Malaria Research, NIAID Fact Sheet: NIAID
Article title: Malaria Research, NIAID Fact Sheet: NIAID
The National Institute of Allergy and Infectious Diseases (NIAID) is a leader in research on the prevention and treatment of malaria. NIAID faces the challenges of malaria with laboratory, field-based, and clinical research efforts within its own laboratories on the National Institutes of Health (NIH) campus in Bethesda, MD; at institutions throughout the United States; and in collaboration with foreign colleagues in sites such as Mali, Cameroon, Ghana, Malawi, Thailand, Kenya, Indonesia, Brazil, and Papua New Guinea. While much of NIAID's collaborative international malaria research is supported through off-site programs of the Parasitology and International Programs Branch, scientists in the on-campus Laboratory of Parasitic Diseases (LPD) International Research Unit have worked closely with scientists and physicians at the National School of Medicine of Mali in the development of the Malaria Research and Training Center in Mali.
In 1997, NIAID, the World Health Organization as well as other organizations and individuals from around the world, launched the Multilateral Initiative on Malaria (MIM). The NIH Fogarty International Center currently coordinates this program. Through cooperation and collaboration, the participants in this initiative hope to improve and expand research on malaria in Africa. For more information about MIM, go to http://mim.nih.gov/index.html.
In response to needs expressed by the international malaria research community, NIAID established the Malaria Research and Reference Reagent Resource (MR4) Center in 1998, through a contract with the American Type Culture Collection. The center distributes malaria research reagents, materials, and protocols, which satisfy quality assurance standards to qualified investigators throughout the world. MR4 also sponsors international workshops to support technology transfer and research capability strengthening. More information on MR4 can be found at http://www.niaid.nih.gov/dmid/malaria/default.htm.
NIAID-supported research efforts include:
- Understanding the biology of malaria parasites and their interaction with the human host as well as their mosquito vectors
- Understanding the various parasite and host factors that contribute to malaria pathogenesis, including cerebral malaria and severe anemia
- Developing new or improved methods to control malaria transmission and prevent disease, including drugs, vector control strategies and vaccines. In 1997, NIAID launched a major new initiative on malaria vaccine development (for more information, see http://www.niaid.nih.gov/dmid/malaria/malvacdv/toc.htm).
Researchers are trying to identify new, more effective antimalarial drugs by conducting wide-scale screening of compounds against malaria parasites in laboratory test tubes and in animal models. Recent advances in techniques for growing plasmodium parasites in the lab, as well as in technologies, such as robotics, and in methods to rapidly synthesize hundreds and thousands of new chemicals, should make this process easier.
Alternatively, other researchers are taking advantage of an increased understanding of parasite biology to find ways to inhibit metabolic and biosynthetic pathways, or other key structures and functions, critical to the survival and growth of the malaria organism within its human host. This so-called "rational approach" to drug design is being pursued by NIAID-supported scientists and other international research programs. 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.
NIAID is a member of an international group of research agencies that supports efforts to sequence the complete genome of the most deadly malaria parasite, Plasmodium falciparum, thereby giving scientists unprecedented access to every parasite gene. The resulting information on gene function and its regulation should allow researchers to identify many new targets for drug development. Scientists are also examining medicinal plants to see if they may contain new chemicals that can be developed in treatments for malaria.
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.
NIAID supports a number of collaborative research programs in malaria-endemic countries. For example, investigators are examining the connection between various parasite drug-resistance genes and malaria-infected patients' lack of responsiveness to treatment. Scientists are also looking at ways to improve treatment outcome by combining medicines that kill the parasite with other medicines aimed at reducing the symptoms of severe disease.
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.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose, and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, and other infectious diseases as well as asthma and allergies.
Press releases, fact sheets, and other NIAID-related information can be found on the NIAID Web site at http://www.niaid.nih.gov/default.htm
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