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Malaria (from the medieval Italian mala aria, "bad air"; formerly also called ague, marsh fever, or paludism) is a life-threatening infectious disease of humans and other vertebrates caused by single-celled parasitic protozoa of the genus Plasmodium (phylum Apicomplexa, order Haemosporida). The parasites are transmitted between people by the bite of infected female Anopheles mosquitoes. Of roughly 500 described Anopheles species, some 30 to 40 are significant vectors of human malaria.

Malaria is the most important vector-borne disease in the world. It causes an estimated 250 to 265 million clinical cases and about 600,000 deaths each year. Roughly 94% of cases and 95% of deaths occur in Sub-Saharan Africa, and most deaths are in children under five years old and in pregnant women.

The illness results from the repeated multiplication of the parasite inside red blood cells. When infected cells rupture together, they release hemozoin and other parasite material that provokes the cycles of chills, fever, and sweating characteristic of the disease. Infected cells also adhere to the walls of small blood vessels, and the destruction of red cells and suppression of their production in the bone marrow lead to severe anaemia, lactic acidosis, cerebral malaria, damage to the placenta, and failure of several organs. Because the parasite's sexual stages develop inside a mosquito whose body temperature follows that of the air, and because mosquitoes breed in surface water, the distribution and intensity of malaria depend closely on climate.

More than 250 species of Plasmodium infect mammals, birds, and reptiles. Five cause malaria in humans, although genome sequencing has shown that Plasmodium ovale consists of two distinct forms that do not interbreed. Monkey parasites such as P. brasilianum and P. cynomolgi occasionally infect people.

The Plasmodium species that infect humans

Exoerythrocytic Hepatic Stage and Hypnozoite Dormancy

All the human malaria parasites alternate between people, in whom they multiply asexually and produce sexual forms, and female Anopheles mosquitoes, in which fertilization and further multiplication occur.

When an infected mosquito probes the skin, it injects sporozoites, typically a few tens of them, into the dermis. Using surface adhesins and an internal motor that drives gliding movement, the sporozoites reach the bloodstream, travel to the liver, pass through the cells lining the liver's blood vessels, and invade hepatocytes within about an hour.

Inside the liver cell, the species follow two different strategies:

• Species without relapse (P. falciparum, P. malariae, and P. knowlesi). Every sporozoite begins to divide at once. Over about a week in P. falciparum, rather longer in P. knowlesi and two weeks or more in P. malariae, it produces tens of thousands of merozoites, which are released into the blood inside packets of host membrane. Once this is complete, no parasites remain in the liver.
• Species with relapse (P. vivax and both forms of P. ovale). Some sporozoites divide immediately, while others become hypnozoites: small, dormant, single-nucleus forms that remain inside liver cells for weeks to years before resuming development and releasing a fresh wave of merozoites. What triggers reactivation is not known.

Erythrocytic Schizogony and Hemoglobin Digestion

Merozoites released from the liver attach to red blood cells, turn so that their front end faces the cell, and enter through a ring-shaped junction formed between the two cells. Inside, the parasite grows from a small ring-shaped form into an actively feeding stage that takes in the cell's contents and digests hemoglobin in an acidic compartment. The heme released by digestion is toxic, and the parasite converts it into an inert crystalline form, hemozoin. The parasite then divides into a cluster of new merozoites.

The length of this cycle determines the rhythm of fever, which follows the synchronized rupture of infected cells:

• 24 hours in P. knowlesi, producing daily fever and very rapid growth in parasite numbers.
• 48 hours in P. falciparum, P. vivax, and P. ovale. Fever on the first and third days gives the old name "tertian", counted inclusively.
• 72 hours in P. malariae, with fever on the first and fourth days, hence "quartan".

Gametocytogenesis and Mosquito Sporogony

A small proportion of parasites stop dividing and develop instead into male and female sexual forms, or gametocytes. This switch is controlled by the transcription factor AP2-G; the signals that trigger it are not fully understood, though the availability of certain host lipids and the stress of drug treatment both appear to play a part. In most species, gametocytes mature within a day or two and circulate at once. In P. falciparum they take 10 to 12 days, developing out of sight in the bone marrow before the mature, crescent-shaped forms re-enter the blood.

When a mosquito takes up gametocytes in a blood meal, the fall in temperature, the rise in pH as carbon dioxide escapes from the blood, and exposure to the mosquito compound xanthurenic acid trigger their release from the red cells within minutes:

• The male form divides rapidly and releases up to eight motile gametes in a process called exflagellation.
• Fertilization produces a zygote, the only stage in the life cycle with two sets of chromosomes.
• Within a day the zygote undergoes meiosis, which reshuffles the genes of any parasites taken up together, and becomes a motile, invasive form called an ookinete.
• The ookinete digests its way through the membrane lining the mosquito gut, crosses the gut wall while evading the mosquito's immune system, and settles on the outer surface as an oocyst.
• Over 7 to 30 days, depending strongly on temperature, the oocyst produces thousands of sporozoites. These are released into the mosquito's body cavity and invade the salivary glands, completing the cycle. This interval is the extrinsic incubation period.

Vectorial Capacity and the Basic Reproduction Number (R₀)

The quantitative study of malaria began with Ronald Ross, who showed in 1897 and 1898 that mosquitoes transmit the parasite and who then built the first mathematical models of transmission. The models were extended in the 1950s by George Macdonald, who showed how heavily transmission depends on how long mosquitoes live, and so explained why killing adult mosquitoes indoors is so effective.

Let X be the proportion of people infected and Y the proportion of mosquitoes that are infectious. The model is:

where:

• m is the number of female mosquitoes per person;
• a = Q_h f is the number of human bites per mosquito per day, the product of the proportion of blood meals taken from humans and the feeding frequency;
• b is the chance that an infectious bite infects a person, roughly 0.3 to 0.5;
• c is the chance that a mosquito biting an infected person becomes infected, roughly 0.02 to 0.2;
• r is the daily rate at which people clear the infection, about 0.005 per day, corresponding to an untreated infection lasting some 200 days;
• μ is the daily death rate of mosquitoes, so that daily survival is p = e^−_μ_ and average lifespan is 1/_μ_;
• n is the extrinsic incubation period, so that the proportion of infected mosquitoes surviving to become infectious is e^−_μn_.

Examining the behaviour of the model when infection is rare gives the basic reproduction number, the number of new human infections arising from one infected person in a fully susceptible population:

In 1964, the entomologist Christopher Garrett-Jones separated out the parts of this expression that depend only on the mosquito, giving the vectorial capacity:

Setting both rates of change to zero gives the steady state the infection settles into. The proportion of people infected is:

Epidemiological Thresholds and Sensitivity to Mosquito Longevity

Three conclusions follow:

1. A threshold exists. Malaria persists only if R₀ exceeds 1. If control measures push it below 1, transmission dies out, and it is not necessary to eliminate every mosquito. This was Ross's central insight.
2. Prevalence responds slowly at first. Where transmission is intense, people are bitten by infectious mosquitoes many times a year, far more often than is needed to keep them infected. Reducing mosquito numbers by a large fraction may therefore have little immediate effect on the proportion of people carrying parasites, even though it reduces transmission. Substantial reductions in prevalence appear only once transmission has fallen a long way.
3. Killing adult mosquitoes has the greatest effect. Examining how sensitive R₀ is to each quantity shows why. Halving mosquito numbers halves R₀. Halving the biting rate reduces it fourfold, because the biting rate enters squared: a mosquito must bite once to become infected and again to transmit. Increasing the death rate has a still larger effect, because mosquitoes must survive the whole incubation period to transmit at all, so μ appears both as a divisor and in the exponent. For typical values this makes mortality the most powerful lever available.

Febrile Paroxysms and Cytokine Cascades

After a symptom-free period while the parasite develops in the liver, typically one to two weeks for P. falciparum and longer for the other species, the rupture of infected red cells begins to cause symptoms. Parasite material released at rupture activates receptors on immune cells, which release tumor necrosis factor, interleukin 1 beta, interleukin 6, and interferon gamma. These raise the body's temperature set-point in the hypothalamus through prostaglandin E2, producing the classic three-stage attack:

1. Cold stage (15 to 60 minutes): intense shivering as the body temperature rises.
2. Hot stage (2 to 6 hours): temperature reaches 39.5 to 41.5 °C, with severe headache, muscle pain, nausea, vomiting, and an enlarged, tender liver and spleen.
3. Sweating stage (2 to 4 hours): heavy sweating as the temperature falls, leaving the patient exhausted.

Cerebral Malaria, Severe Anemia, and Placental Sequestration

Without treatment, and particularly in young children, pregnant women, and travellers with no previous exposure, infection can progress to severe malaria. The World Health Organization recognizes several forms:

• Cerebral malaria, almost always caused by P. falciparum, is the leading cause of malaria death in African children. It presents as coma lasting more than an hour after any seizure, together with characteristic changes at the back of the eye, including whitening of the retina and haemorrhages. Infected red cells displaying particular forms of PfEMP1 bind the endothelial protein C receptor and ICAM-1 on brain capillaries. This prevents the receptor from carrying out its normal protective role, so that the vessel lining becomes activated, the blood–brain barrier breaks down, and the brain swells.
• Severe anaemia (haemoglobin below 5 g/dL in children) arises in three ways: destruction of infected cells when they rupture; removal by the spleen of many uninfected cells, perhaps eight to ten for each infected one, which have been damaged or coated with antibody; and suppression of red cell production in the bone marrow by hemozoin and inflammatory signals. Studies of P. vivax suggest the loss of uninfected cells is even greater, which helps explain why it causes severe anaemia despite low parasite densities.
• Metabolic acidosis, indicated by a blood lactate above 5 mmol/L, is the single strongest predictor of death at any age. It results from obstruction of small vessels, from anaemia reducing oxygen delivery, from lactate produced by the parasite, and from impaired clearance by the liver and kidneys. It appears clinically as deep, rapid breathing.
• Low blood sugar (below 2.2 mmol/L) results from the parasite's enormous consumption of glucose, from depleted liver stores in a child who is vomiting and not eating, and from suppression of glucose production by inflammation. Treatment with quinine makes it worse by stimulating insulin release, which is one reason artesunate is preferred.
• Placental malaria affects pregnant women, especially in a first pregnancy. The parasite switches to expressing a particular protein, VAR2CSA, which binds chondroitin sulfate A on the lining of the placenta. Parasites and inflammatory cells accumulate there, impairing the supply of oxygen and nutrients to the fetus. The results include maternal anaemia, miscarriage, stillbirth, poor fetal growth, and low birth weight, which contributes to a large number of infant deaths each year.
• Kidney injury, lung injury, and splenic rupture. Free haemoglobin released by destroyed red cells removes nitric oxide from blood vessel walls and damages the kidney tubules; the resulting dark urine was historically called blackwater fever, which has been linked to both quinine treatment and G6PD deficiency, though the cause remains debated. Fluid can leak into the lungs, causing acute respiratory distress syndrome, particularly in adults and in P. vivax and P. knowlesi infection. Long-standing exposure can cause massive enlargement of the spleen with excess antibody production, and the spleen may rupture, most often in P. vivax.

Thermal Performance Curves and Diurnal Fluctuations

Because transmission depends on a mosquito whose body temperature follows that of the air, and whose larvae develop in standing water, malaria is unusually sensitive to weather and climate.

The effect of temperature on transmission is the combined result of its effect on several features of the mosquito and the parasite, each of which has an optimum and fails above and below certain limits:

where a is the biting rate, PDR the parasite development rate (the inverse of the incubation period), μ the mosquito death rate, EFD the number of eggs laid per female per day, p_EA the survival of larvae to adulthood, and MDR the rate of larval development.

Approximate temperature limits for transmission

Daily temperature swings also matter. Because these relationships are curved rather than straight, the effect of a fluctuating day differs from that of a constant day at the same average temperature, a consequence of Jensen's inequality. In cool highlands, afternoon warmth allows development to proceed for part of each day, so transmission is possible at lower average temperatures than constant-temperature experiments suggest. In hot lowlands, afternoon peaks exceed the limits for both mosquito and parasite, reducing transmission below what the average would imply.

• Dry air shortens mosquito life. Mosquitoes lose water continuously through the cuticle and when breathing, at a rate that rises as air becomes drier. Because mosquito survival enters the transmission equation exponentially, very dry conditions can halt transmission unless mosquitoes can shelter in humid places such as houses or irrigated land.
• Heavy rain and floods. A warmer atmosphere holds more water vapour, so rainfall increasingly comes in intense downpours. Floods initially wash away mosquito larvae, but as the water recedes it leaves behind large numbers of sunlit pools free of predators, and outbreaks typically follow several weeks later. This pattern was seen after the 2022 floods in Pakistan and after tropical cyclones in Mozambique and Malawi. Drought can have the opposite effect in forested regions, where shrinking rivers leave chains of still, sunlit pools that suit mosquito larvae.
• Year-to-year climate cycles. Epidemics in East and southern Africa, South Asia, and northern South America are linked to El Niño and the Indian Ocean Dipole. Because these develop over months, they give several months' warning, which is used in malaria early warning systems.

Deforestation, Irrigation, and Urban Vector Invasion

1. Deforestation. Clearing forest for farming, mining, or roads removes shade and exposes pools to the sun, raising water temperatures by several degrees and speeding larval development. This contributes to outbreaks on agricultural frontiers in the Amazon, Central Africa, and Southeast Asia. In Borneo, forest clearance also brings people into contact with the macaques that carry P. knowlesi.
2. Irrigation and dams. Reservoirs and irrigated rice fields provide permanent water in otherwise dry regions, turning seasonal transmission into year-round transmission.
3. Urban mosquitoes. African cities have historically had much less malaria than the surrounding countryside. The spread of An. stephensi since 2012, first in Djibouti and then across the Horn of Africa and into West Africa, threatens this advantage, because it breeds in domestic water containers, tolerates urban heat, and is resistant to several classes of insecticide.

Microscopy, HRP2/pLDH Rapid Tests, and Molecular Diagnostics

Confirming the diagnosis before treating is now standard practice:

• Microscopy remains the reference method. A thick blood film, in which the red cells are destroyed to concentrate the parasites, can detect as few as 10 to 50 parasites per microlitre in expert hands and allows the density to be measured. A thin film preserves the appearance of the red cells and allows the species to be identified from features such as Schüffner's dots in P. vivax and P. ovale, band-shaped parasites in P. malariae, and crescent-shaped gametocytes in P. falciparum.
• Rapid diagnostic tests detect parasite proteins on a dipstick.
• Tests for histidine-rich protein 2 are sensitive and specific to P. falciparum, but stay positive for weeks after cure. More seriously, parasites that have lost the genes for this protein and its relative have spread in South America and the Horn of Africa, giving false negative results, so affected countries are switching to tests detecting two proteins.
• Tests for parasite lactate dehydrogenase become negative soon after the parasite dies, which helps assess response to treatment. The protein cannot be dispensed with, since the parasite depends on it, although variants causing false negatives have been reported. These tests are less sensitive at low parasite densities.
• Tests for parasite aldolase detect all species with moderate sensitivity.
• DNA-based tests, including PCR and simpler methods suitable for field use, detect well under one parasite per microlitre. They are needed to find the large reservoir of symptom-free, low-density infections during elimination campaigns, and to distinguish P. knowlesi from P. malariae, which look identical under the microscope.

Artemisinin Combination Therapies (ACTs), Parenteral Artesunate, and Radical Cure

Treatment depends on the species, the severity of illness, and local drug resistance.

1. Uncomplicated P. falciparum malaria is treated with a three-day course of an artemisinin-based combination. Artemisinin derivatives kill parasites very rapidly but are cleared from the body within hours, so they are paired with a slowly eliminated partner drug that removes the remainder over the following days. Combinations in use include artemether–lumefantrine, artesunate–amodiaquine, dihydroartemisinin–piperaquine, artesunate–pyronaridine, and artesunate–mefloquine. In areas of low transmission, a single low dose of primaquine is added to prevent onward transmission by clearing mature gametocytes; this dose is considered safe without prior testing for G6PD deficiency. Partial resistance to artemisinin, caused by mutations in the pfkelch13 gene, emerged in Southeast Asia and has since arisen independently in East Africa. Responses include combinations containing two partner drugs and new compounds with different targets.
2. Severe malaria is a medical emergency, treated with artesunate given by injection, at any age and in any stage of pregnancy, followed by a full oral course once the patient can swallow. Two large trials, SEAQUAMAT in Asia and AQUAMAT in Africa, found that artesunate reduced deaths by about 35% and 22.5% respectively compared with quinine. Artesunate acts on young parasites still circulating in the blood, before they mature and adhere to vessel walls, whereas quinine acts only after this has happened, and it also causes dangerous falls in blood sugar.
3. Relapsing malaria caused by P. vivax and P. ovale requires two drugs: one to clear the parasites from the blood, usually chloroquine or, where chloroquine resistance is established, an artemisinin combination; and a second to destroy the dormant liver stages. The second is either primaquine given for one to two weeks or a single dose of tafenoquine. Both can cause severe destruction of red cells in people with G6PD deficiency, so testing beforehand is essential. Tafenoquine is not given to young children or in pregnancy.

Next-Generation Insecticide-Treated Nets and Chemoprevention

Between 2000 and 2023, expanded malaria control is estimated to have prevented more than two billion cases and about 12 million deaths. Forty-five countries and one territory have been certified by the WHO as having eliminated malaria, among them China and El Salvador in 2021, Azerbaijan and Tajikistan in 2023, and Cabo Verde and Egypt in 2024. Control rests on four approaches.

Widespread use of insecticide-treated nets and indoor residual spraying works by killing adult mosquitoes, the point at which transmission is most vulnerable. Resistance to pyrethroids is now widespread, so programmes have moved from pyrethroid-only nets to nets combining a pyrethroid with piperonyl butoxide, which blocks the enzymes that break down the insecticide, and to nets combining a pyrethroid with chlorfenapyr. Chlorfenapyr must be activated by the mosquito's own detoxifying enzymes, so resistant mosquitoes activate it more readily; in trials these nets reduced malaria in children by about 44% compared with standard nets. Other methods include treating larval habitats, sugar baits laced with insecticide, giving ivermectin to people or livestock so that mosquitoes feeding on them are killed, and experimental gene drives designed to suppress mosquito populations.

• In pregnancy. Monthly doses of sulfadoxine–pyrimethamine from the second trimester onward, given at antenatal visits, clear parasites from the placenta and reduce the number of babies born underweight.
• In infants and young children in areas of year-round transmission, preventive doses are given alongside routine childhood vaccinations.
• Seasonal chemoprevention. In the Sahel, where transmission is concentrated in a short rainy season, monthly treatment courses are given to young children throughout it. Tens of millions of children receive this each year, and it prevents around 75% of malaria episodes.

RTS,S/AS01 and R21/Matrix-M Pre-Erythrocytic Vaccines

Two vaccines against P. falciparum are recommended by the WHO: RTS,S/AS01 and R21/Matrix-M. Both target the circumsporozoite protein on the surface of the sporozoite, presented on particles that stimulate a strong antibody response. RTS,S prevents roughly half of clinical malaria episodes in the first year, with protection waning thereafter; R21 achieved about 75% efficacy over a year in seasonal settings. Giving a vaccine seasonally alongside seasonal chemoprevention has prevented a substantially greater proportion of cases, hospital admissions, and deaths than either approach alone. Long-acting antibodies given by injection, and vaccines aimed at the blood stages or at blocking transmission to mosquitoes, are in development.

Why does killing adult Anopheles mosquitoes reduce malaria transmission much more than killing larvae?

In the Ross-Macdonald model of vectorial capacity (V = ma²e^−μn / μ), larval control reduces mosquito density (*m*) only linearly, whereas adulticidal interventions (such as insecticide-treated nets and indoor residual spraying) increase the daily adult mosquito mortality rate (*μ*). Because a mosquito must survive the entire 10-to-14-day extrinsic incubation period (*n*) for sporozoites to reach its salivary glands, mortality enters the transmission equation exponentially (e^−μn), making adult survival the most sensitive lever in malaria control.

Why is intravenous artesunate superior to quinine for severe malaria?

Quinine acts only on mature trophozoite and schizont stages that have already sequestered inside deep organ capillaries, and it stimulates pancreatic β-cells to cause dangerous hyperinsulinemic hypoglycemia. Artesunate kills young circulating ring-stage parasites before they can express PfEMP1 and obstruct brain or placental microvessels, reducing severe malaria mortality by 22.5% to 35% compared with quinine in randomized clinical trials.

Why do rapid diagnostic tests (RDTs) sometimes give false-negative results in severe P. falciparum malaria?

Most *P. falciparum* rapid diagnostic tests detect histidine-rich protein 2 (PfHRP2) and cross-react with PfHRP3. Because neither gene is essential for blood-stage survival, *P. falciparum* strains carrying subtelomeric chromosomal deletions of both *pfhrp2* and *pfhrp3* have been positively selected by test-and-treat programs in South America and the Horn of Africa, rendering them invisible to HRP2-only dipsticks and requiring dual HRP2/pLDH tests.

• Plasmodium falciparum
• Anopheles
• Antimalarial medication
• Malaria vaccine
• Vector control