One Health Perspective of Malaria Transmission

Abstract

Global efforts towards malaria control and elimination are promising. Despite this, current alterations in transmission continue to modify and frustrate such effort. In 2020 and 2021, malaria transmissions increased significantly. While 2021 showed a decline in malaria deaths by 6000 (1%), the numbers were still 51,000 (9%) higher than malaria deaths in 2019. Two-thirds of the contributing factors were attributed to the COVID-19 pandemic, thus demonstrating the capability of future pandemics and zoonotic diseases to stagger or derail earned achievements towards malaria elimination. Compounded by zoonotic and environmental factors that promote malaria transmission, there will be a need for relevant modelling and an update on current and past disease distribution information and will also be required to shape policy actions and to improve public health decision-making on malaria. These will help strengthen the evidence for the adoption of relevant implementation strategies to aid the 2030 vision of eliminating malaria a reality.

1. Introduction

Malaria is an ancient disease of public health concern, which has scourged and threatened humanity for many centuries till today. The nemesis of it was estimated to be over 400 million deaths recorded globally within the 20th century alone [1]. Archaeological artefacts and relics of clay tablets, papyrus, religious and medical texts, parasite DNA detections in mummified remains, modelled ancient seasonal and climatic indicators are chest of trove suggesting that the disease has since been known perhaps during the Palaeolithic and Neolithic era [2, 3, 4, 5, 6]. The means of disease transmission remained elusive until the discovery of the malaria parasite by Charles Alphonse Laveran in 1880 and the related transmission vector by Sir Ronald Ross in 1897.

Preceding Laveran and Ross’s findings are remarkable leads. These include a 270 BC Chinese canonic account in the “Huangdi Neijing” describing periodic fevers associated with enlarged spleen and prescriptions of Qinghaosu (Artemisinin) for treatment [7, 8, 9, 10]. The Greeks also linked malaria with swampy and marshy environments [1, 9]. Further observed cases of tertian and quartan fevers reported by Hippocrates (460–370 BC), Celsius and Galen were high during the late summer and autumn seasons and coincided with the appearance of Sirius – the dog star illustrated by Homer in his epic [5, 9, 11, 12]. Gleaning from the Greeks, theories of Miasma emerged, with the Romans also attributing the disease transmission to either drinking marsh water or another positing the cause to be due to inhaled vapours from marshes [1, 9, 13]. During these periods Robert Koch introduced the Koch postulate in the era of the germ theory. This led to a new wave of infectious disease research meant to identify and relate pathogens such as the malaria parasites to the respective diseases.

Leveraging on the advances made in infectious disease research and the observation that there were other low malaria transmission areas with no swamp or marsh, Laveran observed and described the malaria parasite from the blood of malaria patients in Algeria in 1880 [14, 15, 16]. His initial finding was first met with scepticism not until 1896 when he further produced inevitable proof, which corrected the erroneous competing ideas of Ettore Marchiafava and Augusto Celli’s attribution of the disease to a bacterium they named Bacillus malaria [13, 14, 17]. Entry of Plasmodium species into humans now became a subject of interest with the initial hypothesis suggesting a possible involvement of Mosquitoes as mooted by Sir Patrick Manson.

Inspired by the work of Laveran and Manson, Ross started his work to prove Manson’s hypothesis at Secunderabad in India [18, 19, 20]. When confronted with a shortage of experimental samples after his posting to Calcutta, Ross resorted to the use of avian malaria models for his studies and this largely gave clues to his discovery [14, 19, 20]. Ross in 1897 established the involvement of mosquitoes in the transmission cycle and described the sexual developmental stages of Plasmodium within the mosquito [18, 19, 20]. This disproved the aspect of Manson’s hypothesis, which suggested that the parasite-infected via an oral route through drinking water infested with the malaria parasite. It further disproved the postulate that transmission was by inhaling bad air from swamps [14, 19, 20]. Grassi and co-workers in 1898 also established that human malaria is solely transmitted by the female Anopheles mosquito [18, 19, 20]. Building on Ross’ publications the team characterised the mosquito species (Anopheles claviger), which was involved in the transfer of the Plasmodium parasite and also described the sporogony stage of human Plasmodium [18, 19, 20].

2. Global malaria trends in pre- and post-COVID era

Past accounts of malaria and its transmissions were dealt with on a local basis and the clarity we have today was a bit blurred in those times. Increased knowledge of malaria and a much-coordinated global effort garnered in the battle against malaria within the early 1900s are yielding fruit today. However, this global effort has been met with various successes and challenges, that have reshaped previous strategies designed to meet milestone targets set from the period of millennium development goals (MDG) through to the current sustainable development goals (SDG). The success of the new wave of revolution against malaria is the disease eliminated in Europe and certain regions of the world as well as a massive decline in deaths due to the disease. In 2021, COVID-19 was estimated to have accounted for two-thirds of the challenges that were raised to have affected targeted milestones for malaria making it important to review the period in question.

Considering the global report on malaria from 2019 to 2022, the burden of malaria is still high showing an increase of 16 million more malaria cases reported in the post-COVID era than in the pre-COVID period (2018) [21]. A global outlook on malaria case fatality rate (CFR) shows a moderately stable CFR of between 0.0% and 0.3% during the pre- and post-COVID period as illustrated in Figure 1 for all the WHO regions. The trend further reflects a marginal decline in mortality from 625,000 in 2020 to 619,000 in 2021 [21]. Despite the slight decline in deaths for 2022, the numbers were still approximately 9% higher than malaria deaths reported during the pre-COVID period in 2018 (567,000) [21].

Figure 1.

Malaria burden in pre- and post-COVID period across WHO regions (author construct: 2023).

Malaria milestone targets set in 2015 are almost midway through the end date [21]. These targets were not entirely met by most of the WHO-endemic regional blocs with the exception of the South East Asia region, which was resilient through the period under purview. The worst-case scenario was observed for the Africa region, which accounted for 94% of the global cases of malaria in 2021 with an average estimated 0.3% case fatality rate (Figure 1). Of the mortalities reported in 2021 within the Africa bloc, 80% occurred in children under the age of 5 with Case incidence (cases per 1000 population at risk) and mortality targets being 45 and 75% off track respectively to the baseline target set for the Global technical strategy for malaria (GTS) for 2020 [21]. South East Asia region with most of its cases reported from India (79%) and the Eastern Mediterranean regions accounted for 2.5% each of the global cases of malaria. Western Pacific and American regions also contributed 0.6 and 0.2%, respectively (Figure 1) [21].

The recent COVID-19 pandemic in 2019, posited to have a zoonotic origin led to the enforcement of various restrictions. This did not only affect global commerce and international travel activities but also impacted health services and deliveries of which malaria is a part. Amid existing robust strategies in place for the elimination of malaria, COVID-19 has demonstrated the potency of potential future zoonotic pandemics to impinge on healthcare delivery and malaria milestone targets towards 2030. The panacea is to expand the strategic scope to include animal and environmental health mitigation strategies, which will demand open discussions and improve upon resilience in the fight against malaria.

3. Human malaria transmissions

Early studies on malaria have identified various forms of malaria and possible routes of entry used by the Plasmodium parasite to invade the host. This includes asymptomatic forms, congenital and neonatal malaria, cerebral malaria and imported malaria cases. These can be transmitted directly by a female Anopheles species or through parenteral transmissions including those acquired through blood transfusion, pricks from sharps and organ transplantation routes. Malaria infections irrespective of the route of entry in humans have been associated with unique cyclical fevers which were known from the past. These fevers could be described as tertian, quartan, and quotidian [5, 22, 23, 24, 25, 26, 27].

Each of these fevers, with their severity and other unique clinical presentations, has been well characterized and known today to be associated with specific Plasmodium species [5, 23, 27, 28, 29, 30]. Four main human Plasmodium species and a zoonotic species Plasmodium knowlesi are currently known to cause the disease in humans [5, 23, 27, 28, 29, 30]. The identification of these Plasmodium species and their related fevers was therefore a remarkable breakthrough that has aided our better understanding of human malaria transmission today. While P. knowlesi, is currently the only known parasite species associated with quotidian malaria parasite-related fevers [5, 23, 27, 28, 29, 30]. Tertian malaria on the other hand, which may exist in benign or malignant forms are known to be the most abundant indicating a high host and vector preference for members (Plasmodium species) of the tertian group [5, 23, 27, 28, 29, 30].

4. Non-human malaria transmission

Non-human Plasmodium infections have played a significant role in unravelling the puzzle of human malaria transmissions. Non-human infections can be transmitted directly through the bite of a vector or congenital means to a non-human susceptible species. Laboratory transmissions to non-human vertebrate models are sustained and made possible parenterally using cell cultures or blood infected with the parasite [26, 31, 32, 33, 34]. Moreover, cell-to-cell based transmissions are also made possible in cell cultures with studies investigating parasite development, drug resistance, host response, and parasite-host interactions benefiting immensely from such culture-based and animal-based model transmissions [26, 31, 32, 33, 34]. Currently, more than 250 species of Plasmodium parasites are known today to infect various vertebrate hosts, including humans, non-human primates (Prosimian, Apes, old and new world monkeys), birds, reptiles, rodents and ungulates among other mammals [31, 35].

The use of transmission models or other vertebrate models, therefore serves as an alternative for complementary studies on confounding factors limiting malaria experimentations in humans [31, 34]. Ross and other independent workers pioneered research on avian malaria in 1897, this led to the discovery of various avian-specific Plasmodium species that are useful for laboratory studies [18, 19, 20]. This included studies on malaria transmission in different bird species and the identification of avian-specific vectors that are competent in the transfer of different Plasmodium species across susceptible bird species [19, 36]. The avian group served as a forerunner host model to unveil the sporogonic developmental stages of human malaria parasites within the mosquito vector.

Rodent malaria parasites, after their discovery in 1940, have also played a significant role in our current knowledge of malaria transmission over time [32, 37, 38]. This spans from basic laboratory research to iterative ones in both immunological and malaria vaccine candidate tests. The rodent PlasmodiumP. berghei ANKA has been found useful as a model for learning about cerebral malaria. Rodents are smaller in size requiring less housing space with a faster perpetuation time and like their bird counterparts they produce more offspring than most primates. Laboratory adaptable strains of rodent Plasmodium transmissions offer a comparative evaluation of malaria within a small controlled environmental condition.

Plasmodium transmission patterns among primates are similar to human malaria infections. Gleaning from the genetic relatedness of humans with great apes and other members of the monkey family, Laveran became the first to observe Plasmodium pitheci in the blood of orangutans in 1905. Further works on great apes in Africa in 1917 by Eduard Reichenow showed human-like Plasmodium parasites in the blood of captive chimpanzees and gorillas in Cameroon. Following Reichenow’s observations, Blacklock and Adler in 1922 also described and confirmed Plasmodium parasites resembling P. falciparum in chimpanzees in Sierra Leone [25, 39, 40]. On the other hand, similar transmissions are also observed in the old and new-world monkeys. P. cynomolgi happens to be the first monkey Plasmodium species detected and characterised by Mayer in 1907 from a Macaca cynomolgus monkey [23, 41]. Further, observations by Robert Koch in Monkeys of East Africa in 1947, also served as the basis for discovering the third malaria cycle in primates [23, 28]. The work of Shortt and Garnham also further described malaria relapse or recrudescence in P. cynomolgi in 1948. Krotoski and co-workers also described the hypnozoite stages of the parasite [5, 23, 30, 42, 43].

5. Emerging zoonotic malaria and transmission concerns

Zoonotic malaria is an emerging form of malaria that affects and is shared by both humans and other mammals. Cross-species malaria transmissions have been observed with certain groups of Plasmodium species transmitted among different mammalian host species in nature and experimental settings. This raises concerns that borders on the need for one-health and it also indicates the possibility for susceptible mammals to double as reservoirs and hosts for their host-specific and non-specific Plasmodium species, which are competent enough to cause the disease across these mammal species. Secondly, frequent misdiagnosis of non-human Plasmodium species of malaria that infect humans is also a contributory factor. The continuous transmissions are also posited to have a great impact on human malaria eradication pegged for 2030 and the conservation of susceptible and highly endangered mammal species [31]. There are also knowledge gaps that are a source of concern and will require continuous and active research to ascertain the posited impact of this form of the disease. This will help develop effective mitigating actions to manage or deal entirely with such malaria transmissions.

Frequent passages of malaria parasite cell lines under laboratory conditions for certain lower mammal and vertebrate species have been successful. This has been adopted in the generation of human adaptable strains and mutants of P. knowlesi, P. berghei, P. falciparum mutants 3D7 and Hb3 among others that are used for various malaria in-vitro studies [32, 37, 44, 45, 46, 47]. The adaptability of such malaria parasite species to subsist and thrive on human red blood cells or non-human host red blood cells within cell cultures is an interesting observation to partly explain the multiple switch postulate, which is believed to account for the evolution of malaria parasites [48, 49]. This suggests that Plasmodium species has evolved with a high tendency to switch to different red blood cells among mammalian species. Though there are currently no known Plasmodium parasites of the lower mammalian species that infect humans in nature since culturing conditions are different from intact physiological conditions, however, it is envisaged that when given factors that frequently promote such contacts continue, human-adapted malaria parasite strains may evolve and circulate. Promoting factors such as laboratory spillovers, the presence of competent transmission vector, environmental conditions and host factors that bring proximity to the human-Plasmodium mutant interphase should be carefully investigated, and managed appropriately with this possibility in mind.

Non-human primate Plasmodium species are naturally and experimentally transmissible to humans and vice versa [31, 50, 51, 52]. Such cross-species infections are an emerging area of concern to current malaria transmission patterns facilitated by increased invasion, contact, and proximity to shared forest environments with non-human primates. Furthermore, host primates and vector confinement to certain geographic regions of the globe also influence the kind of circulating Plasmodium pathogen that can be transmitted [31, 35, 40]. Infections with P. knowlesi a type of monkey malaria, was the first zoonotic malaria to be described in 1965 to naturally infect humans [27, 28, 29, 39, 53]. Such infections are common within South East Asian countries where it is transmitted mainly by the vector Anopheles balabacensis [54]. P. knowlesi infections have been the main cause of malaria in Brunei and Singapore. In Malaysia, of the 2607 malaria cases reported in 2020, all were due to P. knowlesi infections with no report of any of the known human Plasmodium parasites. Malaria trends in Sabah over 5 years from 2014 to 2018 reveal that P. knowlesi over the period, accounted proportionally for 0.78 (13,569/17310) of all malaria cases which were reported [54].

Cases of fatal and mild forms of the disease due to P. knowlesi infections in humans have been reported in endemic communities, but the true prevalence is still not known [28, 55, 56]. Diagnosis using PCR aids in effective speciation and detection but the technique is not easily applicable in remote areas where the main host vertebrate Macaca fascicularis and human contacts are high. Methods such as microscopy are elusive due to their morphological resemblance to human Plasmodium parasites. Furthermore, whether current human infections are through the human-mosquito-human route or the Macaque-mosquito-human route, is not yet clear. Potential for natural human infections and experimental infection has also been demonstrated for other non-human primate Plasmodium species such as P. cynomolgi, P. inui, P. brasilianum, P. coatneyi and P. simiovale [57]. Putaporntip and coworkers after testing 1359 febrile human blood samples from 2007 to 2018 detected 9 cases of P. cynomolgi coinfections within 5 provinces in Thailand [58]. Further works by Yap and coworkers in 2021 also led to the detection of infections with P. coatneyi (3), P. cynomolgi (9) and P. inui (3) among humans [59].

Apes are the main host of Plasmodium representatives of Laverania except for P. falciparum, which is a human Plasmodium pathogen [27, 60, 61, 62]. While Orangutans and Gibbons are found in Asia, Chimpanzees, Bonobos and Gorillas who are humans’ closest relatives are found in Africa [39, 53, 60, 63, 64]. Such host and vector distribution patterns are important to note as they affect the disease transmission dynamics. Special Plasmodium species groups are known to uniquely infect the different Ape hosts of which most share a resemblance with the human Plasmodium versions. Besides these observations, P. rodhain and P. schwetzi infection in humans has been demonstrated and shown to be successful through blood inoculations [5, 23, 30, 62, 65]. Infections of Chimpanzees with Plasmodium vivax and P. malariae have also been demonstrated experimentally [60, 64, 66]. Another investigation into the prevalence of simian malaria identified P. falciparum, which was earlier thought to be a human-specific species for malaria infections to have naturally infected Macaca radiata and Macaca mulatta in India [51]. Suggesting that both humans and the great Apes could serve as reservoirs and hosts for human Plasmodium species and Ape Plasmodium parasite species. The consequence of reverse zoonosis is likely to evolve new and more virulent or attenuate existing species, which will likely change host and pathogen infection and transmission dynamics.

6. Path to the development of malaria

The establishment of the Plasmodium parasite in the blood of humans, non-human primates and other vertebrate hosts is important for malaria to occur [26, 67, 68]. This is mediated through a meal bite from a transmissible competent mosquito vector species harbouring infective stages of the parasite, this is important for malaria to occur as illustrated in Figure 2 [69]. Plasmodium sporozoites after introduction into the host by the mosquito, invade hepatocytes and develop into merozoites, which further invade erythrocytes and develop into schizonts and gametocytes. For further perpetuation, gametocytes of Plasmodium are fed on by a mosquito and Plasmodium completes the sexual stages of their development to form asexual sporozoites and the cycle continues with another blood meal as illustrated below [69].

Figure 2.

Life cycle of Plasmodium species involved in human and non-human primate transmissions [69].

Clinical presentations of human malaria are well characterised and mainly known to be associated with cyclical fevers due to the continuous invasion, infection and re-infection of hepatocytes and erythrocytes by various stages of Plasmodium and the response reactions from the immune system of the host. In the uncomplicated scenario, the disease may be accompanied by chills, nausea, vomiting and headaches. Complicated malaria, which is a more severe form of the disease characterised by cerebral malaria with its accompanying seizures, severe malaria anaemia, coma, metabolic acidosis and death also, do occur. This is often seen among vulnerable groups such as children under 5 years of age, immune-compromised persons and persons with no pre-existing immunity. Furthermore, there is also malaria relapse caused by hypnozoites, which is associated with recurrent and difficult-to-treat malaria infections that may linger on for years.

6.1 Parasite development in vector

Mosquitoes become infected when they ingest human blood containing gametocytes. These gametocytes differentiate into male and female gametes within the mosquito’s gut, facilitated by the mosquito’s blood meal. Following fertilization, the zygote develops into a motile ookinete within 24 hours of having imbibed a blood meal. This extracellular ookinete then departs from the blood mass, navigates through the midgut epithelium and evolves into a growing oocyst in the basal subepithelial region located between the midgut epithelium and the basal lamina (BL) [70, 71, 72]. The midgut’s peritrophic membrane (PM) functions as an initial defence line in Anopheles mosquitoes against ookinetes, providing a physical barrier [73]. Ookinetes release the chitinase enzyme to assist in navigating through the PM [74]. Similarly, ookinetes are confronted with midgut proteases. To counteract these proteases, ookinetes produce surface proteins called P25, P28 and P47, pivotal for their successful invasion of the midgut [75, 76, 77].

Several factors, such as the vector’s type, parasite strain, environmental circumstances and host immunity, influence the development of the malaria parasite inside the vector. Vector competence refers to the inherent capacity of anopheline species or populations to facilitate the progression of Plasmodium parasites, transforming from ookinete to infective sporozoite [78]. Variation in vector competence occurs among different vectors and parasite combinations, and this variability can be influenced by genetic, molecular, immunological and ecological factors [78, 79, 80, 81]. For instance, particular genes within mosquitoes can impact parasite infections, either amplifying or constraining their growth [81, 82]. Similarly, specific molecules produced by parasites can engage with the mosquito’s immune system or midgut microbiota, enabling evasion or overcoming of the vector’s defences [83, 84]. Additionally, environmental elements such as temperature, humidity, rainfall and seasonal variations can shape vector competence by influencing mosquito physiology, behaviour and lifespan [81, 84, 85, 86].

Managing malaria faces a significant challenge in light of the rise and spread of insecticide resistance within Anopheles mosquitoes. The emergence of resistance to insecticides can undermine the efficacy of strategies such as insecticide-treated nets (ITNs) and indoor residual spraying (IRS), which are designed to minimise human-mosquito interactions. While the precise mechanisms and outcomes are not entirely clear, insecticide resistance can also affect the abilities of malaria vectors, as indicated by a study [78]. Several studies have suggested that the impact of insecticide resistance on vector competence can fluctuate, depending on variables like the type of insecticide, the mechanism of resistance, the species of mosquito and the strain of the parasite. For instance, certain research has revealed that the rates of Plasmodium infection in pyrethroid-resistant mosquitoes can either increase or decrease compared to susceptible counterparts [78]. Furthermore, investigations have unveiled that insecticide resistance can have an impact on diverse facets of mosquito behaviour and fitness, including elements such as reproductive capacity, survival, feeding patterns and host preference. These factors, in turn, can shape the vectorial capacity, a measure of the potential for a mosquito population to transmit malaria [78]. As a result, it becomes crucial to observe and control insecticide resistance in malaria vectors, while simultaneously devising new methods and strategies to prevent or decrease the transmission of malaria.

6.2 Plasmodium parasites of malaria

Plasmodium species that cause malaria among vertebrates are diverse. The species responsible for causing malaria in humans are in five distinct forms: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale sensu lato (s.l.), which encompasses P. o. curtisi and P. o. wallikeri and Plasmodium knowlesi [55, 87]. Human Plasmodium species originate from different evolutionary lineages, sharing common ancestors with nonhuman primate species [25, 61, 88]. As anticipated, the five primary malaria-causing parasites exhibit distinct biological characteristics throughout their respective life cycles [5, 89].

One pivotal stage in this life cycle is the invasion of human red blood cells by Plasmodium species. While P. falciparum shows no particular preference for a specific age of red blood cells, P. vivax and the two species within Plasmodium ovale sensu lato (s.l.) tend to infect young red blood cells or reticulocytes. Conversely, Plasmodium malariae is thought to invade older red blood cells [90, 91]. Differences are also apparent in the timing and lifespan of gametocyte production, both of which are critical components of fitness [92, 93]. Plasmodium falciparum undergoes a more extended maturation process, spanning five stages over 9–12 days, and remains infectious for several days compared to other malaria parasites. In contrast, Plasmodium vivax and P. ovales.l. have dormant stages or hypnozoites that lead to relapses after the initial infection; these stages are absent in P. falciparum and P. malariae [42, 94]. Another notable distinction is the ability of P. falciparum-infected red blood cells to adhere to the endothelium of capillaries and venules, a phenomenon called sequestration, which is associated with severe clinical symptoms uncommon in non-falciparum malaria [95, 96]. These traits represent only a fraction of the many variations among Plasmodium species causing malaria in humans.

In addition to Plasmodium species that primarily affect humans, there are zoonotic malaria parasites originating from nonhuman primates. The most prominent example is Plasmodium knowlesi found in macaques across Southeast Asia [55, 97, 98, 99]. However, evidence suggests that other nonhuman primate malaria species also function as zoonotic agents in this region, sometimes causing asymptomatic infections [99, 100, 101]. Moreover, anthropozoonotic malaria parasite cycles involving nonhuman primates in South America have been documented [41, 102, 103]. Despite the focus on zoonotic species, there are at least 39 known Plasmodium species affecting nonhuman primates globally, encompassing both formally described species and detected lineages [26, 67]. Some of these parasites received limited attention until recently, potentially due to challenges associated with studying nonhuman primates. Additionally, there was a significant emphasis on viable animal models to enhance the understanding of malaria biology and to explore treatment or vaccine options. Regardless of the factors that hindered their study, substantial progress has been made in the past two decades.

6.3 Biology and diversity of malaria vectors

Malaria is a severe and occasionally fatal illness caused by a parasite that infects specific mosquito species, which subsequently bite humans. The characteristics and variety of malaria carriers play a pivotal role in influencing malaria transmission and control. These carriers, belonging to the Anopheles genus, consist of over 400 species, with approximately 70 of them recognised as transmitters of malaria to humans [104]. Non-Primate transmissions are also facilitated by Mosquito vectors such as Aedes and Culex species.

The diversity of malaria vectors varies across different regions and habitats, contingent on environmental and climatic factors that impact their breeding, feeding and resting habits. Among the significant malaria carriers are Anopheles gambiae sensu lato (s.l.), Anopheles funestus s.l., Anopheles arabiensis, Anopheles stephensi, Anopheles dirus, Anopheles minimus, Anopheles farauti, Anopheles darlingi and Anopheles albimanus [104]. These vectors exhibit different preferences for host species, biting times, indoor or outdoor locations and larval habitats. For instance, A. gambiae s.l. is highly anthropophilic (prefers to feed on humans) and endophagic (feeds indoors), while A. arabiensis is more zoophilic (prefers to feed on animals) and exophagic (feeds outdoors) [105].

The genetic structure of malaria vectors’ populations constitutes a pivotal facet of their biology and diversity, serving as a reflection of their evolutionary history, adaptability, gene flow and reproductive isolation. Population genetics aids in tracing the origin, distribution and movement of these vectors, as well as their susceptibility or resistance to insecticides and malaria parasites. Molecular methods like polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), microsatellite analysis and DNA sequencing enable the assessment of genetic diversity and population structure of malaria vectors [106]. For example, PCR can distinguish the members of the A. gambiae complex, a group of morphologically similar sibling species differing in their vector capacities.

Comprehending the biology and diversity of malaria vectors is vital for grasping the epidemiology and ecology of malaria transmission, as well as for devising effective strategies for vector control. With knowledge about the attributes and behaviours of diverse malaria vectors in various settings, targeted interventions such as insecticide-treated nets (ITNs), indoor residual spraying (IRS), larval source management (LSM) and genetic modification (GM) can be employed [107]. However, the biology and diversity of malaria vectors are dynamic and influenced by factors like environmental shifts, human activities, insecticide resistance and parasite evolution. Consequently, ongoing monitoring and surveillance of malaria vectors remain indispensable for keeping information up to date and adapting interventions accordingly [107, 108].

7. Transgenic mosquitoes

Transgenic mosquitoes could be a successful choice for developing a range of effective disease-fighting strategies as a result of the advancements made in genetic modification in recent years [109, 110, 111]. Arthropod control by genetic modification is an old concept that was independently researched in the 1930s, 1940s and 1950s by three pioneers: A. S. Serebrovskii (1940), F. L. Vanderplank (1947) and E. F. Knipling (1955) [112, 113]. Furthermore, the 1970s saw a particular focus on studies concerning sterile males [109, 110, 114], which in turn prompted re-evaluation of the original concepts [109, 110, 111, 115, 116, 117, 118].

The genetic modification of mosquitoes for the prevention of malaria is primarily focused on two main strategies: population suppression, which aims to eradicate or drastically reduce mosquito populations; and population modification, which aims to render the natural population immune to infection by expressing anti-plasmodial agents or altering mosquito genes crucial for parasite transmission [119, 120, 121]. Significant progress has been made in developing transgenic mosquitoes that are resistant to the parasites that cause malaria over the past 10 years. These developments include changes to mosquito genes essential for parasite development [122, 123] enhancement of mosquito immune components [124, 125, 126], the introduction of antiparasitic toxins or molecules [125, 127, 128, 129] and the expression of single-chain antibodies targeting parasite proteins [130, 131]. The creation of the first genetically modified mosquito in Africa through the Transmission Zero initiative holds special importance. This global scientific program is led by researchers from Imperial College London and the Ifakara Health Institute (IHI) in Tanzania, in collaboration with the Tanzanian National Institute of Medical Research (NIMR). This mosquito strain has been subject to genetic alterations that will ultimately provide researchers with the ability to hinder malaria transmission by mosquitoes. This noteworthy scientific achievement represents a pivotal advancement in the renewed worldwide efforts to eradicate malaria from the African continent [132].

The generation of transgenic mosquitoes poses a significant challenge, involving issues related to regulations, ethics and social aspects linked with the introduction of genetically modified organisms into the natural environment [133]. The transition of this approach from controlled laboratory settings to field trials in disease-endemic countries (DECs) is a gradual process aimed at maximising potential epidemiological benefits while minimising potential complications during implementation [134]. Among the multitude of factors to be taken into account is the irreversible nature of releasing organisms, as once released, it becomes exceedingly challenging to retrieve them in case issues emerge [133]. Unlike traditional methods of vector control, the utilisation of transgenic mosquitoes will encounter varying expectations from different stakeholders. Effective management of these divergent expectations is crucial to ensure ongoing support and mitigate opposition. This management is essential for a comprehensive assessment of potential public health benefits [134].

8. Environmental impact of Plasmodium transmission

Intriguingly the Plasmodium parasite sits on a knife edge as it will have to navigate different and mandatory environmental landscapes in a bid to survive and procreate. Traversing through the internal environment of a single or more than one vertebrate host or reservoir, the parasite is presented with a myriad of challenges including the need to usurp, manage or adapt to the varying degree of immunity presented by the host or reservoir as well as pressure from antimalarials if in use by the host. Moreover, co-infections be it with other Plasmodium species or other pathogens are also common and unique and may also influence susceptibility patterns of the host vertebrate to invasion and subsequently disease manifestation or an asymptomatic state. Host or reservoir interactions may be facilitated after entry of the pathogen via conduits such as a competent vector direct to the host, indirectly from the mother-to-child transmission and blood transfusion routes. The journey back to complete the sexual phase of the pathogen’s development is precarious as it is greatly dependent on the survivability and existence of a competent vector. Vectoral characteristic consists of sex, feeding behaviour and time and state of internal and external parameters among others which are paramount to sustain the vector role to maintain the sexual stages of the Plasmodium parasite for further development and later transmission.

External environmental factors do influence the survival and the persistence of vectors and subsequently, enhance the transmission of their respective Plasmodium species. Factors promoting transmissions may include seasonal changes with a high prevalence of malaria cases and deaths linked to the wet season in most of Africa [107, 135, 136]. Mosquito populations and bites increase due to enabling conditions that facilitate the breeding of the vector throughout the wet period and summer [57, 105]. Another important factor is temperature, most of the vector species reduce their bites and also have their development from larvae to adult stage extended when temperatures are cold [57, 67, 105]. Changes in land use such as for Agriculture and irrigation, also provide breeding grounds for mosquitoes and a cool hiding place among growing plants for adult mosquitoes [137]. Invasion of the forest environment either legally for the construction of public goods like bridges and roads or illegally for hunting and exploitation of natural resources such as mining of minerals are on the increase, this exposes such workers to non-human primate mosquitoes [61, 137]. Uncovered created pools of water may serve as breeding grounds for mosquitoes. Fragmentation and indiscriminate or uncontrolled degradation of forests due to logging or the creation of human community settlements deplete forest tiers and also increase human exposure to non-human primate mosquitoes and Plasmodium species [137, 138].

Control and preventive programs for the external environment were designed to target mosquito vectors at all stages of development. Insecticide use, use of insecticide-treated bed nets, use of mosquito repellents, draining of swamps and puddles as well as wearing of protective garments that obscure the skin among others are used to exterminate mosquito populations or avoid their bites. Most of such earlier malaria control and elimination campaigns that adopted these strategies were not globally coordinated and though they made some achievements, they could not eliminate malaria or sustain the momentum. The use of chemicals such as DDT came along with its concomitant impact on human health and non-targeted fauna within the environment leading to disturbance in ecosystem balance and this has increased the dominance of some invasive species. The development of resistant mosquitoes to insecticides due to frequent usage has also been observed. Furthermore, DDT and organophosphate usage among other chemicals in Australia, have been shown to contribute to bird poisoning which is often characterized by birds falling from the skies [139]. This reveals the potential effect of DDT on humans through the food chain and other environmental conduits [139].

9. Ending malaria transmissions by 2030 the one-health way

Eradicating malaria by 2030 from the human population is achievable given the current strategies and coordinated momentum. The close observation of benchmarks and prompt interventions are robust. However, an entire win against malaria transmissions will demand a one-health approach to deal with possible re-invasion of Plasmodium and their respective vectors from animal reservoirs. This is a form of systems thinking that tackles at the same time, health matters with a human, animal and environmental outlook. Acting as a paradigm shift from the past approach of independent mono-health perspective adopted. Human health has always been the main agenda, ensuring a healthy environment will therefore demand a fair balance in already existing malaria control and elimination intervention programs. This will require the use of eco-health strategies involving environmental impact and risk assessment, which puts into perspective the consequence of interventions on the health of humans, animals, plants and other components of the environment. On one hand, there will be the need to improve surveillance of non-human primate malaria among non-human primates and humans. Enacting and enforcing conservation laws using strategies such as restoration, maintenance and regulation of deforestation will also be required to control the level of human invasions.

Mosquitoes are hematophagous and have been successful over many years serving as vectors for the transmission of malaria and other infectious diseases. The induction of selective pressures for the mosquito vector from transgenes or by-products of a poorly introduced control or preventive intervention may have dire consequences on malaria transmission and other mosquito-borne diseases [79, 123, 129, 140, 141]. Mosquito vectors under genetic pressures may select new preferences and competency for hosts, bridge and or transmit new infectious disease pathogens across the human-animal interphase. Healthy balance for ecosystems shared with mosquitoes during the introduction of vector control interventions will therefore be required at all times. It is the surest way to contribute to a sound and healthy world for all species involved. This will ensure that potential invasive organisms may not take the opportunity of the tilted balance to proliferate and eliminate other species from extinction. A well-coordinated research effort and shared data for humans, animals and the environment will be required. The recent transgenic mosquito trials ongoing in Tanzania are among the most wonderful achievements of the millennium with a promising outcome to contribute together with other adopted arsenals for eliminating malaria [124, 134]. This will require a careful evaluation of such programs with one health lens in order to be able to anticipate possible impacts on the environment and other species.

10. Conclusions

Fundamental to our understanding of malaria transmission today would have lingered on evasively for many years with its massive toll on human life except for the timely merger of past and current coordinated knowledge. Past information on malaria though was sparse and scattered; it still, resonates with the concept of one health which is a current paradigm for the achievement of holistic health. Drawing from careful observation of patient records, the unique cyclical nature of each Plasmodium-specific fever and environmental events associated with changes in seasonal patterns; land use, and hydrological distribution patterns. Though the level of knowledge in certain cases was not entirely accurate in the past, it paved the way for the discovery of medications for the disease, initiation and adoption of control and preventive interventions that caused a decline in malaria and are also very useful today. The corroborative involvement of the study of other vertebrate species was remarkable in unearthing some unsolved puzzles about the disease cycle and other aspects of malaria research. Zoonotic malaria is currently an emerging challenge and possibly ongoing within the African region where there are great Apes and also in South America. Drawing from the current widespread dominance of P. knowlesi malaria in Malaysia and some Southeast Asian countries, zoonotic malaria will require maximum attention to evaluate the changing dynamics in malaria transmission in these regions that bear the biggest burden of the disease. Past concentration skewed towards human-centred research and programs will require a one-health approach. These will include a well-coordinated approach involving human and animal programs, locale-specific friendly interventions and the environment at large to increase the tendency of achieving the malaria eradication target set for 2030 and beyond.

Conflict of interest

The authors declare no conflict of interest.