areas of South-East Asia.
“In Vietnam we lost more casualties to malaria than to bullets. It was the same in Somalia during Operation Restore Hope,” says Hoffman. “To be effective in combat, we have to develop something that works against malaria, not just today or next week, but long term.”
The point where Hoffman’s concerns and those of other scientific researchers coincide is in the hunt for a vaccine that, ideally, would be both a prophylactic for marines and a cure for African children already infected.
There is nothing new about Hoffman’s “irradiated-mosquito” treatment. It has been known since the mid-1970s that infection with irradiated mosquitoes carrying the cerebral malaria parasite provides full protection against the disease, but only for a limited time, hence Hoffman’s need to “re-inoculate” himself every six months.
Essentially, the treatment works by giving patients a weakened form of the disease that allows malarial sporozoites to reach the liver but not to develop to the second stage of infecting red blood cells – the point where patients become sick and feverish.
The challenge facing researchers since has been to develop a vaccine that mimics the irradiation effect through biological and chemical means, or a combination of both. But the malaria parasite is a formidable foe – it has a thousand times as many genes as HIV – and defeating it takes time and money.
The result is that, although scientists as far afield as Oxford, Melbourne and Bogot are keen to claim that their approach offers the better hope of developing a vaccine, there is a fair degree of caution. “If everything goes well for the leading candidates, there could be a vaccine available in the next 15 years,” says Dr Howard Engers, of the WHO’s vaccination development programme. “But it would be a mistake to be overly optimistic.”
At present the vaccines fall into one of three categories: sporozoite or protein recombinant-based, DNA-based or a combination of the two. Pioneering work on sporozoite-based vaccines began at the Walter Reed Army Institute of Research in Washington DC – not far from Hoffman’s Naval Medical Research Centre in Bethesda, Maryland.
Having observed the way irradiated sporozoites blocked the disease, army doctor Ripley Ballou tried engineering the same effect biologically, then exposed himself, Hoffman and colleagues to malaria to see if it would offer protection. With the exception of one member of the team the vaccine failed, but some team members exhibited elevated antibody levels, suggesting that protective immunity was possible.
The Walter Reed Institute has since developed ever more sophisticated vaccines based on the sporozoite model, culminating with RTS, which in a small- scale trial in 1997 prevented six out of seven test patients developing malaria.
Walter Reed is now conducting wider trials in Ghana in co-operation with SmithKline Beecham in Belgium, the results of which are expected in December. But, although the vaccine is at a more advanced stage than its rivals, it seems to offer only short-term protection.
Walter Reed is exploring a more sophisticated version of the vaccine, MSP-1, which aims to boost the body’s immune response by mimicking the action of the parasite at the merozoite stage, the period about 12 days after infection when young parasites burst from the liver to infect red blood cells.
In contrast, Hoffman’s navy team is pursuing a more scattergun approach, using portions of malarial genes to trigger the same immune response by programming muscle cells to make malaria proteins. The advantage of the DNA approach is that in theory the vaccine can be tailored to be as complex as the parasite itself, training the body to recognise the parasite at every stage of its life cycle and defeating its ability to evolve.
The problem is that the technology is still in its infancy and has had to pass rigorous tests before it can be trialled more widely.
Last year Hoffman’s team immunised 20 healthy volunteers with a malaria DNA vaccine, triggering “killer T-cells”, and established that the vaccine could be tolerated in principle. Next month it is moving to the more critical stage of live trials on four separate groups of volunteers using a vaccine based on five genes that encode proteins expressed by irradiated sporozoites in liver cells.
Another approach is to combine a DNA vaccine with a follow-up “booster” vaccine made by combining a virus such as smallpox with a portion of the malaria parasite.
Using this method Dr Adrian Hill, professor of human genetics at the Nuffield Department of Medicine, Oxford, has developed a vaccine known as MVA. “It is aimed primarily at children in the first year of life in areas where malaria is endemic, but it could work for travellers too,” he says. Trials started last year and have a long way to go.
In a bid to speed up research and encourage more partnerships, this coming year the Program for Appropriate Technology in Health (Path), a Seattle-based non- profit organisation, launched the Malaria Vaccine Initiative. The idea is to use Gates’s $50-million donation to direct resources to the best vaccine candidates and to fill in the gaps left by drug companies. According to Path, the goal is nothing less than a vaccine that is safe, inexpensive, easy to use and, administered in infancy, confers lifelong immunity against all strains of the disease.
“The private sector has failed to place a sufficiently high priority on malaria vaccine development – perhaps because the perceived technical risks are too great and the perceived markets are too difficult,” says Gordon Perkin, president of Path. “From a public health point of view, however, the situation must be remedied.”
With a child somewhere dying of malaria every 20 seconds, even a vaccine that guaranteed short-term protection would be welcome.
But for Hoffman and his navy research team only lifelong protection will do. “As far as we are concerned military people can’t get malaria at all.”