Research on Malaria

As the lessons of the past decades have convincingly demonstrated, conquering malaria is difficult. No one anticipates a quick victory even if new malaria drugs hit the market, or a vaccine proves highly successful. Rather, researchers and health planners expect their best chances lie in a many-sided attack, drawing upon a variety of weapons suited to local environments. Skillfully combining several approaches, both old and new, may at last make it possible to outmaneuver these persistent and deadly parasites.


Medicines 

Medicines to treat malaria have been around for thousands of years. Perhaps the best known of the traditional remedies is quinine, which is derived from the bark of the cinchona tree. The Spanish learned about quinine from Peruvian Indians in the 1600s. Export of quinine to Europe, and later the United States, was a lucrative business until World War II cut off access to the world supply of cinchona bark. In the 1940s, an intensive research program to find alternatives to quinine gave rise to the manufacture of chloroquine and numerous other chemical compounds that became the forerunners of modern antimalarial drugs.

Chloroquine was the third most widely used drug in the world until the mid-1990s. It is cheap to manufacture, easy to give, and does not cause problems for most people. Unfortunately, chloroquine-resistant malaria parasites have developed and have spread to most areas of the world. From the 1950s to the present, chloroquine resistance gradually spread to nearly all P. falciparum malaria-endemic regions.

In the 1960s, the U.S. Government, WHO, and other agencies launched a massive search for new antimalarial drugs. In addition, many doctors treating people in Asia are using yet another new family of drugs based on the parent drug artemisinin, an extract of the Chinese herbal remedy qinghaosu.

Unfortunately, malaria parasites in many geographic regions have become resistant to alternative drugs, many of which were discovered only in the last 30 years. Even quinine, the long-lived mainstay of malaria treatment, is losing its effectiveness in certain areas.

To address the problem of drug-resistant malaria, scientists are conducting research on the genetic mechanisms that enable Plasmodium parasites to avoid the toxic effects of malaria drugs. Understanding how those mechanisms work should enable scientists to develop new medicines or alter existing ones to make drug resistance more difficult. By knowing how the parasite survives and interacts with the human host during each distinct phase of its development, researchers also hope to develop drugs that attack the parasite at different stages.

For example, National Institute of Allergy and Infectious Diseases (NIAID) scientists are studying the molecules on host cells that malaria parasites use to attach to and enter the cells. Malaria parasites invade various tissues such as skin, blood, liver, gut, and salivary glands of human and mosquito hosts, which means the parasites must be able to attach to a diverse array of molecules (called receptors) on the outside of host cells. By determining the three-dimensional structures of these receptors, scientists hope to determine exactly how the parasites target particular types of cells, which may reveal new targets for antimalarial drugs.

NIAID scientists are also working to understand how P. falciparum has adapted to survive and grow within RBCs. An important category of these adaptations involves the trafficking of nutrients across various membranes of the infected RBC. To this end, researchers have identified two nutrient channels unique to the infected cell and plan to study these further to identify their genetic bases and to develop detailed mechanistic models of nutrient transport. With these models, they may be able to design channel blockers that interfere with the parasite’s ability to acquire needed nutrients. These blockers may prove to be novel and useful drugs for treating malaria.

Finally, NIAID scientists are unraveling the mechanisms of natural resistance to malaria infection, which is yielding valuable information for new antimalarial drug development. For example, in regions of West Africa, up to one-fourth of children carry hemoglobin C, a variant of hemoglobin that can reduce the risk of severe and fatal malaria by as much as 80 percent. The way hemoglobin C protects people, however, had been puzzling.

NIAID scientists and their team of international collaborators discovered that hemoglobin C protects against malaria by affecting a key parasite protein, called PfEMP 1, that malaria parasites normally place on host RBCs in knoblike protrusions. The protruding proteins then make the infected RBCs stick to the lining of blood vessels in the brain and other critical tissues, which causes inflammation and circulatory obstruction. Hemoglobin C alters the membrane of RBCs so that the parasites cannot place PfEMP 1 normally at the cell surface. Thus, these RBCs are less able to adhere to vessel walls, which reduces disease severity. Other hemoglobin variants, such as the sickle-cell mutation, may protect against malaria by a similar mechanism. These findings suggest that interventions affecting the display of PfEMP 1 may reduce the impact of malaria.

Mosquito Control 

The appearance and spread of insecticide-resistant mosquitoes, as well as stricter environmental regulations, now limit the effectiveness and use of the insecticide DDT, the mainstay of 1950s and 1960s malaria eradication programs. 

More recently, researchers have found that mosquito netting soaked with pyrethroid insecticides, which prevent mosquitoes from making contact with humans, significantly reduces malaria transmission. Therefore, as part of its Roll Back 

Malaria program, WHO is promoting widespread use of insecticide-treated mosquito netting in malaria-endemic areas. Still, in some parts of Western Africa, mosquitoes have become resistant to pyrethroid insecticide used to treat the nets. Although scientists do not think this development is a serious limitation yet, it points out the need to continue research to identify new tools for mosquito control. 

Vaccines 

Malaria Vaccine


Research studies conducted in the 1960s and 1970s showed that experimental vaccination of people with attenuated malaria parasites can effectively immunize them against getting another malaria infection. Current methods to develop vaccines based on weakened or killed malaria parasites are technically difficult and do not readily lend themselves to being produced commercially. Therefore, much of the research on vaccines has focused on identifying specific components or antigens of the malaria parasite that can stimulate protective immunity. 

In 1997, NIAID launched a Plan for Research to Accelerate Development of Malaria Vaccines based on four cornerstones.
  • Establishing a resource center to provide scientists worldwide with well-characterized reference and research reagents
  • Increasing support for discovery of new vaccine candidates 
  • Increasing capacity to produce vaccine candidates at the quality and quantity that will be required for clinical trials 
  • Establishing research and training centers in endemic areas where potential vaccines may undergo clinical trials. 
The NIAID Malaria Vaccine Development Branch (MVDB) is part of the institute’s initiative to respond to the global need for malaria vaccines. MVDB has developed and produced several proteins on parasite antigens sequences to include in candidate malaria vaccines. This work involves collaborations with colleagues from other Federal agencies, the private sector, and academia in the United States and throughout the world, as well as assistance from a variety of partners, such as the U.S. Agency for International Development and the Malaria Vaccine Initiative.

(Meyda Azzahra)