SCIENCE: A STING IN THE TALE

In 1956 scientists boasted that malaria would soon be eradicated. In 1996 it will kill three million people. What went wrong? Liz Hunt investigat es wrong?
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The Independent Culture
"This is a completely unique moment in the history of man's attack on one of his oldest and most powerful disease enemies. Failure to proceed energetically might postpone malaria eradication indefinitely."

Forty years after those words were penned by Dr Paul Russell, a US malariologist, the disease is once more in the ascendancy. Global eradication as envisaged by Dr Russell, the leader of this ambitious project, in his 1956 report to the United States International Development Advisory Board, remains a dream.

Malaria is one of the world's worst health problems. More people are ill with it - 300 to 500 million clinical cases occur annually - than any other disease. Control measures have all but broken down in certain areas, and there is a growing threat of epidemic malaria in some tropical zones. Now doctors are facing a new crisis: a dwindling range of drugs to treat a disease which annually kills up to three million people.

The World Health Organisation (WHO) warned recently against the global spread of bacteria resistant to antibiotics, but the spread of resistance to anti-malarial drugs arguably poses a greater threat. Man's ability to stay one step ahead of the mosquito-borne malaria parasite is in doubt. In some parts of south-east Asia, resistance to all conventional drugs is occurring, and the spread to Africa and South America is under way. Ironically it is the humble mosquito net, first used over 100 years ago, which made headlines this year. Research showed that the lives of up to half a million African children could be saved each year by the use of bed nets treated with biodegradable pyrethroid insecticide.

Tropical Third World countries are hardest hit by malaria - 90 per cent of deaths occur among African children - but its impact in developed countries is no longer negligible. People are travelling further and more frequently, while publicity over the alarming side-effects of one drug, mefloquine (Lariam), has persuaded some to dispense with prophylaxis, putting their lives at risk. In the old Soviet Union, the collapse of public health services has seen the disease return to once malaria-free zones, most notably Azerbaijan.

Brian Greenwood, professor of communicable diseases at the London School of Hygiene and Tropical Medicine, who researched the disease for 30 years in the Gambia and northern Nigeria, says the bed-net findings are good news: "No other intervention ever has had such a profound effect on child mortality except perhaps the measles vaccine." But he warns that malaria is as big a problem as ever.

"It is getting worse, with political unrest in many parts of the world; possibly global warming which some say is extending malaria zones in Ethiopia, Afghanistan, and Uganda; the movement of population into previously forested malarial areas - and the growth of drug resistance," Professor Greenwood says. "Africa is the problem; in Tanzania some people are bitten by an infected mosquito every night."

Malaria is spread by the blood-sucking, female anopheline mosquito. Its adaptability and breeding potential are responsible for the ubiquitious nature of the disease. For example, the tsetse fly, which spreads sleeping sickness, is restricted to African rivers and rain forests, but 2,200m people in 90 countries are exposed to malarial infections by the mosquito.

When a mosquito infected with a protozoan malaria parasite of the genus Plasmodium bites a human, it transmits the infection in its saliva. The parasite passes into the blood and on to the liver where it multiplies over five to 10 days but causes no symptoms. It then breaks free from liver cells, flooding the blood and invading red blood cells where it multiplies again and again. The invasion/multiplication cycle is repeated, with the victim suffering fever each time. A female mosquito which bites the victim will itself become infected, with the parasites multiplying on its stomach wall before migrating to the salivary glands to be released when the insect next bites a human.

Four species of Plasmodium infect man; three (P vivax, P ovale, P malariae) cause severe illness but are rarely fatal. The fourth, Plasmodium falciparum, the most common malaria parasite in Africa, can lead to death within days. This form of the disease, known as cerebral malaria, is responsible for about 10 deaths each year in Britain.

A vaccine against malaria has long been the Holy Grail of modern malariologists, but Plasmodium is a moving target. A synthetic vaccine was developed in the 1980s by Dr Manuel Patarroyo, an immunologist at the National University of Colombia in Bogota, and is undergoing trials at the Medical Research Council's laboratories in the Gambia. Although it has not lived up Dr Patarroyo's claims, it may be useful in giving some protection to children in some areas.

More effective vaccines will no doubt follow but no one expects them to provide the complete answer, and novel approaches to malaria management are being investigated in light of the drug resistance problems. The "mosquito as flying hypodermic" is the latest wheeze. It would involve a genetically engineered mosquito which would transmit selected proteins in its saliva into the blood of its victim. The proteins would act as an antigen, generating the production of antibodies against Plasmodium which would, in theory, protect the individual against malaria and/or halt transmission of the disease.

Bob Sinden, professor of parasitology at Imperial College, London, and Julian Crampton, professor of molecular entomology at the Liverpool School of Tropical Medicine, have been granted a patent on their proposed technique which has the potential for immunising people and animals against a range of diseases. Any biting insect, not only mosquitoes, could be used to carry any genetically engineered vaccine - one for which a gene has been identified. "We are exceedingly excited by the research," Professor Sinden says.

The technology would involve modification of the insect's salivary gland by introducing a foreign gene into its DNA. When a blood-sucking insect bites a blood-rich source, its salivary glands produce chemicals that inhibit clotting and encourage the victim's blood to flow freely. A gene which is responsible for this is "switched on and off" by another stretch of the insect's DNA lying near the gene, and known as the control region.

"What happens is that we steal this control region and attach it to selected genes [from the parasite] which produces parasite antigens [proteins] which we know will stimulate the body to resist the parasite,'' Professor Sinden says. (Not all parasitic proteins trigger an immunogenic responses in humans.) The parasite gene - plus the control region excised from the insect - would then be reintroduced into the insect's DNA. The result should be an insect that produces sufficient quantities of the parasitic protein in its saliva. Every time it bites a human, it would transmit the protein into the blood where it would trigger an immune response. It would keep on "topping up" the immune system of those it bites, so an antigen that would not necessarily be effective as a single vaccination, could provide long-term protection.

So far, Professor Sinden and Professor Crampton have identified an appropriate antigen gene from a malaria parasite and inserted or "stiched" it into mosquito cells grown in a test-tube. They showed that the cells, under the instruction of the gene, make the protein in such away that it is an effective vaccine. Mice with "mouse malaria" were used to test the prototype vaccine's effectiveness. "We were able to block the transmission of the malaria parasite from the mouse. The chosen vaccine did not stop the mouse developing malaria but it prevented the spread of the parasite from one mouse to the next," Professor Sinden says.

He explains that it is only by chance that he and the scientists in Liverpool have been working with a malaria parasite protein and mosquito cells. This disease may not be the first choice for trials of the novel vaccination should it get that far, but he predicts that a mosquito capable of delivering a protein (vaccine) should be available in the laboratory within three years.

Another scheme for malaria control involves the UN's International Atomic Energy Agency in Vienna. It would mean releasing billions of male mosquitos rendered sterile by irradiation with gamma-rays. This was tried in the1970s in India and El Salvador, and is under scrutiny again because of its success in controlling other pests. The screw worm fly, which kills calves, has been eradicated from Mexico, the southern US and parts of Central America. The Mediterranean fruit fly, which infects citrus fruit and coffee, has been banished from southern Europe and Latin America, while the tstese fly is close to being eradicated in Zanzibar.

The female Anopheles mates once in her life. If she mates with a sterile male then no progeny will result. Professor Chris Curtis, from the London School of Hygiene and Tropical Medicine, who was involved with the 1970s trials, says the scheme is attracting serious interest. "It is under discussion and the agency is gauging the interest of donors to fund the work," he said.

In the 1950s, malaria had seemed a disease waiting to be conquered. Chloroquine and quinine were safe, effective drugs and the new chlorinated hydrocarbon insecticides, such as DDT, killed adult mosquitoes and larvae. Although DDT-resistant mosquitoes had been reported, it had taken five years for resistance to develop, and scientists believed they would be able to beat the clock. They said malaria would not reappear in an area if transmission was interrupted, and all cases in humans aggressively treated for three years. This approach, demanding time and money, would pay off in the long- term. Eradication programmes had been successful in Italy, Greece, Cyprus, Guyana and Venezuela.

In 1955 the Eighth World Health Assembly announced a programme for global eradication, with every country affected by the disease mobilised under the direction of WHO. The United States bore the brunt of the costs because politicians such as Senator John F Kennedy and President Dwight Eisenhower believed that triumph over infectious diseases was as achievable as victory over Nazi Germany.

The project aimed to eradicate malaria by 1963, when the US Congress had decided that funding would end so confident of success was it. And as Pulitzer prize-winning journalist Laurie Garrett wrote in her book The Coming Plague, there was no reason to suspect failure: "The stage was set. The scientists had everything going for them: political support, money, DDT and chloroquine. So certain where they of victory that malaria research came to a virtual halt. Why research something that will no longer exist?"

Eradication was achieved in many places. Sri Lanka had one million cases of malaria in 1955 and 18 in 1963, but funds from the US Government were stopped because near-eradication was not the same as eradication by its reckoning. For the developed world, where malaria was less problematic and there was more money to spend on it, the consequences were insignificant. By 1970, malaria had been eradicated in Europe, the then Soviet Union, most of North America, several Middle Eastern countries, parts of South America and the Caribbean, Australia, Japan, Taiwan, and Singapore.

However, in developing countries where malaria was a greater problem because of geography, the withdrawal of US dollars from the programme had dire consequences. Because of near-eradication, millions of people now lacked all immunity to malaria - premunition, a form of partial immunity, develops after repeated infections - and there was a relentless increase in cases and deaths from the mid-1960s onwards, as control programmes deteriorated, and the populations in these countries boomed.

The growth of air travel added to the numbers at risk everywhere, and cases of imported malaria - brought back by travellers from endemic areas - shot up. Between 1973 and 1977 the number of cases reported to WHO increased by a factor of 2.5. The world malaria figures today show little change year on year as gains in one area are balanced by deterioration in another - but this situation may not hold for long. Man has created an epidemic of iatrogenic (drug-induced) malaria, through careless prophylactic use of drugs, and their routine use to treat any fever, malaria or not, in endemic areas. This created the perfect conditions for the highly-adaptable Plasmodium parasite to develop resistance.

In 1961, two people in South America taking chloroquine, the first-line treatment, developed malaria. Chloroquine-resistant malaria was soon reported in Colombia, Thailand and Venzuela. As anti-malarial drugs were developed and introduced, the pattern became depressingly familiar; the drug would have a major impact followed by the appearance of resistance. In some places - most notably New Guinea - the problem was aggravated by governmental decisions to put chloroquine in table salt, a misguided attempt to protect the population.

Chloroquine is increasingly ineffective in Latin America and parts of Africa and the rate of spread on both continents is causing great concern. Alternative drugs are more expensive and more toxic. Already multi-drug resistant strains are being reported from Gabon, Kenya, Cambodia, Myanmar, Thailand and Vietnam. It is in south-east Asia that most cases of drug resistance first appear, and there is speculation that it is due to the use of anti-malarial drugs by US forces in the 1960s and 70s.

Along Thailand's borders there is only one drug that is effective against malaria, a Chinese herbal remedy called Quinghaosu or artemisinin derived from the shrub Artemesia annua (wormwood). Chemists have produced synthetic analogues, arteflene and artemether, from it. After these there are only one or two potential candidates in the pipeline.

Millions of dollars invested in drug development have yielded no more than 20 effective and safe anti-malarials this century. It is the oldest treatment, quinine, first used in Europe in the 17th century, which remains effective in most areas of the world. But for how long? Around half of the world's production of quinine is used to flavour tonic waters and this, according to the Wellcome Trust, exposes the malaria parasite to low levels of it - ideal conditions for fostering resistance.

As resistance to one drug develops, second-line drugs are called upon but their wider use increases the chance of resistance developing to them too and this is occurring. It may be that the safe, reliable malaria prophylaxis which travellers have come to rely on is a thing of the past, and soon personal protection against mosquito bites - nets and repellents - will be all that we have left.

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