Malaria: a review on its current epidemiological status and management strategies

Abstract

Malaria remains a global health concern, with Africa bearing the highest global burden of malaria, as Plasmodium falciparum malaria remains the leading cause of malaria-related mortality on the continent. The transmission dynamics of malaria are shaped by a combination of factors, including climate conditions, economic constraints, geographic variability, human activities, and security instability. Owing to repeated infections and widespread implementation of early interventions, there has been a notable rise in cases of clinically atypical malaria and asymptomatic Plasmodium carriers, which increases the risk of misdiagnosis and underdiagnosis. Despite these challenges, African nations have made substantial progress in malaria control and elimination. Key advancements include, increased distribution of insecticide-treated nets use, increased indoor residual spraying, widespread rapid diagnostic tests, intermittent preventive treatment in vulnerable populations, deployment of artemisinin-based combination therapies (ACTs), and of late, the deployment of malaria vaccines to children under 5 years. Between 2000 and 2022, the WHO African Region reported a 40% reduction in malaria incidence and a 60% decline in mortality. Nonetheless, the continent faces emerging threats that could hinder further progress. These include persistent poverty, the effects of climate change, inadequate healthcare infrastructure and coverage, increased outdoor transmission linked to changing mosquito behavior, the appearance of new vector species, and rising resistance to both antimalarial drugs and insecticides. To address these challenges, a multi-faceted strategy is essential. This includes cross-border prevention and control efforts, expansion of seasonal malaria chemoprevention programmes, identification of molecular markers of resistance, development of novel antimalarial agents, and scaled-up implementation of vaccines such as RTS,S/AS01 and R21/Matrix-M. Implementation of approaches employed by countries such as China in malaria elimination and strengthening global-Africa cooperation in the fight against malaria could further accelerate progress. This review aims to provide a comprehensive overview of global malaria with a focus on Africa and global efforts toward the continent’s malaria elimination goals.

Introduction

Malaria is an ancient tropical parasitic disease transmitted by certain mosquitoes that remains a persistent public health challenge. It is a leading cause of illness in sub-Saharan Africa, with serious health and economic impacts [1]. Despite considerable progress in malaria control over recent decades, millions of people worldwide continue to be affected by the disease, and significant treatment gaps remain. Malaria is a preventable and treatable parasitic disease, transmitted through the bite of infected Anopheles mosquitoes. It is not contagious from person to person through casual contact. Clinical manifestations of malaria vary depending on the species and disease severity, ranging from mild symptoms such as fever, chills, and headache to more severe complications including fatigue, confusion, seizures, and respiratory distress [2, 3]. Infants, young children, pregnant women, travelers, and people with HIV/AIDS are at increased risk of severe illness. Five parasite species cause malaria in humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi [4, 5]. Malaria is primarily spread through infected Anopheles mosquito bites but also via blood transfusions or contaminated needles. Early symptoms can mimic other diseases, making diagnosis difficult. Remaining untreated, P. falciparum malaria, the most dangerous type and prevalent in Africa, can be fatal within 24 h.

This manuscript provides a critical evaluation of the global burden of malaria with specific attention to its economic impact, current prevention and treatment strategies, and alignment with the WHO 2030 malaria elimination goals. It also examines vector control measures, chemoprevention, antimalarial therapies, and the emerging roles of vaccines and monoclonal antibodies, while also reviewing the current socioeconomic and health system challenges in high-burden settings. Overall, it provides an integrated overview of progress, obstacles and opportunities in advancing global malaria control toward achieving the WHO 2030 targets.

For this review, relevant literature was identified through structured searches in PubMed, ScienceDirect, Scopus, Web of Science, and the WHO IRIS repository, covering publications from 1996–2024. Grey literature, including WHO reports, Global Fund documentation, and national malaria surveillance datasets, was also reviewed. Searches used combinations of MeSH terms and free-text keywords such as: “malaria epidemiology,” “high-transmission,” “P. falciparum Africa,” “vector control,” “Anopheles stephensi,” “insecticide resistance,” “LLIN durability,” “IRS effectiveness,” “malaria diagnosis,” “pfhrp2/3 deletions,” “RDT performance,” “artemisinin resistance,” “chemoprevention,” “malaria vaccine,” “climate change” AND malaria.” Inclusion criteria focused on studies addressing epidemiology, diagnostic accuracy, vector biology and control, drug or insecticide resistance, treatment, prevention, and elimination strategies, with emphasis on high-burden African settings. Only English-language sources were included. While formal quality appraisal was not performed, priority was given to peer-reviewed research, authoritative reports, and recent policy documents to ensure accuracy and relevance.

Classification and etiology

As mentioned, malaria is caused by Plasmodium parasites (specifically falciparum, vivax, ovale, and malariae) and is transmitted through the bite of an infected female Anopheles mosquito. During a blood meal, an Anopheles mosquito ingests the sexual stages of the parasite, known as gametocytes (male micro-gametocytes and female macro-gametocytes) [6]. Within the mosquito (the site of the sporogonic cycle), the microgametes fertilize the macrogametes, forming zygotes. These zygotes transform into motile ookinetes, which penetrate the mosquito's midgut wall and develop into oocysts. The oocysts grow, rupture, and release sporozoites that migrate to the mosquito's salivary glands. When the infected mosquito bites a new human host, these sporozoites are injected, restarting the malaria life cycle. The infected mosquito, acting as the primary host, injects sporozoites (a form of the parasite) present in its salivary glands into the bloodstream of the human (the secondary host) during a blood meal. The parasite's life cycle involves both the mosquito and the human [1]. In humans, the parasite initially multiplies in the liver, developing into schizonts. These schizonts eventually rupture, releasing merozoites and infecting red blood cells (RBCs). Within the RBCs, the parasites destroy hemoglobin and alter the shape and flow of the cells, causing them to adhere to blood vessel walls. This process helps the parasite evade the human immune system. This RBC (or erythrocytic) stage of the infection is what causes the symptoms of malaria, which may not appear for several weeks after infection [2, 7]. Figure 1 illustrates the complete malaria parasite life cycle and transmission between mosquitoes and humans, highlighting the mosquito, human liver and human blood stages. Understanding each of these stages is important, especially with the end goal, complete eradication of malaria, in mind.

Fig. 1.

Malaria parasite life cycle (as adapted from CDC-Malaria-About Malaria-Biology, 2024 and created with the Mind the Graph platform) [8]

Malaria is clinically categorized as either uncomplicated or severe based on factors like the host's immune response, the Plasmodium species involved, the rate of parasite multiplication in RBCs, the number of parasites transmitted, and any previous use of preventative medication. Uncomplicated malaria typically presents with mild symptoms, including fever, chills, vomiting, and general malaise. Individuals may recover without treatment or with first-line antimalarial drugs. Severe malaria, most often caused by P. falciparum, affects multiple organ systems, including the central nervous system (resulting in cerebral malaria), kidneys, lungs, and blood system, often leading to severe anaemia. This form of malaria can require hospitalization, cause lasting tissue damage, and be fatal without prompt treatment [9–11].

Malaria and its global health impact

Malaria remains a significant global health issue, affecting over 80 countries with ongoing transmission. According to the latest World Malaria Report, there were 263 million malaria cases in 2023, up from 252 million in 2022. Malaria-related deaths slightly declined, with 597,000 deaths in 2023 compared to 600,000 in 2022. The WHO African Region continues to bear the highest malaria burden, accounting for 94% of all cases and 95% of deaths globally in 2023. Children under five remain the most vulnerable, making up 76% of malaria deaths in the region. Over half of these deaths occurred in just four countries; Nigeria—30.9%, Democratic Republic of the Congo—11.3%, Niger—5.9% and United Republic of Tanzania—4.3% [12, 13].

While the WHO data from 2024 [13] indicates a decrease in death rates compared to 2022, significant numbers of infections persist, particularly in India and 19 African countries, highlighting the need for sustained global and national efforts toward eradication. Malaria prevention is hampered by limited access to resources such as insecticide-treated nets, mosquito repellents, and environmental management practices that reduce mosquito breeding sites.

Countries that achieve zero indigenous (locally transmitted) malaria cases for at least 3 consecutive years are considered to have eliminated the disease. Recent reports state that Malaysia has maintained zero indigenous cases for 6 years, indicating successful elimination. Saudi Arabia and Timor-Leste have reached the 3-year mark, signifying the possible end of malaria epidemics in these two countries. Cabo Verde and Belize were certified malaria-free in 2023 after 4 years of no reported cases and Egypt was also certified malaria-free in 2024. While Malaysia has eliminated human Plasmodium malaria, it still faces challenges with Plasmodium knowlesi. This species causes malaria, which is capable of being transmitted from animals to humans, a unique battle raising concern on a regional and global scale. Plasmodium knowlesi, initially discovered in monkey blood by Giuseppe Franchini, was later isolated and described in detail through experimental studies in primates and humans. Despite early reports of severe disease, it was once used therapeutically for neurosyphilis until deaths halted the practice. Human infections were sporadically reported in the mid-twentieth century, but interest declined until the early 2000 s when large outbreaks were detected in Malaysia and later across Southeast Asia. The region is now a hotspot for P. knowlesi transmission and exportation, raising challenges for malaria diagnosis and control [14]. Figure 2 shows significant progress made in the fight against malaria.

Fig. 2.

World map indicating countries with indigenous malaria cases in 2000 and their status by 2023 [15]

The effect of malaria infection on vulnerable population groups

Certain populations are particularly susceptible to severe malaria, including pregnant women, children, and immunocompromised individuals. During pregnancy, a woman's immune system is naturally weakened, increasing her vulnerability to malaria. Placental malaria, where parasites accumulate in the placenta, disrupts the flow of nutrients and oxygen to the fetus, leading to severe anemia, maternal death, and adverse birth outcomes [16, 17]. Young children, especially those under 5 years of age, have underdeveloped immune systems, making them highly vulnerable to severe malaria, which can rapidly progress to cerebral malaria and severe anemia [18, 19]. Malaria can also impair cognitive development and contribute to long-term health problems in children. Immunocompromised individuals, including those with HIV/AIDS [20], those undergoing chemotherapy, organ transplant recipients, and individuals with chronic diseases like diabetes, have weakened immune systems that are less able to fight off malaria parasites, resulting in more severe and difficult-to-treat infections. The elderly also experience a natural decline in immune function, increasing their susceptibility to severe malaria, and comorbidities common in elderly populations, such as heart disease and kidney disease, can be exacerbated by malaria. Finally, chronic conditions like diabetes can weaken the immune system and worsen the negative effects of malaria infection [21, 22].

In 2022, the WHO estimated 35.4 million pregnancies of which 12.7 million were exposed to malaria [23], while in 2018, 11% of all neonatal deaths in Africa were attributed to malaria infection, despite ongoing efforts to prevent and treat the disease in these vulnerable groups [24]. These deaths highlight the significant maternal mortality burden caused by malaria and underscores the need for improved access to antenatal care, malaria prevention, and treatment services. The 11% statistic demonstrates the devastating impact of malaria on newborns and emphasizes the importance of preventing malaria during pregnancy to protect infants. However, this high percentage of neonatal deaths, even with current prevention efforts, is a striking statistic that indicates that all current preventative efforts are not sufficient.

Malaria infection during pregnancy can lead to several complications for infants, including low birth weight, intrauterine growth retardation, premature birth, and megaloblastic anemia. Low birth weight occurs when malaria impairs placental function, reducing nutrient transfer to the fetus, and these infants are at increased risk of health problems, including developmental delays and increased susceptibility to infections. Intrauterine growth retardation occurs when a fetus fails to grow at the expected rate in the womb and is associated with increased risks of stillbirth, neonatal death, and long-term health problems. Malaria can also trigger premature labor, resulting in infants born before 37 weeks of gestation, who face increased risks of respiratory distress, infections, and developmental disabilities. Additionally, malaria can disrupt RBC production, leading to megaloblastic anemia, a specific type of anemia characterized by abnormally large, immature red blood cells [25].

WHO data indicates that over 11 million pregnant women in sub-Saharan Africa were exposed to malaria in 2018, resulting in 872,000 (16%) infants born with low birth weight due to inadequate malaria management during antenatal care. This number of 11 million exposed women highlights the widespread prevalence of malaria in sub-Saharan Africa and underscores the need for intensified prevention and control efforts in the region. The 872,000 low birth weight infants represent a significant public health burden and emphasize the importance of improving access to and quality of antenatal care services. This statistic further demonstrates the high percentage of mothers who, when exposed to malaria, will have a child with low birth weight [26].

Management and control of malaria

The health consequences as discussed in preceding paragraphs have a significant financial burden, with an estimated $12 billion spent by governments and global organizations in high-transmission areas. This significant investment reflects the global commitment to malaria control and highlights the economic impact of malaria on affected countries and the international community. The management of this disease includes various malaria control measures as outlined in Table 1.

Table 1.

Outline of the various malaria control measures that is being implemented and resulting outcomes [27]

Malaria control measure	Procedures followed or outcome
Vector control	Insecticide-treated nets Indoor residual spraying Larval control Attractive targeted sugar bait (ATSB)
Intermittent preventive therapy (IpT)	Administering antimalarial drugs to vulnerable groups, such as pregnant women and children
Rapid diagnostic tests	Enable prompt diagnosis and treatment
Artemisinin-based combination therapies	Provide effective treatment for malaria infections
Treatment for severe malaria	Manages life-threatening complications
Staff training	Builds capacity among healthcare workers
Health infrastructure strengthening	Improves healthcare delivery systems
Monitoring and evaluation	Tracks progress and identifies areas for improvement
Epidemic response	Contains outbreaks and prevents further spread

Malaria management encompasses both preventative and curative strategies, primarily through chemotherapy. Malaria management are aimed at disrupting the parasite life cycle which may be achieved by reducing the parasite population through effective infection detection using rapid diagnostic tests and microscopy followed by effective antimalaria treatment through drug administration [28]. The global strategy prioritizes prevention, reserving medication for when necessary, due to cost and the risk of drug resistance. Preventative measures, including insecticide-treated nets (ITN), environmental management to reduce mosquito breeding sites, mosquito repellents, and prophylactic medication for travelers to malaria-prone areas, have been widely promoted and implemented [29, 30].

The global health community aims to eradicate malaria, a goal distinct from regional elimination efforts. Malaria control focuses on reducing the disease burden in endemic populations [31]. The WHO certifies countries with zero indigenous cases for 3 consecutive years as malaria-free, a status currently held by 38 countries, with more expected to join as global efforts continue. While these strategies have significantly reduced malaria's impact, challenges persist, including vector adaptation and insecticide resistance, parasite drug resistance, and cross-border transmission. Consequently, malaria control requires multifaceted strategies, as discussed in the following paragraphs, to achieve lasting success [32, 33]

Vector control

Vector management, a key strategy, aims to disrupt transmission by eliminating mosquitoes through insecticides or by modifying their breeding environments (e.g., clearing vegetation and draining stagnant water). Protecting susceptible individuals through insecticide-treated nets (LLINs) and repellents is another crucial approach [29, 30, 34–36]. Overall, the control of vectors should be aimed at vector species, breeding mechanisms, nature of habitats, feeding time and resting time. Interventions must target specific cycles to break the transmission pattern. The predominant transmission vector, Anopheles mosquitoes, are primarily nocturnal feeders and exhibit varying biting times, with some species biting diurnally in shaded areas or crepuscular. A mosquito's host preference (human or animal) and biting location (indoors or outdoors), coupled with the timing of its peak biting activity relative to human behavior, are critical determinants of malaria transmission and the selection of appropriate vector control interventions.

Furthermore, post-feeding, female mosquitoes require rest for blood digestion and egg maturation. Resting behavior, either indoors or outdoors, is species-dependent and influenced by the availability of suitable resting sites. This behavior is also relevant to the selection of effective control measures. Although Anopheles species typically demonstrate characteristic biting and resting patterns, these are not absolute and can vary among subpopulations and individuals due to genetic factors, host and resting site availability, and environmental conditions such as rainfall, moonlight, and wind. Vector control interventions can also modify these behaviors.

Accurate species identification, often requiring molecular techniques due to the existence of species complexes, is paramount for all vector studies and surveillance. Without precise identification, data regarding behavior, distribution, and infection rates are of limited value for informing malaria control strategies [37]. Additionally, Anopheles stephensi, an invasive mosquito species originally from South Asia and the Arabian Peninsula, has been detected in eight African countries. This species now poses new challenges as it thrives in urban settings, withstands high temperatures, and is resistant to many public health insecticides. Its expansion is strongly influenced by rapid urbanisation, which provides diverse artificial aquatic habitats that differ substantially from those used by traditional African vectors. An. stephensi thrives in household water storage containers, such as plastic drums, metal tanks, and jerry cans, which are increasingly common in settings with unreliable piped water. Studies in Ethiopia and Sudan demonstrate that these domestic containers can support An. stephensi breeding year-round, maintaining vector populations even during dry seasons when other species decline [38–40].

Construction activities also play a significant role. Unfinished buildings, overhead tanks, drainage channels, and construction-site pits frequently accumulate water, forming persistent microhabitats that facilitate breeding in expanding urban centers [41]. These sites are often overlooked by routine vector-control programs, enabling rapid establishment and spread. Similarly, peri-urban expansion creates ecologically diverse environments combining informal settlements, agricultural peripheries, and commercial zones that promote An. stephensi proliferation. Poor waste management, unplanned housing, and intermittent water services contribute to stagnant water accumulation, while high human mobility enables parasite movement between urban and rural settings [42].

These factors significantly shape the transmission dynamics of An. stephensi. High-density human populations provide abundant blood hosts, while warmer urban microclimates accelerate mosquito development and shorten the extrinsic incubation period of An. stephensi, thereby enhancing vectorial capacity [43, 44]. Compounding these ecological advantages, An. stephensi exhibits widespread insecticide resistance, especially to pyrethroids, reducing the effectiveness of standard LLINs and IRS interventions [45]. Modeling from the Horn of Africa suggests that its establishment could increase urban malaria cases by 50–125%, potentially reversing years of progress in cities previously considered low-risk [46]. Understanding how all the abovementioned aspects shape the ecology and spread of An. stephensi is therefore critical for designing targeted surveillance systems and tailored control strategies.

Malaria transmission is highly sensitive to climatic variability, with satellite-based observations offering precise, consistent, and timely data to monitor these environmental changes. Rainfall directly influences the hydrology of aquatic habitats that support the development of Anopheles mosquito larvae [47], while temperature and humidity impact key biological processes, including mosquito population growth, parasite development within the vector, and overall transmission efficiency [48]. In addition, climate exerts indirect effects on malaria through its influence on land use patterns, human settlement distribution, and population mobility [49]. Furthermore, climate variability including rising temperatures, changing precipitation patterns, and extreme weather events is altering malaria risk landscapes. Recent studies indicate that temperature and rainfall shifts may extend transmission to new areas, intensify seasonal peaks, and undermine the relative effectiveness of vector control interventions, particularly in older children and beyond under-five age groups [50]. Long-term predictive models now underscore the importance of integrating climatic and socio-demographic variables into routine malaria surveillance and program planning [51].

Vector control plays a crucial role in malaria prevention by reducing mosquito populations and disease transmission. Figure 3 provides a summary of the current vector control strategies. These include LLINs and vector control strategies which are currently not so widely implemented but for which research proves it to be highly effective, namely genetically modified male mosquitoes (GMMs) and attractive targeted sugar baits (ATSBs). The two core interventions currently implemented are:

• Insecticide-treated nets (ITNs)—Provide long-lasting protection against mosquito bites.

• Indoor residual spraying (IRS)—Involves spraying insecticides inside homes to kill mosquitoes.

Fig. 3.

The most common and effective vector control procedures currently being implemented in malaria endemic areas [60, 64]

The application of insecticide-treated nets (ITNs), the choice of the chemicals and the duration of use should have an adequate impact on vectors with minimal risk to humans and animals. However, progress in malaria control is threatened by increasing insecticide resistance among Anopheles mosquitoes. New-generation nets (NGTs), which offer better protection than traditional pyrethroid-only nets, are becoming more widely available to combat this issue. Furthermore, according to NGT developers, the project has produced critical evidence on the efficacy and cost-effectiveness of new dual-insecticide-treated nets (dual-ITNs), aimed at informing WHO policy recommendations and supporting national malaria control programs in selecting the most appropriate net types, particularly in resource-constrained settings. Through its innovative design combining the parallel collection of epidemiological and economic data the New Nets Project is expected to substantially shorten the timeline for market introduction and policy adoption of dual-AI nets [52–54].

In 2022, the Brazilian Ministry of Health introduced the National Malaria Elimination Plan, setting forth a strategic vision to eliminate malaria nationwide by 2035. This initiative outlines specific targets, including the eradication of P. falciparum malaria by 2025 and P. vivax by 2030. A central component of the plan’s vector control strategy is the establishment of a comprehensive program to monitor and manage insecticide resistance in Anopheles mosquito populations. This underscores the critical role of entomological surveillance in supporting malaria elimination efforts and ensuring the rational selection and use of insecticides based on local resistance patterns [55].

Monitoring insecticide resistance is fundamental to informed insecticide selection and serves as a cornerstone of effective resistance management strategies. A structured surveillance system not only facilitates the initial detection of resistance but also enables the longitudinal tracking of resistance dynamics in local mosquito populations. Such insights are essential for tailoring vector control interventions to specific epidemiological contexts. Importantly, as resistance can sometimes be reversed, proactive and strategic resistance management is both a sustainable and cost-effective approach [56].

Researchers are developing various predators targeting mosquito life stages, from larvae and pupae consumed by insects and fish to adult mosquitoes affected by certain plants. Novel approaches also include introducing Wolbachia-infected mosquitoes, using irradiated mosquitoes to replace Anopheles populations, and suppressing dangerous species with GMMs [57, 58]. The WHO supports this strategy [59], as evidenced by the release of over 750 million GMMs (a modified Aedes aegypti strain) in Florida, United States of America in 2021. These GMMs, when mating with wild females, produce offspring that do not reach maturity, thus limiting disease transmission. Similar GMM trials in Brazil and the Cayman Islands have shown no apparent harm. While environmentally promising, widespread GMM implementation would require significant resources across 80+ endemic countries [60].

In another research study GMMs less capable of transmitting malaria were developed. The team introduced a human gene, PAI-1, into mosquitoes. This gene produces a protein that inhibits plasminogen activation, a process the Plasmodium parasite needs to reproduce and spread. Their study demonstrated that mosquitoes with PAI-1, after ingesting infected blood, had significantly fewer oocysts (the parasite's reproductive form) in their guts compared to mosquitoes without the gene (Fig. 3). Adding activated plasminogen to the infected blood, however, allowed the parasite to multiply normally [61].

The researchers then created modified mosquitoes that produced PAI-1 in their guts, salivary glands, or both. This genetic modification did not affect the mosquitoes' lifespan, blood-feeding ability, or reproduction. Critically, it significantly reduced their malaria transmission potential. All three modified mosquito varieties showed fewer oocysts in their guts and drastically lower numbers of sporozoites (the infectious form) in their salivary glands. This reduction wasn’t solely due to fewer oocysts but also because PAI-1 production altered the salivary gland structure, making it harder for sporozoites to penetrate. The researchers were surprised by the significant reduction in sporozoites in the salivary glands, even with a reduced, but still present, number of oocysts in the gut. This suggests an additional barrier to transmission beyond just the reduction in parasite reproduction within the gut, making it even more challenging for the parasite to infect a human host [61].

Although the GMO approach promises significant progress towards ending malaria transmission, the WHO's recommended process for deploying genetically driven modified mosquitoes (GDMMs) as a public health tool involves a phased approach. Widespread implementation will only be considered after rigorous field trials confirm their safety for both human health and the environment and demonstrate their effectiveness in reducing mosquito populations and/or preventing disease transmission. Implementation will involve controlled GDMM production, followed by systematic releases into the target environment [62]. These released GDMMs will interbreed with wild mosquitoes, introducing the modified trait into the local mosquito population for a specific period. National regulatory authorities will oversee and authorize these releases, potentially in conjunction with those responsible for setting national or regional disease control priorities. Post-implementation monitoring will likely be conducted to assess the GDMMs' safety, efficacy, and overall performance in conjunction with other malaria interventions [63].

Attractive Targeted Sugar Baits (ATSBs) highlighted in Table 1, have emerged as a novel and complementary approach to conventional vector control interventions, particularly in response to escalating insecticide resistance and increased outdoor biting behavior among malaria vectors. ATSBs leverage the natural sugar-feeding behavior of mosquitoes, which typically obtain energy from plant nectar and sap. By incorporating a sugar solution with an oral toxicant, these baits attract and kill adult mosquitoes that ingest the formulation. The efficacy of this “attract-and-kill” mechanism has been substantiated in field and semi-field trials, demonstrating not only successful mosquito feeding but also significant reductions in mosquito density [64].

While ATSBs offer considerable promise, their successful deployment at scale will require robust evidence of public health impact, alongside assessments of cost-effectiveness and operational feasibility in diverse ecological and socio-economic settings. It is also important to recognize that ATSBs are not designed to eliminate malaria transmission entirely but rather to complement existing interventions such as insecticide-treated nets and indoor residual spraying by targeting mosquito populations that evade traditional control measures (Fig. 3). As such, ATSBs may help to interrupt the transmission cycle and reduce the overall malaria burden in affected populations [65].

In addition, despite the availability of a wide array of vector control tools, their effectiveness varies considerably across ecological, epidemiological, and socioeconomic settings. Implementation barriers such as weak entomological surveillance systems, inconsistent supply chains for insecticides, and limited operational capacity continue to undermine program effectiveness in many high-burden countries [66, 67]. In regions where vector behavior has shifted toward outdoor or early-evening biting, the impact of indoor-focused interventions such as ITNs and IRS has been significantly reduced [68, 69]. Programmatic gaps also arise from insufficient adaptation of interventions to local species compositions, resistance profiles, and community practices, which can limit uptake and reduce long-term sustainability [70]. Urban settings affected by emerging vectors such as An. stephensi exemplify the need for flexible and context-responsive strategies, as traditional rural-focused interventions have limited applicability [71]. Socioeconomic inequities including inadequate housing, poverty, and variable access to preventive tools further contribute to uneven intervention coverage, disproportionately affecting marginalized communities [72–74]. These challenges highlight that all current malaria control measures have limitations and that vector control cannot rely on singular interventions but instead requires integrated, context-specific approaches strengthened by robust monitoring, community engagement, and sustained investment to ensure equitable and effective malaria reduction across diverse settings [75]. Consequently, drug use for both prophylaxis and treatment will remain essential for reducing disease burden and mortality. Continued focus on vulnerable groups, particularly pregnant women and children under five, is crucial due to their compromised immunity and developmental stage. Adherence to WHO treatment guidelines and implementing sustainable control measures will be necessary for the foreseeable future.

Chemoprophylaxis

Case management, including chemoprophylaxis, early diagnosis, and prompt treatment with antimalarials, also plays a vital role [76]. Despite progress, vaccine development remains a challenge due to the complex nature of the parasite and the human immune response [77]. Preventive chemotherapy involves administering antimalarial medications at specific times to protect high-risk populations from malaria. These strategies complement vector control, early diagnosis, and treatment.

Perennial malaria chemoprevention (PMC)

The WHO recommends perennial malaria chemoprevention (PMC) to protect children up to 2 years old from Plasmodium falciparum malaria in areas with year-round transmission and a parasite prevalence greater than 10% in children aged 2–10 years. This involves administering sulfadoxine–pyrimethamine (SP) at specific ages alongside the Expanded Program on Immunization (EPI), regardless of a child's infection status [78]. The 2022 WHO guidelines significantly updated previous recommendations for intermittent preventive treatment in infants (IPTi) to promote wider use of this safe and affordable intervention, which has been underutilized [79–81]. Several factors contributed to low IPTi uptake, including inconsistent and short-lived protection [82], limited impact on mortality [83], a rigid dosing schedule that didn’t align with varying EPI schedules across countries, unclear eligibility for seasonal settings, and deployment based on parasite genetic biomarkers (which many countries lack). The revised WHO guidelines now recommend PMC timing aligned with a country’s EPI schedule and have removed the restriction of deployment based on parasite genetic biomarker prevalence, given evidence of SP's continued effectiveness against partially resistant parasites (such as those with mutations in the Pfdhfr and Pfdhps genes) [81].

Seasonal malaria chemoprevention (SMC)

In 2012, the WHO recommended seasonal malaria chemoprevention (SMC) for children aged 3–59 months in Africa’s Sahel subregion, characterised by highly seasonal malaria transmission (most cases occurring within 4 months) [84]. SMC involves monthly administration of up to four courses of antimalarial drugs, typically sulfadoxine–pyrimethamine plus amodiaquine (SP + AQ), at the start of the transmission season in areas with a clinical attack rate of at least 0.1 episodes per child and where SP and AQ remain effective.

SMC aims to maintain therapeutic drug levels throughout the peak transmission season, preventing malarial illness. Research has shown SMC to be highly protective against clinical malaria and all-cause mortality in young children during this period. Since the 2012 recommendation, 13 Sahelian countries have implemented SMC, either nationwide or in specific regions. The access-SMC project (2015–2016) supported large-scale SMC implementation in seven countries, distributing over 25 million treatments to more than 7.5 million children in 2016. In 2021, nearly 45 million children received at least one SMC dose, with almost 180 million doses administered [84, 85].

While this scale-up has provided chemoprevention to millions of children, many national malaria control programs are exploring extending the number of treatment rounds to cover longer transmission seasons or expanding the age range to include older children as the malaria burden shifts. Previous reviews found SMC reduced clinical malaria by 74–82% in children under five. The WHO convened a group to update the SMC evidence base and guidelines to address the inclusion of additional at-risk groups and clarify implementation considerations [85].

Intermittent preventive treatment in pregnancy (IPTp)

To protect pregnant women and their unborn children from P. falciparum malaria in areas with moderate to high transmission, the WHO previously recommended a combination of long-lasting insecticide-treated nets (ITNs), prompt diagnosis and treatment of malaria cases, and intermittent preventive treatment in pregnancy (IPTp) with at least two doses of sulfadoxine–pyrimethamine (SP). IPTp with sulfadoxine–pyrimethamine (IPTp-SP) was introduced in Kenya in 1998 [25, 26]. Dihydroartemisinin–piperaquine may also be used in conjunction with SP, depending on individual patient needs [86, 87]. These doses were to be administered after quickening (fetal movement) in the second and third trimesters, before 36 weeks of gestation, and at least in 1-month intervals. Effective IPTp clears maternal parasitemia and prevents reinfection [88–90]. Ghana adopted this IPTp-SP policy in 2003, recommending three tablets of SP three times during pregnancy. However, the effectiveness of SP has decreased due to drug resistance, prompting suggestions for more frequent dosing and this occurrence therefore also strengthening the rationale for the Papua New Guinea study in which azithromycin was added to the IPTp-regimen [91]. A meta-analysis confirmed that three or more doses of IPTp-SP were more effective than two doses only. Consequently, the WHO revised its policy, recommending IPTp be initiated as early as possible in the second trimester and administered at every scheduled antenatal care (ANC) visit until delivery, provided doses are given at least 1 month apart [92]. Ghana adopted this revised policy in 2012, potentially allowing women to receive up to six SP doses. However, the efficacy and safety of more than three doses of IPTp-SP have not been thoroughly studied. Therefore, a study to evaluate the impact of additional SP doses on placental malaria, other malaria indicators, birth outcomes, and safety in pregnant women was done by Dosoo and co-workers [93] and in contrast to previous findings from studies conducted in Ghana [94, 95] and other regions [96], this study found no significant difference in the risk of low birth weight (LBW) among infants born to women who received three or more doses of intermittent preventive treatment with sulfadoxine and pyrimethamine (IPTp-SP). The negative impacts of malaria during pregnancy, including low birth weight, stillbirth, intrauterine growth retardation, and premature birth, are often worsened by co-infection with treatable sexually transmitted infections (STIs) such as chlamydia, syphilis, gonorrhea, bacterial vaginosis, and trichomoniasis [16]. To address these combined risks during antenatal care, childbirth, and the postpartum period for both mother and child, a 2015 Papua New Guinea study exploring the addition of azithromycin to IPTp-SP treatment gained significant attention from the WHO. Azithromycin, a long-acting macrolide antibiotic effective against both bacteria and P. falciparum [91], may also help reduce the development of parasite resistance to SP when used in combination [97]. Commonly used to treat respiratory infections, urinary tract infections, and STIs, and sometimes used in combination with other antimalarials for less severe malaria, azithromycin’s long half-life allows for convenient dosing regimens, such as two 1-g doses daily [98].

Despite IPTp-SP implementation in some sub-Saharan African countries, malaria remains a significant threat due to increasing parasite resistance to these cost-effective drugs [99]. While the exact resistance mechanism is not fully understood, mutations in the dihydrofolate reductase (DHFR) gene, specifically at codon 108, have been implicated. These mutations alter the DHFR enzyme, reducing its affinity for SP [100, 101]. Furthermore, drug toxicity is a concern, as SP has long half-lives (200 and 100 h, respectively), and the increased dosing frequency recommended by the WHO may have pharmacokinetic implications [102].

Intermittent preventive treatment for school-aged children (IPTsc)

Intermittent preventive treatment (IPT) has emerged as a crucial strategy against malaria, particularly in regions with seasonal transmission [103]. IPT, also known as seasonal chemoprophylaxis, involves administering therapeutic antimalarial doses to individuals in high-transmission areas, irrespective of their infection status. Clinical trials have consistently shown IPT's effectiveness in reducing malaria-related illness and death, with a focus on vulnerable children [104]. A 2013 Cochrane review supported IPT implementation for infants and children under five in seasonal transmission areas [105].

A 2009 study examined IPT in school-aged children (IPTsc) using artemisinin-based combination therapies (ACTs), specifically sulfadoxine–pyrimethamine plus artesunate (SP + AS) and amodiaquine plus artesunate (AQ + AS) [106]. The study revealed significant reductions in clinical malaria, asymptomatic parasitemia, and anemia, with SP + AS demonstrating the highest benefit. The study followed the same group of children for two additional years to see if the effects were consistent. While IPTsc during transmission seasons has shown promise in reducing the malaria burden, the long-term efficacy of ACTs in IPTsc has been understudied. This study aimed to evaluate the effects of longitudinal IPTsc in Malian school children, hypothesising that it would continue to positively impact malaria morbidity in this seasonal transmission area [98].

Post-discharge malaria chemoprevention (PDMC)

In June 2022, the WHO added post-discharge malaria chemoprevention (PDMC) to its malaria guidelines. This new intervention aims to reduce readmissions and deaths in children under 5 years of age who have been hospitalised and discharged after recovering from severe anemia in areas with moderate to high malaria transmission. PDMC involves administering complete courses of long-acting antimalarial drugs at set intervals regardless of the child's malaria status [81].

The WHO recommendation is based on a meta-analysis of three trials involving 3663 children. These trials demonstrated that 3 months of PDMC significantly reduced mortality by 77% and all-cause readmissions by 55%. The trials explored three different drug regimens namely; monthly sulfadoxine–pyrimethamine (SP), monthly artemether–lumefantrine (AL), and monthly dihydroartemisinin–piperaquine (DP). The WHO also considered studies on the acceptability, delivery strategies, cost-effectiveness, and modeling of PDMC [98].

The WHO guidelines do not specify a preferred antimalarial drug or delivery strategy, leaving these decisions to national authorities to adapt to local contexts. The recommendation also emphasises the need for further research on optimal PDMC delivery strategies to inform decision-making [107].

Mass drug administration (MDA)

Mass drug administration (MDA) involves distributing drugs to an entire target population, regardless of infection status, for a limited time. While historically infrequently used for malaria control, this approach is gaining renewed attention as a tool to clear asymptomatic infections and rapidly reduce transmission. However, robust studies, such as cluster-randomized trials, are limited [108].

In 2015, the WHO’s Malaria Policy Advisory Committee recommended MDA for specific scenarios: near-interruption of transmission with high coverage of other interventions, accelerated elimination in the Greater Mekong Subregion due to multidrug resistance threats, and malaria epidemics or complex emergencies. National malaria control programs must determine MDA's role in their strategies and establish optimal operational methods and integration with other interventions [109].

To inform the WHO’s decision, an evidence review group synthesised existing research, including field trials, retrospective analyses, and mathematical modeling. Mathematical models are valuable for assessing MDA's potential in various settings. The Malaria Modelling Consortium compared findings from four established models (OpenMalaria, EMOD DTK, Imperial, and MORU) to evaluate their effectiveness in different contexts. Model development involves defining structure, parameters, and assumptions, validating against epidemiological data, and addressing uncertainties [110]. OpenMalaria models focus on simulating malaria transmission, interventions, and health system interactions at individual and population levels. This predicts that malaria vaccines can significantly reduce clinical incidence and mortality, particularly when combined with other interventions (e.g., bed nets, IRS), shows greater impact when vaccines are administered in areas of moderate to high transmission and demonstrated the importance of coverage and timing, especially for RTS,S and future vaccines. EMOD DTK (Institute for Disease Modeling), is an agent-based model that simulates detailed human and mosquito behavior and malaria transmission. It highlights the sensitivity of vaccine impact to individual behaviors and local transmission dynamics, EMOD scenarios emphasize that long-lasting vaccine efficacy and high coverage are key to achieving elimination in low-transmission settings and shows that combining vaccines with mass drug administration (MDA) could dramatically accelerate transmission reduction [111]. On the other hand, the Imperial Model (Imperial College London) looks at semi-mechanistic models of transmission that focuses on population-level immunity and intervention effects. It demonstrates that RTS,S can have the greatest population-level impact in areas of moderate transmission, suggests timing of doses (especially the fourth booster) is crucial to maintain efficacy and found that integration of vaccine with seasonal malaria chemoprevention (SMC) could be highly synergistic in Sahel regions [112]. The MORU Model (Mahidol Oxford Tropical Medicine Research Unit) looks at the dynamic transmission model focused on Southeast Asia and elimination contexts. This model predicts limited standalone benefit of vaccines in very low transmission or near-elimination settings, supports vaccine deployment in targeted campaigns (e.g., outbreak responses or travel hubs) and shows vaccines can help delay resurgence after withdrawal of other interventions (like IRS) [113]. Overall, all four models agree that malaria vaccines, especially RTS,S and next-gen candidates, offer meaningful reductions in disease burden but optimal results depend heavily on high coverage, strategic timing, and integration with existing interventions. Each model brings a unique perspective depending on geography, intervention combinations, and transmission intensity.

Chemoprevention strategies demonstrate strong efficacy in clinical trials but face operational, biological, and social limitations. Drug resistance, adherence challenges, health system capacity, and variations in transmission patterns complicate sustained impact. Integration with vector control, early diagnosis, and supportive public health interventions is essential. Continuous surveillance, adaptive implementation, and context-specific planning remain critical to ensure chemoprevention contributes meaningfully to malaria control and eventual elimination.

Malaria treatment

Quick access to diagnostics and antimalarial treatments is essential in managing and minimising morbidity and mortality associated with malaria-infected persons. Accurate diagnosis is foundational to effective malaria control, yet real-world diagnostic performance is constrained by multiple, interacting problems. First, a substantial and often hidden reservoir of low-density/subclinical Plasmodium infections escapes routine detection by standard HRP2-based rapid diagnostic tests (RDTs) and microscopy, undermining surveillance and elimination efforts [114, 115]. Second, increasing prevalence of pfhrp2/pfhrp3 gene deletions has produced clusters of HRP2-negative infections that generate false-negative RDT results; WHO now recommends molecular surveillance and transitioning to non-HRP2 diagnostics once deletion prevalence reaches critical thresholds [116, 117]. These two diagnostic limitations together create both under-ascertainment of cases and delayed or inappropriate treatment, perpetuating transmission pockets. A growing threat to malaria diagnosis stems from documented deletions in the pfhrp2 and pfhrp3 genes, which render the commonly used HRP2-based rapid diagnostic tests ineffective. In several endemic settings including recent data from South Sudan showing deletion frequencies of 15.6% (pfhrp2), 20.0% (pfhrp3) and 7.5% double deletions HRP2-negative parasites have already resulted in significant false-negative rates [118]. This has prompted the WHO to update its “Response Plan to pfhrp2 deletions,” advising prompt transition to non-HRP2 diagnostics where prevalence exceeds predefined thresholds, and stressing the need for continuous molecular surveillance [119].

Surveillance systems face both structural and operational weaknesses that reduce the timeliness and reliability of data. Many national programmes rely on paper-based reporting, have fragmented data streams between community health workers and facilities, and lack integrated laboratory networks for molecular monitoring of resistance markers and deletion prevalence [13, 120]. The COVID-19 pandemic exposed and exacerbated these vulnerabilities: disruptions to routine services and supply chains in 2020–2021 were estimated to have caused millions of additional malaria cases and tens of thousands of excess deaths in sub-Saharan Africa due to reduced diagnosis and treatment access [121]. Countries that invested in integrated digital surveillance and rapid response (for example, scaling IDSR and public-health emergency operations centres) were better positioned to maintain essential services [122].

Health-system bottlenecks further limit implementation. Frequently encountered constraints include inconsistent supply of RDTs, antimalarial drugs, LLINs, and insecticides, weak cold-chain or logistics infrastructure, shortages of trained laboratory and entomology staff, and inadequate financing that forces policy trade-offs [13]. Human-resource shortages are particularly acute in rural and conflict-affected areas, where staff turnover and limited supervision lead to variable adherence to diagnostic algorithms and treatment guidelines. In short, gaps in financing, logistics, and workforce capacity convert technical tools into unreliable programmatic outputs. Translating trial-proven tools into population-level impact requires attention to context and operations. First, supply chain failures and mismatched procurement cycles produce intermittent stockouts of diagnostics and antimalarials, which drive inappropriate empirical treatment or missed cases. Second, behavioural and community factors such as limited healthcare-seeking, distrust of health services, inconsistent net use, and improper net-care practices substantially reduce the effectiveness of LLIN campaigns and chemoprevention programs [13, 123]. Third, biological and ecological changes including HRP2 deletions, insecticide resistance, and invasive vectors like Anopheles stephensi interact with implementation gaps to amplify failures: a net distribution campaign will have little impact where HRP2-negative infections are common and RDTs fail to detect cases, or where pyrethroid resistance makes LLINs less lethal to vectors.

Emergency contexts and climate shocks add further complexity. Floods, conflict, and population displacement both increase exposure risk and disrupt routine services; [13]. Finally, funding shortfalls mean that many programmes cannot implement the iterative monitoring and adaptive management needed to tailor interventions to local entomology, diagnostics performance, or emerging resistance patterns; in 2023 global malaria financing met only a fraction of estimated needs, constraining operational flexibility [13].

Uncomplicated malaria treatment

An improvement in first-line malaria therapy was reached by replacing or adding ACT to SP. Initially, in 2015 the WHO recommended four artemisinin-based combination therapies (ACTs): artesunate combined with SP, amodiaquine, or mefloquine, and artemether combined with lumefantrine. Subsequently, dihydroartemisinin–piperaquine and artesunate–pyronaridine have been added to the recommended ACTs [124]. ACT has been the first-line drug treatment approach since it became the cornerstone of malaria treatment in 2001. ACT combines artemisinin for rapid parasite reduction with a partner drug to ensure a complete cure. However, the emergence of antimalarial drug resistance, where parasites survive standard treatment doses, poses a significant threat to malaria control efforts [125].

Specifically, partial artemisinin resistance, associated with Pfkelch13 gene mutations, has recently been observed in several African countries, resulting in prolonged parasite clearance times. While artemisinin partial resistance alone does not lead to ACT treatment failure when the partner drug remains effective, the development of resistance to partner drugs would critically compromise ACT's effectiveness. To mitigate this risk, the WHO launched a drug resistance response strategy for Africa in 2022. This strategy focuses on enhancing detection, enabling timely responses, and minimising the impact of resistance through evidence-based interventions [66]. Additionally, an effort to accelerate the elimination of P. falciparum malaria and mitigate the threat of emerging artemisinin resistance in the Greater Mekong Subregion, mass drug administration (MDA) strategies involving DP in combination with a single low dose of primaquine have been evaluated through prospective clinical studies and showed positive impact in the management of malaria [126].

Severe malaria treatment

Individuals exhibiting any signs of severe malaria, such as impaired consciousness or a comatose state, hemoglobin levels below 7 g/dL, acute kidney injury, acute respiratory distress syndrome, circulatory collapse, shock, acidosis, jaundice accompanied by other severe malaria symptoms, disseminated intravascular coagulation, or a parasite density of 5% or higher, require immediate and aggressive treatment with parenteral antimalarial therapy, irrespective of the Plasmodium species identified in the blood smear. Even if a laboratory diagnosis is initially unavailable, but severe malaria is strongly suspected, a blood sample should be collected for diagnostic testing as soon as possible, and parenteral antimalarial drugs should be administered without delay. In addition, patients undergoing treatment for severe malaria should have blood smears (both thick and thin) taken upon admission and every 12 to 24 h until a negative result is obtained, indicating the absence of Plasmodium parasites [66].

An intravenous therapy should commence immediately for patients who are unable to take oral medications necessitating hospitalization and emergency management, including airway assessment, oxygen administration, and parenteral antimalarial therapy where applicable [127]. If referral to a facility capable of intravenous treatment is delayed beyond 6 h, pre-referral treatment with intramuscular artesunate, artemether, or quinine, or rectal artesunate (10 mg/kg single dose) is recommended. Subsequently, the patient should be referred to a facility for complete parenteral treatment. If referral is impossible, rectal treatment should continue until oral medication is tolerated, followed by a full course of the recommended ACT for uncomplicated malaria [128].

Hospitalization is indicated for cerebral malaria, severe anemia, hemoglobinuria, renal failure, pulmonary edema, coagulopathy, severe thrombocytopenia, shock, high parasitemia, metabolic acidosis, hypoglycemia, intractable vomiting, dehydration, seizures, or altered consciousness. Respiratory distress and impaired consciousness are poor prognostic indicators necessitating immediate parenteral antimalarial treatment. Intravenous diazepam should be administered for seizures lasting over 5 min, even if less efficacious in non-malaria-associated seizures [129].

Parenteral treatment options for severe malaria include cinchona alkaloids (quinine and quinidine) and artemisinin derivatives (artesunate, artemether, and artemotil). However, the AQUAMAT trial, a multi-center study in African children with severe malaria, demonstrated a significant 22.5% mortality reduction with artesunate compared to quinine. This superiority of parenteral artesunate is also supported by the latest Cochrane Review for both adults and children across various regions [11].

Artesunate offers additional advantages, including ease of administration (no cardiac monitoring) and reduced incidence of post-discharge convulsions, coma, and hypoglycemia. The recommended treatment for children is artesunate 2.4 mg/kg IV or IM on admission, followed by doses at 12 and 24 h, and then once daily. Artemether (3.2 mg/kg IM on admission, then 1.6 mg/kg daily) or quinine (20 mg salt/kg IV or IM on admission, then 10 mg/kg every 8 h, with an infusion rate not exceeding 5 mg salt/kg per h) are acceptable alternatives if parenteral artesunate is unavailable [127, 130].

Children with severe malaria-associated anemia may require blood transfusion. Platelet transfusions for thrombocytopenia are generally not recommended due to the lack of associated bleeding problems in children. Blood glucose should be monitored every 4 h, and hemoglobin and parasite counts should be assessed daily. Furthermore, empirical parenteral antibiotic treatment with a third-generation cephalosporin or a quinolone is recommended due to the increased frequency of co-infection with malaria and multidrug-resistant gram-negative bacteria, such as non-typhoidal salmonellae, which may not be consistently identified by current WHO guidelines [131].

A key strategy to address current gaps in malaria treatment is the identification and repurposing of U.S. FDA-approved therapeutics that exhibit antimalarial activity, thereby facilitating a more efficient development process [132]. For instance, a recent Phase 2 clinical trial evaluated the addition of the FDA-approved chemotherapeutic agent imatinib to the standard of care for treating P. falciparum malaria in adult male patients (excluding females due to unknown effects on pregnancy). The results were promising: no increase in the number or severity of adverse events was observed, and a significantly faster reduction in parasite density and fever was achieved without evidence of delayed parasite clearance [133]. Additionally, antibiotics such as macrolides, quinolones, lincosamides, and tetracyclines are also of considerable interest as alternative antimalarial therapies. These agents act through different mechanisms compared to conventional antimalarial drugs and may simultaneously address co-existing bacterial infections [134]. Omadacycline, a novel aminomethylcycline belonging to the tetracycline class, has been approved in the United States for the treatment of adult patients with community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It is available in both oral and intravenous formulations [135]. Omadacycline was developed to overcome key bacterial resistance mechanisms to tetracyclines, including efflux pumps and ribosomal protection proteins. Notably, it retains efficacy against pathogens expressing Tet(M), a ribosomal protection protein associated with doxycycline resistance. Furthermore, its application as a potential antimalarial prophylactic drug, showed superior antimalarial activity compared to doxycycline, demonstrating enhanced efficacy against liver-stage parasites in vitro, overcoming resistance during the blood stage, and improving survival outcomes in an in vivo Plasmodium berghei infection model. These results underscore the potential of omadacycline as a promising candidate for further development in malaria prophylaxis and therapeutic strategies [136].

Antimalarial drug resistance continues to jeopardize malaria control across Africa as Plasmodium falciparum populations adapt under sustained therapeutic pressure. Although artemisinin-based combination therapies (ACTs) remain largely effective, the emergence of artemisinin partial resistance has become increasingly evident. Delayed parasite clearance has been strongly associated with mutations in the Pfkelch13 propeller domain particularly variants such as R561H, C580Y, and R539T which impair ring-stage sensitivity to artemisinin [137]. These Pfkelch13 mutations have now been documented in several African countries, with East Africa reporting the highest frequencies and noticeable reductions in parasite clearance half-life [138]. Although partner drugs still maintain adequate therapeutic efficacy, the rising prevalence of artemisinin-associated mutations raises concerns about the long-term robustness of ACT regimens. Resistance to sulfadoxine–pyrimethamine (SP) is widespread and is underpinned by well-characterised point mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes. The dhfr triple mutation (N51I, C59R, S108N), combined with dhps A437G and K540E, forms the so-called “quintuple mutant,” which correlates strongly with SP treatment failure [101]. In some settings, the emergence of an additional dhps mutation (A581G) produces the “sextuple mutant,” significantly diminishing the protective effectiveness of SP used in intermittent preventive treatment in pregnancy (IPTp) and threatening its utility in seasonal malaria chemoprevention (SMC) [139, 140]. These high-level resistance profiles are particularly prevalent in East and Southern Africa, while parts of West Africa still report lower frequencies of the quintuple and sextuple haplotypes, allowing SP to retain partial preventive efficacy [141].

Insecticide resistance also interacts with malaria epidemiology, primarily through metabolic mechanisms affecting vector survival. Overexpression of cytochrome P450 enzymes such as CYP6P3 widely documented in Anopheles gambiae confers substantial resistance to pyrethroids, undermining the performance of insecticide-treated nets (ITNs) [45]. Although this mechanism does not directly influence antimalarial drug resistance, it contributes to sustained transmission risk by reducing vector mortality and increasing the probability of human–mosquito contact. Integrating metabolic resistance markers with entomological impact assessments is therefore critical for interpreting intervention outcomes.

Regional variation in drug resistance across Africa reflects differences in historical drug use, malaria transmission intensity, and vector population structure. East Africa has reported increasing prevalence of artemisinin-partial-resistance Pfkelch13 mutations along with evidence of slower parasite clearance [137, 138]. Southern Africa exhibits some of the highest levels of SP resistance due to widespread quintuple and sextuple dhfr–dhps haplotypes, limiting the feasibility of SP-based preventive approaches [139, 142]. Conversely, West and Central Africa maintain comparatively lower frequencies of high-risk Pfkelch13 variants and retain largely effective ACT partner drug activity, although rising drug pressure necessitates enhanced molecular surveillance [140]. Collectively, these patterns highlight the importance of integrating molecular marker monitoring with therapeutic efficacy studies to guide evidence-based updates to national malaria treatment policies.

Vaccines and monoclonal antibodies

The efforts to develop a malaria vaccine began in the 1960 s, but significant progress has been made in the past decade. A major milestone was reached on October 6, 2021, when the WHO recommended the RTS,S/AS01 (RTS,S) malaria vaccine for widespread use among children in sub-Saharan Africa and other regions with moderate to high P. falciparum malaria transmission [143, 144]. This recommendation followed the success of the RTS,S malaria vaccine for children, Malaria Vaccine Implementation Programme (MVIP) in Ghana, Kenya, and Malawi. The MVIP, a collaborative effort involving WHO, national health ministries, PATH, United Nations Children’s Fund (UNICEF), GSK, Global Alliance for Vaccines and Immunization (GAVI), the Global Fund, and Unitaid, demonstrated the vaccine's effectiveness. The vaccine’s introduction in these countries led to a 13% reduction in overall child mortality, highlighting malaria’s significant contribution to child deaths in high-burden areas. Over 3 million children have received the RTS,S vaccine in these three countries. Two years later, the WHO recommended the use of both RTS,S and R21/Matrix-M vaccines for P. falciparum malaria prevention in children living in malaria-endemic areas, with a focus on regions with moderate to high transmission [145].

The recommended malaria vaccine schedule involves four doses, starting around 5 months of age, though flexibility exists based on program logistics. A fifth dose, administered a year after the fourth, may be considered in regions with highly seasonal transmission or persistent high malaria risk. Vaccination strategies can be tailored to local transmission patterns. In areas with marked seasonal malaria transmission or perennial transmission with seasonal peaks, countries can employ age-based, seasonal, or hybrid administration approaches. Vaccination should primarily target areas with moderate to high malaria transmission. However, countries may consider expanding to low-transmission settings, factoring in their overall malaria control strategy, cost-effectiveness, affordability, and operational feasibility. It further emphasises that malaria vaccines should be integrated into a comprehensive malaria control strategy, not used as a standalone solution [146].

WHO, GAVI, UNICEF, and other partners agree with African governments and healthcare workers to introduce and expand malaria vaccination programs. Furthermore, in January 2024, the WHO Regional Office for Africa launched the “Accelerating Malaria Vaccine Introduction and Rollout in Africa (AMVIRA)” initiative. AMVIRA aims to assist African Member States in launching and expanding malaria vaccination programs, focusing on strengthening technical support and providing countries with the necessary expertise to effectively and efficiently implement malaria vaccination, enhancing partner coordination to improve collaboration among national, regional, and global partners involved in malaria vaccine rollout [145].

These safe and cost-effective strategies enhance malaria control efforts, helping to reduce infections and severe cases. Antibodies can confer protection against malaria by neutralizing P. falciparum sporozoites in the skin and bloodstream before they reach and infect hepatocytes in the liver [147]. The P. falciparum circumsporozoite protein (PfCSP) the most abundant surface protein on the sporozoite is essential for parasite motility and hepatocyte invasion, making it a key target for neutralizing antibodies and subunit vaccine design. PfCSP comprises three primary domains: an N-terminal domain, a central region rich in repetitive NANP tetrapeptides, and a C-terminal domain. While most known neutralizing monoclonal antibodies against PfCSP target the central NANP repeat region, previous studies identified a novel epitope of vulnerability encompassing the NPDP tetrapeptide located at the junction between the N-terminal and central repeat region as shown in Fig. 4 [148–150]. This epitope was characterized through binding assays involving CIS43, a human monoclonal antibody isolated from a clinical trial participant immunized with an attenuated P. falciparum whole-sporozoite vaccine. CIS43 demonstrated a strong binding preference for the junctional NPDP region and showed potent protective efficacy in multiple preclinical murine models of malaria infection. Moreover, this epitope was found to be highly conserved in 99.9% of over 6500 P. falciparum field isolates analyzed [151, 152].

Fig. 4.

Schematic representation of the binding sites for PfCSF antboies (Adapted with permission from [148])

To enhance its pharmacokinetic properties for clinical use, CIS43 was engineered into CIS43LS via site-directed mutagenesis of the Fc region. This involved substituting methionine with leucine and asparagine with serine to improve neonatal Fc receptor (FcRn)-mediated recycling, thereby extending the antibody’s plasma half-life [153]. Furthermore, eliminating the morbidity, mortality, and economic burden associated with malaria will require the development and implementation of additional preventive strategies. One promising approach is the passive administration of highly potent monoclonal antibodies with extended half-lives, which can provide long-lasting protection from infection through a single dose tailored to the duration of required immunity. Monoclonal antibodies have already received approval or emergency use authorization for the prevention and treatment of various viral infections, including those caused by respiratory syncytial virus (RSV), Ebola virus, and severe acute respiratory syndrome coronavirus (SARS-CoV), demonstrating the viability of this strategy in infectious disease control [152].

Gaps in malaria management

Global impact

The global fight against malaria faces an annual funding shortfall of approximately $4.3 billion, hindering the distribution of preventive tools, such as insecticide-treated bed nets and essential medicines [154]. A 2019 study highlighted that the WHO reported global expenditures on malaria including both governmental and out-of-pocket spending were estimated at $4.3 billion [95% uncertainty interval (UI): 4.2–4.4] in 2016 [155]. This reflects an average annual increase of 8.6% (95% UI: 8.1–8.9) compared to spending levels in 2000. These estimates were primarily derived from national accounting systems across 106 countries and encompassed costs related to both malaria prevention and treatment [156].

Environmental factors

Rising temperatures and extreme weather events, like floods, create favorable conditions for mosquito breeding, leading to increased malaria transmission. For instance, recent floods in Pakistan have exacerbated malaria outbreaks. Among the various strategies employed to control mosquito vectors, environmental management and larval control interventions have proven effective in reducing mosquito populations and interrupting transmission across broad geographic areas. However, these approaches have shown limited success in addressing residual transmission foci. Their large-scale implementation is often constrained by the requirement for detailed knowledge of the ecological characteristics and breeding site dynamics specific to local vector populations, a challenge particularly relevant in residual foci. Since the global resurgence of malaria control efforts in 2000, LLINs and IRS have emerged as the most effective and widely implemented interventions [28]. At the same time, the assumed 3-year lifespan of long-lasting insecticidal nets (LLINs) has come under scrutiny. Field durability studies such as a recent large-scale evaluation in Ethiopia show a median functional survival time of only 19 months under real-world conditions, with rapid physical attrition and loss of insecticidal efficacy [157]. This discrepancy between assumed and actual net survival creates critical protection gaps if replacement cycles follow standard intervals. Additionally, evolving vector behaviour, insecticide resistance, and the emergence of residual transmission highlight the limitations of relying solely on LLINs and indoor residual spraying (IRS). As biting shifts outdoors or early evening, and vector species diversify, interventions must broaden beyond indoor-based methods. Integrated vector management combining larval source reduction, environmental sanitation, community participation, and novel tools like attractive toxic sugar baits is becoming increasingly necessary to address persistent transmission hotspots.

Socioeconomic challenges

Conflicts and forced displacements hinder access to preventive measures, such as bed nets, and essential treatments, disproportionately affecting vulnerable populations. Inadequate access to prompt and effective treatment remains a major issue, particularly for the poorest populations. Barriers related to affordability, acceptability and availability of treatment persist. These include lack of funding for treatment, transport costs, unofficial payments, and distrust in care quality [158].

Healthcare system limitations

Despite the development of effective vaccines like RTS,S and R21, financial constraints limit widespread immunisation efforts. Organisations such as GAVI face budget limitations, hindering the full utilisation of available vaccine doses.

Drug availability remains a critical determinant of access to effective malaria treatment. A survey conducted in Kenya during which individuals who sought care at public health facilities within the 2 weeks preceding the study were asked whether they received the full course of prescribed medications directly from the facility’s pharmacy. Findings revealed that 95 participants (30.0%) did not obtain the prescribed medications at the point of care and were instead issued prescriptions to purchase drugs from private pharmacies. Among this group, only 31 individuals (32.8%) reported that they were able to buy the prescribed drugs. Additionally, exit interviews conducted at health facilities indicated that 140 respondents (38.8%) did not receive any medication due to stockouts at the facility. These consistent shortages of anti-malarial drugs in the public sector discourage timely and appropriate treatment-seeking behaviours [158].

The emergence of resistance to treatments such as artemisinin and insecticides like pyrethroids threatens the efficacy of current malaria control strategies. Additionally, most drugs used in managing malaria are associated with poor aqueous solubility, leading to high dosage requirements and imposing a risk of toxicity on patients. The elimination of malaria necessitates a comprehensive approach involving the integration of key interventions such as strengthened vector control, optimized case management, and enhanced surveillance systems each playing a critical role in identifying, characterizing, and monitoring all malaria cases [159]. When assuming effective case management defined by universal access to accurate diagnosis and efficacious treatment the persistence of malaria is often attributed primarily to shortcomings in vector control. Such failures may stem from suboptimal implementation of vector control strategies, limited exposure of mosquitoes to the insecticidal agents used, or challenges related to community acceptance and participation in the deployment and maintenance of these interventions [28].

Addressing these gaps requires increased funding, innovative solutions to counteract environmental changes, equitable healthcare access, efficient vaccine distribution, and formulating drugs in a system that enhances their solubility to improve their bioavailability, including continuous monitoring of drug and insecticide resistance patterns.

Conclusion

A comprehensive review of malaria epidemiology, diagnosis, prevention, treatment, and the associated progress and challenges in the high transmission malaria zone, aiming to foster global awareness and contribute to the broader goal of malaria elimination across Africa and worldwide has been provided. Malaria continues to impose a significant public health burden globally with a higher proportion in the African continent malaria zone, particularly due to P. falciparum, the most virulent and lethal species. Although various international health organizations have supported the implementation of effective malaria control strategies resulting in notable reductions in both morbidity and mortality, several persistent challenges remain. These include Africa’s unique climatic conditions, widespread poverty, high population mobility, and the rising prevalence of drug and insecticide resistance. To meet the MDGs, it is imperative that African governments, with support from international partners, increase investments in healthcare infrastructure, enhance malaria diagnostic capacity, prioritize the development of new antimalarial drugs, enhance treatment and vaccine coverage and strengthen surveillance. Universal access to IRS and LLINs should be ensured, particularly among high-risk groups such as women and children. Free diagnostic testing and treatment services must be made widely available for pregnant women and children, and prophylactic measures should be extended to foreign travelers and aid workers to help contain the global spread of malaria. Adoption of strategies such as stringent surveillance for malaria cases, prompt case reporting systems, diagnosis and treatment, already implemented by other countries such as China, underscores the importance of sustained and deepened global-Africa collaboration.

A successful path toward malaria elimination requires stronger alignment with the WHO Global Technical Strategy 2024–2030, emphasizing adaptive vector control, climate-responsive early-warning systems, enhanced diagnostic reliability, and improved performance of prevention tools such as LLINs. Key research priorities include tracking resistance trends, evaluating next-generation vector-control technologies, optimizing chemoprevention and vaccination, and improving interventions for urban malaria. Sustained surveillance, equitable access to prevention and treatment, and continued innovation are crucial for addressing emerging threats, building resilient health systems, and achieving the 2030 global malaria reduction and elimination targets.

Abbreviations

ACTs

Artemisinin-based combination therapies

AL

Artemether–lumefantrine

AMVIRA

Accelerating Malaria Vaccine Introduction and Rollout in Africa

DP

Dihydroartemisinin–piperaquine

EPI

Expanded Program on Immunization

GAVI

Global Alliance for Vaccines and Immunization

GDMMs

Genetically driven modified mosquitoes

GMMMs

Genetically modified male mosquitoes

IPT

Intermittent preventive treatment

IPTi

Intermittent preventive treatment in infants

IPTp

Intermittent preventive treatment in pregnancy

IPTsc

Intermittent preventive treatment for school-aged children

IPTp-SP

IPTp with sulfadoxine–pyrimethamine

IRS

Indoor residual spraying

LLINs

Long-lasting insecticidal nets

MDA

Mass drug administration

MDGs

United Nations Millennium Development Goals

MVIP

Malaria Vaccine Implementation Programme

NGTs

New-generation nets

RBC

Red blood cells

P. falciparum

Plasmodium falciparum

PDMC

Post-discharge malaria chemoprevention

PMC

Perennial malaria chemoprevention

SP + AS

Sulfadoxine–pyrimethamine plus artesunate

SP

Sulfadoxine–pyrimethamine

SMC

Seasonal malaria chemoprevention

UNICEF

United Nations Children’s Fund

WHO

World Health Organisation

Author contributions

GO: Conceptualised the manuscript, major contributor in writing the manuscript. MA: Provided editorial input, contributed towards the writing and editing of the manuscript. All authors read and approved the final manuscript.

Funding

No funding to declare.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.