Version May 2024
INTRODUCTION — Malaria is transmitted throughout most of the tropics; ongoing transmission occurs in 84 countries and territories [1]. In 2023, the World Health Organization (WHO) reported 247 million cases (up from 245 million in 2020) and 619 thousand deaths (down from 625,000 in 2020) due to malaria [2].
The annual number of malaria cases decreased steadily between 2000 and 2015 but thereafter, malaria cases have increased. Between 2019 and 2021 the number of malaria cases increased by 13 million, significantly more than any inter-annual increase since 2000. This increase is attributed largely to interruption of services due to the coronavirus disease 2019 (COVID-19) pandemic [3]. The COVID-19 pandemic was also associated with an estimated increase of 63,000 deaths attributed to malaria between 2019 and 2021 [4].
In 2019, WHO revised its approach to calculating the number of deaths attributed to malaria. With the revised WHO calculation, malaria accounts globally for 7.8 percent of the fraction of deaths in children aged less than 5 years (rather than 4.8 percent as reported previously).
The emergence of Plasmodium falciparum artemisinin partial resistance in the African region is of great concern [4], as are increasing reports of Anopheles spp resistance to pyrethroid insecticides [2]. The expansion of the range of an Asian malaria vector, An. stephensi, to the African continent has prompted WHO to launch a new initiative aimed at stopping its spread. An additional threat to malaria control and elimination is the continued increase in parasites that have lost the genes that express proteins detected by rapid diagnostic tests [4].
In 2021, the WHO recommended the first malaria vaccine, RTS,S/AS01, for use in children who reside in regions with moderate to high P. falciparum transmission [3]. In 2023, 12 African countries (three countries that conducted a pilot introduction of the vaccine plus nine more nations) received approval to deploy the vaccine through their routine immunization programs [5]. WHO recommendation of a second malaria vaccine (R21/Matrix-M™) in 2023 is expected to expand available supply.
In addition to these positive developments, an increasing number of countries have become malaria free and received WHO certification of malaria elimination; these include El Salvador (2021), China (2021), Azerbaijan (2023), Tajikistan (2023), and Belize (2023) [6].
EPIDEMIOLOGY
Transmission — The malaria parasite is transmitted primarily via the bite of an infected female Anopheles spp mosquito, which occurs mainly between dusk and dawn. Other rare routes of transmission include congenitally acquired disease, via blood transfusion, sharing of contaminated needles, organ transplantation, and nosocomial transmission [7-9].
The entomologic inoculation rate (EIR; the number of infectious female anopheline bites per person per year) is a term used to indicate transmission intensity. While there are seasonal and geographic differences, an EIR of <10/year is low transmission, 10 to 49/year is intermediate, and ≥50/year is a high transmission area. In general, the higher the EIR, the greater the burden of malaria, particularly in young children [10].
The principal determinants of the epidemiology of malaria are the number (density), the human-biting habits (indoors or outdoors), and the longevity of the female anopheline vectors. The transmission of malaria is directly proportional to the density of the vector, the square of the number of human bites per day per mosquito, and the 10th power of the probability of the mosquito's survival for one day [11,12].
Mosquito longevity is particularly important, because the portion of the parasite's life cycle that takes place within the mosquito (sporogony; from gametocyte ingestion to subsequent inoculation) lasts for 8 to 30 days, depending on the species of Plasmodium and ambient temperature; thus, to transmit malaria, the mosquito must survive for >10 days. The most effective mosquito vectors of malaria are those such as Anopheles gambiae in Africa, which are long lived, occur in high densities in tropical climates, breed readily, rest and bite within dwellings, and bite humans in preference to other animals.
Geographic burden
●Worldwide – Over 95 percent of the burden occurs in the WHO defined African region, followed by 2 percent each in the Southeast Asian and Eastern Mediterranean regions, with the American and Western Pacific regions contributing the remainder. There are no countries in the European region with ongoing malaria transmission.
Twenty-nine countries account for 96 percent of cases; Nigeria (27 percent), the Democratic Republic of Congo (12 percent), Uganda (5 percent), Mozambique (4 percent), and Angola and Burkina Faso (each 3 percent) account for 55 percent of all cases globally.
Deaths due to malaria continue to occur mainly among African children <5 years of age [2], who make up 76 percent of global malaria deaths.
Ascertainment of cases and deaths is the biggest challenge to understanding malaria control program success. Among 55 countries where the burden was estimated, 31 countries had a malaria reporting rate of less than 50 percent; this includes the high burden countries of Nigeria, the Democratic Republic of Congo, and India [3].
•Regional and seasonal variability – The epidemiology of malaria may vary considerably even within relatively small geographic areas. Traditionally, the intensity of transmission has been defined in terms of parasitemia rates or palpable spleen rates in children two to nine years of age as hypoendemic (≤10 percent), mesoendemic (11 to 50 percent), hyperendemic (51 to 74 percent), and holoendemic (≥75 percent).
Subsequently, WHO has used annual malaria incidence rates and parasite prevalence to broadly classify areas as very low (<100 cases per 1000 population or <1 percent parasite prevalence), low (100 to 250 cases per 1000 or 1 to 10 percent prevalence), moderate (250 to 450 cases per 1000 or 10 to 35 percent prevalence) or high (>450 cases per 1000 or >35 percent prevalence) [13].
In areas with high levels of P. falciparum transmission (eg, certain regions of tropical Africa or coastal New Guinea where there is intense transmission), people may receive more than one infectious mosquito bite per day and are infected repeatedly throughout their lives. In such settings with intense transmission, morbidity and mortality due to malaria during 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.
Relatively constant, year-round infection is termed perennial transmission; occurrence of cases in just a few months of the year is termed seasonal transmission. In areas where population immunity to malaria is low, malaria behaves like an epidemic disease, particularly in areas with highly seasonal transmission such as northern India (Rajasthan), Afghanistan, Iraq, Turkey, Ethiopia, Eritrea, Burundi, southern Africa (Botswana, Mozambique, Namibia, South Africa, Swaziland, Zimbabwe), and Madagascar. An epidemic can develop if there are changes in environmental, economic, or social conditions, such as heavy rains following drought or migrations (usually of refugees or workers) from a non-malarious region to an area of high transmission; a breakdown in malaria control and prevention services can intensify epidemic conditions. This situation usually results in considerable morbidity and mortality among all age groups [14]. .
●United States – Malaria transmission was eliminated in the United States in the mid-1950s. However, malaria continues to be acquired by travelers to malaria-affected areas and approximately 2000 imported cases of malaria are reported in the United States each year. Most of the cases imported to the United States come from Africa (85 percent) with the majority from West Africa (70 percent). Overall, P. falciparum caused 70 percent of cases followed by P. vivax (10 percent) and P. ovale (5 percent) in 2018. Virtually all patients became ill within three months of returning to the United States. Of the 95 percent who did not take prophylaxis properly, 25 percent took none at all. Severe illness occurred in 14 percent of patients, and seven persons died [15].
In 2023, nine locally acquired cases of P. vivax malaria were reported in Florida and Texas [16]. A single case of locally acquired P. falciparum was identified in Maryland [17,18]. These were the first locally acquired cases of malaria since 2003.
Distribution by species — Malaria occurs throughout most of the tropical regions of the world, with P. falciparum causing the largest burden of disease, followed by P. vivax (figure 1A-C) [19]. P. falciparum predominates in sub-Saharan Africa, New Guinea, and Hispaniola (Haiti and the Dominican Republic); P. vivax is much more common in the Americas and the western Pacific. The prevalence of these two species was approximately equal in the Indian subcontinent, eastern Asia, and Oceania in the late 1900s but P. falciparum is now responsible for two-thirds of cases (table 1) [20-22].
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 and comprises <1 percent of isolates. P. knowlesi, similar morphologically to P. malariae, has been identified by molecular methods in patients in Malaysia, the Philippines, Thailand, and Myanmar [23]; this is a zoonotic infection and there is no evidence of sustained transmission of this species between humans (ie, a monkey reservoir is required to infect mosquitoes) [24]. P. simium is a malaria species resembling P. vivax that occurs in primates; in contrast to P. knowlesi, it has been shown to be transmitted between humans in Brazil [25]. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)
Surveillance — Clinical, epidemiologic, entomologic, and parasitologic surveillance of malaria is required to determine the effect of malaria control and elimination programs. Depending on resources and the burden of malaria disease, emphasis should be on detecting clinical manifestations of illness in public and private hospitals and health units initially (passive surveillance). As transmission is reduced, active detection of malaria infections house by house (active surveillance) may become important in areas without access to passive surveillance or with hard-to-reach or at risk populations [26]. Modern information technologies (eg, cell phones, hand-held data entry devices, computerized reporting, feedback bulletins) will be necessary to assure prompt and accurate sharing of information. Surveillance of morbidity, mortality, disability, drug, and insecticide resistance and of commodities including quality of drugs, nets, and insecticides will be the key to malaria elimination and ultimately eradication [27]; additionally, provider practices and patient compliance require monitoring and evaluation [28].
An article summarizing nearly 27,000 malaria parasite prevalence surveys in Africa indicated that there was a 40 percent reduction in the prevalence of malaria infection across most of sub-Saharan Africa in the decade 2000 to 2015 [29-31]. Interventions averted 1.7 billion malaria cases between 2000 and 2020 [2]. Reductions in the malaria burden, while encouraging, were not sustained; since 2016, the number of malaria cases and deaths have increased.
An analysis of deaths due to malaria in Africa noted highest mortality rates and lowest coverage of bed nets and antimalarial drug use in Nigeria, Angola, Cameroon, Central African Republic, Democratic Republic of Congo, Guinea, and Equatorial Guinea [32].
A review of antimalarial drug quality in Asia and Africa showed an alarming prevalence of counterfeit drugs on the shelves of pharmacies in multiple countries [33]; up to 36 percent of antimalarial drugs and 43 percent of the artemisinin combination drugs were falsified. This criminal behavior requires more attention, including definition of the problem locally, scientific and technological means to identify rapidly poor quality drugs and other commodities (eg, diagnostic tests), regulatory action, and national and international laws [34].
DEFINITIONS — To consider interventions to reduce the burden or transmission of malaria, it is important to define the goals of control, elimination, and eradication. Control is reduction of disease incidence and prevalence to levels that do not pose a threat to public health or that are acceptable to a community. Elimination is reduction of incidence and transmission to zero in humans in a defined geographic area. Eradication is global elimination of human disease. In all instances, a surveillance system that could detect, respond to, and report malaria cases and infections promptly is essential.
Despite progress, one problem with the Millennium Development Goals (MDGs; now Sustainable Development Goals [SDGs], which aimed to reduce malaria incidence and prevalence by 75 percent by 2015 compared with 2000) is that baseline epidemiologic information for malaria is incomplete in most malaria-affected countries. Following successful elimination, ongoing rigorous surveillance is needed to identify imported cases, which must be detected, treated, and contained promptly to prevent reestablishment of transmission.
In the past, clinical diagnosis alone, based on signs and symptoms, has been used in most malaria-affected African areas for diagnosing and recording malaria cases, contributing to substantial imprecisions. Training and supervision of clinicians in proper diagnosis of suspected malaria remain the most important keys to effective case management and surveillance [35]. Microscopic confirmation of malaria, the historic "gold standard," is frequently delayed and inaccurate; hence, rapid diagnostic tests (RDT) are being used with increasing frequency especially in Africa. Advantages of RDTs include improved diagnosis, rapidity, and more rational use of antimalarial drugs. Diagnosis of malaria is discussed in detail separately. (See "Laboratory tools for diagnosis of malaria".)
With the Bill and Melinda Gates challenge in 2007 to eradicate malaria, there is increasing enthusiasm to reassess older control methods and develop and evaluate new ones through research. The approach to malaria eradication proposed by the WHO in 1955 includes the preparatory, attack, consolidation, and maintenance phases (figure 2). Progression between these phases depends on reducing the incidence of parasitemia in the population, which requires an understanding of the intrinsic and extrinsic factors of malaria transmission. Intrinsic factors include the relationships between human, parasite, and mosquito; extrinsic factors include the environment, socioeconomic milieu, and control initiatives [36]. The most important epidemiological criterion for moving from the attack to the consolidation phase of malaria eradication (in which surveillance is the key) is annual incidence of <0.1 infections/1000 persons (1 case per 10,000 population) [11].
Research in support of malaria eradication is a major component of the current global effort. The malaria eradication research agenda has been defined by task forces addressing specific themes [37,38].
ELEMENTS FOR MALARIA CONTROL AND ELIMINATION — Strategies to reduce and interrupt malaria transmission include effective deployment of antimalarial drugs, personal mosquito protection, mosquito vector control, and research (including vaccine development) [11]. Optimal malaria control (eg, leading to elimination) using these tools requires the following elements of the updated WHO Global Technical Strategy for Malaria 2016 to 2030 [39]. In addition to national and community ownership of malaria programs and innovation in tools and implementation, the technical foci are:
●Maximizing the effectiveness of vector control, including adequate entomological surveillance, management of insecticide resistance and identification of solutions to residual transmission
●Expanding chemoprevention to vulnerable groups
●Ensuring diagnostic confirmation of all suspected malaria cases, including at the community level, and effective treatment of all confirmed cases, including management of antimalarial drug resistance
●Strengthening surveillance of malaria to provide data needed for all technical areas
In 2021, there were 84 countries with ongoing malaria transmission, compared with 108 in 2000 [2]. Since 2000, there have been 15 countries certified malaria-free while 11 more have attained three consecutive years of zero indigenous cases. WHO focuses most efforts on the 11 highest burden countries that make up the 'High Burden – High Impact' initiative catalyzed by WHO and the RBM Partnership to End Malaria [40], as well as the 25 countries closest to elimination that make up the E-2025.
HOST PROTECTION
Overview — Tools for human protection from malaria infection include protection from mosquito bites, chemoprevention, and vaccination. It is uncertain whether combining these interventions may confer increased protection.
In one trial including more than 6000 children age 5 to 17 months in Burkina Faso and Mali (regions of seasonal transmission) randomly assigned to receive seasonal vaccination (primary three-dose series of RTS,S/ASO1 vaccine, followed by two annual boosters), chemoprevention (four monthly courses of sulfadoxine-pyrimethamine and amodiaquine each year), or both, a lower three-year incidence of uncomplicated malaria, severe malaria, and death from malaria was observed among those who received both interventions rather than either alone [41]. The protective efficacy of both interventions compared with chemoprevention alone against these outcomes (calculated as [1-hazard ratio] x 100) was 62.8 percent (95% CI 58.4-66.8), 70.5 percent (95% CI 41.9-85.0), and 72.9 percent (95% CI 2.9-92.4), respectively; the protective efficacy of both interventions compared with vaccine alone was 59.6 percent (95% CI 54.7-64.0), 70.6 percent (95% CI 42.3-85.0), and 75.3 percent (95% CI 12.5-93.0), respectively. These findings support a promising approach to reducing the burden of disease in areas with seasonal transmission of malaria; optimization of delivery to perennial transmission areas are needed.
Protection from mosquito bites
Repellents — Repellents applied to exposed skin may be used to protect against mosquito bites. Effective repellents include synthetic preparations such as DEET (N,N-diethyl-m-toluamide), Picardin (KBR3023), and IR 3535, as well as PMD (P-MENTHANE-3,8-DIOL), which is derived from lemon eucalyptus [42]. For maximal protection against mosquitoes, DEET is preferable over other agents. Selection and use of mosquito repellents are discussed separately. (See "Prevention of arthropod and insect bites: Repellents and other measures".)
The efficacy of mosquito repellents for protection against malaria is variable depending on the mosquito vector. Repellents are most effective in areas where vectors feed in the early evening (as with many South American and Asian vectors) rather than later in the night (as with African vectors such as An. gambiae). Repellents may also be more effective in regions with zoophilic vectors as in the Americas and south Asia (where mosquitoes may be diverted from a repellent-treated person to an animal) than in regions with anthropophilic vectors (Africa). This was illustrated in a cluster-randomized study of 4008 participants in rural Bolivia, where the principal vector is Anopheles darlingi [43]. All participants slept under treated nets; one group also used a plant-based insect repellent each evening, while a second group used placebo. Rates of P. vivax malaria episodes were reduced by 80 percent. A protective but not significant effect was observed for P. falciparum as the number of cases was small.
Repellents have also been protective against malaria in refugee camps on the Pakistan-Afghan border; in this region, the main vectors of malaria are Anopheles stephensi, An. culicifacies, An. pulcherrimus, and An. nigerrimus [44]. Among 127 families randomized to receive repellent soap (20% DEET/0.5% permethrin) or placebo, fewer cases of P. falciparum malaria were observed among those using repellent soap (3.7 versus 8.9 percent). There was no effect against P. vivax malaria.
In regions where vectors feed in the middle of the night, repellents might not increase the degree of protection afforded by use of insecticide-treated nets alone; this requires further evaluation.
Insecticide-treated nets (ITNs)
●Benefit − Use of ITNs is an important tool for malaria control. In a 2018 systematic review including 23 trials enrolling more than 275,000 adults and children between 1987 and 2001, use of ITNs was associated with a reduction of child mortality from all causes by 17 percent (rate ratio 0.83, 95% CI 0.77 to 0.89) [45]. 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).
Thus far use of pyrethroid-impregnated nets does not appear to have toxicity for humans [45].
●Approach to selection − Use of ITNs treated with pyrethroids has been an important tool for malaria control since the 1990s; however, pyrethroid resistance among mosquitoes has become widespread. Subsequently, new ITNs have been developed that contain a chemical (piperonyl-butoxide, PBO) that renders some pyrethroid-resistant mosquitoes susceptible to the insecticide. Additionally, next generation ITNs that contain a second active ingredient (AI, either a second insecticide or an insect growth regulator) in addition to a pyrethroid insecticide have received WHO recommendations for use in areas with pyrethroid resistance.
In areas where pyrethroids remains effective, WHO continues to recommend use of pyrethroid-only ITNs. In areas where the main malaria vector(s) exhibit confirmed pyrethroid resistance, WHO guidelines favor use of one of the ITNs intended for areas with pyrethroid resistance. [46].
●Insecticide formulations − Pyrethroids remain the principal insecticide class on WHO-recommended ITNs. PBO-ITNs add the chemical synergist PBO to the net to render resistant mosquitoes susceptible to pyrethroids. Next-generation dual AI nets include pyrethroids plus chlorfenapyr, an insecticide, or pyriproxyfen, an insect growth regulator. Combining pyrethroids with a second AI with a different mode of action helps to overcome pyrethroid resistance; additional dual AI nets currently are being evaluated by WHO.
•Pyrethroids − Pyrethroids have been the mainstay insecticide class for ITN treatment since the late 1990s. However, pyrethroid resistance among mosquitoes has become widespread; failure of pyrethroid-based ITNs has been reported in West Africa and elsewhere [47-50].
Laboratory detection of resistance genes may or may not correlate with epidemiologic observations. Genes for pyrethroid resistance were first demonstrated among mosquito vectors in the Ivory Coast; however, pyrethroid-based ITNs remained effective for preventing malaria in this region [51].
•Piperonyl butoxide (PBO) – Emergence of pyrethroid resistance has prompted development of ITNs incorporating a chemical synergist, PBO [52,53]. PBO inhibits the metabolic enzymes found in resistant mosquitoes that detoxify insecticides before they reach their target within the mosquito. As a result, mosquitoes that encounter the PBO are effectively rendered susceptible to pyrethroids. PBO-treated nets are not expected to confer any additional benefit in areas where the main malaria vectors are susceptible to pyrethroids.
In a 2020 cluster-randomized including more than 100 subdistricts in Uganda with high pyrethroid resistance, use of PBO-treated LLINs was associated with reduced parasite prevalence compared with conventional LLINs at 18 months (12 versus 14 percent; prevalence ratio 0.84, 95% CI 0.72-0.98) [54].
Similarly, in a 2018 cluster-randomized trial among more than 3600 children in Tanzania, the malaria prevalence after was lower among those who used PBO-treated nets than among those who used pyrethroid-treated nets (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 [55].
However, in a 2022 cluster-randomized study including more than 39,000 households in a Tanzania region with high prevalence of pyrethroid resistance, there was no difference in malaria prevalence among children who used PBO-treated nets and children who used pyrethroid-treated nets (adjusted odds ratio 0.99, 95% CI 0.67-1.45) [56].
•Chlorfenapyr-pyrethroid – Chlorfenapyr is an insecticide from the pyrrole class. Insecticides in this class disrupt energy production in the mosquito, leading to death. Chlorfenapyr-pyrethroid 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 chlorfenapyr-pyrethroid, pyriproxyfen-pyrethroid, or pyrethroid only [57]. More than two years after ITN distribution, lower malaria incidence was observed in clusters where ITNs treated with chlorfenapyr-pyrethroid 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). Pyriproxyfen-pyrethroid 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 chlorfenapyr-pyrethroid were used (rather than nets treated with pyrethroid only; incidence rate ratio 0.56, 95% CI 0.37-0.86) [56]. 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.
•Pyriproxyfen-pyrethroid − Pyriproxyfen is an insect growth regulator that effectively sterilizes female mosquitoes. In the 2022 and 2023 trials of chlorfenapyr-pyrethroid ITNs described above, there was no difference in malaria prevalence among children who used pyriproxyfen-treated nets and those who used pyrethroid-only nets [56,57].
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) [58].
●Local ITN implementation − Community health education is essential for correct ITN installation, maintenance, and timing of use.
•ITN durability – Long-lasting ITNs must demonstrate efficacy after 20 washes and manufacturer claims may suggest that ITNs remain effective for three years or longer. However, multiple field studies have demonstrated that fewer than half of ITNs remain functional three years after distribution [59].
●ITN use does not appear to delay acquisition of natural immunity against malaria − It has been postulated that ITN use might delay acquisition of natural immunity against malaria, with increased risk for illness 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 [60]. Reported use of ITN 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). Although most deaths occurred prior to age 5, that level of ITN use was still associated with a trend towards lower mortality between five years and adulthood (hazard ratio 0.93, 95% CI 0.58-1.49).
●Use of ITNs with indoor residual spraying − Methods of interrupting malaria transmission must be considered carefully and evaluated both individually and in combination. A systematic review of adding IRS to areas where ITNs are already deployed found no additional benefit when IRS used a pyrethroid-like insecticide. However, IRS using non-pyrethroid insecticides was found to reduce malaria prevalence, although it did not have an effect on malaria incidence [61]. WHO recommends against co-deployment of ITNs and IRS and suggests that priority should be given to providing better coverage of one or the other rather than trying to implement both [62].
Preventive chemotherapies
Specific target groups
Infants and children
Children in areas with perennial transmission — WHO recommends administration of a full treatment course of an antimalarial medicine at predefined intervals to children in moderate to high transmission areas where malaria occurs year-round. Formerly known as intermittent preventive treatment in infants (IPTi), the new strategy is referred to as 'perennial malaria chemoprevention' (PMC) [62]. PMC strategies target the age groups of children at increased risk of severe malaria or death, which may include children up to 24 months. Countries are encouraged to adapt the medicine and timing and number of doses to local conditions; various countries in sub-Saharan Africa are working to evaluate different models of PMC. [63].
PMC with slowly eliminated antimalarials appears to be effective for reducing episodes of malaria in infants and does not appear to affect serologic response to routine vaccinations [64]. A 2021 Cochrane review of IPTi using various antimalarial medicines included 12 trials and more than 19,000 infants in sub-Saharan Africa. IPTi 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) [65]. The effect of IPTi with SP appeared to attenuate over time; trials conducted after 2009 demonstrated little or no effect when SP was used although trials with ACTs showed more benefit.
SP has been used safely for chemoprevention in Africa for several decades; while ACTs have been proven effective in clinical studies, evidence is limited on their safety, efficacy and cost-effectiveness [62].
Children in areas with seasonal transmission — Implementation of seasonal malaria chemoprevention (SMC) among children in six West African countries with high malaria transmission has been associated with marked decrease in morbidity and mortality [66]. In a case-control study including 2185 cases of confirmed malaria and 4370 controls during the 2015 and 2016 transmission seasons in Burkina Faso, Chad, the 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). 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 the 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 the Gambia.
A review of seven trials including more than 12,000 participants noted that IPTc prevented 75 percent of malaria episodes [67]. A subsequent study of SMC in Senegal with AQ-SP among children <10 years noted reduction in malaria incidence (60 percent) and severe malaria (45 percent) [68].
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 [69].
Children in areas with perennial or seasonal transmission
●IPT may be beneficial among school children [70,71]. 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 [70]. 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).
●The role of IPT during the dry season is uncertain. It has been postulated that subclinical malaria infection during the nontransmission (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 [72].
●In areas with seasonal flooding, mass drug administration is very effective for reducing malaria. In one study including more than 550 Ugandan children ≤12 years of age treated with three monthly doses of dihydroartemisinin-piperaquine (with two neighboring villages as controls), lower malaria incidence was observed among those who received treatment (53.4 percent, 95% CI 0.34-0.62) after six months [73].
Infants with congenital HIV exposure — To reduce the likelihood of opportunistic infection among infants exposed to HIV, the WHO recommends that these individuals begin trimethoprim-sulfamethoxazole (cotrimoxazole) between four and six weeks of age and continue until at least six weeks after cessation of breastfeeding and until HIV infection has been ruled out [74]. 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) [75]. 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) [76].
Pregnant women — Intermittent preventive treatment (IPT) is effective for reducing the risk of malaria infection among pregnant women (IPTp) [11,77]. This issue is discussed in detail separately. (See "Malaria in pregnancy: Prevention and treatment".)
Patients with HIV infection — We favor use of trimethoprim-sulfamethoxazole (TMP-SMX; cotrimoxazole) for prevention of malaria in HIV-infected patients with any CD4 count living in malaria-affected areas.
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 [78-82].
Patients with sickle cell disease — Routine malaria prophylaxis 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".)
Mass drug administration — Issues related to chemoprevention for specific groups are discussed above. (See 'Specific target groups' above.)
Antimalarial agents — Mass drug administration (MDA) campaigns can rapidly reduce malaria parasitemia in low-transmission areas, and have been used in the setting of threatened P. falciparum drug resistance [83]. This was demonstrated by a randomized trial in Zambia in which patients received two doses of dihydroartemisinin-piperaquine or no treatment [84]. In low-transmission areas, an 87 percent reduction in parasite prevalence (from 7.71 to 0.54 percent) and 70 percent decrease in parasitemia was observed after five months.
However, in high-transmission areas, MDA may not be effective at reducing transmission. A systematic review of cluster-randomized controlled trials conducted in moderate to high transmission areas showed no overall impact of MDA on parasite prevalence (risk ratio 1.76; 95% confidence interval 0.58-5.36) one to three months after the MDA was over [85].
Regionally targeted MDA may be beneficial in some circumstances:
●A regional elimination program in Myanmar included identification of malarial "hotspots" (defined as presence of malaria in >40 percent of individuals, of which 20 percent was P. falciparum); hotspot villages had incidence of P. falciparum three times higher than neighboring villages [86]. MDA (dihydroartemisinin-piperaquine plus single-dose primaquine once per month for three consecutive months) was targeted to individuals in these areas; the intervention was associated with an 80 percent reduction in incidence of P. falciparum (adjusted incidence rate ratio 0.19, 95% CI 0.13-0.26).
●In the Gambia (where there is seasonal falciparum malaria transmission), annual MDA with dihydroartemisinin-piperaquine in 2014-2015 in six village pairs prior to malaria season was associated with reduced infection and clinical disease during the first months. Reduction was maintained in low-transmission areas in eastern Gambia, but not in high-transmission areas [87].
Another approach to targeted MDA consists of identifying asymptomatic individuals with malaria followed by "focal" MDA:
●In Zanzibar (an area of low falciparum transmission), 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 [88].
●In a Cambodian trial of MDA (three monthly rounds of a three-day course of dihydroartemisinin-piperaquine) in four malaria-affected villages, the incidence of P. falciparum was lower in intervention villages than in the control villages during the subsequent 12 months (1.5 versus 37.1 cases per 1000 person years; incidence rate ratio 24) [89]. Artemisinin and incipient piperaquine resistance has emerged in the study area; the research team used artesunate-mefloquine for treatment failures.
●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 [90]. The observed poor impact was ascribed to untreated microscopically subpatent infections in the control group.
●A study in Zambezi (Namibia) a setting with low levels of malaria transmission compared "reactive case detection" (finding and treating patients only) with treating persons in nearby areas around the malarious patients with focal MDA 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) [91].
Systemic insecticides — Mass administration of systemic insecticides (also known as endectocides) to reduce malaria transmission is an area of growing interest.
Ivermectin is promising systemic insecticide; it is capable of killing anopheline mosquitoes when they blood feed on ivermectin-treated individuals [92]. 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 [93]. 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.
Membrane feeding of mosquitoes on patients' venous blood (rather than direct skin feeding) has been proposed as an alternative method for assessment of ivermectin mosquitocidal efficacy. In one study including comparing these approaches, mosquitocidal effects of ivermectin were similar across a range of drug concentrations [94].
Further study is needed to use of ivermectin in other areas, establish the optimal dose or formulation, and evaluate the effects of repeated ivermectin treatment.
Vaccination — A successful malaria vaccine has potential to reduce the global disease burden due to malaria [95,96]. Many antigens have been identified as potential targets for malaria vaccine development.
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 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/ASO1 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 [3,97].
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 3) [98-103]. "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 [104].
●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 [103]. 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 [99]. 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 [101]. 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 [105]. Additional follow-up for those who received a four-dose vaccine regimen is pending.
The RTS,S/AS01 vaccine has been observed to afford 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 [106].
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 [107]. 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 [108]. 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. These data are under peer review prior to publication.
●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 [109]. There were no serious adverse events related to vaccination. The trial was performed in the context of substantial ITN use, moderate seasonal malaria prophylaxis, 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.
Monoclonal antibodies — Use of monoclonal antibodies represents a novel approach to providing immune protection for malaria prevention.
●L9LS – A phase 1 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 [110].
The trial enrolled healthy adults in the United States with no history of malaria infection or vaccination; 18 individuals received L9LS (serum half-life 56 days) and a control group of 9 individuals did not receive L9LS. Both groups underwent controlled malaria infection; protection against infection was greater among those who received L9LS than those who did not (88 versus 0 percent). No serious adverse events were reported. A subcutaneously delivered preparation also demonstrated good protection, and phase 2 studies are underway.
●CIS43LS – A phase 2 clinical trial evaluated CIS43LS, a different monoclonal antibody against the Plasmodium falciparum sporozoite circumsporozoite protein [111].
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 is needed.
MOSQUITO CONTROL — Important mosquito vectors in malarious areas are summarized in the table (table 1).
Mosquito vector control methods that can be deployed over large areas include use of insecticide-treated nets (ITNs) and household insecticide indoor residual spraying (IRS). Larval source management, which includes application of larvicides, is considered a supplemental vector control methods that may complement ITNs and IRS in areas where larval habitats are few, fixed and findable. Genetic control methods remain an area of research. Since effective insecticides have become available for use against adult Anopheles, ITNs and IRS have become the most important measures for mosquito vector control.
Requirements for effective sustained implementation of vector control include [112]:
●Continual monitoring for Anopheles resistance and cross-resistance to the insecticides deployed
●Entomology expertise (including mosquito species identification and their biting and feeding habits) and vector control technology
●Close supervision and monitoring of the effect of the intervention on the entomological inoculation rates and on clinical and parasitologic indices
The behavior of the vector is important for determining the choice of control method [113]. For mosquitoes that prefer to rest indoors (endophilic) and feed indoors (endophagic) at night, both IRS and ITNs are effective methods of control. For mosquitoes that prefer to rest outdoors (exophilic) and feed outdoors (exophagic) earlier in the day (eg, the South American vector Anopheles albimanus), the use of repellents may be the only feasible method of control. If the vector has clearly defined breeding sites (for example, Anopheles stephensi), then larval control measures can be applied [113]. However, an integrated control strategy is often the most successful approach [114].
Studies carried out prior to the implementation of a mosquito control program should survey the local mosquito population, identify vector species, and identify the most anthropophilic species [115]. The type and degree of insecticide resistance present in the mosquito population should also be investigated [116,117].
Mosquitoes progress through four distinct life stages: egg, larva, pupa, and adult [118]. The full life cycle usually takes approximately 10 days and varies according to species, season, temperature, and available nutrition.
Mosquito life cycle — Stages of the mosquito life cycle include egg, larva, pupa and adult.
●Eggs – Female mosquitoes lay up to 200 cigar-shaped eggs per reproductive cycle (figure 4). Anopheles eggs have "floats" (sacs on the side of the egg). Anopheles and Aedes mosquitoes lay eggs individually; Culex mosquito lay eggs in groups ("egg rafts").
Anopheles mosquitoes lay eggs in clean water (such as rain puddles, water tanks, and irrigation ditches). Aedes mosquitoes (sometimes called "floodwater mosquitoes") lay eggs in moist environments with potential to be submerged; the eggs can withstand desiccation until a flooding event occurs.
●Larva – Eggs hatch into larvae that live in the water and come to the surface to breathe (figure 4). Anopheles larvae lie in a horizontal position parallel to the water surface and do not have a siphon. Culex larvae maintain a position vertical to the water surface and breathe via a siphon, which extends to the water surface.
●Pupa – Pupae float on the water surface (figure 4). In the pupa stage, the head and thorax are fused to form a comma-shaped cephalothorax; during this stage, there are no distinguishing characteristics between the genera. Pupae breathe but do not feed, so larvicide cannot be ingested during this stage, although surface oil can induce suffocation. Metamorphosis from pupa into an adult mosquito takes about two days.
●Adult – The newly emerged adult female is able to mate immediately; the male mosquito is able to mate 24 hours after emergence. Only female mosquitoes bite humans or animals to obtain protein needed for producing eggs; both males and females feed on flower nectar for food. Female mosquitoes begin blood feeding approximately three days post-emergence.
Mosquito head appendages consist of a proboscis, a pair of antennae, and a pair of maxillary palps (figure 5). Female mosquitoes use the proboscis to pierce skin and suck blood. Male antennae are bushier than female antennae and are visible with the naked eye. The palp characteristics are the most reliable for differentiation between anopheline and culicine mosquitoes. Anopheline female palps are about the same length as the proboscis, while Anopheline male palps are club shaped at the ends. Culicine female palps are shorter than the proboscis, and Culicine male palps are long with a tapered point.
Live adult mosquitoes are recognizable 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 6).
Residential interventions — Residential interventions include house screening, indoor residual spraying, and lethal house lures. The WHO recommends house screening [46], although there are no good data evaluating the effectiveness of this intervention. Data evaluating indoor residual spraying and lethal house lures are discussed below.
Indoor residual spraying — Indoor residual spraying (IRS) involves spraying insecticide on indoor residential walls and ceilings; depending on the insecticide and surface, the effect can last for extended periods. The WHO recommends that effort be focused on optimal implementation of either ITNs or IRS, rather than deploying both in the same area. In settings where ITNs remain effective and optimal ITN coverage has been achieved, additional implementing of IRS may have limited utility [46]. (See 'Insecticide-treated nets (ITNs)' above.)
IRS is performed with hand-operated compression sprayers containing an aqueous suspension of insecticide. Spray teams must be trained and supervised closely in applying the correct dose to walls and ceilings and protecting themselves from toxicity [119]. Frequency of IRS application varies from once or twice yearly for organochlorine compounds (eg, DDT) to three or more times for organophosphates (eg, malathion) [120].
Mosquito contact with insecticide-treated surfaces is generally lethal; sublethal exposure drives mosquitoes outside the house. Ideally, the mosquito is killed or repelled before feeding on humans within the dwelling [121]. Widespread community IRS reduces the proportion of mosquitoes surviving long enough to transmit malaria since each mosquito attempt at a blood meal results in a potentially lethal insecticide exposure [113,120,122]. Community health education about IRS is essential; spraying may require furniture rearrangements, the walls may become streaked with chemical treatments, and there may be a residual odor from the IRS.
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 [22,123,124].
In the mid-1990s, many regions switched from DDT to pyrethroids for IRS. This resulted from environmental concerns about toxicity and pressure against DDT use, and there has been a reduction in production of the compound. Given the environmental concerns and the lack of a WHO prequalified DDT product, DDT is now rarely used in IRS programs.
The combined effect of IRS and ITNs is uncertain. One study in Uganda noted that the combination of IRS and ITNs was associated with a marked decline in the burden of malaria; use of ITNs alone had a modest impact [125]. However, a study in Uganda (where high-level coverage of ITNs was achieved) showed that stopping IRS after four years of twice-yearly household spraying was associated with a rapid increase in malaria morbidity to pre-IRS levels [126]. Mosquito resistance to pyrethroids used in the ITNs is one of the possible reasons for resurgence of malaria; in one review, of communities using ITNs, the addition of IRS with 'non-pyrethroid-like' insecticides was associated with reduced malaria prevalence [61].
In some cases, use of IRS, even with ITNs and selective drug use, is not effective for elimination of transmission. In one study including more than 400 individuals in northern Uganda from 2014 to 2016, three rounds of IRS with carbamate bendiocarb reduced the incidence of clinical malaria and the prevalence of parasitemia; however, the parasitemia prevalence remained at 11.3 percent among children <5 years of age and at >15 percent in older age groups [127]. A subsequent study among more than 300 children between 6 months and 10 years of age in Uganda observed that multiple rounds of IRS (three rounds of carbamate bendiocarb followed by one round of an organophosphate, Actellic CS) was associated with decreased incidence of clinical malaria (by 83 percent) and increased hemoglobin level (by 10 percent) [128].
In areas with relatively low transmission and a strong surveillance program, targeted IRS (use of IRS only at the houses of individuals with malaria and their neighbors) may be more cost-effective than mass IRS. 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 targeted IRS (0.95 cases versus 1.05 cases per 1000 person-years) [129]. At this disease incidence, use of targeted 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. The generalizability of the findings in higher transmission settings warrants further study.
Lethal house lures — A lethal house lure is a novel intervention for mosquito control. One approach 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) [130]. No serious adverse events associated with the intervention were reported during follow-up. Further study is needed for additional optimization.
Vector control strategies — Tools for vector control include larval control and genetic control.
Larval source management — Larval source management (LSM) includes modification and manipulation of larval sites, larviciding and biological control (eg. Larvivorous fish). For regions with ongoing malaria transmission, WHO recommends that larviciding may be used as a supplementary intervention for malaria control in settings where aquatic habitats are few, fixed, and findable [46]. Larviciding should not be considered a substitute for ITNs or IRS; larviciding reduces vector density, which does not have the same potential impact as ITNs and IRS (which reduce vector longevity and provide protection from biting vectors).
Evidence for other LSM activities are limited and highly context specific. However, several temperate countries, for example, the US and Italy, achieved significant reductions in malaria through large-scale environmental manipulation of aquatic habitats.
LSM is one of the strategies recommended by WHO to contain the spread of An. stephensi in urban and peri-urban areas [131]. LSM includes, where feasible, removal of larval sites, modification of larval sites to prevent mosquito access and larviciding with WHO-prequalified chemical or biological larvicides.
Prior to availability of insecticides for use against adult mosquitoes, a concerted effort was directed toward making potential breeding sites unsuitable for Anopheles larvae. Famous historical examples include fluctuation of water levels in the reservoirs of the Tennessee Valley Authority and the draining of the Pontine Marshes near Rome [114].
Larval control is challenging in that virtually all potential breeding places within mosquito flight range of the human community must be identified and addressed. To prevent anopheline population explosions, drainage and filling of water collection sites as well as careful management of large engineering projects such as dam and building construction are needed.
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) [132]. This strategy was implemented in a series of villages in south India; from 1998 (over one year after release of fish) until 2003, no malaria cases were detected in the villages [114,133]. This method also allows villagers to continue their traditions of raising indoor silkworm moths without the threat of insecticide damage.
Insect growth regulators 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 was used in Sri Lanka, where malaria eradication was nearly achieved in the 1960s but disease persisted in areas where pits were dug in search of gems (subsequently, the pits filled with rainwater and became breeding sites for malaria vectors) [134]. 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.
Use of larval control techniques in Africa has been nearly impossible since breeding sites of An. gambiae tend to be small and impermanent. However, a major reduction in the density of adult An. gambiae was achieved in a Kenyan village by use of the bacterial toxin Bacillus thuringiensis israelensis (Bti). This toxin is highly specific for mosquito larvae and targets very few other species [135]. Bti has a short half-life, and 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 given that its breeding sites are larger and more permanent.
A problem with many of the biological control approaches to larval control has been that they are difficult to expand to large scale or national public usefulness. This is because of the site-specific nature of the research and other constraints. In some projects, the imported fish species did not adapt to local conditions and they were avidly consumed by the human populations they were to protect.
Genetic control — Genetic strategies for malaria control entail using male mosquitoes to introduce genetic factors that prevent the eggs from hatching, prevent the larvae from surviving, or produce adult insects incapable of transmitting human disease. Despite years of investigation, genetic control remains a promising research theme.
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 [136]. 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 [137].
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 [138]. It is hoped that similar approaches will soon produce strains completely non-susceptible to P. falciparum [138,139]. However, the optimal approach for creating genetic factors that selectively incorporate themselves into later generations in a wild population is under intense study but remains uncertain [140-142].
PROGRESS TO ELIMINATION — In 2014, 16 countries reported zero indigenous cases (Argentina, Armenia, Azerbaijan, Costa Rica, Iraq, Georgia, Kyrgyzstan, Morocco, Oman, Paraguay, Sri Lanka, Tajikistan, Turkey, Turkmenistan, the United Arab Emirates, and Uzbekistan). Another three countries and territories reported fewer than 10 indigenous cases (Algeria, El Salvador, and Mayotte [France]). The WHO European Region reported zero indigenous cases for the first time in 2015, and Sri Lanka was declared free of malaria in 2016 [143].
Globally, the elimination net is widening; 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 [143]. A total of 15 countries have been certified malaria-free since 2000, including Azerbaijan, Belize, China, El Salvador and Tajikistan [6].
Stringent environmental management and "integrated vector control" (concurrent use of multiple approaches) are required for eradication. Long-lasting insecticidal nets and indoor residual spraying are strategic components for all three groups; these and other strategies are discussed above. (See 'Elements for malaria control and elimination' above.)
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
●Malaria is the most important parasitic disease of humans, with transmission in 84 countries affecting over 3 billion people and likely causing over 600,000 deaths each year. Important challenges to malaria elimination include parasite drug resistance, mosquito insecticide resistance, geographic expansion of mosquito species from other regions and the spread of parasites that do not express the proteins detected by rapid diagnostic tests. (See 'Introduction' above.)
●To consider interventions for malaria control, it is important to define goals of control, elimination, and eradication. Control is reduction of disease incidence and prevalence to levels that do not pose a threat to public health or that are acceptable to a community. Elimination is reduction to zero transmission in humans in a defined geographic area. Eradication is global elimination of human disease. (See 'Definitions' above.)
●Chemoprevention appears to be useful for reducing the consequences of malaria infection among individuals at high risk, particularly pregnant women. IPTp, and seasonal and perennial chemoprevention of high risk groups are important recommendations in WHO’s malaria guidelines. (See 'Specific target groups' above.)
●Mosquito vector control methods include use of ITNs, household insecticide residual spraying (IRS), larval control, and genetic control methods. Since effective insecticides for use against adult Anopheles have become available, ITNs and IRS have become the most important measures for mosquito vector control. (See 'Mosquito control' above.)
●The efficacy of mosquito repellents for protection against malaria is variable depending on the transmitting mosquito vector. (See 'Repellents' above.)
●Mass drug administration may be a useful tool in regions where elimination of falciparum malaria is a feasible goal. An effective drug, rapid diagnostics, and sensitive monitoring system for adverse events are required for such an intervention. (See 'Mass drug administration' above.)
●Malaria vaccines used in conjunction with other control interventions could reduce the global disease burden of malaria. (See 'Vaccination' above.)
●Measuring progress by continuous, timely, widely shared surveillance information is the key to control and eradication. Surveillance of the quality of antimalarial drugs (and other commodities) is essential to assure effective treatment and prevention. (See 'Surveillance' above.)
●Continuing research on the issues noted above is required to achieve control, elimination, and eradication of malaria in the 21st century. (See 'Elements for malaria control and elimination' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Joel G Breman, MD, DTPH, who contributed to earlier versions of this topic review.
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