What is malaria?

Malaria is a major public health problem in more than 90 countries, inhabited by more than 2.4
billion people - 40% of the world’s population. The disease is estimated to kill a child every 30
seconds and to cause up to 600 million new infections worldwide annually.

Malaria is a major killer disease in Africa and a primary cause of death and poverty - undermining
development in some of the poorest countries in the world. Though the majority of the cases and
approximately 90% of the malaria deaths are found in Sub-Saharan Africa, the disease is growing
in Asia and Latin America.

The causes of human malaria

The four malaria species that produce human disease are P. vivax, P. falciparum, P. malariae and
P. ovale. Plasmodium falciparum, the most lethal strain, is the most prevalent species throughout
the tropics and subtropics.(1)

Malaria is usually transmitted when a person is bitten by an infected female Anopheles mosquito.
Only Anopheles mosquitoes transmit malaria and to do so the mosquito must have been infected
by having drawn blood from a person already infected with malaria.(2)

The disease
Malaria is a serious disease, which can be fatal. Malaria is caused by a parasite and the clinical
symptoms of the disease include fever and flu-like illness, such as chills, headache, muscle
aches, and tiredness. These symptoms may be accompanied by nausea, vomiting, and diarrhea.
Malaria can also cause anemia and jaundice (yellow coloring of the skin and eyes) because of
the loss of red blood cells.(2)

Infection with one type of malaria, Plasmodium falciparum, if not promptly treated, may cause
kidney failure, seizures, mental confusion, coma, and death.(2)

Although malaria can be fatal, illness and death can be prevented with proper diagnosis
and treatment.

Biology of Malaria
History
The existence of malaria as an enemy of humankind certainly predates written history. For
thousands of years malaria has been a deadly scourge, and it remains one today. From American
president John Adams who nearly succumbed to malaria in Amsterdam while on a diplomatic
mission, back down the timeline to the early Chinese, Indians, Greeks, and Romans, malaria has
not spared its victims, rich or poor.
It wasn’t until the 19th century that information about the true cause of malaria became known.
Yet despite this knowledge, malaria still ravages Sub-Saharan Africa, South-East Asia and Latin
America, taking as its victims mainly young children and pregnant women.

However, without certain discoveries leading to a better understanding of the biology of malaria,
organizations like MMV would not be in the position to seek new solutions to treating this deadly
disease, creating a glimmer of hope that one day malaria will be truly just another page in the
history books.

Malaria discoveries
1880 - discovery of the malaria parasite
The malaria parasite was discovered by Charles Louis Alphonse Laveran on 20 October 1880.
While examining blood from a soldier suffering from malaria, Dr Laveran saw crescent-shaped
bodies that were nearly transparent except for one small dot of pigment. After examining blood
from 192 other malaria patients, he identified the same crescents in 148 of the samples. Later he
recognized the four distinct forms in human blood that would prove to be the malaria parasite in
different stages of its life cycle (see further information below). Laveran received the Nobel Prize
in 1907 for his discovery of the single-celled protozoan that causes malaria.(1)

1897 - discovery that mosquitoes transmit malaria

On 20 August 1897, Ronald Ross, a British officer in the Indian Medical Service was the first to
demonstrate that malaria parasites could be transmitted from infected patients to mosquitoes. He
also demonstrated in his investigations of bird malaria that mosquitoes could transmit malaria
parasites from bird to bird. Ross was awarded the Nobel Prize for his discovery in 1902.(3)

1898-1899 - discovery of the transmission of human malaria parasites

A group of Italian scientists (G. Grassi, A. Bignami, G. Bastianelli, A. Dionisi, A. Celli) confirmed
that human malaria parasites pass through the same developmental stages in the mosquito as
the bird parasites observed by Ross.(1)

1948 - discovery of the malaria parasite in human tissue

It wasn’t until the 20th century that the third piece of the human malaria puzzle was solved. The
question of where sporozoites inoculated by mosquitoes undergo early development in the
human host was only answered in 1948 by researchers at the Ross Institute of the London
School of Hygiene and Tropical Medicine. They detected malaria parasites in the livers of rhesus
monkeys infected with the primate malaria species. They found similar stages in the livers of
humans infected with P. vivax and later confirmed the same for P. falciparum.(1)
Malaria Life Cycle
(2) adapted from the Center for Disease Control (CDC) malaria website, 2005
Malaria parasites spread by infecting successively two types of hosts: humans and the female Anopheles mosquito.
In humans, the parasites grow and multiply first in the liver cells and then in red blood cells. In the blood, groups of
parasites grow inside the red blood cells and destroy them, releasing daughter parasites ("merozoites") that
continue the cycle by invading other red blood cells.

The blood stage parasites are the ones that cause malaria symptoms. When certain forms of blood stage parasites
("gametocytes") are picked up by a female Anopheles mosquito during a blood meal, they start another, different
cycle of growth and multiplication in the mosquito.

After 10-18 days, the parasites are found (as "sporozoites") in the mosquito's salivary glands. When the Anopheles
mosquito takes a blood meal on another human, the sporozoites are injected into the human with the mosquito's
saliva and start infection in the human when they parasitize the liver cells.

Thus the mosquito carries the disease from one human to another, acting as a "vector". In contrast to the human
host, the mosquito vector does not suffer from the presence of malaria parasites.
To view the malaria life cycle visit: www.cdc.gov/malaria/biology/life_cycle.htm

A photomicrograph of Plasmodium falciparum of a Triple infection of erythrocyte with young

schizonts, using Wright’s stains. x1500
The ring stage trophozoites mature into schizonts, shown here, which rupture releasing
merozoites . Some of these parasites differentiate into sexual erythrocytic stages (gametocytes).
Blood stage parasites are responsible for the clinical manifestations of the disease. Image
courtesy of CDC

REFERENCES

(1) Text, where referenced, was adapted with permission of the US Institute of Medicine (IOM)
from the report, Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance,
2004, pp. 126-128
View full report
MMV is extremely grateful to the IOM.

(2) Additional material adapted from the Center for Disease Control (CDC) malaria website, 2005

(3) CDC malaria history site, 2005

Treatment Milestones
Background
Two important currently used antimalarial drugs are derived from plants whose medicinal values
had been noted for centuries: artemisinin from the Qinghao plant (Artemisia annua L, China, 4th
century) and quinine from the cinchona tree (South America, 17th century).(2)

Malaria treatment milestones

Quinine
Quinine comes from the bark of a tree native to South America. According to legend it was first
brought to Europe by a Countess who had been treated with it in Peru in the 1600s. The bark was
named cinchona in 1742 by Linnaeus. In 1820, two French chemists isolated quinine from the
cinchona bark and quinine became a treatment of reference for intermittent fever throughout the
world. Quinine remains an important and effective treatment for malaria today, despite sporadic
observations of quinine resistance.(1)

Chloroquine
Research by German scientists to discover a substitute for quinine led to the synthesis in 1934 of
Resochin (chloroquine) and Sontochin (3-methyl-chloroquine). These compounds belonged to a
new class of antimalarials, the four-amino quinolines. The German research went no further and
the formula for Resochin was passed to a US sister company. During World War II, French
soldiers happened upon a stash of German-manufactured Sontochin in Tunis and handed it over
to the Americans. American researchers made slight adjustments to the captured drug to
enhance its efficacy. The new formulation was called chloroquine. Only after comparing
chloroquine to the older and supposedly toxic Resochin, did they realize that the two chemical
compounds were identical.(1)

Following the war, chloroquine and DDT emerged as the two principal weapons in WHO’s global
eradication malaria campaign. Subsequently, chloroquine resistant P. falciparum probably arose
in four separate locations starting with the Thai-Cambodian border around 1957; in Venezuela
and parts of Colombia around 1960; in Papua New Guinea in the mid-1970s and in Africa starting
in 1978 in Kenya and Tanzania and spreading by 1983 to Sudan, Uganda, Zambia and Malawi.(1)

Sulfadoxine/Pyrimethamine
A pyrimidine derivative, proguanil, also emerged from the antimalarial pipeline during World War
II. Proguanil’s success in treating humans led to further study of its chemical class and to the
development of pyrimethamine. Resistance to the two monotherapies appeared quickly (within
one year in the case of proguanil). Sulfones and sulfonamides were then combined with proguanil
or pyrimethamine in hopes of increasing efficacy and forestalling or preventing resistance. By
1953, P. falciparum resistance had already been noted in Tanzania. When
Sulfadoxine/Pyrimethamine (SP) was introduced in Thailand in 1967, resistance appeared that
same year and resistance spread quickly throughout South-East Asia. Resistance to SP in Africa
remained low until the late 1990s but since then it has spread rapidly.(1)

Mefloquine
The development of mefloquine was a collaborative achievement of the US Army Medical
Research and Development Command, WHO/TDR and Hoffman-La Roche, Inc. Mefloquine’s
efficacy in preventing falciparum malaria when taken regularly was shown in 1974 and its
potential as a successful treatment agent was shown soon after. Resistance to mefloquine began
to appear in Asia in 1985, around the time the drug became generally available.(1)

Artemisinin
Artemisinin was isolated by Chinese scientists in 1972 from Artemisia annua (sweet wormwood),
better known to Chinese herbalists for more than 2000 years as Qinghao. In the early 1970s,
initial testing by Chinese scientists of Qinghao extracts in mice infected with malaria showed it to
be as effective as chloroquine and quinine in clearing the parasite. Mao Tse Tung’s scientists then
began testing in humans and in 1979 published their findings in the Chinese Medical Journal.(1)

Artemisinin and other artemether-group drugs are currently the main line of defense against drug
resistant malaria in many parts of South-East Asia. To date there have been no reported cases of
resistant to artemisinin.(1)

Artemisinin is today a very potent and effective antimalarial drug, especially when used in
combination with other malaria medicines.(3)

More information about Artemisinin-based combination therapy (ACT)

The future
Synthetic drugs
MMV’s main contribution to the antimalarial arsenal will
be the development of new antimalarial combination
therapies, such as the synthetic peroxides, that do not
rely on artemisinin production. In principle, these
synthetic drugs will be superior drugs not only in safety
and efficacy, but will also cost less and be
easiAntimalarial Databases
Antimalarial Databases
prepared by Lena Lim in Mike Gelb’s lab, University of Washington. Mike is a principal
investigator on MMV’s protein farnesyltransferase inhibitors (Pf-PFT) project.

The initial databases represent all antimalarials reported in J. Med. Chem from the 1950s through
August 2004. There are plans to expand the databases to cover all major literature sources,
including patent literature.

er to manufacture, thus mitigating problems of artemisinin shortage.