Version July 2025
INTRODUCTION —
Malaria, a parasitic disease caused by Plasmodium species, is transmitted by anopheline mosquitoes throughout most of the tropics; malaria transmission occurs in 85 countries and territories [1].
The annual number of cases decreased steadily between 2000 and 2015, but subsequently cases have increased. In 2023, the World Health Organization (WHO) reported 263 million cases (an increase of 16 million compared with 2021) and 597,000 deaths (down from 619,000 in 2021) due to malaria [1].
Tools for malaria prevention include surveillance, vector control, chemoprevention, and vaccination; these are discussed here.
Other issues related to malaria are discussed separately:
●(See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)
●(See "Laboratory tools for diagnosis of malaria".)
●(See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)
●(See "Treatment of severe malaria".)
●(See "Malaria in pregnancy: Epidemiology, clinical manifestations, diagnosis, and outcome".)
●(See "Malaria in pregnancy: Prevention and treatment".)
●(See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)
●(See "Non-falciparum malaria: Plasmodium knowlesi".)
BIOLOGY
Malaria species — Malaria is caused by the single-celled parasite of the genus Plasmodium.
●Human species – Five species are transmitted between humans through the infected bite of an Anopheles spp mosquito: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale curtisi, P. ovale wallikeri, and Plasmodium malariae. P. falciparum and P. vivax pose the greatest threat to human health (figure 1A-C) [2]. P. falciparum is the deadliest species and the most prevalent on the African continent. P. vivax is the dominant species in most countries outside of sub-Saharan Africa (table 1) [3-5]. P. malariae is uncommon but is found in most malaria-affected areas, especially in sub-Saharan Africa. P. ovale, less common, is relatively unusual outside of Africa; it comprises <1 percent of isolates. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)
●Zoonotic species – Two zoonotic species of malaria occasionally cause disease in humans. P. knowlesi (similar morphologically to P. malariae) has been identified by molecular methods in patients in Malaysia, the Philippines, Thailand, and Myanmar [6]; P. knowlesi is a zoonotic infection and there is no evidence of sustained transmission of this species between humans; a monkey reservoir is required to infect mosquitoes [7]. P. simium is a malaria species resembling P. vivax that occurs in primates; in contrast to P. knowlesi, it has been shown to be occasionally transmitted between humans in Brazil [8]. (See "Non-falciparum malaria: Plasmodium knowlesi".)
●Malaria life cycle – The malaria parasite life cycle includes two stages (figure 2): a sexual reproductive stage inside the mosquito host, and an asexual reproduction stage in the human host. Within the human host, there are two cycles: one in red blood cells (the erythrocytic cycle), and another in the liver (the exo-erythrocytic cycle). (See "Pathogenesis of malaria", section on 'Life cycle'.)
Transmission — Malaria parasites are transmitted primarily via the bite of an infected female Anopheles mosquito. Other rare routes of transmission include congenitally acquired infection, blood transfusion, sharing of contaminated needles, and organ transplantation [9-11].
●Mosquito species – There are about 400 species of Anopheles mosquitoes worldwide. Approximately 60 to 70 species can transmit malaria; of these, about 40 are vectors of major importance (table 1) [12]. The most efficient vectors include the principal vectors in Africa, Anopheles gambiae and Anopheles funestus.
●Determinants of transmission – The principal determinants of malaria transmission are the density, longevity, breeding, and biting habits of the female anopheline mosquito vectors [13-15]. The most effective vectors are those that occur in high densities, are long-lived, breed readily, bite humans (in preference to other animals), and prefer to feed within dwellings.
Mosquito longevity is particularly important because the portion of the parasite life cycle that occurs within the mosquito (sporogony; from gametocyte ingestion to subsequent inoculation) lasts for 8 to 30 days (depending on the Plasmodium species and ambient temperature). Therefore, to transmit malaria, an Anopheles mosquito must survive for at least 10 days.
●Mosquito life cycle – Mosquitoes progress through four distinct life stages: egg, larva, pupa, and adult (figure 3) [16]. The full life cycle usually takes approximately 10 days and varies according to species, season, temperature, and available nutrition.
Live adult mosquitoes can be identified by genus by their stance at rest. Anopheline mosquitoes are oriented with head, thorax, and abdomen in a straight line at an acute angle to the surface, while culicine mosquitoes rest with the head and body angled and the abdomen directed back to the surface (figure 4). Mosquito head appendages consist of a proboscis, a pair of antennae, and a pair of maxillary palps (figure 5).
Only female mosquitoes bite humans or animals, to obtain protein needed for producing eggs; both males and females feed on flower nectar for food. After blood feeding, a female mosquito rests for a few days while the blood digests and the eggs develop. After the eggs develop, the female lays them in water bodies. The average lifespan of Anopheles mosquitoes is about two weeks, depending on climatic factors.
Anopheles mosquitoes generally do not fly more than 1.2 miles (2 km) from their larval habitats; exceptionally, mosquitoes can fly longer distances (2.4 miles, 4km) and can migrate for more than a hundred miles when aided by the wind [17].
EPIDEMIOLOGY —
Malaria disproportionately affects individuals in resource-limited settings. Within endemic areas, people with lower socioeconomic status are at highest risk of infection.
Geographic distribution
●Worldwide – Malaria is a major cause of morbidity and death in many countries. The World Health Organization (WHO) African Region accounts for about 94 percent of cases globally, followed by 2 percent each in the WHO Southeast Asian and Eastern Mediterranean regions; the WHO American and Western Pacific regions comprise the remainder. There are no countries in the European region with ongoing malaria transmission [18].
In 2022, 29 countries accounted for 95 percent of malaria cases reported globally. Four countries accounted for almost half of all malaria cases: Nigeria, the Democratic Republic of Congo, Uganda, and Mozambique (27, 12, 5, and 4 percent, respectively). Worldwide, 96 percent of malaria deaths occurred in 29 countries. Four countries accounted for over half of all malaria deaths: Nigeria, the Democratic Republic of Congo, Niger, and the United Republic of Tanzania (31, 12, 6, and 4 percent respectively). Deaths due to malaria continue to occur mainly among African children <5 years of age, who comprise 76 percent of malaria deaths globally [18].
Global maps developed using data from 2000 to 2022 demonstrated a plateau in malaria prevalence within sub-Saharan Africa, with no improvement since 2015 [19]. In 2022 there were an estimated 234.8 million (95% CI 179.2–299.0 million) cases of P. falciparum malaria, the most since 2004. The plateau occurred in more densely populated areas; sparser areas continued a trajectory of modest improvement. Outside Africa, an outbreak in Pakistan after flooding in 2022 contributed to a global total of 12.4 million (95% CI 10.7–14.8 million) cases of P. vivax malaria. The analysis was not able to evaluate the impact of new malaria vaccines implemented since 2022. The findings demonstrate the heterogeneity of malaria and highlight that control interventions need to be tailored to individual geographic locations.
●United States – Malaria transmission was eliminated in the United States in the mid-1950s. Malaria is acquired by travelers to endemic areas; approximately 2000 imported cases of malaria are reported in the United States each year. Most imported cases come from Africa (85 percent) with the majority from West Africa (70 percent).
In 2018, P. falciparum caused 70 percent of cases, followed by P. vivax (10 percent) and P. ovale (5 percent). Virtually all patients became ill within three months of returning to the United States. Of the 95 percent who did not take chemoprevention properly, 25 percent took none at all. Severe illness occurred in 14 percent of cases, and seven patients died [20].
In 2023, ten locally acquired (autochthonous) cases of P. vivax malaria were reported in Florida, Texas, and Arkansas [21,22]. A single case of locally acquired P. falciparum was identified in Maryland [23,24]. These were the first locally acquired cases of malaria since 2003.
Risk groups — More than half of the world's population is at risk of malaria. In areas with high levels of P. falciparum transmission (eg, certain regions of tropical Africa or coastal New Guinea, where there is intense transmission), individuals are infected repeatedly throughout their lives. In such settings with intense transmission, morbidity and mortality due to malaria during pregnancy and early childhood are considerable. By the time residents reach adulthood, most infections are asymptomatic due to host immunity gained from frequent exposure. In contrast, in areas where transmission is low to very low, full protective immunity is not acquired, and symptomatic disease occurs at all ages.
Infants and children <5 years of age, pregnant patients, and patients with HIV infection are at particular risk of developing severe malaria. Other at-risk groups include people entering areas with intense malaria transmission who have not acquired partial immunity from long exposure to the disease or who are not taking chemopreventive therapy (such as migrants, mobile populations, and travelers).
Transmission intensity definitions — The incidence of malaria varies considerably; globally, there are approximately 33 cases of malaria per 1000 population at risk each year [25]. In the past, some African regions had malaria prevalence rates in excess of 80 percent, with many children experiencing more than one infection per year [26,27]. The situation has improved considerably; in 2015, the population-weighted mean parasite prevalence among children age 2 to 10 years across Africa was 16 percent [28].
Previously, the intensity of malaria transmission was described as hyperendemic, mesoendemic, or hypoendemic based on rates of splenomegaly. The use of these terms has declined as measurement of incidence has become easier.
Many researchers now use the following categories to describe malaria transmission (based on the WHO Framework for malaria elimination) [29]:
●High transmission: Annual malaria incidence ≥450 cases per 1000 population, and a P. falciparum prevalence rate of >35 percent.
●Moderate transmission: Annual malaria incidence of 250 to 450 cases per 1000 population, and a prevalence of P. falciparum/P. vivax malaria of 10 to 35 percent.
●Low transmission: Annual malaria incidence of 100 to 250 cases per 1000 population, and a prevalence of P. falciparum/P. vivax of 1 to 10 percent.
●Very low transmission: Annual malaria incidence <100 cases per 1000 population, and a prevalence of P. falciparum/P. vivax malaria >0 but <1 percent.
Malaria transmission is highly heterogeneous; even within a district, there may be regions at different points along the transmission continuum.
Seasonal variability — Malaria is highly affected by weather and climate. While the relationships between temperature, rainfall, humidity, and malaria transmission are complex, there are some weather-related patterns that are fairly constant:
●In higher latitude areas with significant temperature changes over the course of a year (such as South Africa), malaria transmission peaks during warmer period and declines (or does not occur at all) during the colder period.
●In tropical areas with a single rainy season, malaria transmission peaks after the rains have started and declines to negligible levels during the dry season.
●In areas where rain occurs throughout the year, malaria may demonstrate one or two seasonal peaks associated with heavier rains, but is transmitted throughout the year and considered perennial.
●Settings with very low to low transmission are prone to epidemics when conditions become more favorable for transmission to occur. An epidemic can develop if there are changes in environmental, economic, or social conditions, such as heavy rains following drought, or migrations (of refugees or workers) from a non-endemic area. A breakdown in malaria control and prevention services can intensify epidemic conditions. Malaria epidemics usually result in considerable morbidity and mortality among all age groups [30].
SURVEILLANCE —
Surveillance provides information to facilitate decisions on when, where and for whom to implement preventive strategies.
Forms of malaria surveillance include:
●Disease surveillance – Disease surveillance tracks malaria burden and intensity, the populations at risk (and their geographic distribution), access to, use and equity of malaria prevention and treatment interventions, and the effectiveness of these interventions. Forms of surveillance include passive, active, case-based:
•Passive surveillance - Passive case detection at health facilities is the backbone of disease surveillance efforts. At high transmission levels, this approach may be the only form of surveillance required.
•Active surveillance - As transmission levels decline, active surveillance may also be needed [31]. Active surveillance, where cases are detected through outreach, may be needed in areas or populations at increased risk of infection that are under-served by the healthcare system.
•Case-based surveillance - At very low levels of malaria transmission, surveillance transitions from providing aggregated case counts to performing case-based surveillance (with investigation of individual case details to determine the likely location of infection).
In regions that are very close to elimination, reactive case detection focuses extra surveillance efforts in the areas where cases are more likely to be found, to improve the sensitivity of the surveillance system.
●Entomologic surveillance – Entomologic surveillance tracks malaria vectors, their density, geographic distribution and biting habits, and insecticide resistance levels.
●Molecular surveillance – Molecular surveillance provides data on the prevalence and distribution of markers of antimalarial resistance.
PREVENTION —
Tools for malaria prevention include vector control, chemoprevention, and vaccination; these may confer protection to an individual, household, and/or community. In addition, effective treatment of individual cases is important to reduce ongoing transmission [32].
Optimal malaria control requires several elements, as outlined in the World Health Organization (WHO) Global Technical Strategy for Malaria (2016 to 2030) [33,34]:
●Ensuring early access to diagnostic tools (including at the community level) and effective treatment of all confirmed cases. (See "Laboratory tools for diagnosis of malaria" and "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)
●Strengthening malaria surveillance, to facilitate decisions on when and where to implement preventive strategies. (See 'Surveillance' above.)
●Ensuring access to chemoprevention for vulnerable groups, particularly pregnant women. (See 'Chemoprevention' below.)
●Maximizing the effectiveness of vector control; this includes quality distribution programs, entomological surveillance, and management of insecticide resistance. (See 'Vector control' below.)
●Vaccines are expected to be an important addition to preventive efforts, with further study. (See 'Vaccination' below.)
The approach to tailoring prevention activities to a particular region depends on the local characteristics of malaria transmission (include the incidence and age-distribution of infection, the mortality rate, the parasite species present, the types of malaria vectors, and the seasonality of transmission), as well as available resources (such as diagnostic tools and antimalarial drugs).
Vector control — Properties of mosquito vectors that are important for malaria transmission are described above. (See 'Transmission' above.)
●Vector control tools – Vector control tools reduce contact between humans and the mosquitoes that carry malaria. The mechanisms by which vector control tools impede mosquitoes from transmitting malaria include:
•Physical prevention of bites, through use of nets, screens, curtains, and housing modifications
•Repelling mosquitoes through chemical repellents, used topically or spatially
•Killing or disabling adult mosquitoes with insecticide sprayed into surfaces
•Reducing the reproductive capacity or sterilizing mosquitoes through chemicals or genetic modifications
•Managing potential larval habitats to prevent development of mosquitoes, including killing larvae using insecticides
A particular intervention may reduce mosquito bites through one or more of these mechanisms.
●Implementation of vector control tools for mosquito prevention – The most important vector controls are insecticide-treated nets (ITNs) and indoor residual spraying (IRS). The WHO recommends either ITNs or IRS (but not both) for populations at risk of malaria; priority should be given to optimizing coverage of one or the other [35]. Larval source management (LSM) is recommended by WHO as a supplementary strategy once ITNs or IRS have been deployed, for specific settings where mosquito aquatic habitats are few, fixed and findable.
Insecticides
Insecticide-treated nets (ITNs) — ITNs provide a physical barrier for preventing mosquito bites; in addition, insecticides on the netting material may kill, repel, disable, or reduce the viability of adult mosquitoes [32]. ITNs are a foundation of malaria prevention in most endemic areas. They are recommended by WHO for large-scale deployment, given their proven protective efficacy; they are broadly applicable for most populations at risk of malaria [18]. To maximize benefit of ITNs, ideally users should retire to ITNs early in the night, and stay until after dawn (when mosquito biting rates decrease).
●Definitions – In the mid-1990s, when bed nets were first treated with pyrethroids on a wide scale, nets had to be re-impregnated every six months by dipping them in a solution containing the insecticide. In the early 2000s, manufacturers found ways to incorporate insecticide into or around the fibers of the nets, such that retreatment was not needed. For some time, these were referred to as long-lasting ITNs or LLINs; since most nets are now long-lasting, they are simply referred to as ITNs.
●Benefits – ITNs prevent mosquito bites and may reduce the size of the mosquito population, thereby decreasing transmission overall. In a 2018 systematic review including 23 trials and more than 275,000 adults and children, ITN use was associated with a reduction in all-cause child mortality by 17 percent (rate ratio 0.83, 95% CI 0.77 to 0.89) [36]. In addition, a 44 percent reduction in the incidence of severe malaria episodes was observed among those who used ITNs (rate ratio 0.56, 95% CI 0.38 to 0.82).
A 2015 modelling analysis suggested that 68 percent of the decline in malaria between 2005 and 2015 may have been attributable to ITNs [28].
●Insecticide resistance – Insecticide resistance is a significant threat to malaria control. Over-dependence on a single class of insecticides (ie, pyrethroids) for malaria control has accelerated the development of insecticide resistance among mosquitoes.
Insecticide resistance is measured during entomological surveillance by exposing unfed mosquitoes to a known concentration of the insecticide and measuring their mortality at 24 hours.
●Insecticide formulations – The pyrethroid class of insecticides used to be the only insecticide used on ITNs due to its low toxicity. Subsequently, additional active ingredients (including synergists, insect growth regulators, and other insecticide classes) have been added to ITNs to mitigate pyrethroid resistance.
•Pyrethroids − Pyrethroids have been the principal insecticide class for ITNs since the late 1990s and include alpha-cypermethrin, deltamethrin, and permethrin. However, pyrethroid resistance among mosquitoes has become widespread; reduced effectiveness of pyrethroid-only ITNs has been reported in West Africa and elsewhere [37-40].
•Piperonyl butoxide (PBO) – To counter rising pyrethroid resistance, the chemical synergist piperonyl butoxide (PBO) may be used in conjunction with pyrethroids, to render resistant mosquitoes susceptible to pyrethroids [41,42]. PBO inhibits the metabolic enzymes that detoxify insecticides before they reach their target within the mosquito.
In areas where the malaria vectors remain susceptible to pyrethroids, PBO-pyrethroid ITNs are not expected to confer any additional benefit over pyrethroid-only ITNs.
In a 2020 cluster-randomized including more than 100 subdistricts in Uganda with high pyrethroid resistance, use of PBO-pyrethroid ITNs was associated with reduced parasite prevalence compared with pyrethroid-only ITNs at 18 months (12 versus 14 percent; prevalence ratio 0.84, 95% CI 0.72-0.98) [43].
Similarly, in a 2018 cluster-randomized trial among more than 3600 children in Tanzania, malaria prevalence was lower among those who used pyrethroid-PBO ITNs than among those who used pyrethroid-only ITNs (follow-up 9 months; 29 versus 42 percent; odds ratio 0.37, 95% CI 0.21-0.65); use of indoor residual spraying was not associated with additional benefit [44].
However, in a 2022 cluster-randomized study including more than 39,000 households in a region of Tanzania with high prevalence of pyrethroid resistance, there was no difference in malaria prevalence among children who used pyrethroid-PBO ITNs and children who used pyrethroid-only ITNs (adjusted odds ratio 0.99, 95% CI 0.67-1.45) [45].
•Pyrroles – Insecticides in this class disrupt energy production in the mosquito, leading to death. Chlorfenapyr is a pyrrole that is now used in combination with pyrethroids on ITNs to mitigate pyrethroid resistance. Pyrethroid-chlorfenapyr ITNs have been evaluated in two large trials:
-In a 2023 cluster-randomized study including more than 53,000 households in Benin, clusters were randomly assigned to receive ITNs containing either pyrethroid-chlorfenapyr, pyrethroid-pyriproxyfen, or pyrethroid only [46]. More than two years after ITN distribution, lower malaria incidence was observed in clusters where ITNs treated with pyrethroid-chlorfenapyr were used (rather than ITNs treated with pyrethroid only; incidence 0.56 versus 1.03 cases per child-year; hazard ratio 0.54, 95% CI 0.42-0.70). Pyrethroid-pyriproxyfen ITNs conferred protection similar to pyrethroid-only ITNs (incidence 0.84 cases per child-year; hazard ratio 0.86, 95% CI 0.65-1.14).
-In a 2022 cluster-randomized study including more than 39,000 households in a Tanzania region with high prevalence of pyrethroid resistance, lower malaria incidence among children age 6 months to 10 years was observed in clusters where nets treated with pyrethroid-chlorfenapyr were used (rather than nets treated with pyrethroid only; incidence rate ratio 0.56, 95% CI 0.37-0.86) [45]. Similarly, at two-year follow-up, malaria prevalence was lower among children who used pyrethroid-chlorfenapyr ITNs (25.6 versus 45.8 percent; odds ratio 0.45, 95% CI 0.30-0.67). The cost per disability-adjusted life-year averted with pyrethroid-chlorfenapyr ITNs was below plausible cost-effectiveness thresholds.
•Insect growth regulators − Insect growth regulators (IGRs) sterilize female mosquitoes. Pyriproxyfen is an IGR that has been added to pyrethroids on ITNs to combat pyrethroid resistance. In the 2022 and 2023 trials of pyrethroid-chlorfenapyr ITNs described above, there was no difference in malaria prevalence among children who used pyriproxyfen-treated nets and those who used pyrethroid-only nets [45,46].
These findings differ from those of an earlier randomized trial in 2018 in Burkina Faso (an area of intense malaria transmission and high pyrethroid resistance) including more than 4000 children <5 years of age; the likelihood of malaria among children using ITNs treated with pyriproxyfen-pyrethroid was lower than among children using ITNs treated with permethrin only (1.5 versus 2.0 episodes per child-year; incidence rate ratio 0.88, 95% CI 0.77-0.99) [47].
●Approach to insecticide selection − In areas with pyrethroid resistance, dual active-ingredient (AI) ITNs containing pyrethroids as well as an additional AI (either an insecticide, synergist or an IGR) are recommended by the WHO. The WHO maintains a list of prequalified ITNs [48]. While pyrethroid resistance is expanding, WHO has not yet called for use of dual AI nets everywhere as they are more costly.
●Durability and distribution – ITNs must demonstrate efficacy after 20 washes. Manufacturer claims may suggest ITNs remain effective for three years or longer; however, field studies have demonstrated that fewer than half of ITNs remain functional three years after distribution [49]. Concern over the durability of ITNs has increased, with studies showing median lifespans for ITNS of less than three years in many countries [50].
Rather than moving to shorter intervals between mass campaigns, modeling efforts suggest that ITN coverage is better maintained by scaling up distribution at other encounters with the healthcare system (such as visits for antenatal care and immunizations) [51]. Countries have also experimented with school-based distribution to reduce the gap in ITN use in school-age children.
●ITN use does not appear to delay acquisition of natural immunity against malaria − It was once postulated that ITN use might delay acquisition of natural immunity against malaria, with increased risk for infection at older ages; however, this does not appear to be the case.
In a long-term cohort study of ITN use including more than 6700 individuals during early childhood in rural Tanzania between 1998 and 2003, follow-up on vital status in 2019 was obtained for 89 percent of participants [52]. Reported ITN use at more than half of the early-life study visits was associated with a reduced risk of death from early childhood to adulthood (hazard ratio 0.57, 95% CI 0.45-0.72). Most deaths occurred prior to 5 years of age; however, that level of ITN use was still associated with a trend toward lower mortality between 5 years of age and adulthood (hazard ratio 0.93, 95% CI 0.58-1.49).
●No role for use of ITNs in conjunction with indoor residual spraying (IRS) − The WHO recommends against co-deployment of ITNs and IRS; priority should be given to optimizing coverage of one or the other, rather than trying to implement both [35]. In settings where ITNs remain effective and optimal ITN coverage has been achieved, implementing IRS may have limited utility [53].
In a systematic review of studies evaluating the addition of IRS to areas where ITNs were already deployed, IRS with pyrethroid insecticides conferred no additional benefit [54]. IRS with non-pyrethroid insecticides was found to reduce malaria prevalence but had no effect on malaria incidence.
Indoor residual spraying (IRS) — IRS involves spraying insecticide on indoor residential walls and ceilings. IRS campaigns must be undertaken at least once a year, are logistically challenging to manage and are very costly.
IRS was the primary vector control tool during the Global Malaria Eradication Programme, but fell out of favor after resistance to dichloro-diphenyl-trichloroethane (DDT) developed. IRS experienced a resurgence in the late 2000's with the United States President's Malaria Initiative (US PMI), but insecticide and delivery costs have resulted in withdrawal of IRS from many countries.
In very low transmission areas prone to malaria outbreaks, or in areas close to elimination, IRS may be more rapidly deployed than other vector control measures, if the capacity for IRS has already been developed by the public health team. In elimination settings, the WHO recommends reactive IRS in the houses around confirmed malaria cases to reduce onward transmission [32].
●Approach – IRS is performed with hand-operated compression sprayers containing an aqueous suspension of insecticide. Teams must be trained and supervised closely in applying the correct dose to walls and ceilings and protecting themselves from toxicity [55]. Community health education is essential; IRS may require furniture rearrangements, the walls may become streaked with chemical treatments, and there may be a residual odor. The frequency of IRS application ranges from once or twice yearly for organochlorine compounds (eg, DDT) to three or more times for organophosphates (eg, malathion) [56].
Mosquito contact with insecticide-treated surfaces is usually lethal; sublethal exposure drives mosquitoes outside the house. Ideally, the mosquito is killed or repelled before feeding on humans within the dwelling [57]. Widespread community IRS reduces the proportion of mosquitoes surviving long enough to transmit malaria [15,56,58].
●Benefits – In a study among more than 300 children between 6 months and 10 years of age in Uganda, application of multiple rounds of IRS (three rounds of carbamate bendiocarb followed by one round of an organophosphate) was associated with decreased incidence of clinical malaria (by 83 percent) and increased hemoglobin level (by 10 percent) [59].
In areas with very low transmission and a strong surveillance program, reactive IRS (use of IRS only at the houses of individuals with malaria and their neighbors) may be more cost-effective than large-scale IRS deployment. In a cluster-randomized study in South Africa, the incidence of malaria among clusters managed with mass IRS was similar to the incidence among clusters managed with reactive IRS (0.95 cases versus 1.05 cases per 1000 person-years) [60]. At this disease incidence level, use of reactive IRS would have a 94 to 98 percent probability of being cost-effective, up to an incidence of 2.0 to 2.7 cases per 1000 person-years. As reactive IRS requires case-based surveillance that is not feasible at high levels of transmission, reactive IRS is likely to be effective only in areas of very low transmission.
●Insecticide resistance – The benefit of IRS is threatened by development of insecticide resistance. Pyrethroids have been the most common insecticide class used in IRS, but increasing resistance has prompted rotation of pyrethroids with other insecticide classes to mitigate development of resistance. Pyrethroid resistance confirmed in 55 of the 64 countries where it was monitored between 2018 and 2023. Resistance to neonicotinoids has also been reported in 5 of the 16 countries where it was monitored [1].
●Insecticide formulations – Insecticide classes used in IRS include organochlorines, organophosphates, carbamates, and neonicotinoids [61]. Insecticides should be selected based on local malaria vector susceptibility.
•Organochlorines – DDT was once a widely used IRS insecticide based on its efficacy, low cost, low toxicity, and length of effect. DDT was used for IRS programs that achieved malaria elimination in many areas in the 1940s and 1950s (including the southern United States, most Caribbean islands, southern Europe, most of the former USSR, and Taiwan). It has also been used successfully for reducing malaria prevalence in south Asia, southern Africa, South America, and Zanzibar [5,62,63].
Given the environmental concerns and the lack of a WHO prequalified DDT product, DDT is now rarely used in IRS programs.
•Pyrethroids – Many regions switched from DDT to pyrethroids for IRS in the mid-1990s. The main compounds used include alphacypermethrin, deltamethrin, and lambda cyhalothrin. Pyrethroids were relatively inexpensive and IRS expanded in sub-Saharan Africa with support from the US PMI. Increasing pyrethroid resistance has required use of other, more expensive compounds, contributing to reduced deployment of IRS.
•Organophosphates – Pirimiphos-methyl is the only organophosphate that is prequalified by WHO. It has a residual effect of up to 12 months on sprayed wall surfaces and was one of the first insecticides used for IRS in areas of pyrethroid resistance. Resistance to pirimiphos-methyl has been found in West Africa.
•Carbamates – Bendiocarb may be used for IRS but has a shorter duration than most insecticide classes. Resistance to bendiocarb is more widespread than for pirimiphos-methyl.
•Neonicotinoids – Neonicotinoids are the newest insecticide class to receive WHO prequalification; compounds include broflanilide and clothianidin. These are slow-acting insecticides that cause mosquito mortality at 72 hours (rather than 24 hours observed for other insecticide classes).
•Pyrroles – There are no pyrrole insecticides approved for IRS use by WHO. Chlorfenapyr is used in ITNs and is being evaluated for use in IRS. Pyrroles disrupt mitochondrial ATP production, leading to insect killing.
Dual IRS products are available that mix insecticide classes, such as pyrethroids and neonicotinoids.
Other vector control tools — Other tools for vector control include insect repellants, housing modifications, larval source management, endectocides, and genetic control.
●Insect repellents
•Topical repellents – Insect repellents applied to exposed skin may be used to protect against mosquito bites. Topical repellents are not recommended to control malaria at the community level, although they may provide protection for travelers and high-risk individuals who may have more limited access to other vector control interventions. Issues related to the selection and use of mosquito repellents are discussed further separately. (See "Prevention of arthropod bites: Repellents and other measures".)
•Spatial repellents – Spatial insect repellent products are designed to release active ingredients into the air to disrupt human-vector contact and reduce human exposure to mosquito-borne pathogens.
A cluster-randomized trial in Kenya evaluated the efficacy of a transfluthrin-based spatial repellent against human malaria infection among 58 clusters (3072 children age 6 months to <10 years) following mass distribution of ITNs; at 24-month follow-up, spatial repellents reduced the hazard of first-time malaria infections by 32.7 percent (95% CI 12.6–48.2) and reduced the hazard of overall new infections by 29.5 percent (95% CI 12.0–43.5) [64]. The efficacy of spatial repellents in the absence of ITN use remains uncertain.
In an earlier systematic review including two randomized trials in China and Indonesia, spatial repellents had no impact for prevention of malaria (risk ratio: 0.24; 95% CI 0.03-1.72) [65].
●Housing modifications – Housing modifications include:
•Screening for windows and doors – The WHO recommends house screening [53], although there are no good data evaluating the effectiveness of this intervention.
•Lethal house lure – One approach to lethal house lure consists of window screening in combination with installation of ventilation tubes in house eaves; the tubes funnel heat and odor cues (which attract mosquitoes) and contain powdered insecticide. In a cluster-randomized trial in Côte d’Ivoire including more than 8000 houses and 2000 children, a lower incidence of malaria was observed among the intervention group (use of a lethal house lure in addition to ITNs) than the control group (use of ITNs alone; 1.43 versus 2.29 per child-year; hazard ratio 0.62, 95% CI 0.51-0.76) [66]. No serious adverse events associated with the intervention were reported during follow-up. Further study is needed for additional optimization.
●Larval source management (LSM) – LSM includes habitat manipulation as well as use of larvicides to kill immature mosquitoes, preventing development into adults.
•Use – LSM consists of tools to reduce mosquito density; these include removal or modification of mosquito larval sites, use of chemical or biologic larvicides, and/or manipulation of aquatic habitats (such as deployment of larvivorous fish) (figure 3).
Larviciding is not a substitute for use of ITNs or IRS; these interventions reduce mosquito longevity and provide protection from biting mosquitoes. For regions with ongoing malaria transmission, WHO recommends that LSM may be used as a supplementary intervention for malaria control in settings where aquatic habitats are few, fixed, and findable [53]; as an example, it has recommended use of LSM to contain the spread of An. stephensi in urban and peri-urban areas [67,68].
Historically, prior to availability of insecticides with activity against adult mosquitoes, efforts were directed toward making potential breeding sites unsuitable for Anopheles larvae. Examples include draining of the Pontine Marshes near Rome and fluctuation of water levels in the reservoirs of the Tennessee Valley Authority [69].
•Limitations – LSM approaches are difficult to implement on a broad scale. All potential breeding sites within mosquito flight range of human communities must be identified and addressed. To prevent increases in anopheline mosquito populations, drainage of water collection sites and careful management of large engineering projects (such as dam and building construction) are needed.
•Larvicides – A number of insecticide classes and products have been prequalified by WHO for use in larviciding. Some include:
-Insect growth regulators (IGR) – IGRs such as pyriproxyfen (in a sand granule formulation) may be used in water-filled pits to prevent metamorphosis from larva to pupa to adult. This technique has been was used in Sri Lanka, where malaria eradication was nearly achieved in the 1960s; however, malaria persisted in areas where pits were dug in search of gems (the pits filled with rainwater which became mosquito breeding sites) [70]. Treatment of all the pits in four villages achieved reduction in incidence of malaria cases (compared with untreated villages). Retreatment two to three times a year was sufficient.
-Microbial agents – The bacterial toxin Bacillus thuringiensis serotype israelensis (Bti) is highly specific for mosquito larvae and targets very few other species. A reduction in the density of adult An. gambiae was achieved in a Kenyan village by use of the bacterial toxin Bacillus thuringiensis serotype israelensis (Bti) [71]. Bti has a short half-life; over 400 potential breeding sites were checked weekly and retreated if necessary. An. funestus may be a more feasible target for antilarval control measures in Africa since its breeding sites are larger and more permanent.
-Organophosphates – Temephos is an organophosphate formulated both as granules and emulsifiable concentrate, and is often used in water storage containers for larval control as it is considered safe for potable water at appropriate concentrations. However, temephos is toxic to non-target organisms.
•Larvivorous fish – Larvivorous fish species (eg, Gambusia and Poecilia) are avid feeders on mosquito larvae and may be used to stock village wells and ponds (the breeding places of local mosquito vectors) [72]. This strategy was implemented in a series of villages in south India; between 1998 and 2003, no malaria cases were detected in the villages [69,73]. However, in some projects, imported fish species have not adapted to local conditions or have been consumed by the human populations they were intended to protect.
●Endectocides – Mass administration of systemic insecticides to humans (also known as endectocides) for reduction of malaria transmission is an area of growing interest.
Ivermectin is capable of killing anopheline mosquitoes when they blood feed on ivermectin-treated individuals [74]. In a cluster-randomized trial including more than 2700 children in Burkina Faso (median age 15 years, including 590 children ≤5 years) treated with single oral doses of ivermectin (150 to 200 mcg/kg) and albendazole (400 mg), those in the intervention group received five additional doses of ivermectin at three-week intervals over the 18-week treatment phase [75]. The cumulative malaria incidence was lower in the intervention group than the control group (2.0 versus 2.49 episodes per child; risk difference -0.49, 95% CI -0.79 to -0.21); there was no difference in adverse events between the groups.
Further study is needed to use ivermectin in other areas, establish the optimal dose or formulation, and evaluate the effects of repeated ivermectin treatment.
●Genetic control – Genetic strategies for malaria control consist of using male mosquitoes to introduce genetic factors that prevent eggs from hatching, prevent larvae from surviving, or produce adult insects incapable of transmitting human disease. Genetic control remains a promising area of research.
To prevent eggs from hatching or larvae from surviving, males carrying sterilizing factors (dominant lethal mutations introduced by irradiation of the adult male) compete for mates in a target population of females who have not already mated with fertile males [76]. This is known as the sterile insect technique (SIT). Experience with SIT for Anopheles mosquitoes is limited, although the technique has been successful for eradication of other pests [77].
To produce adult insects incapable of transmitting disease, a transgenic system has been developed that greatly reduces susceptibility of An. stephensi to infection with rodent malaria [78]. It is hoped that similar approaches will produce strains completely non-susceptible to P. falciparum [78,79]. However, the optimal approach for creating genetic factors that selectively incorporate themselves into later generations within a wild population remains uncertain [80-82].
Chemoprevention — Chemoprevention refers to intermittent administration of a curative dose of antimalarial medicine during the malaria season, regardless of whether the individual is infected with malaria, with the goal of establishing antimalarial drug concentrations that will clear existing malaria infection and prevent new infection during the period of greatest malaria risk.
Different preventive strategies are possible based on the target population, the malaria transmission intensity, the drug used, and the timing of administration. The WHO provides guidance for malaria chemoprevention [32].
Issues related to chemoprevention in endemic areas are discussed here; issues related to chemoprevention in travelers are discussed separately. (See "Prevention of malaria infection in travelers".)
Mass drug administration (MDA) — MDA refers to administration of a full therapeutic course of an antimalarial medication across a population in a defined geographical area (at approximately the same time, and often at repeated intervals) [83]. Examples include perennial malarial chemoprevention (PMC), seasonal malaria chemoprevention (SMC), post-discharge malaria chemoprevention (PDMC), and intermittent preventive treatment of school-age children (IPTsc); these are discussed further below.
The WHO recommends the use of a combination medicine for MDA that is different from that used as first-line malaria treatment. A drug regimen that can be administered as a directly observed single dose is preferable to a multiday regimen.
The goals of MDA include reduction of malaria disease burden and reduction of transmission:
●Reduction of malaria disease burden – MDA campaigns can be used for short-term reductions in disease burden in areas of moderate to high P. falciparum transmission, or during emergencies or periods of health service disruption in defined geographical areas. In this context, the effect of MDA wanes within one to three months; MDA should be implemented as part of a robust malaria control program with effective case management and appropriate prevention tools and strategies.
In moderate to high transmission settings, MDA can be effective in reducing clinical malaria incidence and the incidence of P. falciparum infection one to three months post-MDA [84,85]. Whereas in emergency settings, MDA can reduce laboratory confirmed malaria zero to one month post MDA [86].
●Reduction of malaria transmission
•Areas with very low to low P. falciparum transmission – In these regions, MDA can be used to quickly reduce transmission. In this context the effect of MDA wanes within one to three months. To reduce the risk of resurgence at the end of the MDA program, MDA should be implemented as part of a robust malaria elimination program with case-based surveillance with parasitological diagnosis, effective antimalarial treatment, and appropriate prevention tools and strategies.
This approach should be considered only for geographical areas where the risk of malaria importation is limited. In these settings, MDA has been shown to reduce P. falciparum prevalence between one to three months and the incidence of P. falciparum clinical malaria between 12 to 24 months [87-89].
MDA is not recommended for reduction of transmission in areas with moderate to high P. falciparum transmission although it is recommended to reduce the burden of disease.
•Areas with P. vivax transmission – MDA can be used to reduce transmission in areas with P. vivax transmission. In addition to the considerations discussed above for reduction of P. falciparum transmission, countries considering implementing MDA for P. vivax should consider strategies to safely and feasibly administer treatment to prevent relapses [90-92].
Other chemoprevention strategies include use of chemoprevention in populations at high risk, such as forest workers (termed targeted drug administration [TDA]), and use of chemoprevention around a confirmed case in areas approaching elimination (termed reactive drug administration [RDA]):
●In Zanzibar (a low transmission area), drug treatment of all individuals residing within 300 to 1000 meters of individuals with positive rapid diagnostic tests enabled elimination of malaria in up to 66 percent of asymptomatic individuals [93].
●In Indonesia, a trial of malaria screening (with microscopy) and targeted treatment (with dihydroartemisinin-piperaquine) in a low transmission area did not impact the level of parasitemia level among school children [94]. The observed poor impact was ascribed to untreated microscopically subpatent infections in the control group.
●A study in Zambezi (Namibia), a low transmission area, compared "reactive case detection" (finding and treating patients only) with focal MDA for individuals in areas around the patients malaria and reactive focal vector control. The incidence of malaria was lower among those who received focal MDA plus reactive focal vector control than among those receiving reactive case detection only (adjusted incidence rate ratio 0.26, 95% CI 0.10-0.68) [95].
All moderate to high transmission settings
Intermittent preventive treatment of school-age children (IPTsc) — In areas of seasonal or moderate-to-high perennial transmission, the WHO recommends IPTsc. Countries may use local malaria epidemiology to make decision on the antimalarial agent, the dosing schedule, and the delivery approach.
●Approach – The delivery of IPTsc should be timed to give protection during the period of greatest malaria risk. First- and second-line malaria treatments for case management should not be used for IPTsc if safe and effective alternatives are available. Schools may be used as a delivery channel; alternative delivery channels may be considered to maximize impact.
●Efficacy – IPTsc has been evaluated in children aged 5 to 15 years but evidence is limited [96,97].
In one trial in Uganda, 740 children aged 6 to 14 years were randomly assigned to receive dihydroartemisinin-piperaquine (once a month), dihydroartemisinin-piperaquine (once a school term; 4 treatments over 12 months), or placebo and were followed for 12 months [96]. In the placebo arm, the incidence of malaria was 0.34 episodes per person-year and the prevalence of parasitemia and anemia was 38 and 20 percent, respectively. Monthly IPT reduced the incidence of malaria by 96 percent (95% CI 88-99 percent), the prevalence of asymptomatic parasitemia by 94 percent (95% CI 92-96 percent), and the prevalence of anemia by 40 percent (95% CI 19-56 percent). IPT given once each school term had no significant effect on the incidence of symptomatic malaria or the prevalence of anemia, but reduced the prevalence of asymptomatic parasitemia by 54 percent (95% CI 47-60 percent).
During the dry season, the role of IPTsc is uncertain. It has been postulated that subclinical malaria infection during the dry season is important in maintaining protective immunity, and that administering treatment for asymptomatic infection may predispose to more severe infection during the following rainy season. A prospective study of over 600 individuals in a region of seasonal malaria transmission in Mali demonstrated that treatment of asymptomatic infection with artemether-lumefantrine was not associated with increased risk of symptomatic malaria during the following two rainy seasons [98].
Post-discharge malaria chemoprevention (PDMC) — For children <5 years of age hospitalized for severe anemia in moderate to high malaria transmission settings (more than 250 P. falciparum malaria cases per 1000 population per year) [99], we suggest administration of post-discharge malaria chemoprevention (PDMC) [100]. This issue is discussed further separately. (See "Treatment of severe malaria", section on 'Role of post-discharge malaria chemoprevention'.)
Perennial transmission settings — In areas of moderate-to-high perennial malaria transmission, the WHO recommends perennial malarial chemoprevention (PMC), which refers to administration of antimalarial medicine at predefined intervals for children up to 24 months; this group is at increased risk of severe malaria or death. This practice was previously referred to as intermittent preventive treatment in infants (IPTi) [35].
●Approach – Typically, PMC is delivered through the expanded program on immunization (EPI) platform using sulfadoxine-pyrimethamine (SP). SP has been used safely for chemoprevention in Africa for several decades. ACTs have been proven effective in clinical studies of PMC, but evidence is still limited on their safety, efficacy, and cost-effectiveness in the context of PMC [35]. Countries may adapt the drug, timing of administration, and number of doses to local conditions. Various countries in sub-Saharan Africa are working to evaluate different models of PMC [101].
●Efficacy – PMC using antimalarial agents with slow elimination appears to be effective for reducing episodes of malaria in infants and does not appear to affect serologic response to routine vaccinations [102]. A 2021 Cochrane review evaluating PMC using various antimalarial agents included 12 trials and more than 19,000 infants in sub-Saharan Africa; the intervention was associated with a 30 percent reduction in the incidence of clinical malaria infection (rate ratio 0.70, 95% CI 0.62-0.80; 10,602 participants) [103].
Seasonal transmission settings — In areas of seasonal transmission, the WHO recommends seasonal malaria chemoprevention (PMC), which refers to administration of antimalarial medicine for children <5 years of age. Definitions for seasonal malaria transmission and groups at high risk change over time and among regions; countries may use local malaria epidemiology to determine the approach to SMC.
●Approach – SMC involves the administration of sulfadoxine-pyrimethamine plus amodiaquine (SPAQ); typically, the medication is delivered monthly during the peak malaria transmission season. This intervention has been shown to be efficacious, safe, well tolerated, and cost effective.
●Efficacy – SMC among children in West African countries with high malaria transmission has been associated with marked decrease in morbidity and mortality. In a 2020 case-control study including 2185 cases of confirmed malaria and 4370 controls during the 2015 and 2016 transmission seasons in Burkina Faso, Chad, Gambia, Guinea, Mali, Niger, and Nigeria, the pooled estimate of SMC effectiveness in reducing the incidence of clinical malaria within 28 days was 88.2 percent (95% CI 78.7-93.4) [104]. SMC was associated with reductions in the number of in-hospital malaria deaths during the high-transmission period in Burkina Faso by 42.4 percent (95% CI 5.9-64.7) and in Gambia by 56.6 percent (95% CI 28.9-73.5). The estimated reduction in confirmed outpatient malaria cases ranged from 25.5 percent (95% CI 6.1-40.9) in Nigeria to 55.2 percent (95% CI 42.0-65.3) in Gambia.
In a 2012 review of seven trials including more than 12,000 participants, SMC prevented 75 percent of malaria episodes [105]. A 2016 cluster-randomized trial of SMC in Senegal among children <10 years noted reduction in malaria incidence (60 percent) and severe malaria (45 percent) [106].
Addition of azithromycin to antimalarial agents among children 3 to 59 months of age in Burkina Faso and Mali was not associated with a reduction in mortality [107].
Targeted drug administration
Pregnant patients — Intermittent preventive treatment (IPT) is effective for reducing the risk of malaria infection among pregnant women (IPTp) [13,108]. This issue is discussed in detail separately. (See "Malaria in pregnancy: Prevention and treatment".)
Infants with congenital HIV exposure — Among infants with congenital HIV exposure, the WHO recommends initiation of trimethoprim-sulfamethoxazole (cotrimoxazole) between four and six weeks of age, with continuation until at least six weeks after cessation of breastfeeding and until HIV infection has been ruled out [109]. Prophylaxis with trimethoprim-sulfamethoxazole protects against malaria as well as Pneumocystis jirovecii infection.
This approach is supported by findings from an observational cohort study of HIV-exposed infants between 6 and 36 weeks of age in Malawi in which use of trimethoprim-sulfamethoxazole preventive therapy was associated with a relative reduction in the risk of asymptomatic infection by 70 percent (95% CI 53-81 percent) [110]. Similar findings have been observed among older children; in a randomized trial among 541 children 1 to 14 years of age with HIV infection in Zambia randomly assigned to receive daily trimethoprim-sulfamethoxazole or placebo, the mortality rate after median follow-up of 19 months was lower among those who received cotrimoxazole (28 versus 42 percent; hazard ratio 0.57, 95% CI 0.43-0.77); a similar reduction in mortality was observed in a subgroup of children <5 years (RR 0.68, 95% CI 0.51-0.91) [111].
Patients with HIV infection — Trimethoprim-sulfamethoxazole (TMP-SMX; cotrimoxazole) is commonly used for prevention of opportunistic infections in patients with HIV infection with any CD4 count living in areas with high burden of infectious and parasitic diseases.
Prophylaxis with TMP-SMX reduces morbidity and mortality rates due to malaria in HIV-infected individuals, even in areas with a high rate of malaria resistance [112-117].
Patients with sickle cell disease — Malaria chemoprevention is warranted for patients with sickle cell disease in areas where malaria is transmitted; this issue is discussed further separately. (See "Sickle cell disease in sub-Saharan Africa".)
Vaccination — A successful malaria vaccine has potential to reduce the global disease burden due to malaria [118,119]. Many antigens have been identified as potential targets for malaria vaccine development.
●Approved vaccines - The WHO has approved two vaccines for prevention of malaria: the RTS,S/AS01 vaccine and the R21/Matrix-M vaccine for children living in areas of moderate to high transmission. It is difficult to compare vaccine efficacy between these vaccines based on available data due to differences in study settings and study design.
•RTS,S/AS01 vaccine – The WHO approved the RTS,S/AS01 vaccine in October 2021 for children in sub-Saharan Africa and other regions with moderate to high transmission, based on studies of 830,000 children in Ghana, Kenya, and Malawi [104,120].
The RTS,S/AS01 vaccine consists of a recombinant fusion protein created based on an antigen target consisting of a repetitive sequence of four amino acids in the circumsporozoite antigen on the surface of the P. falciparum sporozoite (figure 2) [121-126]. "RTS" stands for "repeat T epitopes" derived from the circumsporozoite protein, "S" stands for the S antigen derived from hepatitis B surface antigen (HBSAg), and AS01 is a proprietary adjuvant [127].
The RTS,S/AS01 vaccine has been observed to have greater protection against clinical malaria infection caused by parasites that match the vaccine in the circumsporozoite protein allele than malaria infection caused by parasites with a mismatched allele [128].
-Phase 3 trial results of the RTS,S/AS01 vaccine among 15,459 infants demonstrated that the vaccine induced partial protection against clinical malaria among children ages 5 to 17 months over the follow-up period of the trial (median 48 months) and demonstrated benefit of the 20-month booster [126]. In the intention-to-treat population, vaccine efficacy among children ages 5 to 17 months who received three doses plus a booster (months 0, 1, 2, and 20) was 36 percent (95% CI 32-40). This finding is a decline from the 50 percent efficacy (95% CI 46-55) reported over the 14 months from the first dose [122]. No significant efficacy against severe malaria was noted in the 6 to 12 week age group over the duration of the trial, even with a booster.
-Another RTS,S/AS01 vaccine trial including 447 children ages 5 to 17 months who received three doses of RTS,S/AS01 vaccine noted a decline of vaccine efficacy against malaria between the first and fourth years of follow-up, from 44 percent (95% CI 16-62) to zero [124]. Subsequent follow-up of the vaccine recipients in the intention-to-treat cohort at seven years was notable for overall efficacy of 4.4 percent; efficacy was 16.6 percent in the low-exposure group but was negative (-2.4 percent) in the high-exposure group [129]. Additional follow-up for those who received a four-dose vaccine regimen is pending.
-The RTS,S/ASO1 was incorporated into national immunization programs in Ghana, Kenya, and Malawi in 2019. Geographical clusters were randomly assigned to receive early or delayed vaccination; three doses (months 0, 1, and 2) were administered to more than 490,000 children age 5 to 9 months [130]. All-cause mortality was reduced by 9 percent (95% CI 0-18 percent). In addition, rates of hospital admission with severe malaria were reduced by 32 percent (95% CI 5-51 percent). Further follow-up is needed to assess the impact of a fourth (booster dose) administered at 24 months.
•R21/Matrix-M vaccine – The WHO approved the R21/Matrix-M vaccine in October 2023 for prevention of malaria in children living in areas of moderate to high transmission [131]. The R21 vaccine is a virus-like protein based on the circumsporozoite protein from P. falciparum strain NF54, fused to the N-terminus of HBsAg; it is manufactured using Matrix-M, a proprietary adjuvant.
-In a phase 3 trial in Burkina Faso, Kenya, Mali, and Tanzania, 4800 children (age 5 to 36 months) were randomly assigned to receive a three-dose vaccine series or placebo [132]. At 12 months, vaccine efficacy against clinical malaria was 75 percent (95% CI 71-79) at the sites with seasonal malaria transmission and 68 percent (95% CI 61-74) at the sites with year-round malaria transmission. The vaccine was well tolerated; injection site pain and fever were most frequent adverse events.
-In a phase 2 trial including 450 children (age 5 to 17 months) in Burkina Faso (a highly seasonal transmission setting) randomly assigned to receive three doses of R21/MM vaccine (with low- or high-dose adjuvant MM) or rabies vaccine, vaccine efficacy in the two treatment groups more than 6 months after vaccination was 74 percent (95% CI 63-82 percent) and 77 percent (95% CI 67-84 percent), respectively [133]. There were no serious adverse events related to vaccination. The trial was performed in the context of substantial ITN use, moderate seasonal malaria chemoprevention, and minimal indoor residual spraying.
Data on the durability of protection are particularly important for malaria vaccines, since, depending on the regional transmission intensity, the risk of death due to malaria may continue for many years.
●Investigational vaccines – Immunization with live-attenuated P. falciparum parasites is a potential vaccination strategy [134]. Messenger RNA (mRNA)-based vaccine strategies are also under investigation [135].
Monoclonal antibodies — Use of monoclonal antibodies represents a novel approach to providing immune protection for malaria prevention.
●L9LS – A phase 2 clinical trial evaluated L9LS, a monoclonal antibody against P. falciparum infection that targets the circumsporozoite protein on the parasite surface during the sporozoite stage (when infection is transmitted to establish infection in the liver); this is also the target of the RTS,S/ASO1 and R21-Matrix vaccines [136,137].
The trial enrolled 225 children 6 to 10 years of age in Mali over a 6-month malaria season; they were randomly assigned to receive subcutaneous administration of 150 mg of L9LS, 300 mg of L9LS, or placebo [137] P. falciparum infection (as detected on blood smear performed at least every 2 weeks for 24 weeks) occurred less frequently among those who received L9LS (40 percent in the 300-mg group, 48 percent in the 150-mg group, and 81 percent in the placebo group). Compared with placebo, the efficacy of the 300-mg dose against P. falciparum infection was 70 percent (adjusted 95% CI, 50 to 82). Further study of monoclonal antibodies, including geographic and age-dependent variation in efficacy, is needed.
●CIS43LS – A phase 2 clinical trial evaluated CIS43LS, a different monoclonal antibody against the Plasmodium falciparum sporozoite circumsporozoite protein [138].
The trial included more than 200 healthy adults in Mali who were randomly assigned to receive an infusion of CIS43LS dosed at 10 mg/kg, 40 mg/kg, or placebo. In addition, artemether-lumefantrine was administered prior to infusion to clear subclinical infection if present. The efficacy for the primary endpoint (first P. falciparum infection detected on blood smear examination performed at least every 2 weeks for 24 weeks) among those who received high-dose CIS43LS was 88 percent (adjusted 95% CI 79-93). Moderate headache occurred 3.3 times more frequently among those who received high-dose CIS43LS compared with placebo.
Study limitations include lack of information on the incidence of clinical malaria (since this was not a secondary endpoint) and limitation of study enrollment to healthy nonpregnant adults (whose lifelong malaria exposure confers substantial immunity). In addition, intravenous infusion is impractical; development of a more robust formulation would be needed for subcutaneous administration.
This tool for malaria prevention may be useful for individuals who are unable to mount an immune response to vaccination, as well as for individuals in regions with emerging antimalarial resistance and in settings of malaria outbreaks. Larger studies in malaria-affected settings and among children and pregnant patients are needed.
ELIMINATION
●Definitions – Goals of control, elimination, and eradication may be defined as follows:
•Control refers to reduction of malaria disease incidence and prevalence to levels that do not pose a threat to public health or that are acceptable to a community.
•Elimination refers to reduction to zero malaria transmission in humans in a defined geographic area.
•Eradication is global elimination of human disease due to malaria.
●Effect of changes in malaria epidemiology – As malaria declines and a region approaches elimination of transmission, the average age at first infection increases and immunity among older age groups declines, due to reductions in exposure. As a result, the age at greatest risk of infection shifts away from the youngest children, spreading more evenly across age groups [139-141]. The number of malaria cases is substantially reduced and infections cluster in people with continued exposure to infective mosquitoes, largely outdoors [142]. As elimination approaches, malaria cases tend to cluster at the household or neighborhood level [143,144].
For regions with low to very low levels of transmission, borders with areas or countries that have higher levels of transmission are likely to be sites of increased transmission due to a high rate of importation of infections. For individuals in regions approaching malaria elimination, travel to areas with higher rates of transmission becomes a significant risk factor for infection; such individuals also serve as a source of imported cases.
Elimination programs must account for the changes in epidemiology that occur with reduced transmission [29]. In particular, the final stage of malaria elimination requires attention to small geographic areas or populations and individual infections, with interventions to reduce the chances of onward transmission.
●Approach
•Case management – Components of malaria elimination include early identification of suspect cases, parasitological diagnosis, observed treatment, and follow-up to ensure parasite clearance.
-Definition of a suspect case – The definition of a suspect case should consider the local burden of malaria epidemiology, transmission season, and patient travel history.
-Treatment – Malaria programs in elimination settings must often invest additional resources in monitoring patient adherence as well as ensuring that infections are cured completely to prevent onward transmission.
In areas approaching elimination, treatment for P. falciparum includes the addition of primaquine to reduce the transmissibility of P. falciparum infection (except pregnant women, infants aged <6 months, and women breastfeeding infants aged <6 months). (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children", section on 'Reducing transmissibility'.)
•Adjusting surveillance and preventive measures in areas approaching elimination – Approaches to surveillance and prevention are described above. (See 'Surveillance' above and 'Prevention' above.)
-Surveillance – In areas approaching elimination, case-based surveillance is important to determine the location where the patient was most likely infected, so that targeted preventive measures can be implemented in areas where cases are most likely to occur.
-Prevention – The scope of prevention efforts should be adjusted with decline in risk, to target areas with greatest risk of transmission. When transmission falls to levels that allow for residence-based case investigations, the at-risk population consists of individuals living near the location where a patient was likely infected, or individuals who were co-exposed with the index case. In such cases, vector control may consist of ITN coverage as well as reactive IRS for the homes of the index case and their neighbors. Similarly, chemoprevention may be administered to individuals at greatest risk of transmission (eg, those in the same household or near the location where a person was likely infected).
●Progress to date – Between 2000 and 2021, the number of countries with ongoing malaria transmission declined from 108 to 84 [145]. Since 2000, 18 countries have been certified malaria-free, while 11 more have attained three consecutive years of zero indigenous cases [146].
An increasing number of countries have received WHO certification of malaria elimination; these include El Salvador (2021), China (2021), Azerbaijan (2023), Tajikistan (2023), Belize (2023), Cabo Verde (2024), and Egypt (2024) [146].
In 2021, 46 countries reported fewer than 10,000 cases (up from 40 countries in 2010). The number of countries with less than 100 indigenous cases increased from 17 to 27 countries between 2010 and 2017 [147].
The WHO focuses efforts on the 11 highest burden countries comprising the 'High Burden – High Impact' initiative catalyzed by WHO and the Roll Back Malaria Partnership to End Malaria [148], as well as the 25 countries closest to elimination comprising the E-2025 (a program to help 25 countries eliminate malaria by 2025).
●Challenges – Important challenges to malaria elimination include:
•Parasite drug resistance. (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children", section on 'Partial artemisinin-resistant malaria'.)
•Mosquito insecticide resistance. (See 'Insecticides' above.)
•Geographic expansion of mosquito species. (See 'Geographic distribution' above.)
•Emergence of parasites that do not express the proteins detected by rapid diagnostic tests. (See "Laboratory tools for diagnosis of malaria", section on 'HRP2 (may detect P. falciparum)'.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Malaria".)
SUMMARY AND RECOMMENDATIONS
●Definition – Malaria, a parasitic disease caused by Plasmodium species, is transmitted by anopheline mosquitoes throughout most of the tropics. (See 'Introduction' above.)
●Epidemiology
•Geographic distribution – More than half of the world's population is at risk of malaria; in 2023 there were 253 million cases and 597,000 deaths. The World Health Organization (WHO) African Region accounts for about 94 percent of cases globally, followed by 2 percent each in the WHO Southeast Asian and Eastern Mediterranean regions; the WHO American and Western Pacific regions comprise the remainder. (See 'Geographic distribution' above.)
•Risk groups – Infants and children <5 years of age, pregnant patients, and patients with HIV infection are at particular risk of developing severe malaria. Other at-risk groups include people entering areas with intense malaria transmission who have not acquired partial immunity from long exposure to the disease or who are not taking chemopreventive therapy (such as migrants, mobile populations, and travelers). (See 'Risk groups' above.)
●Transmission and seasonal variability – Definitions for transmission intensity and concepts related to seasonal variability of malaria are described above. (See 'Transmission intensity definitions' above and 'Seasonal variability' above.)
●Surveillance – Disease surveillance tracks malaria burden and intensity, the populations at risk (and their geographic distribution), access to, use and equity of malaria prevention and treatment interventions, and the effectiveness of these interventions. This information is important for decisions regarding implementation of preventive strategies. (See 'Surveillance' above.)
●Prevention – Tools for malaria prevention include vector control, chemoprevention, and vaccination; these may confer protection to an individual, household, and/or community. (See 'Prevention' above.)
•Vector control – Tools for vector control include physical prevention (through use of nets, screens, and housing modifications), chemical repellants, killing larvae or mosquitoes with insecticides, and sterilizing or reducing the fecundity of mosquitoes. The most important vector controls are insecticide-treated nets (ITNs) and indoor residual spraying (IRS). The WHO recommends either ITNs or IRS (but not both) for populations at risk of malaria; priority should be given to optimizing coverage of one or the other. (See 'Vector control' above.)
•Chemoprevention in all moderate to high transmission settings – Chemoprevention refers to intermittent administration of a curative dose of antimalarial medicine during the malaria season, regardless of whether the individual is infected with malaria, with the goal of establishing antimalarial drug concentrations that will clear existing malaria infection and prevent new infection during the period of greatest malaria risk. (See 'Chemoprevention' above.)
-Intermittent preventive treatment of school-age children (IPTsc) – In areas of seasonal or moderate-to-high perennial transmission, we suggest IPTsc (Grade 2C). Countries may use local malaria epidemiology to make decision on the antimalarial agent, the dosing schedule, and the delivery approach. (See 'Intermittent preventive treatment of school-age children (IPTsc)' above.)
-Post-discharge malaria chemoprevention (PDMC) – For children <5 years of age hospitalized for severe anemia in moderate to high malaria transmission settings (more than 250 P. falciparum malaria cases per 1000 population per year), we suggest administration of PDMC. (See 'Post-discharge malaria chemoprevention (PDMC)' above and "Treatment of severe malaria".)
•Other circumstances for chemoprevention
-Perennial malaria chemoprevention (PMC) – In areas of moderate-to-high perennial malaria transmission, we suggest administration of antimalarial medicine at predefined intervals for children up to 24 months (Grade 2C). (See 'Perennial transmission settings' above.)
-Seasonal malaria chemoprevention (SMC) – In areas of seasonal transmission, we suggest administration of antimalarial medicine for children <5 years of age (Grade 2C). Definitions for seasonal malaria transmission and risk groups change over time and among regions; countries may use local malaria epidemiology to determine the approach to SMC. (See 'Seasonal transmission settings' above.)
-Specific patient groups – Issues related to chemoprevention for pregnant patients, infants with congenital HIV exposure, patients with HIV infection, and patients with sickle cell disease are discussed above. (See 'Targeted drug administration' above.)
●Vaccination – In areas of moderate-to-high malaria transmission, we suggest vaccination for children (Grade 2C). Choice of vaccine formulation, age and timing of administration, and number of doses is determined by vaccine availability and each country's national guidelines. (See 'Vaccination' above.)
ACKNOWLEDGMENT —
We are saddened by the death of Joel G Breman, MD, DTPH, who passed away in April 2024. UpToDate acknowledges Dr. Breman's past work as an author for this topic.
