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Article title: Malaria, NIAID Fact Sheet: NIAID
Listed below are research highlights from NIAID-supported malaria programs.
NIAID is one of 17 institutes of the National Institutes of Health (NIH), the federal focal point for biomedical research. NIH is an agency of the U.S. Public Health Service, Department of Health and Human Services.
How Big a Problem is Malaria?
Malaria is very common. Each year, 300 to 500 million people develop malaria and 1.5 to 3 million–mostly children–die, according to the World Health Organization (WHO). Countries in tropical Africa account for more than 90 percent of the cases and more than 6 percent occur in India, Brazil, Sri Lanka, Afghanistan, Vietnam and Colombia.
Malaria control is difficult. A third of the world's population–1.78 billion–lives where malaria once was reduced or eliminated, but the disease has returned and its control is unstable or deteriorating, WHO reports. In some areas, severe malaria problems have occurred after major ecological or social changes, such as agricultural or other economic exploitation of jungles or sociopolitical unrest.
Malaria parasites have developed resistance to the most common and cheapest drugs used to treat the disease. Among the countries where the P. falciparum parasite causes malaria, only those of Central America have not recorded resistance to the drug chloroquine. The rapid evolution of such resistance in Africa increasingly complicates malaria treatment. Resistance to the drug combination sulfadoxine/pyrimethamine has developed in Southeast Asia, South America and Africa. In some areas of Thailand, more than 50 percent of cases no longer respond to mefloquine therapy. Sensitivity to quinine is diminishing in parts of Thailand and Vietnam.
What Causes Malaria?
A parasite causes malaria. The parasite spends most of its life in the red blood cells of humans. Female mosquitos transmit the parasites by first ingesting them when feeding on an infected person's blood and then injecting them when biting another person.
The parasite has a complex life cycle. On entering a human, the parasite invades a liver cell, takes on a new form and makes copies of itself. Eventually, the liver cell ruptures and releases the parasites to the bloodstream where they infect red blood cells. Within the blood cells, most parasites reproduce again, which kills the cells and the parasites then invade more blood cells. Other parasites, while in the blood cells, develop into male and female forms. When these cells are sucked up by a mosquito, the cells burst, freeing the sexual forms of the parasite. Within the mosquito, the two forms merge to create an oocyst. After maturing, the oocyst ruptures to release thousands of parasites, which migrate to the mosquito's salivary glands, awaiting her next bite.
Four species of malaria parasites cause disease in humans: Plasmodium vivax, P. malariae, P. falciparum and P. ovale. P. falciparum is the most common and causes the most deaths. The disease begins with chills and, likely, a headache, nausea and vomiting. A fever develops and as it falls, a person is drenched in sweat. The symptoms can occur 10 to 16 days after infection and may appear in regular intervals of every two or three days. Depending on the species of parasite, an infected person may feel well between bouts and recover, or may never feel fine and can die from the disease.
Why Can't the Immune System Kill Malaria Parasites?
NIAID investigators have found genetic clues as to why the immune system cannot kill malaria parasites.
Preliminary results from ongoing studies at NIAID have shown regions on P. falciparum chromosomes that house clusters of highly variable genes. The genes appear to make the large proteins that parasites put on the surfaces of blood cells after infection. The proteins may allow infected blood cells to stick to blood vessel walls. Parasites make the cells attach to avoid circulating about the body, specifically to elude the spleen, where the parasites are killed. In the brain, such attachments lead to life-threatening cerebral malaria.
However, the proteins make the infected cells more recognizable to the immune system. To avoid attack, the parasites constantly switch the proteins during infection, as the genes change and turn on and off. The diversity of proteins masks the cells from the immune system. As the system recognizes a protein and mounts an attack, the protein disappears and others emerge.
The research team includes Louis H. Miller, M.D., and Thomas E. Wellems, M.D., Ph.D., of the NIAID Laboratory of Parasitic Diseases, and Chris Newbold, Ph.D., of Oxford University. Dr. Miller is chief of the NIAID lab.
Getting a Grip: Parasites' Invasion of Blood Cells Provides Clues for Vaccines, Drugs
When attacking a red blood cell, a malaria parasite uses special molecules to grip the cell surface. NIAID investigators have identified the key areas of these molecules, information useful for designing malaria vaccines and drugs.
The scientists found that binding regions for two parasites, P. falciparum and P. vivax, have similar structures. The researchers are examining ways to make copies in the laboratory of binding regions common to both parasite forms. A vaccine using these copies could prompt the immune system to make antibodies, which would then bind to the parasites and prevent them from attacking blood cells. The investigators are examining similar strategies for antimalarial drugs. In related work, the researchers have identified the region of the surface receptor on blood cells that is targeted by the parasites.
Louis H. Miller, M.D., chief of the NIAID Laboratory of Parasitic Diseases, directs this project.
First Human Trial of Transmission-Blocking Malaria Vaccines Planned
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.
Transmission-blocking vaccines do not directly protect people against the disease. Instead, the vaccine triggers an antibody response from the immune system, which prevents development of the sexual stage of the parasite's life cycle after they are ingested by the mosquito. The parasites then cannot complete their life cycle and will not develop into the stage that infects people when the mosquito next feeds.
The first-generation vaccine contains man-made copies of Pfs25, a molecule on the surface of malaria parasites. So far, NIAID researchers have identified five molecules in addition to Pfs25 to try in such vaccines, and they have cloned the genes for four, which can be used in other candidate vaccines. Both Pfs25 and Pfs28 can induce transmission-blocking antibodies in laboratory animals. Preliminary evidence from additional studies indicates that a vaccine using Pfs25 and a second molecule, Pfs28, may be more effective than either alone, so NIAID scientists are developing a vaccine for clinical testing that contains both.
David C. Kaslow, M.D., chief of the Molecular Vaccine Section in the NIAID Laboratory of Parasitic Diseases, directs this project.
Synthetic Herbs Fight Drug-Resistant Malaria
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.
Scientists want to develop more effective drugs based on the synthetic artemisinin. In addition, the synthetic drugs provide insights into the molecular mechanism of action of these compounds, which could reveal the parasite's vulnerability.
This research is conducted by scientists from Johns Hopkins University, Walter Reed Army Institute of Research and University of Miami School of Medicine. Medicinal chemist Gary H. Posner, Ph.D., of Johns Hopkins, is the principal investigator.
Right or Resistant: Which Drug Will Work?
Chloroquine is the cheapest (9 cents per dose) and most-used antimalarial drug, but resistance has made the drug virtually useless in East Africa and threatens its use in West African countries. WHO reports that only Central American countries have not reported chloroquine resistance.
NIAID investigators have found a region on one of P. falciparum's chromosomes responsible for chloroquine resistance. With further study, the scientists plan to specifically locate the gene or genes involved and determine how they allow the parasite to get rid of the drug. The scientists plan to design new drugs that avoid the parasite's mechanism of resistance.
Currently, health care providers use pyrimethamine and proguanil alone or in combination as a second-line defense against parasites resistant to chloroquine. A new rapid test developed by NIAID researchers identifies parasites resistant to these drugs. Such tests allow clinicians to determine quickly if the drugs will be effective in their area.
The tests recognize mutations in the parasite's gene for the enzyme dihydrofolate reductase. Both pyrimethamine and proguanil inhibit the enzyme, but the mutations change the structure of the enzyme, allowing it to escape the drugs. Using the tests, the scientists found that the occurrence of the mutation in areas of Brazil, Mali and Kenya correlates with rates of resistance to these drugs.
Thomas E. Wellems, M.D., Ph.D., chief of Malaria Genetics Section in the NIAID Laboratory of Parasitic Diseases, directs this project.
Overcoming Genetic Diversity–Vaccines For Everyone
Because people differ genetically, their immune responses to malaria parasites vary subtly, but significantly. Vaccine designers supported by NIAID have overcome such differences by using a collection of laboratory-made proteins, a formula that might protect more people than a vaccine based on a single protein.
During infection, the immune system responds by making antibodies, but they only protect a person for a short time. The same reaction occurs in mice. In the laboratory, the scientists gave the experimental vaccine to mice infected with malaria parasites. As a result, their naturally occurring immune response lasted longer and they did not develop malaria.
NIAID, in collaboration with the United States Agency for International Development, plans to test this malaria vaccine in clinical trials. The animal research is conducted by scientists from New York University. Elizabeth Nardin, Ph.D., and Ruth Nussenzweig, M.D., Ph.D., both of NYU, are the principle investigators.
Prepared by: Public Health Service
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National Institute of Allergy and Infectious Diseases
National Institutes of Health
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U.S. Department of Health and Human Services
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