The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Malaria
Johanna P. Daily, M.D.,1,2 and Sunil Parikh, M.D.3,4​​

M
Author affiliations are listed at the end of alaria is a preventable mosquito-borne illness caused by
the article. Dr. Daily can be contacted at plasmodium parasites. An estimated 263 million cases of malaria and
­johanna​.­daily@​­einsteinmed​.­edu or at the
Division of Infectious Diseases, Depart- 597,000 deaths from malaria occurred worldwide in 2023.1 Nearly half
ment of Medicine, Albert Einstein Col- the global population lives in regions where malaria is endemic, and outbreaks of
lege of Medicine, 1301 Morris Park Ave., locally acquired infection can also occur in regions where malaria is not endemic,
Bronx, NY 10461.
such as the United States.2 Malaria therefore represents a major global public
This article was updated on April 3, 2025, health challenge. Recent progress in the fight against malaria includes the intro-
at NEJM.org.
duction of malaria vaccines to prevent infection in children residing in regions
N Engl J Med 2025;392:1320-33. where malaria is endemic. In addition, malaria-control efforts between 2000 and
DOI: 10.1056/NEJMra2405313
Copyright © 2025 Massachusetts Medical Society. 2024 have led the World Health Organization (WHO) to certify 18 additional coun-
tries as malaria-free.1 However, achievements in combating malaria have been tem-
CME pered by parasite and vector adaptations. The resulting challenges include a reduc-
tion in the reliability of rapid diagnostic tests and the emergence of partial resistance
to artemisinin in Plasmodium falciparum and insecticide resistance in the mosquito
vectors.3 We review the current epidemiologic trends of malaria and the best prac-
tices, recent progress, and challenges in the prevention, diagnosis, and treatment of
this deadly infection.

Epidemiol o gy
Malaria is a clinical illness that is inextricably linked to environmental conditions
and sociodemographic factors, such as poverty.3,4 Plasmodium species and their
vectors are widespread, and persons residing in or traveling to sub-Saharan Africa
and malaria-endemic regions in Southeast Asia, the Eastern Mediterranean and
Western Pacific regions, and the Americas are at risk for infection. Although six
plasmodium species cause malaria, P. falciparum accounted for approximately 97%
of malaria cases worldwide in 2023 and is highly endemic in sub-Saharan Africa
(Fig. 1A). The WHO African region continues to have the highest burden of ma-
laria, with an estimated 94% of the cases of malaria and 95% of the deaths from
malaria worldwide during 2023.1 In 2023, P. vivax accounted for approximately
3.5% of the cases of malaria worldwide and was prevalent in South America, South
and Southeast Asia, the Western Pacific, and Oceania (Fig. 1B).1 P. vivax is also pres-
ent in certain areas of Mexico and Central America and is increasingly reported in
several countries in sub-Saharan Africa. P. knowlesi is restricted to regions in South-
east Asia, particularly Indonesia and Malaysia.6 P. malariae and both P. ovale species
(P. ovale curtisi and P. ovale wallikeri) are less prevalent than the other plasmodium
species but are widely distributed.7,8
A mean of 2000 cases of primarily P. falciparum malaria occur annually among
travelers returning to the United States from regions where the disease is en-
demic.9 The majority of the cases are associated with a lack of antimalarial che-
moprophylaxis in persons who visited friends and relatives in Africa.9 One study
showed that the number of imported cases in three jurisdictions along the U.S.

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 Malaria

Key Points

Malaria
• Malaria remains a major threat to human health worldwide.
• Malaria necessitates a prompt laboratory-based diagnosis and expedited treatment.
• Microscopy and rapid diagnostic tests are the most widely used tools for the diagnosis of malaria. The
accuracy of rapid diagnostic tests has decreased because of mutations in the gene encoding the target
plasmodium protein.
• Vaccines to prevent malaria have been approved for use in children in regions of endemicity.
• Artemisinin-based combination therapy is the standard treatment for Plasmodium falciparum malaria.
However, partial resistance to artemisinin has emerged in Africa.
• Challenges to vector control include insecticide resistance, changes in feeding behavior, and
geographic expansion of vector species.

southern border increased from 28 cases in 2022 cause symptoms months to years after expo-
to 68 cases in 2023.10 In 2023, locally acquired sure.21 P. knowlesi is the primary agent of zoo-
mosquito-transmitted malaria occurred in four notic malaria in humans, and locally acquired
U.S. states in residents who had not traveled to infections are limited to areas where humans
regions where malaria is endemic.2,11 A rapid live near the reservoir host (e.g., long-tailed and
public health response that included active case pig-tailed macaques).22,23 Other zoonotic plasmo-
detection, enhanced targeted mosquito surveil- dium species with simian host reservoirs, such as
lance, and control measures limited ongoing P. brasilianum, P. simium, and P. cynomolgi, can oc-
transmission.12 casionally infect humans and cause malaria.24,25

Biol o gy of Pl a smodium Dise a se Ch a r ac ter is t ic s

During a bite by a plasmodium-infected anoph- Plasmodium infection can lead to asymptomatic
eles mosquito, invasive sporozoites, which have parasitemia or result in mild clinical symptoms
a tropism for the liver, are inoculated and infect (uncomplicated malaria) or severe disease. Pa-
hepatocytes (Fig. 2).13 During this clinically silent, tients with malaria typically present with chills
preerythrocytic liver stage, the parasite undergoes and fever, which may be accompanied by head-
massive replication to generate merozoites, which ache; altered mentation; abdominal pain, diarrhea,
enter the bloodstream and invade erythrocytes. or both; and other nonspecific symptoms. Abnor-
These intraerythrocytic asexual-stage parasites mal results of laboratory tests include leukocy-
can cause the classic clinical manifestations of tosis or leukopenia, elevated levels of aspartate
malaria. A small percentage of intraerythrocytic aminotransferase and alanine aminotransferase,
parasites become gametocytes, which do not and an elevated creatinine level; anemia and
cause symptoms. Gametocytes that are ingested thrombocytopenia are also common and help
by an anopheles mosquito during a blood meal differentiate malaria from other infectious dis-
develop into sporozoites, and transmission is eases.26 In high-transmission areas, repeated bouts
propagated by the mosquito during subsequent of malaria within months after treatment are
blood meals.14 Plasmodium parasites can also be common in children.27 Although clinical immu-
spread through blood donations, shared contami- nity increases with repeated exposure to plasmo-
nated needles and syringes, bone marrow and or- dium organisms, sterilizing immunity does not
gan transplantation, and in rare cases, congeni- occur.28
tally or during childbirth.15-18
P. vivax and P. ovale species have a prolonged Severe Malaria
dormant liver stage (the hypnozoite stage), and Severe P. falciparum malaria is defined by the
clinical symptoms may not occur until months presence of one or more of the clinical and labo-
or years after the initial infection.19,20 Despite the ratory features shown in Table 1; similar criteria
absence of a hypnozoite stage, P. malariae can are used to define severe malaria due to other

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 The n e w e ng l a n d j o u r na l of m e dic i n e

plasmodium parasites. Children and pregnant sitemia and sequester in the microvasculature,
women living in regions where malaria is en- resulting in impaired organ function and severe
demic and nonimmune travelers to such areas anemia. Acute kidney injury during severe ma-
are at greater risk for severe illness and death.1 laria is common, is associated with higher mor-
The clinical presentation of severe malaria dif- tality than severe cases without acute kidney
fers according to age, with pulmonary edema injury, and may be underrecognized in chil-
being more common among adults and seizures dren.31,33,34 P. knowlesi infection is also associated
and severe anemia being more common among with severe disease, with high parasitemia and
children.32 P. falciparum infection causes the ma- mortality.22,35,36 P. ovale species and P. malariae
jority of severe cases; the virulence of this para- rarely cause severe disease, whereas P. vivax may
site is due to its capacity to generate high para- occasionally be associated with severe disease

Prevalence of
Pf Malaria (%)
100
75
50
25
<0.1

Prevalence of
Pv Malaria (%)
>10
7.5
5.0
2.5
<0.1

Figure 1. Geographic Distribution of Malaria Cases in 2022.

Shown in Panel A is the predicted age-standardized prevalence of Plasmodium falciparum (Pf ) malaria per 5-km2 area (corresponding to
one pixel) during 2022 among children 2 to 10 years of age. Gray shading indicates areas in which P. falciparum has not been endemic
since at least 2000. Lighter gray shading indicates areas with a predicted prevalence of more than 0% and a population density of 5 people
or less per 5 km2; these areas are present only in South America. Unshaded areas are those in which there were no cases of P. falciparum
malaria during 2022 according to the model output or where P. falciparum has become nonendemic since 2000. Panel B shows the pre-
dicted prevalence of P. vivax (Pv) malaria per 5-km2 area (corresponding to one pixel) during 2022 among persons between 1 and 99
years of age. With the exception of several countries in East Africa, the burden of P. vivax malaria in Africa remains poorly measured. Areas
in Africa where P. vivax transmission may be possible but there was not sufficient information to generate a prediction are mapped as
having a very low prevalence. Gray shading indicates areas in which P. vivax has not been endemic since at least 2000. Darker gray shad-
ing indicates areas in which the predicted prevalence was very low. Unshaded areas are those in which there were no cases of P. vivax
malaria during 2022 according to the model output or where P. vivax has become nonendemic since 2000. Data were generated with
the use of methods and mapping outputs from the Malaria Atlas Project.5

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 Malaria

and has been found to accumulate in the bone outcomes.41 During pregnancy, the adherence of
marrow and spleen.37-40 P. falciparum parasites to placental chondroitin
sulfate A induces placental inflammation and
Pregnancy and Malaria dysregulated placental angiogenesis, which may
Women living in regions where malaria is en- result in placental insufficiency, preterm deliv-
demic are at risk for the infection during preg- ery, and low birth weight.42 The risk of placental
nancy. Malaria during pregnancy is associated malaria can be reduced with the use of chemo-
with a high risk of severe maternal disease, prophylaxis, which is a standard practice in some
maternal and fetal death, and poor pregnancy regions where malaria is endemic.29

Life Cycle of Plasmodium Interventions in Malaria-Endemic Regions

Residents Travelers

Bed nets, housing modifications, Bed nets, insecticide-impregnat-

Mosquitoes transmit sporozoites indoor residual spraying ed clothing, mosquito
to host during blood meal targeting anopheles vector repellents, screened windows

Sporozoites
Merozoites
Sporozoites travel
from bloodstream RTS,S/AS01 and R21/Matrix-M
Liver stage ranges from 5 to 14 days
to liver vaccines
Hepatocytes
SINUSOID

LIVER
Hypnozoites
Treatment with primaquine or Treatment with primaquine or
Prolonged dormant stage of tafenoquine results in tafenoquine results in
P. vivax and P. ovale species; elimination and prevents elimination and prevents
clinical symptoms can occur infection relapse infection relapse
mo to yr after initial infection

Treatment with ACT (first line) Treatment with ACT (preferred),

Asexual blood-stage parasites or chloroquine (in regions with atovaquone–proguanil, quinine,
Symptomatic stage; chloroquine-sensitive parasites) or mefloquine (least preferred)
late-stage P. falciparum for mild disease; treatment with for mild disease; treatment with
sequester in vasculature artesunate for severe disease artesunate for severe disease
and placenta
Chemoprophylaxis includes Chemoprophylaxis with
24 to 72 hr seasonal malaria chemopreven- atovaquone–proguanil,
tion, intermittent preventive doxycycline, mefloquine,
B LOOD
V ESSEL
treatment in pregnant women chloroquine, primaquine, or
and school-age children, tafenoquine as indicated
perennial malaria chemopreven-
tion, chemoprevention after
discharge, and mass drug
administration

Gametocytes
Addition of low-dose
BL OOD Gametocytes ingested by anopheles primaquine to ACT reduces
VE S S E L during blood meal develop into gametocytemia in malaria-
sporozoites; transmission is propagated endemic areas
during subsequent blood meals

Figure 2. Plasmodium Life Cycle and Interventions.

Shown are major stages of the Plasmodium life cycle and an overview of interventions at each stage for residents of and travelers to re-
gions where malaria is endemic. Housing modifications include putting screens on windows and doors and draining standing water.
Monoclonal antibodies that target sporozoites and prevent infection of liver cells are in development. Perennial malaria chemopreven-
tion was previously known as intermittent preventive treatment in infants. ACT denotes artemisinin-based combination therapy.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Criteria for the Diagnosis of Severe Plasmodium falciparum Malaria.*

Criterion Description
Signs and symptoms
Impaired consciousness A Glasgow coma score of <11 (range, 3 to 15; lower scores indicate lower levels
of consciousness) in adults or a Blantyre coma score of <3 (range, 0 to 5;
lower scores indicate lower levels of consciousness) in children
Multiple convulsions More than two seizures within a 24-hr period
Prostration Inability to sit, stand, or walk without assistance
Clinically significant bleeding Recurrent or prolonged bleeding from the nose, gums, or venipuncture sites;
hematemesis; or melena
Shock or circulatory collapse A systolic blood pressure of <80 mm Hg (<70 mm Hg in children), plus evi-
dence of impaired perfusion (cool extremities or prolonged capillary refill)
Laboratory and radiologic findings
Acidosis A base deficit of >8 meq/liter, a plasma bicarbonate level of <15 mmol/liter, or
a venous plasma lactate level of ≥5 mmol/liter
Anemia A hemoglobin level of <7 g/dl or a hematocrit of <20% (≤5 g/dl or ≤15%, re-
spectively, in children <12 yr of age) plus a parasite density of >10,000/μl
Hypoglycemia A plasma or serum glucose level of <40 mg/dl (<2.2 mmol/liter)
Parasitemia† >10% (≥5% in nonimmune travelers)
Jaundice A plasma or serum bilirubin level of >50 μmol/liter (3 mg/dl) plus a parasite
density of >100,000/μl
Renal impairment‡ A plasma or serum creatinine level of >3 mg/dl or a blood urea level of >20
mmol/liter
Pulmonary edema Confirmed edema on radiologic examination or an oxygen saturation of <92%
while breathing ambient air with a respiratory rate of >30 breaths/min

* A diagnosis of severe P. falciparum malaria is based on the presence of one or more of the indicated criteria.29 Severe
P. vivax malaria is defined according to the same criteria as for severe P. falciparum malaria but with no parasite density
thresholds. Severe P. knowlesi malaria is defined according to the same criteria as for severe P. falciparum malaria but
with a parasite density of more than 20,000 per microliter in patients with jaundice. Severe malaria due to P. ovale or
P. malariae is rare and is defined according to the same criteria as for severe P. falciparum malaria but with no parasite
density thresholds.
† Differences in parasitemia thresholds according to malaria immunity status have been suggested.29,30
‡ Acute kidney injury is underrecognized in children. Use of the Kidney Disease: Improving Global Outcomes criteria
should be considered to assess the level of renal impairment.31

Di agnosis of international travel history, particularly if the

person has been to areas with recent cases of
Patients with malaria often present with nonspe- locally acquired malaria.12
cific symptoms, which leads to a delay in diag-
nosis and treatment that is associated with un- Laboratory-Based Diagnostic Tests
toward consequences.43 Thus, a high suspicion If malaria is suspected, a laboratory-based as-
for malaria must be maintained in patients who sessment for the presence of plasmodium infec-
present with current or recent fever and a his- tion is needed without delay. Diagnostic tests are
tory of travel to a region in which malaria is used to identify the infecting species, assess
endemic. Malaria can also occur without expo- parasitemia as a marker of disease severity, and
sure to a region where the disease is endemic; monitor the response to antimalarial therapy.
for example, locally acquired cases have been Microscopy of Giemsa-stained thick and thin
reported in the United States. According to an peripheral-blood smears is the standard method
advisory issued by the Centers for Disease Con- of diagnosis and facilitates the identification of
trol and Prevention, a diagnosis of malaria in plasmodium species and quantification of para-
the United States should be considered in any sitemia. Counts of only asexual-stage parasites
person with fever of unknown origin, regardless that cause disease (i.e., not gametocytes) should

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 Malaria

be obtained as an indicator of the total parasit- T r e atmen t

emia. The accurate identification of plasmodium
species with the use of microscopy requires a Most approaches to the treatment of malaria
high level of training, and in some cases it is not include combination therapy because of the risk
possible to distinguish species on the basis of of drug resistance. Drug resistance should be
morphologic characteristics.44 suspected if there is a delay in parasite clearance
In contrast to microscopy, rapid diagnostic from the blood after the initiation of treatment.29
testing requires minimal training. Rapid diag-
nostic tests are used to assess blood samples for Mild Malaria
the presence of plasmodium proteins, most Most P. falciparum infections are resistant to chlo-
commonly P. falciparum–specific histidine-rich roquine and should be treated with artemisinin-
protein 2 (HRP2). Rapid diagnostic tests have a based combination therapies (ACTs). Artemisinin
sensitivity similar to that of microscopy for the derivatives (artesunate, artemether, and dihydro-
detection of P. falciparum but a lower sensitivity artemisinin) are highly potent and have very short
for the detection of other plasmodium species.45 half-lives. ACTs include one artemisinin derivative
After a malaria diagnosis has been made on plus a second, longer-acting antimalarial agent
the basis of microscopy or rapid diagnostic test- (such as lumefantrine, amodiaquine, piperaquine,
ing, parasite species can be confirmed by means mefloquine, or pyronaridine), often in coformula-
of polymerase-chain-reaction assay, which has tions.29 Artemether–lumefantrine is the most
limited availability in underresourced areas but widely used antimalarial combination therapy
is often available in highly resourced health care worldwide. Alternative therapies for chloroquine-
systems. Nucleic acid–based tests are not used in resistant plasmodium infection include other
the diagnosis of clinical disease. However, they ACTs, atovaquone–proguanil, quinine, and meflo-
are highly sensitive for the detection of parasites quine; mefloquine is used as a second-line therapy
in patients with low parasitemia, which can in- because of its associated gastrointestinal and
form malaria control and elimination programs.46 neuropsychiatric side effects (Table 2). The use of
Serologic tests for the detection of plasmodium chloroquine is restricted to only a few regions
antigens cannot be used to distinguish active in- where P. falciparum is still sensitive to chloroquine,
fection from past infection. Thus, serologic tests such as the Middle East and parts of Central
have no role in the diagnosis of acute infection, America and the Caribbean.
but they may play a role in epidemiologic studies. In contrast to P. falciparum, P. vivax is gener-
ally sensitive to chloroquine and can be treated
Challenge — Accuracy and Sensitivity of with chloroquine or ACT.29 Chloroquine-resistant
Rapid Diagnostic Tests P. vivax parasites are present in a few geographic
A reduction in the sensitivity of rapid diagnostic locations, such as Indonesia and Papua New
tests due to genetic deletions in P. falciparum has Guinea, and in rare cases have been reported in
emerged as a major concern, particularly in sub- other regions where ACT is now first-line thera-
Saharan Africa. Approximately 80% of the rapid py.51 P. ovale species, P. malariae, and P. knowlesi can
diagnostic tests used in Africa exclusively target be treated with ACT or chloroquine.29 In areas
the HRP2 antigen, yet P. falciparum parasites with where chloroquine resistance in any plasmodium
deletions in genes encoding HRP2 have emerged, species is present, ACT should be used if the
which can result in false negative tests.1,47,48 Other species cannot be determined with certainty.
limitations of rapid diagnostic tests include per-
sistent positivity after treatment, which precludes Severe Malaria
the use of this diagnostic tool in monitoring the Regardless of the infecting plasmodium species,
therapeutic response; inability to quantify the the administration of parenteral artesunate is ur-
parasite burden; challenges with the identifica- gently indicated for patients with severe malaria,
tion of species in infections due to plasmodium including those who are pregnant or lactating.29,52
parasites other than P. falciparum and those due At least three doses of intravenous artesunate are
to more than one plasmodium species; and low administered initially. When the asexual-stage
reliability for the detection of P. knowlesi infec- parasitemia is 1% or less and oral antimalarial
tion.49 treatment does not result in unacceptable side

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Malaria Treatment and Relapse Prevention.*

Indication and Drug Dose Frequency Adverse Reactions†

Treatment of mild malaria
Chloroquine resistance or
unknown resistance
Artemether–lumefantrine‡ Adults: four tablets (20 mg artem- Adults and children: One dose at Headache (56%)
ether and 120 mg lumefantrine baseline and 8 hr on day 1 and Anorexia (40%)
per tablet) one dose twice per day on days Dizziness (39%)
Children 5 to <15 kg: one tablet 2 and 3 Asthenia (38%)
Children 15 to <25 kg: two tablets
Children 25 to <35 kg: three tablets
Children ≥35 kg: four tablets
Atovaquone–proguanil§ Adults: four adult tablets (250 mg Adults and children: one dose per Abdominal pain (17%)
atovaquone and 100 mg proguanil day for 3 days Nausea or vomiting (12%)
per tablet) Headache (10%)
Children 5 to <8 kg: two pediatric
tablets (62.5 mg atovaquone and
25 mg proguanil per tablet)
Children 8 to <10 kg: three pediatric
tablets
Children 10 to <20 kg: one adult
tablet
Children 20 to <30 kg: two adult
tablets
Children 30 to <40 kg: three adults
tablets
Children ≥40 kg: four adult tablets
Quinine plus doxycy- Quinine: adults, 542 mg base (650 Quinine: adults and children, one Quinine: cinchonism (e.g.,
cline, tetracycline, or mg salt); children, 8.3 mg base/ dose orally three times per day headache, vision dis-
clindamycin¶ kg (10 mg salt/kg) for 3–7 days turbances, sweating)
Doxycycline: adults, 100 mg; children, Doxycycline: adults and children, Doxycycline: esophageal
2.2 mg/kg one dose orally twice per day ulcers (<1%), photo-
Tetracycline: adults, 250 mg; children, for 7 days sensitivity (>10%),
25 mg/kg/day Tetracycline: adults, one dose diarrhea (5%)
Clindamycin: adults and children, orally four times per day for Tetracycline: photosen-
20 mg/kg/day 7 days; children, one dose orally sitivity, abdominal
per day (divided into four equal discomfort, nausea,
doses) for 7 days vomiting
Clindamycin: adults and children, Clindamycin: diarrhea
one dose orally per day (divided
into three equal doses) for
7 days
Mefloquine‖ Adults: 684 mg base (750 mg salt) Adults: one dose of 684 mg base Vomiting (3%)
Children: 13.7 mg base/kg orally at baseline and one dose Neuropsychiatric effects
(15 mg salt/kg) of 456 mg base (500 mg salt) Dizziness
at 6–12 h
Children: one dose of 13.7 mg
base/kg orally at baseline and
one dose of 9.1 mg base/kg
(10 mg salt/kg) at 6–12 hr
Chloroquine sensitivity
Chloroquine Adults: 600 mg base (1000 mg salt) Adults: one dose of 600 mg base Vision disturbances
Children: 10 mg base/kg (16.7 mg orally at baseline and one dose Nausea or vomiting
salt/kg) of 300 mg base (500 mg salt) Pruritus
at 6, 24, and 48 hr
Children: one dose of 10 mg base/
kg orally at baseline and one
dose of 5 mg base/kg (8.3 mg
salt/kg) orally at 6, 24, and 48 hr

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 Malaria

Table 2. (Continued.)

Indication and Drug Dose Frequency Adverse Reactions†

Hydroxychloroquine Adults: 620 mg base (800 mg salt) Adults: one dose of 620 mg base QT prolongation
Children: 10 mg base/kg orally at baseline and one dose Neuropsychiatric effects
(12.9 mg salt/kg) of 310 mg base (400 mg salt) Abnormal results of liver-
at 6, 24, and 48 hr function tests
Children: one dose of 10 mg base/
kg orally at baseline and one
dose of 5 mg base/kg (6.5 mg
salt/kg) at 6, 24, and 48 hr
Prevention of relapse due to
P. vivax or P. ovale
species**
Primaquine†† Adults: 30 mg base Adults and children: one dose Hemolytic anemia in G6PD
Children: 0.5 mg base/kg orally once per day for 14 days deficiency
Nausea
Vomiting
Tafenoquine‡‡ Patients ≥16 yr of age: 300 mg Patients ≥16 yr of age: one dose Hemolytic anemia in G6PD
orally deficiency (<1%)
Diarrhea (18%)
Headache (15%)
Reversible vortex keratopathy
(21–93%)
Treatment of severe malaria
Artesunate§§ Patients <20 kg: 3 mg/kg All patients: one dose intravenously Acute renal failure (8.9%)
Patients ≥20 kg: 2.4 mg/kg at baseline and 12 and 24 hr Jaundice (2.3%)
(minimum of three doses)¶¶ Hemoglobinuria (6.7%)

* Information in the table is adapted from a report by the Centers for Disease Control and Prevention.50 G6PD denotes glucose-6-phosphate
dehydrogenase.
† Shown are adverse reactions included in the product label approved by the Food and Drug Administration (FDA). For select drugs, the
percentage of patients with adverse reactions has not been defined by the FDA.
‡ Artemether–lumefantrine should be administered with food in order to increase absorption and may be used during all trimesters of preg-
nancy. Other artemisinin-based combination therapies recommended by the World Health Organization include artesunate–amodiaquine,
artesunate–mefloquine, dihydroartemisinin–piperaquine, artesunate plus sulfadoxine–pyrimethamine, and artesunate–pyronaridine.
§ Atovaquone–proguanil therapy is contraindicated in pregnant women, infants weighing less than 5 kg, and women who are breast-feeding
infants weighing less than 5 kg unless no other treatment options are available.
¶ The use of doxycycline or tetracycline is preferred over clindamycin treatment because of greater efficacy. Treatment with clindamycin is
preferred for pregnant women and children younger than 8 years of age; treatment with doxycycline or tetracycline is not recommended in
these populations unless no other options exist and the benefits of treatment outweigh the risks.
‖ The use of mefloquine is not recommended if other options are available or in patients with a history of neuropsychiatric conditions.
Mefloquine treatment is not recommended for plasmodium infections acquired in Southeast Asia owing to drug resistance.
** Treatment with primaquine or tafenoquine is contraindicated during pregnancy; either drug can be given after delivery and during lacta-
tion if the mother and neonate have a normal G6PD level and no contraindications. To prevent relapse during pregnancy, chloroquine
should be administered at a dose of 300 mg base (500 mg salt) weekly until delivery.
†† The indicated doses and frequency of primaquine therapy are for patients with a normal G6PD level (≥70% G6PD activity). The World
Health Organization recommends a total dose of 7 mg per kilogram (given as 0.5 mg per kilogram per day for 14 days or 1 mg per ki-
logram per day for 7 days) for the prevention of relapse in patients with uncomplicated P. vivax or P. ovale malaria. For patients with an
intermediate G6PD level (30–70%), treatment at a dose of 45 mg base orally once weekly for 8 weeks may be considered with close moni-
toring for hemolysis; as an alternative, chloroquine chemoprophylaxis (at a dose of 300 mg base orally once weekly) can be administered
for 1 year after acute disease.
‡‡ Tafenoquine (brand name, Krintafel) can be used only in patients who received chloroquine for treatment during the acute phase of disease
and in patients who are at least 16 years of age. A normal result of a G6PD quantitative test is needed before the administration of treatment.
§§ A full oral antimalarial regimen should be completed after initial therapy. If intravenous artesunate is not readily available, oral or paren-
teral treatment should be administered until intravenous artesunate is available. Patients should be monitored for delayed hemolysis
for 4 weeks after the initiation of intravenous artesunate treatment.50
¶¶ Parasitemia should be assessed 4 hours after the third dose. If the patient is receiving oral therapy and parasitemia is ≤1%, a full course
of oral therapy should be completed. If the patient is unable to take oral medication or if parasitemia is >1%, intravenous artesunate
should be continued daily for up to 6 more days, followed by completion of a full course of oral therapy.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

effects, a full course of oral treatment is subse- Partial resistance to artemisinin in P. falciparum
quently administered, in accordance with guid- is associated principally with mutations in the
ance for the treatment of uncomplicated malaria.53 propeller domains of the parasite gene kelch13.66-68
If intravenous access is delayed, oral antimalar- Reduced susceptibility to partner drugs can also
ial agents should be administered during the decrease the efficacy of ACT against malaria
interim period. In regions where malaria is en- parasites.69,70
demic, patients can be treated with intramuscu- The WHO recommends the use of multiple
lar artesunate, rectal artesunate, intramuscular first-line therapies as part of the response to
artemether, or intramuscular quinine, with ex- drug resistance in sub-Saharan Africa.71 Other
pedited follow-up care at a referral center for the approaches include the use of triple ACTs (arte-
administration of intravenous artesunate. misinin plus two partner drugs), continued de-
Patients with severe malaria need intensive velopment of non–artemisinin-based combina-
care. Close evaluation of fluid status and the tion therapies, and improvement of current ACT
need for blood transfusions, empirical antibiotic regimens.72-74 If parasite clearance is delayed or
therapy, or both should be conducted.29,54-56 Un- there is concern about resistance to ACT because
conscious patients with malaria should undergo of recent travel to a malaria-endemic area where
a lumbar puncture to rule out meningitis; this plasmodium parasites with partial resistance to
procedure has been shown to be safe in patients artemisinin are present, the use of antimalarial
with cerebral malaria.57 Brain swelling associat- drugs other than ACT agents should be consid-
ed with cerebral malaria is linked with high ered if available. The WHO recommends the use
mortality; adjunctive therapy for this complica- of parenteral artesunate and parenteral quinine
tion is under investigation.58 The administration in patients with severe malaria in areas with
of acetaminophen as a renal protective agent is established artemisinin resistance.29
safe in patients with severe disease, and early
evidence suggests that acetaminophen may be Challenge — Prevention of Relapse
associated with improved renal function.59 Ad- Patients with malaria due to P. vivax or P. ovale
junctive therapies such as exchange transfusion species are at risk for relapse of infection be-
have not been shown to provide benefit to pa- cause hypnozoite-stage parasites are not killed by
tients with severe malaria.60 standard antimalarial agents. Treatment with an
Delayed hemolysis is an uncommon compli- 8-aminoquinoline (primaquine or tafenoquine) is
cation that can occur after the administration of needed to eliminate hypnozoites and prevent a
intravenous artesunate, particularly in patients relapse (Table 2). Among primaquine doses, a
with high parasitemia.61,62 Weekly laboratory mon- total dose of 7 mg per kilogram of body weight
itoring of hemoglobin and hemolytic markers for is associated with the highest efficacy in pre-
4 weeks after the administration of intravenous venting relapse.75 Primaquine is administered at
artesunate is recommended.53 In rare cases, de- a dose of 30 mg base per day for 14 days.30 Ac-
layed hemolysis has been associated with the use cording to the WHO, a 7-day course of prima-
of oral ACT.63 quine at a higher daily dose of 1.0 mg per kilo-
gram per day is efficacious and may improve
Challenge — Artemisinin Resistance adherence to treatment but should be given only
In addition to the long-standing presence of to patients with at least 70% glucose-6-phosphate
chloroquine resistance among malaria parasites, dehydrogenase (G6PD) activity. Higher total doses
artemisinin resistance has emerged as another of primaquine, whether given over 7 or 14 days,
threat to successful antimalarial treatment. Par- are more beneficial in areas with a high risk of
tial resistance to artemisinin manifests as a delay relapse.29 A single dose of tafenoquine prevents
in P. falciparum clearance from the blood after relapse after treatment of malaria with chloro-
treatment with a drug containing an artemisinin quine and is noninferior to primaquine.76,77 How-
derivative. This phenomenon was first observed ever, tafenoquine is less efficacious if ACT is
nearly 20 years ago in Southeast Asia and is now used initially to treat malaria; in this scenario,
present in multiple countries in East Africa, in- primaquine should be used to prevent relapse.78
cluding Uganda, Rwanda, Tanzania, Eritrea, Ethi- Both primaquine and tafenoquine can cause
opia, and the Democratic Republic of Congo.64,65 hemolysis in patients with G6PD deficiency, so

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 Malaria

a quantitative G6PD test must be performed (N,N-diethyl-3-methylbenzamide), picaridin, and

before either agent is administered. Tafenoquine IR3535 (ethyl butylacetylaminopropionate).
therapy is contraindicated in patients with mild- The selection of an antimalarial chemoprophy-
to-moderate G6PD deficiency; a lower dose of laxis regimen for persons traveling to regions
primaquine (0.75 mg per kilogram given once where malaria is endemic is based on the season-
weekly for 8 weeks) and close monitoring for ality and intensity of transmission, plasmodium
hemolysis is recommended in such patients.29 species, drug-sensitivity pattern, antimalarial side-
The administration of 8-aminoquinolines to pre- effect profile, and patient preference regarding
vent relapse is an underused approach in some the frequency of dosing. Each antimalarial chemo-
regions where malaria is endemic owing to the prophylaxis regimen has specific dosing sched-
lack of a widely available and reliable point-of- ules, contraindications, and adverse-event pro-
care G6PD test. files (Table 3). Chemoprophylaxis is initiated
before travel and continued for 1 to 4 weeks upon
return. Antimalarial agents for the prevention of
Pr e v en t ion a nd
Chemoproph yl a x is in Tr av eler s chloroquine-resistant P. falciparum infection in-
clude atovaquone–proguanil, doxycycline, and
Malaria is a common illness among interna- mefloquine. The 8-aminoquinolines primaquine
tional travelers who visit regions where the dis- and tafenoquine can be used for chemoprophy-
ease is endemic, with more than 30,000 cases laxis in patients with normal G6PD activity. These
worldwide reported annually to the GeoSentinel agents are also ideal for malaria prevention in re-
network.79 A detailed travel itinerary, current gions where P. vivax is endemic because they pre-
medications, pregnancy status, and allergy his- vent infection due to blood-stage parasites and kill
tory should be reviewed with travelers to regions hypnozoites. Chloroquine or hydroxychloroquine
in which malaria is endemic. Travelers should be can be used as chemoprophylaxis in regions
counseled to avoid mosquito bites through use with chloroquine-sensitive plasmodium parasites.
of bed nets, protective clothing, vector-control If the plasmodium antimalarial resistance pro-
devices, and mosquito repellents such as DEET file is uncertain, chemoprophylaxis that is indi-

Table 3. Chemoprophylaxis Regimens for Travelers to Malaria-Endemic Regions.*

Drug Dose Frequency of Administration Adverse Events

Before During After

Travel Travel Travel
Atovaquone–proguanil 250 mg atovaquone, Once daily for Once daily Once daily Nausea or vomiting (12%)
100 mg proguanil 1–2 days for 7 days
Doxycycline 100 mg Once daily for Once daily Once daily Esophageal ulcers (<1%),
1–2 days for 30 days photosensitivity (>10%)
Primaquine† 30 mg base Once daily for Once daily Once daily G6PD deficiency–associated
1–2 days for 7 days anemia
Chloroquine‡ 300 mg base Once weekly for Once weekly Once weekly Nausea or vomiting
1–2 wk for 4 wk
Mefloquineठ228 mg base Once weekly for Once weekly Once weekly Neuropsychiatric conditions
1–2 wk for 4 wk (14%)
Tafenoquine¶ 200 mg Once daily for Once weekly Once during wk G6PD deficiency–associated
3 days after return anemia

* Information in the table is adapted from the report by Chen et al.80

† Primaquine can be used for prevention in regions where more than 90% of malaria cases are attributable to P. vivax. Primaquine may
also be used as presumptive antirelapse therapy to clear hypnozoites in travelers returning from areas where P. vivax or P. ovale species
are endemic.
‡ Chloroquine and mefloquine may be used as chemoprophylaxis during all trimesters of pregnancy.
§ Patients who receive a prescription for mefloquine should be counseled to discontinue the drug and use an alternative medication if psychi-
atric or neurologic symptoms occur. An FDA black-box warning exists for mefloquine owing to rare reports of persistent dizziness after the
use of the drug.
¶ Tafenoquine (brand name, Arakoda) is approved by the FDA for use as malaria chemoprophylaxis. Once weekly administration should begin
7 days after the last loading dose.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

cated for chloroquine-resistant parasites should review suggests that 20% of the mosquito bites
be used. Drug costs and availability should be in Africa occur when persons are not lying in
addressed before departure to improve adher- bed.83 In addition, the geographic distribution
ence and lower the risk of imported malaria on of anopheles mosquitoes that are highly adept at
return.81 transmitting both P. falciparum and P. vivax (i.e.,
Anopheles stephensi) has increased.84-86
Pr e v en t i v e Me a sur e s in
M a l a r i a-Endemic R egions Challenge — Human and Zoonotic Reservoirs
One of the biggest challenges to malaria control
On the basis of recent trends, the 2030 targets and elimination programs is asymptomatic in-
of the WHO global technical strategy for reduc- fection, which represents the bulk of infections
ing global malaria mortality and morbidity will worldwide and serves as a major reservoir for
not be achieved.3 In response, new strategies that ongoing transmission.27,87,88 In special circum-
address the root causes of malaria, such as pov- stances, the use of mass drug administration to
erty, climate change, and drug and insecticide eliminate the reservoir of infection in humans
resistance, have been developed. The hope is can be considered in regions in which malaria is
that a broad-based platform supported by close endemic; however, the reduction in malaria trans-
working relationships with all interested stake- mission is often not sustained after mass drug
holders will facilitate the achievement of newly administration is discontinued.29,89 P. knowlesi has
established goals to reduce transmission and a simian reservoir, which presents unique chal-
disease.3 lenges that will require new control interven-
tions to achieve eradication.23
Vector Control
Insecticide-treated bed nets are used for the pre- Chemoprophylaxis
vention and control of malaria in children and Prevention of infection in vulnerable populations
adults living in areas with malaria transmission. such as pregnant women and children younger
Indoor residual spraying of WHO-prequalified than 5 years of age in areas where malaria is en-
insecticides can be an effective intervention when demic is a cornerstone of malaria-control pro-
the chemicals in the spray are tailored to local grams. School-age children have more recently
vector-susceptibility patterns and the use of spray- been identified as a vulnerable population and
ing is sustained. Additional investigational ap- may also benefit from chemoprophylaxis in cer-
proaches to vector control include the introduction tain settings.88,90 The administration of chemo-
of genetically modified mosquitoes and the use prophylaxis is dependent on local transmission
of endectocides and toxic-sugar baits that attract characteristics and national guidelines. Current
mosquitoes. programs recommended by the WHO include sea-
sonal malaria chemoprevention, perennial malaria
Challenge — Vector Adaptations to chemoprevention (previously known as intermit-
Insecticides tent preventive treatment in infants), intermittent
Resistance to insecticides, particularly pyrethroid- preventive treatment in pregnant women and
based agents in insecticide-treated bed nets, is school-age children, malaria chemoprevention af-
widespread in sub-Saharan Africa, with resis- ter discharge from the hospital, and mass drug
tance to pyrethroids, organochlorines, carbamates, administration strategies to reduce the burden of
and organophosphates present at multiple sites.1 disease, transmission, or both.29
The use of bed nets that are treated with multi- Strategies to interrupt transmission in low
ple chemical classes of insecticides is now rec- transmission settings include killing gameto-
ommended, and these bed nets are being deployed cytes with the administration of primaquine at a
in areas with known resistance to insecticides.29 single low dose (0.25 mg per kilogram) with an
Other challenges include a lack of effective out- ACT for nonpregnant adults and children who
door strategies to target biting mosquitoes and are 1 month of age or older with P. falciparum
problematic changes in mosquito behavior, which malaria.29,91 To decrease transmission, single-
include shifts in biting times that reduce the dose primaquine therapy is also recommended
efficacy of indoor residual spraying and insec- in areas with malaria parasites that have partial
ticide-treated bed nets.82 A recent systematic resistance to artemisinin.29

1330 n engl j med 392;13 nejm.org April 3, 2025

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 Malaria

Progress — Malaria Vaccines and parasites, and insecticide-resistance patterns in

Monoclonal Antibodies anopheles mosquitoes. These strategies must
In 2024, malaria vaccinations were introduced be driven by input from scientists in countries
into routine child immunization schedules in a where malaria is endemic and the populations at
handful of African countries.92 Malaria vaccines risk to ensure their feasibility, effectiveness, and
approved by the WHO for use in children resid- sustainability.
ing in regions with moderate-to-high transmis-
sion include RTS,S/AS01 and R21/Matrix-M. These C onclusions
recombinant circumsporozoite protein–based sub-
unit vaccines target preerythrocytic-stage para- Exciting progress has been made in the fight
sites (sporozoites) in order to prevent infection against malaria, with the development of vac-
with blood-stage parasites and provide partial cines and an increase in the number of countries
protection against severe disease.93,94 Vaccines that are now free of malaria. Yet malaria re-
targeting malaria parasites in other stages of the mains a formidable global health challenge.84
life cycle are under development. Continued investment in malaria-control pro-
Monoclonal antibodies that target the cir- grams, health care access, and research to dis-
cumsporozoite protein are being developed to cover new interventions may allow a future in
prevent P. falciparum malaria in regions where which malaria no longer poses a threat to hu-
infection due to this species is endemic.95 Mono- man health.
clonal antibodies can rapidly provide a reliable Disclosure forms provided by the authors are available with
level of protective antibodies, and subcutaneous the full text of this article at NEJM.org.
We thank Dr. Barbara H. McGovern for critical review of an
administration would facilitate broader use of earlier version of the manuscript and Jennifer Rozier (Malaria
this approach. Atlas Project) for assistance with an earlier version of Figure 1.
Combining preventive measures such as vac-
cination with seasonal chemoprevention has been Author Information
1
Division of Infectious Diseases, Department of Medicine, Al-
shown to increase protective efficacy.96 The best bert Einstein College of Medicine, New York; 2 Department of
strategies for reducing the transmission and bur- Microbiology and Immunology, Albert Einstein College of Med-
den of malaria in a given region are those that are icine, New York; 3 Department of Epidemiology of Microbial
Diseases, Yale School of Public Health, New Haven, CT; 4 Sec-
tailored to the local ecology and transmission dy- tion of Infectious Diseases, Department of Internal Medicine,
namics, drug-resistance profiles in plasmodium Yale School of Medicine, New Haven, CT.

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