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Abstract
In 1987, a group of 15 researchers infected themselves with malaria to see if the vaccine they were investigating would protect them from the onslaught. All except one of the 15 valorous volunteers developed the disease [1].
| Can a vaccine protect against malaria? |
According to Stephen L. Hoffman, then with the Naval Medical Research Center, who was one of the unlucky 14, "the protection of that one individual was the clearest demonstration that we could protect humans from malaria with a vaccine." The vaccine, called FSV1, is a recombinant DNA vaccine produced in Escherichia coli. "We were off and running, and we have been working to refine that approach ever since," Hoffman says.
Researchers have been working to refine that and other approaches toward developing a malaria vaccine since the sixties and seventies. Promising vaccine candidates have emerged, perhaps as many as are needed to dangle a carrot before researchers in the field, but none show overwhelming efficacy. But researchers are optimistic. Many seem to think that an effective vaccine will emerge within the next few years; none seem to doubt that one will emerge eventually.
| Nearly 3.5 million die from malaria every year. |
Malaria strikes an estimated 500 million people a year, mostly in Africa and mostly women and young children. It kills nearly 3.5 million of its victims. Three stages characterize the symptoms of the disease: a "chill" stage, in which patients experience shaking chills, lasting from a few minutes to several hours; a "hot" stage, in which the patient's temperature rises to as high as 104° F; and a "sweating" stage, in which the fever subsides, but the patient experiences debilitating fatigue. If left untreated, this cycle returns every two or three days.
The life cycles of the strains of plasmodia that cause malaria are complicated and render the plasmodia invisible to the human immune system for a large part of the cycle. This complicates the development of a vaccine and is one of the reasons that it cannot be approached in the same way as developing, say, a polio vaccine.
| The plasmodia is invisible for a large part of its life cycle. |
Take the life cycle of just one causative agent of malaria, for instance, Plasmodium falciparum. Malaria infection begins when an infected mosquito punctures human flesh to take its blood meal. While doing so, it injects P. falciparum sporozoites, which end up in the person's bloodstream.
Within minutes, the sporozoites submerge themselves in liver cells and are now secluded from the person's immune system. During this stage, an infected person shows no symptoms of malaria. But after about two weeks, each sporozoite will have developed into about 40,000 merozoites, all of which will burst out of the hepatocytes and enter the bloodstream. At this point, physical symptoms of malaria begin to surface.
| A sporozoite develops into about 40,000 merozoites. |
Within minutes, the merozoites, now circulating in the bloodstream, enter red blood cells where they are once again hidden from the immune system. Every two days or so, they collectively rupture the red blood cells in which they are lurking, causing the cyclical symptoms of malaria. After about ten days, some of the merozoites mature into sexual forms. At this time, a mosquito, while eating a blood meal, will become infected with mature merozoites in the person's blood, thus completing the cycle.
Developing an effective vaccine has been about as complex an affair as the life cycle of Plasmodium falciparum itself. "A number of clinical grade recombinant proteins and synthetic peptides targeting different stages of the falciparum's life cycle are being made," says Filip Dubovsky, senior program officer with the Malaria Vaccine Initiative, a program funded by a grant from the Bill and Melinda Gates Foundation and part of PATH (Program for Appropriate Technology in Health).
| Recombinant proteins have not been as immunogenic as hoped. |
"I envision that these will be tested alone and in various combinations," he says. "But, in general, these recombinant proteins have not been as immunogenic as people have hoped, so formulations with novel and powerful adjuvants are the rule," he says.
Perhaps more exciting, says Dubovsky, is the development of a number of novel vaccine platforms that will not need adjuvants. These include hepatitis B core virus-like particles (Apovia), nonreplicating pox viral vectors (Oxxon Pharmaccines), molecular adjuvants that target antigen-presenting cells (AdProTech), multiepitope multistage recombinant peptides (Centers for Disease Control and Prevention), epitope and full-length-based DNA vaccines (Epimmune and the Navy Medical Research Center).
| Where to target Plasmodium? |
One of the challenges has been to decide which part of Plasmodium's life cycle to target. If a fully effective vaccine acts before the merozoites emerge from the liver, a person will suffer no malarial disease. This type of vaccine might be most useful to people traveling to malaria-endemic countries. The problem is, though, that if the vaccine fails to neutralize each and every sporozoite, the person will develop full-blown malaria, although the resulting disease might be less severe because the number of sporozoites that reach the liver would be reduced.
Another strategy is to stimulate a cell-mediated immune response that will trigger CD4+ and CD8+ lymphocytes to destroy infected liver cells, thereby destroying the parasites once they have submerged themselves in liver cells. Yet another strategy is to produce a vaccine that will attack the merozoites once they have escaped from the liver into the blood. With this type of vaccine, a person would still contract malaria, but the severity and lethality of the disease would be reduced. The last option is to generate a vaccine against the sexual stages of the parasite, which would prevent a mosquito from transmitting sporozoites in the first place.
| No one route is better. |
"Because there are so many different approaches, which we have been considering for years, this leads me to believe that there is no one route that we could say is going to be the better one," says Mary Galinski, assistant professor of medicine and malaria vaccine researcher at the Robert W. Woodruff Health Sciences Center at Emory University.
As well as the complexity of the life cycle, the stage-specific expression of plasmodia has variations as well. "If we were to go to Kenya today and take blood from a child who is infected, that child might have five to ten different strains of the parasite inside of him or her," Hoffman says. "This means that if you made a vaccine against one of those strains it might not recognize the others," he says. "You have stage-specific expression of protein, you have very complex infectious agents with five or six thousand genes, and then you have variations of those genes from parasite to parasite," he says.
| Many approaches have been taken. |
"I don't think there is a single most promising approach," says Carole Long, head of immunology with the Malaria Vaccine Development Unit at the National Institute of Allergy and Infectious Diseases. "Our group is taking the approach of generating a vaccine based on malaria proteins directed toward the erythrocytic and sexual stages," she says. "Other groups have taken other approaches to try to limit infection by the infectious sporozoites and liver stages," she says.
| Vaccine development is empirical. |
"The important thing is to try a number of different approaches and investigate a number of vaccine candidates since much of vaccine development is empirical. We need to explore options and to set aside those that are not productive," she says.
One vaccine that is furthest along in its development is a vaccine called RTS,S produced by GlaxoSmithKline Biologicals (GSK), according to Dubovsky. The vaccine consists of a protein from the Plasmodium sporozoite fused to a hepatitis B surface antigen. The vaccine went into clinical trials in Gambia in 2000 and showed about a 70% efficacy in a group of adult males semi-immune to malaria. The protection lasted only about 2 to 3 months, though, not as long as a typical malaria season [2].
| The mechanism of vaccine action may be prolonged in children. |
But with the second round of clinical trials in 6- to 10-year-olds, which began in May, GSK hopes that the efficacy will be just as good, but will last longer. "We have reason to believe that the mechanism of action may be prolonged in these children and that perhaps it will be further prolonged when we test it in children who are younger than 6," says Anne Walsh, spokesperson for GSK Biologicals.
Researchers seem to be optimistic about the development of a vaccine - eventually. "We would expect to have a vaccine by the end of the decade," Walsh says. "But it really depends on how things go. We are going as fast as we can, but these things take time," she says.
| A vaccine will launch the battle, not end it. |
George Ben Thornton, executive vice president of research and development with Apovia, says he does think a vaccine will be developed. Apovia is developing a vaccine using hepatitis B core virus-like particles, which Thornton says will be in a phase I clinical trial this fall. "There's a lot of activity going on right now and a lot of different concepts being pursued, so I think from all this will come a vaccine," he says. He did not want to put a time frame on it, however.
Despite the promise of a vaccine in years to come, the battle against malaria will not end there. Having just returned from a trip to Senegal, Long points out that "there were a number of seriously ill people in hospital with tetanus, and we have had a tetanus vaccine for a long time." But a malaria vaccine will at least launch the battle.
Emma Patten-Hitt is a freelance writer based in Atanta, Georgia. She has a Ph.D. from Emory University in nutrition with a molecular biology emphasis, and is about to complete a master's degree in technical communication.
Susan Wolsborn is Web designer of HMS Beagle.
Malaria Vaccines - outlines oral and poster presentations from a session of the Molecular Approaches to Malaria conference, Lorne, Australia, February 2-5, 2000. From Parasitology Today, 2000, 16:10:444-447.
Malaria Vaccine Development: Current Status - a review of recent advances. From Parasitology Today, 1998, 14:2:56-64.
DNA-Based Vaccines Against Malaria: Status and Promise of the Multi-Stage Malaria DNA Vaccine Operation - summarizes the current status and future directions of the project. From the International Journal for Parasitology, 2001, 31:8:753-762.
The Immunology of Malaria Infection - reviews recent advances in protective immune mechanisms and then summarizes recent advances in vaccine design and development. From Current Opinion in Immunology, 2000, 12:437-441. Full text available from BioMedNet.
Pre-erythrocytic Immunity to Plasmodium falciparum: The Case for an LSA-1 Vaccine - discusses the immunobiology of hepatic stage parasites, including the rationale for developing liver-stage vaccines. From Trends in Parasitology, 2001, 17:5:219-223 Full text available from BioMedNet.
Genome Projects, Genetic Analysis, and the Changing Landscape of Malaria Research - a review of genome analysis of Plasmodium falciparum relative to therapeutic- and vaccine-related research. From Current Opinion in Microbiology, 1999, 2:415-419. Full text available from BioMedNet.
Malaria - a comprehensive site from the World Health Organization.
Malaria Database - a resource for researchers that goes beyond sequence data and provides a discussion group, job postings, and conference information.
Malaria: An Online Resource - detailed information for clinicians and researchers organized under the topics of diagnosis, prophylaxis, treatment, history, and test and teach.
Nature Medicine: Special Focus: Malaria - offers a selection of recent scientific papers, News & Views articles, a status report on malaria vaccine development, and an update on the effort to sequence the Plasmodium falciparum genome.
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