Basic Research
Basic research is the key to developing new ways to prevent and treat malaria. By researching the underlying biology of malaria parasites and how they interact with people and mosquitoes, scientists can identify new molecular targets for malaria drugs and vaccines. Researchers are also conducting studies on the specific human, mosquito and parasite factors that contribute to malaria, including serious complications such as cerebral malaria and anemia. Additional basic research is ongoing to learn how a person's immune system responds to malaria infection and fights off the disease.
In October 2002, researchers reported a major advancement in all areas of basic malaria research when they announced the complete genetic blueprints of the major malaria vector, the Anopheles mosquito, and of Plasmodium falciparum, the deadliest malaria parasite. Combined with the recently completed human genome sequence, scientists now have the complete set of human, parasite and mosquito genes involved in malaria transmission. These accomplishments provide an unprecedented look at the underlying genetics of malaria and will enable scientists to use that information to develop new ways to treat and prevent the disease.
By mining the genome information for P. falciparum alone, National Institute of Allergies and Infectious Diseases (NIAID) scientists recently showed the parasite to be more genetically diverse and much older-at least 100,000 years old-than previously thought. Their research also showed that resistance to the malaria drug chloroquine arose independently on multiple continents and spread across the globe from at least four points of origin.
In 1998, NIAID funded and formed the Malaria Research and Reference Reagent Resource Center (MR4), which is managed by the Centers for Disease Control and Prevention and the American Type Culture Collection. The MR4, founded in response to the needs of researchers, provides reagents, materials and protocols necessary for malaria research. All resources are provided free-of-charge, and more than 270 researchers have received assistance from MR4 to date. In collaboration with the World Health Organization and other agencies, MR4 also organizes workshops and training programs to help move potential products from the laboratory into clinical trials. Recently, MR4 has provided key reagents for a study of anti-malarial drug resistance in Uganda, sponsored a drug-resistance workshop in Benin, and provided malaria research training in India and Cameroon.
Collaborating With the World to Combat Malaria
Malaria is a global health problem and therefore requires a global research approach. NIAID participates in many collaborative projects with other U.S. agencies, international organizations and foreign governments. Within the United States, NIAID participates in the Federal Malaria Vaccine Coordinating committee, an interagency working group that provides for timely exchange of information and collaborative efforts to accelerate malaria vaccine research and development.
The Institute also works with the U.S. Agency for International Development to support collaborative vaccine development research. NIAID also has joined with the Malaria Vaccine Initiative, administered by the Program for Appropriate Technology in Health (PATH), to support a promising vaccine candidate and to develop additional candidates for future testing. Within the National Institutes of Health (NIH), NIAID recently teamed with the National Institute of Child Health and Human Development and the Fogarty International Center (FIC) to fund research targeted at understanding malaria-associated anemia.
In 1997, NIAID joined with FIC, the World Health Organization, and other institutions to form the Multilateral Initiative on Malaria (MIM). MIM's mission is to increase and enhance worldwide research on malaria by facilitating multinational research cooperation. The Institute also has established malaria research facilities in Mali and Ghana and has trained local scientists and physicians to conduct malaria research from within endemic countries. In addition to studies conducted by the Mali and Ghana laboratories, NIAID supports research on multiple aspects of malaria infection in Kenya, Cameroon, Indonesia, Malawi, The Gambia and Gabon.
Vaccine Research
An effective vaccine that will prevent malaria is a major goal of NIAID. In 2001, the Institute opened its Malaria Vaccine Development Unit (MVDU) at its Rockville, Maryland, research facility. The MVDU is an 8,000-square-foot, state-of-the-art biotechnology laboratory designed to develop and produce promising malaria vaccine candidate antigens. The facility is part of a joint effort by NIAID researchers and the Institute's administrative scientists who oversee NIAID-funded malaria research conducted at universities, private industries, and international research sites. The MVDU serves a vital function by moving potential vaccines through the pipeline for testing in people. The unit assists with production, scale-up, clinical-grade manufacturing and clinical trials in the United States and malaria-endemic countries.
Scientists from the Institute's Laboratory of Parasitic Diseases are conducting exciting studies on malaria vaccines. Through the NIAID-sponsored Malaria Research and Training Center in Bamako, Mali, researchers are accelerating preparations and training for testing several vaccine candidates. Phase I clinical trials are expected to begin in early 2003. NIAID scientists also recently reported they could genetically modify mice to produce promising vaccine antigens in their milk. Once extracted from the milk, the experimental vaccine protected four out of five monkeys from an otherwise lethal dose of the malaria parasite. That research suggests that milk-giving animals such as goats may serve as inexpensive vaccine-manufacturing units.
NIAID also supports extensive research on malaria vaccines conducted by researchers from academia and industry. The Institute currently funds multiple studies aimed at developing vaccines against different stages of the malaria parasite and has conducted Phase I and Phase II clinical trials of several of the most promising candidates. Vaccines under study include those directed against the parasite both before and after it moves into red blood cells.
Another promising approach under investigation is transmission-blocking vaccines. Those vaccines do not prevent a person from contracting malaria, but they prevent the malaria parasite from developing inside a mosquito that has bitten a vaccinated person. NIAID researchers and grantees from Unites States universities are working to develop such vaccines, which could reduce symptoms in infected people and slow the spread of malaria by breaking the cycle of mosquito transmission.
Research is also underway on combination vaccines derived from multiple parasite life stages, and early candidates are being prepared for use in Phase I human safety trials. DNA vaccines, one of the newest vaccine technologies, are an additional area under investigation by NIAID grantees, and several examples have been tested in animal models of malaria.
NIAID employs a number of mechanisms to generate corporate interest in malaria vaccines. Using grants, contracts and other cooperative funding agreements, the Institute has enlisted the support of several pharmaceutical and biotechnology companies in producing an effective vaccine. Following the NIH lead, the European Union recently launched a small European Malaria Vaccine Initiative to try to develop links with industry and accelerate the movement of vaccine candidates through the development pipeline and into clinical trials.
Drug Research
New drugs to treat malaria, particularly those infections caused by forms of Plasmodium that are resistant to current medications, are greatly needed. Because the parasite has a complex life cycle, researchers are seeking to understand the molecular biology of the parasite and how it interacts with its human host at each stage in that cycle. Using that information, scientists hope to develop new drugs that block different molecular processes required for parasite survival.
NIAID researchers have made tremendous strides in elucidating Plasmodium biology, and they hope to use that information for developing new drugs. Scientists have identified key temperature-regulated genetic elements that switch on and off different phases of the parasite's life cycle. Other scientists have discovered additional genes or their regulatory elements that control the ability of the parasite to change its appearance and avoid immune detection, resist the effects of the malaria drug chloroquine, invade red blood cells via multiple ports of entry, bind to the human placenta, and invade the mosquito digestive tract. Scientists have also used studies of the three-dimensional structure and physical properties of human and mosquito cell membranes to learn more about how the parasites infect and grow inside red blood cells and the mosquito midgut. NIAID researchers have made seminal discoveries about how Plasmodium inserts a key channel in red blood cell membranes that enables the parasite to acquire nutrients and grow.
NIAID grantees are also hard at work identifying promising targets and compounds for new malaria drugs. Researchers have developed compounds that destroy a key reproductive stage of Plasmodium and others that appear to block the parasite's development within red blood cells. Other investigators are scanning the genes revealed by the P. falciparum genome project to identify new targets that exist in the malaria parasite but not in people. New drugs designed to attack those targets would therefore damage the parasite but not its human host.
Mosquito Research
Research on mosquito genetics, physiology, and ecology may lead to new ways to treat, prevent, or control malaria. NIAID funds many research projects at institutions in the United States and abroad aimed at developing a comprehensive understanding of the insect's biology.
One cutting-edge area of mosquito research is the development of genetically modified insects that are incapable of harboring and transmitting the malaria parasite. Researchers have identified small proteins that interfere with Plasmodium development within the mosquito; other scientists have shown that genes can be successfully introduced into the insects and maintained in future generations.
Because some mosquitoes support malaria parasites while others do not, researchers are attempting to understand the biological basis of that difference. Towards that end, some scientists are studying the fates of Plasmodium sexual stages in mosquitoes and the process by which the parasites may be encapsulated within the mosquito gut. Other grantees are studying the genetic basis behind an insect's susceptibility or refractoriness to Plasmodium infection.
One NIAID scientist also has developed a new tool for studying how mosquitoes and parasites interact with one another. He recently developed a model of Plasmodium infection in fruit flies, which are well-studied laboratory animals whose genetic blueprints are known. Although those insects are not natural hosts of the malaria parasite, the new laboratory model allows scientists to study how insect physiology can affect the survivability of Plasmodium.
Investigators also are looking at the ecology of mosquitoes to determine the distribution of different species, their preferred ecological niches, the factors that affect where individual species and subspecies live, and how the partitioning of those species affects malaria transmission. Specifically, NIAID grantees are studying the relationship between vegetation and mosquito abundance in Belize and mosquito behavior and larval ecology in Kenya; the effect of rice irrigation on malaria prevalence in Mali; and how mining and deforestation are leading to the emergence of important new malaria vectors in Brazil.
Revision Date: October 2002
Source: National Institute of Allergy and Infectious Diseases, National Institutes of Health
