Aris Persidis is managing director of RHeoGene,
706 Forest Street, Charlottesville, VA
22903 (apersidis@rheogene.com).
Each year, 300−500 million people contract malaria and about 3 million
die, most of whom are children under five years old. In absolute numbers,
malaria kills 3,000 children per day under the age of five. The total number
of deaths readily exceeds that from AIDS. Malaria is easily the world's largest
parasitic disease, killing more people than any other communicable disease
except tuberculosis. Malaria is a major public health problem in more than
100 countries, inhabited by a total of some 2.4 billion people, or close to
half of the world's population.
In many developing countries, especially in Africa, malaria is a huge disease
burden in lives, medical costs, and days of labor lost. Although malaria is
typically associated solely with the developing world and the tropics, its
geographic distribution extends beyond those areas and includes occasional
small outbreaks in Europe and North America. Because of its global and massive
implications, malaria is the focus of numerous therapeutic and preventive
efforts that are often international in nature.
Historical perspective Malaria is caused in humans by four species of single-celled Plasmodium
protozoa parasites: P. falciparum, P. vivax, P. ovale
, and P. malaria, with P. falciparum accounting for the
majority of infections and being the most lethal. Transmission of the parasites
is via the Anopheline mosquitoes, and is affected by climate and geography.
The causative agent of malaria was discovered in 1880 by Charles Alphonse
Louis Laveran.
In the early 1960s, initial efforts to determine the nature of any immune
response to malaria infection in animal models were reported1.
At the same time, the generation of resistance of malarial pathogens to chloroquine
and 4-aminoquinolines—the main treatment at the time—was also
reported and discussed2.
The early 1970s saw the application and evaluation of antifolic sulfametopyrazine
and trimethoprim drugs against malaria parasites3. Interferon
was also being examined for its ability to generate a protective response
in animal models of the disease4, and tetracyclines were being
evaluated in humans5.
In the 1980s, the generation and description of monoclonal antibodies against
specific malarial antigens were explored for diagnostic and potentially therapeutic
purposes6. In a few years, systematic efforts to generate vaccines
were in full swing, and there were increasing reports describing the generation
of human T lymphocyte clones specific for malaria antigens, these being important
tools for the development of vaccines7. These efforts were helped
by additional advances, including the sequencing of immunodominant epitopes
from the surface protein of malarial pathogens8.
The early 1990s saw continued development and testing of new medications
alone or in combination therapies, including artesunate and mefloquine9. By the mid-1990s, the sophistication of the tools and methodologies
available to clinicians enabled the description of important new dimensions
to classical preventive measures. One example was the description of delayed
onset malignant tertian malaria as a result of inappropriate use of a commonly
used medication, doxycycline10.
Current state A relatively small number of drugs against malaria are available today.
Although new drugs have in fact appeared in the last 20 years, including atovaquone,
malarone, halofantrine, mefloquine, proguanil, artemisinin derivatives, and
co-artemether, new and affordable drugs as well as better formulations of
existing drugs are needed. This is compounded by the emergence of resistance
to these and to more classical drugs, such as chloroquine, by malarial pathogens.
As a result, there are concerted efforts to develop vaccines against malaria,
and according to the World Health Organization (Geneva), the hope is that
an effective vaccine will be available within the next 7−15 years. There
are three main types of vaccines being developed: anti-sporozoite vaccines
designed to prevent infection, anti-asexual blood stage vaccines designed
to reduce severe and complicated manifestations of the disease, and transmission-blocking
vaccines aimed at arresting the development of the parasite in the mosquito
itself. Table 1 lists several companies developing
vaccines and small molecule drugs against the disease.
Table 1. Selected companies with antimalarial programs.
Malaria is also the target of major international initiatives focusing
on assisting the development of new therapies as well as coordinating efforts,
fostering integration, and putting in place basic education programs for populations
at risk.
One example is the Roll Back Malaria initiative announced by WHO in May
1998—a global strategy to improve health systems with the goal of a
50% reduction in malaria deaths by the year 2010. Another program, the Malaria
Vaccine Initiative (MVI), was created through a grant of the William H. Gates
Foundation to PATH (Program for Appropriate Technology in Health). The objective
of the MVI is to significantly accelerate the clinical development of promising
malaria vaccine candidates. WHO's new Medicines for Malaria Venture is a joint
public−private sector initiative that aims to develop antimalarial drugs
and drug combinations for distribution in poor countries. The Multilateral
Initiative on Malaria is an alliance of organizations and individuals concerned
with malaria, and is coordinated by the Wellcome Trust (London). It aims to
maximize the impact of scientific research against malaria in Africa by facilitating
global collaboration and coordination. Finally, the African Malaria Control
Initiative (AFRO/WHO/World Bank), launched in 1999, is a 25-year plan that
specifically targets malaria control in Africa. This is another multiagency,
multidisciplinary, and multinational initiative. In combination, these and
other programs clearly show the seriousness attributed to the malaria problem
by both developed and developing countries.
Industry challenges Although much less of the world is affected by malaria today than it was
50 years ago, this downward trend is slowing, and may in fact be stopped or
reversed due to several factors. Deforestation, road building, mining, and
massive agricultural and irrigation projects in developing regions such as
the Amazon and Southeast Asia are linked with significant outbreaks of the
disease, as is the mass movement of refugees due to armed conflicts. The ever-increasing
rates of international travel also result in imported cases of malaria being
observed in developed countries and in areas where it was previously under
control or eradicated, as in the Central Asian republics of Tajikistan and
Azerbaijan, and in Korea. The re-emergence of the malaria threat is thus a
major challenge to the global economy.
On the therapeutic side, a key challenge to the development of small molecule
drugs against malarial pathogens is the development of resistance. Recent
findings are beginning to shed some light on the origin of this resistance
in specific cases. For example, a recent report describes the correlation
between mutations in the cytochrome b gene of Plasmodium berghei and
resistance of the pathogen to the antimalarial drug atovaquone11.
Resistance is also being explored by the application of molecular epidemiology
and analysis. For example, a novel P. falciparum gene, denoted
cg2, has been recently discovered, and a distinct genotype, characterized
by 12 point mutations and 3 size polymorphisms, has been shown to be associated
with chloroquine resistance in laboratory-adapted parasite strains. These
markers are under intense investigation for their potential as prognostics
of drug responses12.
Another major challenge is that often, the appropriate medication is lacking
in parts of the world suffering from this disease spread. For example, injectable
quinine is not always available, and in its absence, children in particular
are especially susceptible to cerebral malaria. Recent reports describe how
another agent, mefloquine, which may be more readily available, can be administered
through a nasogastric tube and still result in complete recovery13.
The future The fight against malaria will only escalate in the future. New medicines
will consist of small molecules and vaccines being developed as a result of
the increasing understanding and analysis of molecular and epidemiological
factors. For example, a single-chain antibody fragment specific for the
P. berghei ookinete protein Pbs21 that blocks transmission in the mosquito
midgut was recently reported. This is a useful tool not only as a potential
therapeutic, but also because the Pbs21 gene itself can be used to generate
a model system to study how mosquitoes themselves can be made resistant to
the transmissible forms of malaria14.
Malaria is also being targeted by traditional functional genomics methods.
One recent study describes how the targeted disruption of the CTRP gene of
the pathogen confirmed and revealed its critical role in the disease, thus
making it a bona fide validated target for new therapeutics15.
As more such genes are validated as targets, they will invariably lead to
more precisely targeted therapies.
The future will also see the increasing use of simpler, yet effective,
preventive measures in developing nations. For example, it has been shown
in large trials in Africa that insecticide-treated bednets and curtains can
reduce child mortality in malaria-endemic communities by 15−30%. Nevertheless,
there are significant implementation issues regarding these approaches, and
the future will see concerted efforts to address them, especially given their
effectiveness16.
Finally, with the completion of the effort to map the malaria genome, which
is being carried out by a consortium including the US National Institutes
of Health, the US Department of Defense, the Burroughs-Wellcome Fund, and
the Wellcome Trust, researchers will soon be able to identify and validate
good drug targets much more rapidly, leading to effective new therapies and
vaccines.
Conclusions Malaria is a curable disease if promptly diagnosed and adequately treated.
In addition, significant lessening of its effects and spread can be accomplished
by preventive measures, including personal measures such as adequate clothing,
repellents, and bednets, or community measures such as insecticides or environmental
management. In combination with new drugs and formulations, some of which
will arise from genome sequencing projects, malaria will hopefully soon come
under complete control.
