Cure Research for Malaria
Research list: The list of research areas and treatments under analysis mentioned in various sources for Malaria includes:
Research discussion: Enzymes called "proteases," which are involved in hemoglobin digestion by malaria parasites, are attractive targets for developing new inhibitors. Another potential set of drug targets is contained within the apicoplast, an intracellular organelle of the malaria parasite that has recently been discovered to be related to chloroplasts in plants. 1
NIAID also supports research to determine the mechanism of action of currently available drugs and to understand how drug resistance develops. One mechanism by which chloroquine and some other antimalarial drugs appear to function is through interfering with the parasite's ability to detoxify products of the hemoglobin digestion process that would be harmful to the parasite. A genetic cross between chloroquine-sensitive and chloroquine-resistant strains of P. falciparum is being systematically analyzed to identify the gene(s) responsible for resistance to this once most useful antimalarial drug. Because of increasing chloroquine resistance, antifolate-sulfa drug combinations like Fansidarô are becoming increasingly important in treating falciparum malaria. Minute mutations in the parasite's dihydrofolate reductase gene, however, lead to resistance to the antifolate drugs. By identifying the genetic basis of drug resistance, scientists should be able to design better treatment strategies. In addition, this research is providing molecular markers of drug resistance that will be helpful in determining the best therapy for individual patients, as well as for the national surveillance efforts of countries where malaria is endemic. 1
Scientific investigators now realize the best approach to malaria control will involve integrated methods that consider the biological, epidemiological, and ecological factors that influence disease transmission in a given area. Many NIAID-sponsored studies are aimed at understanding the biology of the mosquito vector, as well as its interaction with both the parasite and people. This information is critical to identifying accessible targets for alternative control strategies. Some NIAID-supported scientists are working to identify new environmentally safe insecticides. Researchers also are using satellite-based remote sensing technology to understand the effects of climate change on transmission of malaria and other vector-borne diseases. This may allow prediction of changing patterns of malaria distribution, including the appearance of epidemics.
As a long-term approach, scientists are using molecular biology to invent new ways of modifying the mosquito so it cannot transmit malaria. They are working to sequence the genome of the Anopheles gambiae mosquito, the most efficient of the malaria vectors. This work should help ongoing efforts to identify genes controlling critical stages of parasite development within the mosquito. Other investigators have made important progress in finding ways to introduce new genes into the mosquito, such as those that produce substances toxic to the parasite. Together, these studies could lead to the development of mosquitoes that cannot support parasite growth. In addition, field studies of mosquito population dynamics in endemic regions are under way, which will provide a basis for understanding how introduction of such "vector-incompetent" mosquitoes might control or stop malaria transmission.
During the 1960s and 1970s, early clinical studies showed that experimental vaccination with weakened malaria parasites could effectively immunize patients against a subsequent malaria infection. Because vaccines based on live, inactivated or killed malaria parasites are not currently economically or technically feasible, much of the research on vaccines focuses on identifying specific components or antigens of the malaria parasite that can start a protective immune response. Scientists encounter difficult obstacles in attempting to develop malaria vaccines, in terms of parasite biology, human immune responses, and both preclinical and clinical evaluation. Although four different species of protozoan parasites cause human malaria, most vaccine efforts have been directed toward falciparum malaria because of its severity.
Parasite of the same species but isolated from different geographic locations may be genetically and immunologically distinct, so vaccines that protect against one geographic isolate may not protect against another. In addition, malaria parasites have complex life cycles with multiple distinct developmental stages creating potentially thousands of different antigens that could serve as targets of an immune response. Finally, because protection appears to require both antibody-mediated and cell-mediated immune responses, identifying delivery systems and formulations that stimulate all the aspects of immune reactivity represents an enormous technical challenge.
A sporozoite vaccine would protect against the infectious form injected into a person by a mosquito. But if a single sporozoite were to escape the body's immune defenses, it could eventually lead to full-blown disease. A merozoite (blood-stage) vaccine, in addition to safeguarding against that possibility, could prevent or diminish symptoms in persons already infected. A gametocyte (sexual stage) vaccine does not protect the person being vaccinated, but instead interrupts the cycle of transmission by inhibiting the further development of gametocytes once they-along with antibodies produced in response to the vaccine-are ingested by the mosquito. Although a sporozoite vaccine could be useful for protecting tourists or other persons exposed only briefly, the vaccine best suited for malarious parts of the world may well be a "cocktail" combining antigens from several parasite forms, and perhaps also from two or more species.
A number of candidate vaccine antigens have been identified from different developmental stages of the parasite, and some have advanced to the point of preliminary clinical evaluation. Researchers have largely focused on candidate vaccine antigens that are expressed on the parasite surface and/or are involved in some critical aspect of parasite development or disease. For example, the circumsporozoite (CS) protein is the dominant surface antigen of the sporozoite stage, and is believed to interact with receptors on the hepatocyte (human liver cell) surface during the initial infection.
Several antigens have been identified that are involved in binding merozoites to the human red blood cell or in the cell-invasion process. One, a merozoite surface protein (MSP-1), repeatedly has been found to elicit protective immunity in rodent and monkey models of malaria. Inhibition of such crucial steps in parasite growth would form a good strategy for a vaccine.
Other studies have identified a parasite-derived molecule (PfEMP1) on the surface of infected red blood cells that mediates their binding to endothelial cells and other red cells. The parasite, however, has developed ways to prevent the immune system from attacking the infected red cell by regularly changing the structure of such surface proteins-a process known as antigenic variation. Recent studies of the P. falciparum genome have revealed two major families of variant genes, known as "var" (including PfEMP1) and "rif," in P. falciparum expressed at different times during the course of an infection. Better understanding of antigenic variation may help scientists identify new strategies to interfere with parasite development.
Researchers are also investigating the immune mechanisms involved in severe malaria disease. For example, recent studies indicate that binding of plasmodium-infected red cells to a molecule found on the surface of cells within the placenta contributes to the adverse outcomes associated with malaria during a woman's first pregnancy, and may provide the basis for developing a vaccine to prevent this aspect of pathology. A few vaccine candidates, mostly based on sporozoite antigens, have undergone clinical trials. A vaccine made up of a combination of CS antigen and hepatitis B surface antigen showed sufficient protective efficacy in a small clinical trial to justify further testing in an endemic area. Only one candidate vaccine, Spf66, based on antigens from both merozoite and sporozoite stages, has undergone extensive field trials. It showed efficacy in early clinical trials in South America, but results from subsequent trials in Africa and Southeast Asia were not as promising. Other vaccine candidates derived from multiple parasite life cycle stages are currently being prepared for Phase I human safety trials. NIAID is working with African scientists to expand the capability to conduct clinical trials of new malaria vaccines.1
NIAID investigators are planning the first human trial of a vaccine designed specifically to block the transmission of malaria parasites from infected people. The trial will take place at the NIH Clinical Center in Bethesda, Md. 2
Designer drugs based on a successful herbal treatment for malaria used in traditional Chinese medicine have cured the disease, even drug-resistant forms, in NIAID-supported studies. In the absence of effective vaccines, drugs are the best way to prevent disease and treat patients with malaria. New drugs are urgently needed because of the emergence and spread of drug-resistant malaria parasites, especially among P. falciparum.
The investigators developed a synthetic, simpler version of
artemisinin, derived from the Artemisia annua herb
(qinghaosu) used in traditional Chinese medicine to cure people with
malaria. Having a synthetic version would allow for easier, cheaper
production of drugs than either relying on natural supplies or
chemically creating complete artemisinin or its derivatives.
1. excerpt from Malaria Research, NIAID Fact Sheet: NIAID
2. excerpt from Malaria, NIAID Fact Sheet: NIAID
Last revision: June 2, 2003
Medical Tools & Articles:
- Risk Factor Center
- Medical Statistics Center
- Medical Treatment Center
- Prevention Center
- Medical Tests Center