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Big bite

Big bite DESPITE efforts to prevent the spread of malaria, the disease strikes as many as 300 to 500 million people each year and claims over a million lives. Not only have the mosquitoes that carry the malaria parasite -- Plasmodium -- become increasingly tolerant of pesticides, the parasite"s defence mechanism also has evolved resistance to the drugs used to fight it.

In such a situation, one of the most promising tools for malaria control appears to be vaccines. Efforts to develop vaccines against malaria are being made worldwide, and several groups have reported encouraging results.

Says V P Sharma, director of the Delhi-based Malaria Research Centre, "A vaccine to prevent cerebral malaria, caused by the Plasmodium falciparum parasite, is essential, because this disease can be fatal." He says that in India almost 30 per cent of the 1.6 million malaria cases are of this kind.

Vaccines use an inactivated form of the disease-causing parasite to build immunity against it. Small amounts of the parasite"s proteins, known as antigens, when introduced into the human body, prime the immune system to release substances known as antibodies, which protect the body from the disease-causing germ.

But the malaria parasite is not simple to deal with. It produces several antigens as it goes through the many stages of its life cycle in mosquitoes and human beings, and so single antigen-based vaccines could be ineffective against it.

Moreover, experts point out it is difficult to culture the parasite if one wants to produce the inactive form of whole parasite. "It is impractical to produce a large scale parasite culture and there is the additional risk of contamination from blood and serum-derived products in a human vaccine," explains Virander S Chauhan, a malaria expert at the Delhi-based International Centre for Genetic Engineering and Biotechnology (ICGEB).

But scientists believe that through biotechnology a vaccine might eventually be possible. "A malarial vaccine will have to be synthetic or be based on recombinant DNA technology," says Chauhan. He suggests that an appropriate vaccine should be a "cocktail" vaccine, which would be effective against the different antigens associated with the parasite.

Scientists have identified over 100 malarial antigens, which are produced during the different stages of the parasite"s life and provide potential vaccine targets.

Earlier attempts to immunise humans zeroed in on the sporozoite stage -- when spores are formed-- of the parasite since sporozoites can be easily grown in mosquitoes. The most abundant protein found on the surface of the sporozoite, circumsporozoite protein (CSP), contains several repeated amino-acid sequences, denoted "NANP". However, several clinical trials of NANP vaccines do not show much success against malaria, especially against P falciparum.

Multi-antigen vaccine
Malaria researchers are now targeting several Plasmodium stages simultaneously, so that if the creature eludes a person"s immune system at one stage, it can be knocked out in the next stage. A Colombian physician, Manuel Patarroyo, who heads the Instituto de Immunologia in Bogota, has developed the first multi-stage, multi-antigenic, synthetic vaccine against malaria.

Called SPf66, this vaccine has undergone several field trials involving more than 30,000 people in Latin America, mostly in Colombia. While a scientist, who did not wish to be named, told Down to Earth that the SPf66 had been clearly unsuccessful, World Health Organization malaria scientist Howard Engers, says, "The results are clearly promising, but they are only a first step and do need confirmation through further research." SPf66 is made from 3 fragments of protein antigens from the merozoite or blood-stage of the malarial parasite.

The vaccine is now undergoing largescale field trials involving some 600 children in Tanzania, under WHO"s supervision. This trial is a crucial and tough test for SPf66 as it is in an area of perennial malaria transmission. A person in Kilombero, Tanzania, suffers an average of 300 mosquito bites a year from malaria-infected mosquitoes -- 100 times the rate in Colombia -- and at any moment, 2 out of 3 people in Kilombero are infected with malaria parasites. Moreover, 15-20 per cent of the malaria parasites in this area show resistance to chloroquine, the traditional malaria drug.

Says epidemiologist Pedro Alonso, a leading member of the Spanish team working on the trial, "We may be giving the vaccine too hard a task in Tanzania. It could fail here and still work elsewhere, perhaps in an area of less intensive transmission, such as Colombia." Patarroyo estimates that the vaccine will cost less than $5 an injection.

Other scientists say that SPf66 -- even if it is successful -- may prove to be only one component of the vaccine arsenal necessary to fight malaria, because the parasites keep on updating their defence. Through a process of evolution, the parasites can modify their antigens. Moreover, scientists explain that these parasites occur in different strains that vary with the region.

Besides SPf66, there are atleast 5 other vaccines against malaria which are being readied for human testing in endemic countries. And about 20 vaccines are under development in the US, Australia, Switzerland and other countries.

In the US, the National Institutes of Health, the Walter Reed Army Institute of Research (WRAIR) and the US Navy are major participants in malaria research. The US is interested in developing malaria vaccines for its military personnel who frequently operate in areas where malaria is rampant. American research is concentrating on developing vaccines against the sporozoite stage and on what are called transmission blocking vaccines.

Transmission blocking, or anti-transmission, vaccines employ antibodies active against the Plasmodium"s sexual stage, which occurs in the mosquito. When the mosquitoes feed on human blood, they imbibe the parasite and the injected antibodies. The antibodies destroy the male and female parasite"s reproductive cells, preventing the mosquitoes from carrying the infection further. One such antigen -- Pfs25 -- has been identified and a vaccine based on it will be ready by 1995 for largescale trials in the US and Kenya.

The WRAIR and the Berne-based Swiss Serum and Vaccine Institute have jointly developed a vaccine called R32Tox-A, which will target the sporozoite stage of P falciparum. The scientists have isolated a single antigen which they are producing using recombinant DNA technology, and trials to test its efficacy on a small population in Thailand reveal that it is both safe and effective.

Australian efforts are focused on the antigens called merozoite surface proteins (MSP) which enable the merozoite stage of the parasite to invade the red blood cells in humans. Michael Good and his colleagues at the Queensland Institute of Medical Research in Brisbane found that antibodies developed against one such protein called MSP-1 blocked parasite growth. They found that the vaccine protected monkeys against infection. WHO is interested in conducting largescale human trials of this vaccine and is working out details to produce the vaccine in sufficient quantities, using recombinant DNA technology.

In Holland, a group is targeting another protein found inside the merozoite -- the apical membrane antigen. Immunisation with this protein protects monkeys against cerebral malaria. Field trials on human beings by WHO"s Tropical Disease Research Programme (TDR) are expected to begin in 1996.

The ring-infected erythrocyte surface antigen (RESA) is one of the several soluble antigens released by the merozoite to help the multiplying creatures burst out of an infected red blood cell. Peter Perlmann at the University of Stockholm, Sweden, has shown that recombinant forms of RESA produced in yeast provided significant protection against P falciparum in monkeys. Field trials of this antigen are also on the TDR"s agenda.

Erythrocyte binding antigen (EBA) is a protein used by merozoites to bind to red blood cells before they make a forced entry and gobble up the haemoglobin. Louis Miller at the Laboratory of Malaria Research of NIH at Bethesda, USA, has shown that antibodies to EBA block merozoite invasion and trials with EBA could begin within 4 years.

In India and Sri Lanka, attempts are being made to develop vaccines against malaria strains endemic to the Indian subcontinent. Ranjan Ramasamy and his colleagues at the Institute of Fundamental Studies in Kandy, Sri Lanka, have synthesised several proteins from the merozoite surface antigens and their safety and efficacy has been tested in human volunteers. Recently, Ramasamy presented his results at the International Conference on Biochemistry and Molecular Biology held in New Delhi. Largescale trials on his vaccines are being planned by the Sri Lankan government.

Because of the diversity of the Plasmodium parasite, scientists have realised that a single vaccine alone will not be effective across the world. Says TDR director Tore Godal, "To realise all the accumulated potential, we need a global collaboration among institutions working on malaria vaccines, so each can make its own special contribution."

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