Malaria Research, NIAID Fact Sheet: NIAID
Article title: Malaria Research, NIAID Fact Sheet: NIAID
Conditions: Malaria
Source: NIAID
February 2000
Malaria Research
NIAID Research
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).
Drugs 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 Fansidar™ 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.
Mosquito Control 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.
Vaccines 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
Prepared by:
Office of Communications and Public
Liaison
National Institute of Allergy and Infectious
Diseases
National Institutes of Health
Bethesda, MD
20892
U.S. Department of Health and Human Services
