The Malaria Burden: A South African Perspective

Malaria is a deadly disease caused by protozoan pathogens of the Plasmodium parasite. Transmission to humans occurs through the bite of an infected female Anopheles mosquito. According to the World Health Organization (WHO), an estimated 247 million cases of malaria were recorded worldwide in 2021, with approximately 619 000 malaria deaths. The initial signs of malaria can be mild and challenging to diagnose due to the signs and symptoms being similar to those of other illnesses. The malaria burden remains largely concentrated in the WHO sub-Saharan African region and has been recognised as a significant contributor to morbidity and mortality. This review aims to contribute to the existing knowledge on malaria in South Africa, a region within sub-Saharan Africa, focusing on the epidemiology and life cycle of the malaria parasite as well as diagnostic approaches for detecting malaria. In addition, nonpharmacological and pharmacological interventions for treating and preventing malaria infections will also be discussed herein. While there has been a significant reduction in the global burden of this disease, malaria remains a public health issue in South Africa. As such, the implementation of effective preventative measures and strategies, early diagnosis, and appropriate treatment regimens are crucial to reducing the malaria burden in South Africa.


Introduction
Malaria is a life-threatening infectious disease and is considered one of the leading contributors to the ongoing global health crisis.Malaria, which is caused by the Plasmodium parasite, is a mosquito-borne disease that spreads from person to person through the bite of an infected female Anopheles mosquito [1].In 2021, approximately half of the global population was at risk for malaria, with the World Health Organization (WHO) African region accounting for 95% of the global malaria burden [2].In addition, malaria was responsible for approximately 80% of deaths in children under the age of fve on the WHO African continent [2].It is important to note that while there are several diferent species of the Plasmodium parasite, only fve are known to cause malaria in humans, namely, Plasmodium falciparum (P.falciparum), Plasmodium vivax (P.vivax), Plasmodium malariae (P.malariae), Plasmodium ovale (P.ovale), and Plasmodium knowlesi (P.knowlesi) [3].Of these, P. falciparum is the most common in humans [2], with African countries, including South Africa, bearing the burden of P. falciparum infections [4], due to factors such as high transmission rates and socioeconomic challenges [5] that limit their access to healthcare services [3,6].Of note, P. falciparum is widely considered to be the most virulent and potentially fatal if not promptly diagnosed and treated [7][8][9].As such, this review will focus on the malaria burden in South Africa, a country located in the southernmost part of the African continent in sub-Saharan Africa, which has been stricken by at least two major outbreaks in the last two decades, resulting in numerous people succumbing to the disease [10].By providing an in-depth understanding of the malaria burden in South Africa, this review aims to contribute to the ongoing global eforts in the fght against this devastating disease.

Epidemiology of Malaria in South Africa
Te transmission of malaria is closely linked to specifc ecological conditions [11].In South Africa, malaria infections are almost exclusively caused by P. falciparum and remain endemic to the northeastern parts of the country in certain South African provinces, including Limpopo, KwaZulu-Natal, and Mpumalanga (Figure 1) [12], especially during the humid and rainy months of summer [12,14].

Malaria Statistics in South Africa
Over the past decades, South Africa has shown consistent improvement in reducing both the morbidity and mortality rates associated with malaria [15].For many years, annual malaria cases in South Africa were maintained below 10,000 due to vector control and case management eforts, with approximately 8750 reported cases in 1995 [12].However, beginning in 1996, the efectiveness of insecticides and treatments decreased, leading to a sharp increase in malaria cases and deaths that peaked in 2000 [12].During this period, malaria cases rose by 67% in 1996 and reached over 60 000 in 2000, resulting in more than 400 deaths [12].Te decline in efcacy of sulphadoxine-pyrimethamine might have contributed to the signifcant increase in mortality [12].
In 2000, when the frst-line malaria drug sulphadoxinepyrimethamine failed in South Africa, they reintroduced dichlorodiphenyltrichloroethane (DDT) for traditional structures while maintaining pyrethroids for modernised housing, using a mosaic strategy for resistance management [16,17].Artemisinin-containing combination treatment (ACT) was also introduced for malaria treatment [17,18].Despite global pressure against insecticide use, South Africa decided to bring back DDT to control the malaria epidemic [17,19].Following the adoption of regional malaria control strategies in South Africa, Swaziland, and Mozambique, the implementation of ACTs and the introduction of an efective insecticide, national case numbers decreased to 26 506 in 2001 [12].In 2007, South Africa reported fewer than 6000 malaria cases and subsequently started internal discussions on malaria elimination based on WHO recommendations [20,21].Tese statistics continued to fall to below 10 000 by 2011 [12].In 2012, South Africa formally adopted an elimination strategy aiming to stop local malaria transmission within the country's borders by 2018 [20,22].South Africa has achieved an 87% reduction in malaria cases, with a decline from 64,622 cases in 2000 [17] to 8,126 cases in 2020 [15].Furthermore, the number of malaria-related deaths has decreased by 91% (459 deaths in 2000 to 38 deaths in 2020) [15].

Factors Influencing the Transmission of Malaria in South Africa
4.1.Vector.Te predominant vector for malaria in South Africa is the Anopheles mosquito [23], which uses stagnant water sources like ponds, puddles, and irrigated felds to create the ideal breeding ground [24,25].Given the variations in breeding preferences among Anopheles mosquitoes, their prevalence and distribution are infuenced by numerous factors such as rainfall patterns, temperature, soil characteristics, vegetation cover [26], and human activities (e.g., deforestation and migration) [27].Areas with higher vector populations are at a greater risk of malaria transmission, especially when combined with other factors such as the presence of infected individuals and inadequate protective measures [24].While infection with P. falciparum continues to be the primary cause of malaria infections in South Africa, efective control measures have aided in successfully suppressing malaria infection rates until the early 1980s [12].As a result, South Africa established a monitoring system aimed at assessing the in vitro efectiveness of frst-line treatments and gaining insights into the impact of drug resistance on the ever-changing malaria trends [12].In South Africa, eforts to control malaria focus on targeting these vectors with the use of measures like (i) indoor residual spraying (IRS), which involves applying an insecticide to the walls and surfaces of a house where the insecticide remains active for several months, efectively eliminating mosquitoes that come into contact with the treated areas [28], (ii) the distribution of insecticide-treated bed nets (ITNs) which creates a protective barrier against mosquitoes and aids in repelling and eliminating mosquitoes [29], and (iii) larviciding by destroying larval habitats [30].Tese measures aim to reduce vector populations, limit human-mosquito contact, and disrupt the cycle of transmission.

Environmental Factors.
Climatic factors heavily infuence the distribution of malaria, such as high temperatures, humidity, and rainfall [31].Malaria occurs predominantly in tropical and subtropical areas where the Anopheles mosquito can survive and reproduce, allowing the malaria parasite to complete its life cycle in the mosquito [32].Elevated temperatures have been known to lead to the production of smaller and fecund mosquitoes [33].As temperatures rises, the maturation period for mosquitoes decreases, while their feeding frequency increases [24].Tus, temperature is crucial, as P. falciparum is unable to complete its growth cycle in the Anopheles mosquito at cooler temperatures below 20 °C and as a result, cannot be transmitted [34].
Transmission is favourable in warmer regions, with the highest transmission found in sub-Saharan Africa (Figure 1) [11,34].In South Africa, malaria transmission increases around the month of October, reaching a peak during the months of January and February, followed by a decline in May [35].Notably, South Africa's climate plays a signifcant role in shaping the malaria statistics in the country.

Human Behaviour.
Human behaviour is also known to play a signifcant role in the transmission of malaria.Individuals living in malaria-endemic regions are often more exposed to mosquito bites due to various factors, including sleeping outdoors, going outdoors at night [36], inadequate utilisation of mosquito nets, or limited access to protective or preventative measures [37].Furthermore, population movement and travel, such as migration, tourism, and labour migration to malaria-endemic areas, can introduce or 2 Journal of Tropical Medicine spread malaria parasites to previously unafected regions [38,39].It is also important to consider the impact of human behaviour on the transmission of malaria in South Africa.
During the peak transmission period, human behaviour and practices, such as travel [40,41], outdoor activities (such as farming) [42], and the use of protective measures [43], play a crucial role in the spread of malaria [40].In addition, compliance with protective measures, such as the use of insecticide-treated nets and antimalarial medication, can also infuence the dynamics of malaria transmission [44].In addition, cultural practices and community perceptions in South Africa are also known to infuence the spread of malaria [45].As such, it is important to consider targeted interventions and preventive measures to help mitigate malaria transmission.Access to malaria diagnostic services in South Africa during the peak transmission period is particularly crucial for disease management.Healthcare facilities need to be well-equipped with diagnostic technologies and services.However, the South African healthcare system grapples with resource constraints, overburdened facilities, and a high burden of infectious diseases, such as human immunodefciency virus (HIV)/acquired immunodefciency syndrome (AIDS) and other noncommunicable diseases, placing additional pressure on an already strained healthcare system [46,47].

Socioeconomic Factors and Vulnerable Populations.
Socioeconomic conditions also infuence malaria transmission in South Africa.Tese include a lack of education [5], limited access to healthcare and diagnostic services [48], inadequate housing facilities, and poverty [5].A delay in diagnosis and treatment often leads to the progression of infection and further transmission within the community [49,50].Socioeconomic factors majorly infuence vulnerable populations, with children under the age of 5 in the sub-Saharan Africa region accounting for two-thirds of these deaths [51].It is estimated that 1% of children infected with P. falciparum will develop cerebral malaria [52].Furthermore, it is well known that HIV increases an individual's susceptibility to malaria [53] and that South Africa is among the many countries predominantly afected by the global HIV burden [54].Pregnant women are among the most vulnerable, and pregnancy-associated malaria may lead to severe malaria, cerebral malaria, anaemia, premature birth, abortions, low birthweight babies, congenital malaria, and a higher risk of coinfections [55].From the authors' perspective, in a developing country like South Africa, people living in poverty or with poor access to healthcare may also be more likely to contract malaria due to factors such as inadequate housing, water, sanitation, hygiene, and limited access to efective antimalarial treatments.A malaria-infected female Anopheles mosquito injects sporozoites into the human host during a blood meal.Sporozoites enter the liver and infect liver cells (hepatocytes) [6,56].Sporozoites then mature into schizonts and rupture, releasing merozoites [6,56].Following replication in the liver, in a process known as exoerythrocytic schizogony (Figure 2(a)), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony) (Figure 2(b)) [6,56].Merozoites infect and infltrate RBCs (erythrocytes) [6,56] (Figure 2).Te ring-stage trophozoites proliferate into mature trophozoites, which then mature into schizonts.Te latter rupture and release merozoites, which infect erythrocytes [6,56].Some infected blood cells break the asexual multiplication cycle.Instead of replicating, the merozoites in these cells mature into gametocytes, which circulate in the bloodstream as sexual forms of the parasite [6,56].When a mosquito bites an infected person, the gametocytes are ingested.Te parasites' multiplication in the mosquito is known as the sporogonic cycle [6,56] (Figure 2(c)).While in the mosquito's stomach, the microgametes penetrate the macrogametes, generating zygotes [6,56].Zygotes become motile and elongated (ookinetes) that burrow through the mosquito's midgut wall and form Affected regions oocysts on the outside surface [6,56].As the oocyst bursts, sporozoites are released into the body cavity and travel to the mosquito's salivary glands [6,56].When a mosquito bites another individual, the human infection cycle starts over again [6,56] (Figure 2).Te life cycle allows the malaria parasite to spread between the mosquito and human, making it difcult to control and eliminate the disease.Te clinical signs and symptoms of malaria can vary depending on the stage of the malaria parasite's life cycle and the severity of the infection.

Clinical Signs and Symptoms of Malaria.
Initial symptoms of malaria are nonspecifc and similar to those of minor systemic viral illnesses (Table 1) making it difcult to diagnose malaria in its early stages, particularly in areas where the disease is common and other illnesses with similar symptoms are prevalent [58].Classical symptoms are recurrent 6-10 hour attack cycles with three distinct stages, namely, a cold stage (rigors) [59], a hot stage (fever up to 40 degrees Celsius ( °C)) [59], accompanied by headaches, vomiting, joint pain, and seizures in young children, and a perspiration stage (sweating, regaining thermal control, and fatigue) [59].

Guidelines for Malaria Diagnosis.
Diagnosing malaria can be challenging due to an overlap in signs and symptoms that are also common to other diseases such as viral infections and enteric fever [60].A delay in the diagnosis and treatment of malaria is the leading cause of malaria deaths [60].Malaria must be diagnosed promptly to prevent complications from developing.A rapid and efective malaria diagnosis is essential to ease sufering and decrease community transmission [61].According to WHO guidelines, malaria must be diagnosed with a parasitological test, including light microscopy or immunochromatographic rapid diagnostic tests (RDTs), of which the results must be available [62].Despite microscopy being historically regarded as the gold standard for diagnosing malaria [63], it is not without its limitations, which include its detection threshold and a lack of infrastructure and skilled personnel in South African laboratories [64].Te use of RDTs somewhat addresses these drawbacks, particularly the logistical difculties.As a result, both microscopy and RDTs are used in South Africa to diagnose malaria under the National Malaria Diagnostic and Treatment Guidelines [57].Tere are several ways to detect and diagnose malaria; however, only a few will be discussed in this review.A clinical assessment (Table 1) is usually performed, followed by a parasitological lab test to confrm the diagnosis.

Microscopic Blood Assay.
Conventionally, malaria has been diagnosed through the microscopic examination of Giemsa-stained peripheral blood smears [61,65].Parasitic infection is confrmed through thick blood flms, whereas species are confrmed through thin blood flms [61].With 100% specifcity, microscopic examination remains the gold standard for the diagnosis of malaria [52].Further advantages of this method are that it is quick, inexpensive, and provides both quantitative (parasite density, with a threshold of 50-500 parasites per microliter (μL)) and qualitative (Plasmodium species) data, which allow for the diagnosis of the stage of malaria infection [66,67].
4.9.Rapid Diagnostic Tests.New and cost-efective malaria diagnostic procedures have been identifed and developed, namely, the rapid diagnostic test (RDT), which has a specifcity of 90% or higher and provides results [68] within 5-20 minutes [69].Te RDT works by detecting a malarial antigen in an individual's blood passing through a membrane that contains specifc antimalaria antibodies [70].Tis method allows for the identifcation and detection of plasmodial proteins, specifcally histidine-rich protein 2 (HRP-2) and parasite-specifc aldolase or parasite-specifc lactate dehydrogenase (pLDH) [61].To perform RDT, a blood specimen acquired from the patient is applied, along with certain reagents, to a sample pad on the test card [71,72].Te presence of specifc bands in the test-card window following a short incubation period indicates whether the patient is infected with P. falciparum or one of the other species of human malaria [72].For P. falciparum histidinerich protein 2 (PfHRP-2), this method has a detection threshold of 2.6-14.6 nanogram (ng) per millilitre (mL) [52].
Of note, deletion of the histidine-rich protein 2 and 3 (HRP-2/3) genes in P. falciparum can have signifcant implications with respect to the diagnosis of malaria.Tese deletions can lead to the reduced sensitivity of RDT, thus impacting its ability to accurately detect P. falciparum infections [73].For example, false negative results could mean that those individuals that are infected with P. falciparum could go undetected and subsequently untreated, leading to the underestimation of malaria cases [74].It is also important to consider that the prevalence of HRP-2/3 deletions may vary across regions, necessitating tailored diagnostic approaches [73,75].In addition, HRP-2/3 deletions could pose a threat to malaria control programmes [76].Tese deletions highlight the need to explore alternative diagnostic approaches to increase the reliability of results in regions where these deletions are widespread.Another drawback to RDTs is that the majority of these tests can only detect one malaria species, which is P. falciparum, P. vivax, human Plasmodium species, or a combination of species [75].Furthermore, this method cannot diferentiate between past and present infections and is unable to quantify parasite density [52].4.10.Quantitative Bufy Coat.Te quantitative bufy coat (QBC) technique was designed to simplify and enhance the microscopic detection of parasites in peripheral blood and to improve malaria diagnosis [61].Tis highly sensitive method is based on microcentrifugation and involves utilising fuorescent dyes, such as acridine orange, to stain parasite deoxyribonucleic acid (DNA) in specialised capillary tubes with a plastic foat [77].Te components of the bufy coat segregate according to their densities during centrifugation, generating distinctive bands [78].Separation and metachromatic labelling of these cells are aided by reagents that cover the QBC test tube [78,79].Tereafter, fuorescent microscopy can be used to detect malaria in infected cells and plasma [78].

Immunofuorescence Antibody
Testing.Malaria can also be diagnosed using serological methods, which rely on the identifcation of antibodies against asexual blood-stage malaria parasites [80].With a specifcity of 90-95% and a detection threshold of 100 parasites per μL [52], immunofuorescence antibody (IFA) testing is a time-consuming yet extremely sensitive method for diagnosing malaria [61].Te principle of IFA is that specifc antibodies are produced within two weeks of infection with any Plasmodium species and remain for 3-6 months after the parasite has been cleared [61].IFA testing uses a unique antigen produced on a slide, coated, and stored at −30 °C before use [61].In addition, immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies are quantifed in serum samples collected from patients [61].Despite its usefulness as a species-specifc test, this method cannot diferentiate between past and present infections [52].
4.12.Polymerase Chain Reaction.Molecular diagnostic methods, including the polymerase chain reaction (PCR), have been employed in the molecular diagnosis of malaria, allowing for the precise detection of Plasmodium sp.DNA from peripheral blood [81].It has a specifcity of nearly 100% and high sensitivity, requiring only 1-5 parasites per μL for malaria detection [52].Compared to QBC and RDT methods, the PCR approach was found to be more sensitive and is now widely used to confrm malaria infection, followup therapeutic response, and identify drug resistance [61].A further advantage is that, in cases with very low parasitaemia, PCR may be more sensitive than traditional microscopy and can distinguish between diferent species [52].

Prevention of Malaria Infection.
A combination of pharmacological and nonpharmacological measures is used to prevent malaria in travellers [82].While pharmacological prophylaxis is extremely vital, nonpharmacological strategies for preventing malaria are just as important; however, they are only meant to supplement existing therapies and should not be used in place of antimalarial drug prophylaxis [37].It may be benefcial to wear insecticide-treated nets or light-coloured clothing with long sleeves and long trousers [37].Compared to routinely treated bed nets, long-lasting insecticidal nets (LLINs) and repellents are anticipated to have a longer period of activity [37].Other forms of protection include avoiding going outside after dusk [83].Malaria control interventions such as IRS with insecticides and the use of ITNs are known to impact malaria transmission [84].Insecticides commonly used for LLINs are pyrethroids, and for IRS, they include pyrethroids, carbamates, organophosphates, and DDT [85].However, emerging vector resistance to these insecticides threatens recent progress in malaria control [85].Adequate implementation and coverage of these interventions can signifcantly reduce mosquito populations and the risk of malaria transmission [37].High-risk patients, including pregnant women, children under the age of fve, elderly persons, and immunocompromised persons should avoid exposure to malaria [14].In addition, people should avoid visiting malaria-endemic countries during the dry season [14].

Treatment of Malaria.
Over time, the emergence and spread of drug-resistant malaria parasites, such as P. falciparum, have posed signifcant challenges to malaria control eforts, making malaria drugs less efective in the fght against the disease [86].Tis has subsequently led to treatment failures and increased transmission, especially in infected individuals who are not appropriately treated [87,88].Addressing drug resistance is crucial to the success of malaria control programmes or interventions, especially in malaria-endemic areas.Te steady increase in malarial deaths may be partially attributed to the rise in resistance to sulphadoxine-pyrimethamine, a staple in the treatment and prophylaxis of malaria at the time [89].Te development of resistance has become a major obstacle to the efcient treatment of malaria, particularly malaria caused by P. falciparum [90].Despite advances in understanding the molecular mechanisms of resistance, factors that promote the development and transmission of these resistant parasites remain unclear [91].Ultimately, resistance led to the introduction of ACT and regional malaria control strategies in parts of Southern Africa [12].While the signs and symptoms associated with P. falciparum infection usually begin between 7 and 21 days subsequent to exposure, longer incubation periods may be observed in patients who failed chemoprophylaxis or received antibiotic therapy during this period [57].In addition, fewer than half of the travellers who contract malaria pursue pretravel consultation [92].Individuals who are at risk for malaria include those who do not take the necessary precautions when travelling [83].
As alluded to earlier, Plasmodium sp. has a complicated life cycle, and most approved drug treatments target the blood stages by (i) inhibiting haem crystallisation, (ii) acting as antifolates, or (iii) producing free radicals [93].Te inhibitors of haem crystallisation include chloroquine and hydroxychloroquine, as well as amine alcohol derivatives of the same 4-aminoquinoline ring-containing molecule, i.e., lumefantrine, quinine, and mefoquine [93].All these compounds lead to the accumulation of toxic-free haem in the parasite by preventing its metabolism subsequent to the breakdown of haemoglobin [80,94].Antifolates, on the other hand, prevent the production of essential amino acids in the parasite by competing with para-aminobenzoic acid (PABA) for incorporation into folate by inhibiting the dihydropteroate synthase (DHPS; class I antifolates) enzyme or by inhibiting dihydrofolate reductase (DHFR; class II antifolates).Te former includes sulphadoxine and dapsone, and the latter includes proguanil and pyrimethamine.However, due to the parasite's ability to scavenge folate from its host, these drugs have limited efcacy when used as monotherapy, and the use of the DHPS inhibitors has largely been negated due to resistance and its propensity for inducing toxicity in individuals [93,95].While artemisinin is associated with poor bioavailability, both artemether and artesunate were derived to improve artemisinin's pharmacokinetic properties.Free radicals produced by these compounds induce oxidative stress, which causes damage to proteins and other macromolecular structures within the parasite [80], and ACT therefore remains an important therapeutic option for uncomplicated malaria [8].Another well-known chemoprophylactic, doxycycline, a tetracycline antibiotic, has been shown to act as a schizonticide during the human blood stage of infection by interfering with protein and pyrimidine biosynthesis.It ofers efective chemoprophylaxis against P. falciparum even in regions that commonly experience drug resistance, and while being efective in the treatment of acute infection, doxycycline should not be used as monotherapy and is therefore commonly combined with other antimalarials, i.e., quinine or artesunate, for this purpose [93,96].
Te three most prominently prescribed drugs available in South Africa for malaria prophylaxis include doxycycline, atovaquone/proguanil, and mefoquine.While appropriateness is based on the patient profle (Table 2), a combination of atovaquone and proguanil is recommended due to its shorter course of treatment and low incidence of adverse efects.Furthermore, both this combination and doxycycline are available as a pharmacist-advised therapy [99].Patient compliance and adequate dosing are essential when taking any of these options, as noncompliance results in a signifcant increase in the failure of chemoprophylaxis [100].

6
Journal of Tropical Medicine

Journal of Tropical Medicine
Considering that the majority of malaria cases in South Africa result from P. falciparum infections, the treatment guidelines (Tables 3 and 4) are aimed at this species [50,88].4.15.Antimalarial Drug Resistance.P. falciparum has developed resistance to all currently used antimalarial drugs, rendering the use of chloroquine and sulphadoxinepyrimethamine either alone or in combination inefective [102].Resistance to sulphadoxine-pyrimethamine is linked to mutations in the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes, whereas resistance to chloroquine is linked to mutations in the P. falciparum chloroquine-resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes [53].In an attempt to overcome P. falciparum-induced resistance, combination treatment has been implemented in several countries including South Africa and is now the preferred approach to treating malaria [103,104].Te rationale behind combination treatments is to inhibit the spread of parasites resistant to one component of the combination by adding another component with a diferent mechanism of action.Importantly, the combination will preferably include drugs with similar half-lives so that resistance cannot be acquired when the parasite is exposed to only one drug, with a shorter half-life than the other, for prolonged periods [53].Advances in uncomplicated falciparum malaria treatment include the replacement of chloroquine and sulphadoxinepyrimethamine with an alternative to chloroquine, namely, ACTs, which are now recommended as frst-line treatments, including in pregnancy [102].
Currently used combinations of antimalarial drugs include nonartemisinin combinations, such as quinine and sulphadoxine-pyrimethamine, quinine and doxycycline, sulphadoxine-pyrimethamine and chloroquine, and sulph adoxine-pyrimethamine and amodiaquine, as well as artemi sinin-based combinations, such as artemether-lumefantrine, artesunate and amodiaquine, dihydroartemisinin-piperaq uine, artesunate and mefoquine, and artesunate and sulph adoxine-pyrimethamine [53].While P. ovale, P. malariae, and P. knowlesi are still considered to be generally chlor oquine-sensitive, patients should be treated with artem ether-lumefantrine if infected with P. vivax or in regions known to experience chloroquine resistance.If doubt exists about the ofending species, standard treatment guidelines for P. falciparum infection should be followed.In the case of oral treatment, frst doses should be administered under supervision and the patient should be observed for at least an hour due to the common occurrence of vomiting in patients sufering from malaria.Paracetamol is the antipyretic agent of choice due to the increased risk of renal complications with nonsteroidal anti-infammatory drugs (NSAIDs) in malaria [57].A recent report by the WHO emphasised the emergence of artemisinin resistance in Africa, which remains a growing concern.However, strategies are currently being put in place to help minimise resistance in countries like South Africa [88].

Novel Antimalarials in Development.
As a result of acquired resistance to most of the current malaria treatments and subsequent limited treatment options, the modifcation of existing treatments as well as the design of novel treatments has emerged (Table 5).
In South Africa, malaria treatment is generally efective, particularly with the use of ACTs [57].However, the efcacy of treatment can be compromised in cases of drug-resistant strains of the malaria parasite [87].In terms of afordability, malaria treatment in sub-Saharan Africa poses a signifcant obstacle [107].South Africa provides free malaria diagnosis and treatment through its public healthcare system [108].However, access to healthcare can be limited in certain rural or remote areas, and private healthcare can be expensive for those who cannot aford it [109].
4.17.Malaria Vaccine.In October 2021, the WHO recommended the use of the RTS, S/AS01 (RTS, S) malaria vaccine among children living in sub-Saharan Africa and regions with moderate to high P. falciparum malaria transmission [110].Tis was based on outcomes from a clinical trial conducted in Ghana, Kenya, and Malawi in approximately 900,000 children [110].Te RTS, S vaccine is considered a pre-erythrocytic vaccination because it specifcally targets the circumsporozoite protein (PfCSP) on the surface of the sporozoite and P. falciparum parasites prior to invading and infecting hepatocytes [111].Te vaccine was created as a virus-like particle (VLP) containing two parts, namely, 18 copies of the central repeat and the C-terminal domain of PfCSP fused to a hepatitis B virus surface antigen [112].RTS, S/AS01 is the only vaccine that has shown protective efcacy against clinical malaria in a phase III clinical study, albeit protection is very partial, diminishes over time, and might depend on age [112].

Malaria Control and Prevention Programmes.
Most children who die from malaria do so because they do not seek treatment promptly.In response, the WHO has suggested implementing Community Case Management of Malaria (CCMm), previously known as home-based management of malaria [113].Tis strategy aims to reduce the malaria burden by enhancing early access to malariadirected healthcare through trained community-based providers like community health extension workers, coordinators, and private vendors.CCMm ensures that effective anti-malarial drugs and referral guidelines are accessible at the community level [113].Te Southern African Malaria Control (SAMC) programme has implemented a systematic and standardised approach to tackle malaria epidemics in the region since 1998 [114].Tis comprehensive strategy involves strategic planning, forecasting, prevention, preparedness, and early warning mechanisms to enable a more efective and timely response [114].Several SAMC countries utilise residual house spraying and insecticide-treated net distribution for 8 Journal of Tropical Medicine     preventing epidemics, while residual house spraying is mainly employed as an early response measure to mitigate the impact of outbreaks [114].Vector control is an essential element of the global malaria control strategy (GMCS) and is widely acknowledged as the most efective approach to preventing malaria transmission [115].Nevertheless, Ediau et al. reported that inadequate knowledge and negative attitudes toward IRS are prevalent, particularly among individuals living in rural areas with lower education levels [116].WHO/AFRO (Regional Ofce for Africa) is promoting the Integrated Disease Surveillance and Response (IDSR) programme, which helps epidemiologists choose and utilise precise indicators, initially on a monthly basis [114].
In districts prone to epidemics, a second step involves gathering weekly malaria morbidity and mortality data to swiftly detect any abnormal rise within two weeks and take prompt action [114].Te programme has great potential to enhance early epidemic detection for malaria and other diseases, and its implementation is advancing efectively across the continent [114].

Conclusion
Despite South Africa having made signifcant progress in the control, prevention, and treatment of malaria, this disease continues to pose a serious public health threat.Since 2000, the prevalence of malaria has decreased as a result of signifcant advancements.However, the issue of drug resistance as well as malaria importation from neighbouring countries still poses a threat.Various chemoprophylactic and treatment approaches are still considered highly efective, albeit subject to patient compliance.With that being said, malaria is preventable and curable if diagnosed and treated early.Te Malaria Control Programme in South Africa aims to implement malaria control interventions or measures to help signifcantly reduce the incidence of malaria in the country.However, despite ongoing eforts to treat malaria and eliminate emerging strains of multidrug resistance, the eradication of malaria remains a challenge in current global eforts to minimise the impact and spread of the disease.

Figure 1 :
Figure 1: A map of regions afected by malaria transmission in (a) sub-Saharan Africa and (b) provinces afected by malaria in South Africa, including Limpopo, Mpumalanga, and KwaZulu-Natal [12, 13].

(i) Auphen Aquaporin- 3
inhibitors inhibit the entry of glycerol into P. berghei and contributes to the replication of the parasite during the asexual intraerythrocytic stages Aquaporin-3 inhibitor, Auphen, previously inhibited P. berghei in hepatocytes and Choline transport inhibitors inhibit choline infux into the parasite, which is essential for the production of phosphatidylcholine (an important component of parasite cell membranes) Albitiazolium is currently in phase II clinical trials G25 previously exhibited potent and highly selective cytotoxicity against P. falciparum and P. vivax in vitro inhibit 1-deoxy-D-xylulose-5-phosphate (DOXP) reductoisomerase in pathways specifc to P. falciparum for asexual replication MMV019313 previously displayed selective cytotoxicity towards parasites P. falciparum translational elongation factor 2 inhibitor (i) Sordarin (ii) M5717 P. falciparum elongation factor 2 inhibitors inhibit a ribosome component responsible for catalysing the GTP-dependent translocation of the ribosome along messenger RNA and thus inhibit protein synthesis in eukaryotes M5717 is currently in phase I clinical trials Journal of Tropical Medicine

Table 1 :
[57]nostic criteria for suspected cases of malaria (adapted from the algorithm for the management of malaria in South Africa)[57].