Confronting Malaria – Addressing a Critical Health Crisis among Vulnerable Groups in Nigeria

Abstract

Malaria is caused by parasites of the Plasmodium genus and transmitted to humans through infected Another’s bites. The common symptoms are fever, headaches and chills. The parasites enters the blood stream and infect the red blood cells. Malaria can be treated with anti-malarial drugs and it can also prevented using mosquitoes bed net and repellant.

1. Introduction

Malaria is an important neglected tropical disease (NTD) that has a substantial impact on a large population across the globe, with a particular focus on tropical and subtropical areas. The etiology of this condition can be attributed to a specific microorganism belonging to the genus Plasmodium, which is classified as a protist. Malaria fever is the result of being bitten by mosquitoes carrying the malaria parasite. The transmission of the disease occurs solely through the bites of Anopheles mosquitoes that are infected.

The symptoms may range from mild to severe, potentially posing a threat to one’s life. Common symptoms include a low-grade fever, accompanied by chills and a headache. Prominent manifestations encompass profound fatigue, cognitive impairment, epileptic episodes, and respiratory distress.

Malaria presents a significant global health challenge, particularly in nations with limited economic resources. Based on data provided by the World Health Organization (WHO), it is estimated that there were approximately 241 million instances of malaria and 627,000 fatalities in the year 2020, with the majority of cases concentrated in the sub-Saharan African region. The disease exhibits a disproportionate impact on populations that are particularly vulnerable, such as young children and pregnant women, thereby leading to elevated rates of morbidity and mortality [1].

Malaria prevention can be achieved through the implementation of strategies aimed at minimizing mosquito bites and the utilization of appropriate pharmaceutical interventions. The implementation of treatments has the potential to prevent the progression of mild cases.

Anopheles mosquito bites from females that have been infected with malaria are the main way that the disease is spread. Additionally, blood transfusions and the use of contaminated needles are two ways that malaria can be spread. The initial symptoms of malaria can often be mild, resembling various febrile illnesses, which can make it challenging to promptly identify the disease. If left untreated, P. falciparum malaria has the potential to rapidly advance into a severe medical condition, ultimately resulting in mortality within a span of 24 hours.

1.1 Ecology of the vector

The presence of malaria vectors can be influenced by climatic conditions. For example, Ojo and Mafiana [2] noted that the equatorial region provides favorable conditions for mosquito growth, while the low incidence of malaria in Northern Africa may be attributed to the dry Sahara Desert. The transmission of malaria depends on the presence of human hosts carrying Plasmodium parasites and a sufficient number of anopheline mosquitoes in suitable environmental conditions, particularly temperature and humidity [3].

The morbidity and mortality rates associated with malaria are influenced by various factors [2]. According to Nasir et al. [4], Plasmodium undergoes complex development and multiplication processes in both humans and mosquitoes before it can be transmitted further. Thus, understanding the ecology of these vectors is crucial for malaria eradication efforts. Mosquito ecology is closely linked to poor sanitation, as unsanitary conditions such as stagnant water, inadequate waste disposal, and unclean drainage systems provide breeding grounds for the vectors [5]. Environmental conditions that promote mosquito breeding contribute to the proliferation of Plasmodium species [6].

Transmission dynamics of malaria are influenced by a combination of climatic and anthropogenic factors that affect vector ecology and can increase transmission rates in certain areas [7]. Human behaviors and activities also play a role in human-vector contact and, consequently, affect the prevalence of malaria. Factors such as population demographics, environmental sanitation practices, and drainage patterns influence malaria prevalence [7].

Environmental attributes, including rainfall patterns, relative humidity, and temperature, are determinants that affect the ecology of malaria vectors [8]. Temperature, in particular, plays a significant role in the transmission dynamics of the vector and the growth and development of the parasite. The duration of extrinsic incubation, during which the parasite develops in the mosquito, is influenced by temperature. As temperatures rise, the feeding rate and blood digestion frequency of adult female Anopheles mosquitoes increase [7].

Malaria prevalence tends to be higher in rural areas compared to urban centers, which can be attributed to lifestyle factors. Iloh et al. [9] and Bassey and Nwakaku [10] reported that malaria is holoendemic in rural areas and mesoendemic in urban areas in Nigeria.

1.2 Causative agent

The causative agent of malaria is a group of parasites known as Plasmodium. These protozoan parasites belong to the Phylum Apicomplexa. Malaria in humans can be caused by several species of Plasmodium, with the most common and medically recognized species being Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax and Plasmodium ovale.

The parasite Plasmodium falciparum is widely recognized as the most significant in terms of mortality. Plasmodium falciparum is responsible for inducing the most severe manifestation of malaria, frequently resulting in critical complications that pose a threat to an individual’s life. The phenomenon is widespread in sub-Saharan Africa as well as certain regions across the globe.

Plasmodium vivax is a significant contributor to morbidity in various regions worldwide, and there is a growing body of evidence suggesting that mortality associated with this parasite has been underestimated [11]. This particular species is accountable for a substantial proportion of malaria cases on a global scale. Relapses may occur as a result of the emergence of dormant liver-stage parasites, known as hypnozoites, which have the ability to reactivate following a latent period. Plasmodium vivax exhibits a wide distribution in regions outside the African continent.

Plasmodium malariae is associated with chronic and milder malaria infections. It has a more limited geographic distribution compared to P. falciparum and P. vivax.

Plasmodium ovale is less common than other species but can cause relapses due to the presence of hypnozoites. It is mainly found in West Africa. Plasmodium ovale curtisi, Plasmodium ovale wallikeri, and Plasmodium malariae are infrequently encountered aetiological agents of clinically significant conditions. In recent times, the simian parasite Pheidole knowlesi has emerged as a significant local factor contributing to disease in Malaysia and other regions of southeast Asia. It is primarily a zoonosis, with no conclusive evidence supporting direct transmission from human to human [12].

1.3 Life cycle/transmission of the malaria parasite

Plasmodium species are widely distributed pathogens that exhibit an intricate life cycle involving female Anopheles mosquitoes and vertebrate hosts.

The complex life cycle of malaria parasites necessitates the expression of particular proteins in order to ensure their survival in both invertebrate and vertebrate hosts. These proteins are essential for intracellular and extracellular survival, making it possible for a variety of cell types to invade the body while dodging host immune responses. P. ovale and P. vivax sporozoites can either initiate immediate schizogony or undergo delayed schizogony as they pass through the aforementioned hypnozoite stage after being injected into the human host, in contrast to P. falciparum and P. malariae sporozoites. Figure 1 shows the life cycle of the malaria parasite, which can be divided into several stages beginning with the entry of sporozoites into the bloodstream.

Figure 1.

Life cycle of plasmodium spp. in man.

This life cycle necessitates the development of distinct zoite forms, which enable the invasion of specific cell types at particular stages. Upon entering the host, sporozoites proceed to invade hepatocytes, initiating the subsequent asexual replication cycle within the bloodstream. The sexual forms that arise during the blood stage are consumed by a mosquito during its feeding process, thereby concluding the life cycle.

1.4 In human host

Schizogony: The Anopheles mosquito bite, which introduces sporozoites into the human bloodstream, is what starts the human infection process. These tiny sporozoites set out for the liver, where they invade the cells of the liver. Once inside these hepatocytes, they go through a transformational process that causes them to develop into multi-nucleated structures called schizonts. These schizonts eventually burst, releasing merozoites, the next stage in the life cycle of the malaria parasite [13].

Intraerythrocytic Stage: The merozoites then start a crucial phase inside the host’s bloodstream after being released. They invade erythrocytes, the red blood cells, and find refuge there. The merozoites undergo a different maturation process inside these erythrocytes, where they eventually turn into schizonts. As this maturation comes to a close, the schizont-infested erythrocytes burst, releasing a new wave of merozoites. The recurring fever episodes that distinguish malaria infections are brought on by this cycle [14].

Gametocyte Stage: Some of the merozoites undergo a remarkable transformation into male or female gametocytes, the sexual forms of the malaria parasite, as the infection progresses. Until a mosquito carrying the infection bites the host, these gametocytes are still present in the bloodstream. The gametocytes begin the next stage of the malaria life cycle after being ingested by the mosquito, leading to the development of sporozoites inside the insect that can then spread the disease to other people through bites [15].

1.5 Transition to mosquito

During successive cycles of schizogony within the bloodstream, a subset of parasites undergo a pivotal developmental transition that triggers their commitment to sexual development, leading to the formation of male and female gametocytes. The successful transmission of malaria from humans to mosquitoes is contingent upon the maturation of the sexual stages. This aspect has been acknowledged as a promising target for potential interventions, such as the utilization of transmission-blocking drugs or vaccines. However, it is known that the transition occurs during the preceding schizogony cycle, and that daughter merozoites originating from a single schizont-infected cell are predetermined to differentiate into either gametocytes or asexual schizonts. The presence of environmental stimuli, such as a high level of parasitemia and exposure to drugs like chloroquine, has been observed to be correlated with an elevated rate of conversion to gametocyte production. This suggests that parasites possess the ability to perceive and respond to their surroundings. The transportation of extracellular vesicles containing protein, RNA, and DNA between parasites in a controlled environment has been observed, indicating a mechanism for intercellular communication that enhances the production of gametocytes [16, 17]. The maturation of P. falciparum gametocytes is characterized by a prolonged duration compared to that of other species. After the initiation of commitment, the development of mature gametocytes that are capable of infecting mosquitoes requires a duration of 11 days. During this period, the parasites remain confined within the bone marrow [18], evading removal by the spleen until they eventually enter the peripheral circulation for an undetermined duration before being acquired by a mosquito during feeding.

1.6 In mosquito

Following a blood meal taken from an individual infected with malaria, a subsequent Anopheles mosquito becomes the carrier of this disease. During its feeding process, the mosquito ingests male microgametocytes and female macrogametocytes, both of which are transmitted through the initial mosquito’s bite. Inside the mosquito’s digestive tract, the fertilized gametocytes eventually unite, forming a zygote. This zygote then matures into an ookinete. As the ookinete progresses through the mosquito’s gut wall, it transforms into an oocyst, which becomes populated with sporozoites. The oocyst, in turn, matures, ruptures, and liberates sporozoites. These sporozoites journey to the mosquito’s salivary glands, awaiting their transfer to a human host during the insect’s subsequent blood-feeding episode. This cyclical process thus initiates anew, perpetuating the malaria life cycle [19].

The life cycle of Plasmodium vivax quite different from that of Plasmodium falciparum. P. vivax parasites establish a dormant liver stage referred to as hypnozoites, which exhibit resistance to drugs targeting the erythrocytic stages. This unique feature complicates the eradication of P. vivax, as prevailing interventions struggle to counteract the dormant hypnozoites, leading to multiple relapses and the absence of effective treatments for this stage [20]. The life cycle of Plasmodium spp. is presented in Figure 1.

2. Pathogenesis

In the case of an individual with no previous exposure to malaria, infection typically results in the development of a feverish illness expressed as: abdominal discomfort, headache, joint aches, muscle aches, vomiting, lethargy and anorexia [21]. The concomitant symptoms are nonspecific and frequently encompass rigors, cephalalgia, emesis, and myalgia (Figure 2).

Figure 2.

Symptoms of malaria.

If administered with suitable pharmaceutical interventions during this phase, the symptoms subside within a few days, albeit frequently accompanied by significant fatigue. In the context of P. falciparum, the administration of a comprehensive treatment regimen will result in the elimination of the infection. The reappearance of symptoms following treatment cessation can be attributed to inadequate treatment, drug resistance, or the occurrence of a new infection.

In instances involving P. vivax and P. ovale, recurring infections may transpire periodically due to the reactivation of the latent hypnozoite stage residing in the liver, unless it is eliminated through an extended course of treatment involving an 8-aminoquinolone medication. The comprehensive understanding of the progression of untreated or partially treated infection has been extensively documented through numerous observations conducted during the era when induced infections with both P. falciparum and P. vivax were employed as a therapeutic approach for neurosyphilis [22].

Typically, following a period of symptoms that may vary in intensity, the illness diminishes and the levels of parasites are effectively regulated at a minimal level. However, symptoms may reoccur periodically over the subsequent weeks and months, coinciding with increases in the presence of parasites in the bloodstream. Subsequent instances of parasitemia typically exhibit diminished intensity, resulting in less pronounced symptoms, ultimately leading to the resolution of the infection.

2.1 Severe malaria

In a subset of individuals who have not received adequate treatment or have received only partial treatment, the initial infection is not effectively managed and advances to a severe or complicated form of malaria, potentially resulting in mortality. The depiction of severe malaria exhibits variations that are influenced by both age and transmission level, which in turn reflect the immune status of populations. The majority of malaria-related fatalities in Africa are observed in the pediatric population and are primarily characterized by three distinct syndromes, which can manifest either independently or concurrently: severe anemia, cerebral malaria, and respiratory distress [23]. Cerebral malaria can be operationally defined as the manifestation of a comatose state resulting from infection with the Plasmodium falciparum parasite. The clinical presentation described can be attributed to various factors and should not be equated with the histopathological characterization of cerebral malaria, which involves the accumulation of mature-infected parasites in the cerebral microvasculature [24]. The manifestation of respiratory distress in children afflicted with severe malaria is primarily characterized by metabolic acidosis, which predominantly arises as a consequence of tissue hypoxia. The destruction of both infected and uninfected red blood cells is commonly observed in cases of acute malaria infection. However, the occurrence of severe malarial anemia in young children is likely the result of a culmination of factors, including chronic anemia as a pre-existing condition, immune mechanisms, and ineffective erythropoiesis.

Severe malaria in older children and adults is infrequently observed in stably endemic regions of Africa due to the presence of naturally acquired immunity. Consequently, our comprehension of this syndrome in older individuals primarily relies on research conducted in regions with lower transmission rates, particularly in Asia. Severe malaria is typically characterized by the presence of cerebral malaria, hypoglycemia, and anemia. However, it is important to highlight that severe malaria is frequently observed as a multi-system disorder, often accompanied by notable renal and hepatic dysfunction. Such dysfunction is relatively uncommon in pediatric cases. Respiratory distress frequently arises as a consequence of pulmonary edema, a condition that is infrequently observed in pediatric patients but exhibits a significant fatality rate among adult individuals. As regions that were previously highly affected by a particular disease witness reductions in its transmission, resulting in a decrease in population immunity, there is an observable increase in the average age of individuals experiencing severe illness and death. Additionally, the nature of severe disease is shifting towards resembling the patterns observed in older patients in other global regions.

2.2 Interaction with other infections

Malaria presents a substantial obstacle to susceptible populations, particularly those who are exposed to multiple health hazards that frequently interact with each other. Co-infection with the human immunodeficiency virus (HIV) is a significant contributing factor that amplifies the gravity and mortality rate of malaria. According to van Eijk et al. [25], individuals of both pediatric and adult populations who are infected with HIV face an elevated susceptibility to severe illness and mortality as a result of malaria. Moreover, pregnant women afflicted with malaria exhibit an increased propensity to transmit the human immunodeficiency virus (HIV) to their fetuses, thereby exacerbating the health consequences for both the maternal and neonatal populations.

An additional significant interaction to be taken into account from a public health standpoint pertains to the correlation between malaria and invasive bacterial illnesses. The study conducted by Church and Maitland [26] reveals that there is a higher prevalence of concurrent invasive bacterial diseases in African children suffering from severe malaria compared to what would be anticipated based on random chance. It is of utmost significance to note that individuals who are afflicted with dual infections exhibit a markedly elevated case fatality rate. Multiple mechanisms have been postulated to elucidate this correlation, encompassing the translocation of gram-negative microorganisms across a compromised intestinal barrier, distinct impairment of macrophages, and functional hyposplenism [27].

It is worth noting that according to Scott et al. [28], there is an estimation that malaria could potentially account for approximately 50% of inflammatory bowel disease (IBD) cases in specific geographical areas. This counterintuitive discovery implies that malaria may have an indirect impact on mortality rates that surpasses its direct effects. The notion is further supported by the significant decrease in childhood mortality rates that is observed during periods of intensive malaria control.

2.3 Malaria in pregnancy

In populations lacking immunity, the occurrence of malaria during pregnancy has been found to have a correlation with stillbirth and severe maternal illness, particularly with an increased susceptibility to hypoglycemia. In regions with high prevalence of malaria, where the local populations acquire a certain level of immunity, infection results in maternal anemia and reduced birth weight of the offspring [29]. While it is commonly referred to as a loss of immunity, it is important to note that this is not entirely accurate. Instead, the presence of the placenta provides a novel opportunity for parasites to sequester themselves by selectively binding to chondroitin sulfate A (CSA) on the syncytiotrophoblast [30].

2.4 Diagnosis

The Plasmodium parasite can be diagnosed using the following methods:

• The identification of malaria-specific antigens in the bloodstream through the utilization of rapid diagnostic tests (RDTs), OR

• The identification of parasite DNA that is specific to a particular species through the application of a Polymerase Chain Reaction (PCR) assay on a peripheral blood sample (Note: It is necessary for laboratory-developed malaria PCR tests to meet the requirements of the Clinical Laboratory Improvement Amendments [CLIA], which includes the completion of validation studies.) OR

• The identification of malaria parasites in thick or thin peripheral blood films, species determination based on morphological characteristics, and quantification of the proportion of red blood cells infected by asexual malaria parasites (parasitemia) are essential diagnostic approaches (Figure 3).

Figure 3.

Thick blood smear for diagnosis of plasmodium parasite.

2.5 Treatment and management

The World Health Organization (WHO) has issued a recommendation for the use of antimalarial combination therapy in the treatment of uncomplicated falciparum malaria. This recommendation is in response to the growing concern over the development of resistance to monotherapies, which poses a significant threat to effective malaria treatment [31, 32, 33]. This refers to the concurrent administration of two or more blood schizonticidal drugs that possess distinct mechanisms of action and therefore target different biochemical pathways within the parasite. Artemisinin-based combination therapies (ACTs) are presently considered the primary treatment for uncomplicated falciparum malaria, as stated by the World Health Organization in 2021.

The treatment options for severe malaria consist of two categories of drugs administered intravenously: the cinchona alkaloids, which include quinine and quinidine, and the artemisinin monotherapies, which encompass artesunate, artemether, and artemotil. According to Piccoli et al. [34], during the period before the introduction of artemisinin-based combination therapies (ACTs), chloroquine demonstrated efficacy in the treatment of malaria caused by blood transfusion. Furthermore, due to the absence of an exoerythrocytic phase, the administration of tissue schizonticides like primaquine was deemed unnecessary. One particular case necessitated further intervention involving the administration of sulfadoxine-pyrimethamine and doxycycline in order to achieve the eradication of parasitemia and alleviate symptoms. Additionally, another patient received primaquine as part of their treatment regimen [35].

To relieve symptoms, avoid serious complications, and stop the spread of parasites that are resistant to medication, efficient treatment methods are essential. To treat this condition, a number of antimalarial medications have been created with various modes of action. It is significant to remember that different Plasmodium species, infection severity, patient age and health status, and the presence of drug resistance all affect treatment methods. Below is a Table 1 showing different drugs used in treating malaria worldwide.

Drug class	Examples of drugs	Mechanism of action	Side effects
Chloroquine	Chloroquine, Hydroxychloroquine	Inhibits haeme polymerase, preventing haeme detoxification in parasites	Nausea, headache, blurred vision
Artemisinin-based Combination Therapies (ACTs)	Artemether-Lumefantrine, Artesunate-Mefloquine	Artemisinin disrupts parasite’s intracellular calcium balance	Dizziness, vomiting, fever
Mefloquine	Mefloquine	Interferes with parasite’s ability to metabolize haeme	Nausea, vomiting, dizziness
Quinine	Quinine	Interferes with parasite’s ability to metabolize heme	Tinnitus, blurred vision, nausea
Atovaquone-Proguanil	Atovaquone-Proguanil	Disrupts mitochondrial electron transport chain	Nausea, abdominal pain, rash
Primaquine	Primaquine	Targets dormant liver stage (hypnozoites) of P. vivax	Haemolysis in G6PD-deficient individuals

Table 1.

Drugs used in treating malaria worldwide.

2.6 Prevention and control

The goal of controlling malaria has led to the implementation of a wide range of control methods. Different strategies have been adopted to combat the spread of diseases spread by vectors. These strategies include the use of insecticides, the destruction of disease vector breeding grounds and habitats, the use of insecticide-treated bed nets, indoor residual spraying, and targeted chemoprophylaxis [6]. Adefioye et al. [36] and other researchers have found that improving sanitation practices and raising public awareness have the potential to significantly reduce malaria incidence.

Insecticides have been widely used to get rid of or reduce the population of disease-carrying mosquitoes, to elaborate further on these tactics. The technique of indoor residual spraying involves applying insecticides to the interior walls of buildings to kill mosquitoes immediately upon contact. According to Okonko et al. [6], this strategy has shown promise in lowering disease transmission rates by reducing vector populations.

Targeting breeding grounds and habitats for vectors has also proven essential in stopping the life cycle of disease-carrying insects. Eliminating sources of stagnant water where mosquitoes can breed will stop their spread, which will reduce the likelihood of disease transmission. In addition, using bed nets treated with insecticide is now essential to preventing malaria. These nets protect people while they sleep, which is when mosquitoes are most active and feeding, by either repelling or killing any that come into contact with them.

Chemoprophylaxis is a strategy that involves giving medication to people in high-risk areas in an effort to stop the disease from spreading. In areas with a high malaria prevalence, this proactive approach has been especially helpful. The work of Adefioye et al. [36] highlights the importance of societal factors in malaria control in addition to medical interventions. Their findings highlight the significance of promoting better sanitation practices and educating the public about preventive measures, both of which can make a significant difference in the burden of the disease.

In a broader sense, community involvement and cooperation between governmental, medical, and non-governmental organizations are essential to the effective application of these strategies. A multi-pronged approach to malaria control emerges through the integration of scientific research, targeted interventions, and a thorough understanding of local contexts, showing promising potential to eventually eliminate the prevalence and impact of the disease.

2.7 Current status

Despite the implementation of extensive control and elimination measures at both international and national levels through malaria control programs, malaria remains the predominant parasitic disease worldwide. The Global Malaria Eradication Program, which began in 1969, failed to achieve its objectives, resulting in millions of people contracting malaria, primarily in sub-Saharan Africa. The disease claimed the lives of tens of millions, particularly affecting pregnant women who faced malaria-related complications during childbirth. Additionally, millions of children were born with low birthweight, leading to early mortality or disability [1].

However, the first two decades of the 21st century have been regarded as a significant period in malaria control efforts [1]. According to the latest annual global malaria report released by the World Health Organization (WHO), approximately 229 million malaria cases were estimated in 2019 across 87 countries where malaria is endemic. This figure represents a decrease of 9 million cases from the year 2000, but it remains higher than the 218 million estimated cases reported in 2015 as part of the Global Technical Strategy (GTS) for malaria 2016–2030 [1].

The decline in global malaria case incidence, measured as the number of cases per 1000 people at risk, demonstrates this trend. From 80 cases in 2000, the incidence dropped to 58 in 2015 and further to 57 in 2019. This signifies a 27% reduction between 2000 and 2015, followed by a less than 2% decline between 2015 and 2019, indicating a slower rate of decrease since 2015.

In Africa, the majority of malaria infections are caused by the highly virulent P. falciparum parasite, which also accounts for the majority of malaria-related deaths globally. However, the prevalence of P. vivax infections, particularly in the Indian subcontinent, presents distinct challenges in terms of diagnosis and treatment [37]. In 2019, P. falciparum malaria comprised almost 99% of cases in Africa and 94% of all malaria cases and deaths worldwide [1].

2.8 Future perspectives

At present, there is no available vaccine for malaria. However, it is widely recognized that the development of new tools, including vaccines, is crucial for maintaining the progress made in disease control and advancing towards the elimination and eventual eradication of malaria. Over the past three decades, efforts to develop vaccines have targeted various stages of the malaria parasite, including the pre-erythrocytic (sporozoite and liver stages), blood stages, and sexual stages.

Malaria would be halted by a highly effective pre-erythrocytic vaccine that prevented the development of blood-stage infection. It has been thought that vaccinations against the blood stages that reproduce asexually are crucial for lowering morbidity and mortality. The transmission cycle would be broken by vaccines that target the sexual stages, but an infection that has already taken hold inside the vaccinated person would not be directly impacted. Based on the bottleneck hypothesis, vaccine development efforts shifted towards the pre-erythrocytic and sexual stages as the idea of elimination gained popularity. In contrast to replicating blood stages, which are more numerous and have developed immune evasion mechanisms for long-term survival, this hypothesis suggests that targeting the numerical bottlenecks in parasite development, such as the injected sporozoites prior to liver invasion and the mosquito midgut transmission stages, would result in higher vaccine effectiveness. The problem with this strategy is that the pathogenic replicative cycle can continue if one sporozoite or ookinete manages to evade the vaccine. Additionally, it appears that the immunity developed against these particular targets is strictly stage-specific [38].

As we progress towards elimination, this challenge becomes even more critical. A combination of population loss of naturally acquired blood-stage immunity, waning vaccine efficacy, and the presence of drug-resistant strains could create a dangerous situation for the resurgence of malaria transmission. The ideal malaria vaccine would be based on conserved targets that provide lifelong sterile protection from an early age with minimal doses. However, achieving this ideal has proven elusive thus far [31, 32, 33].

The most advanced candidate vaccine in clinical development is RTS,S/AS01, which targets the sporozoite stage. This vaccine has undergone phase III clinical trials involving over 15,000 African children and serves as the benchmark against which future vaccines will be evaluated. After 1 year of follow-up, a three-dose series of RTS,S/AS01 reduced clinical malaria cases by 28% in young children and 18% in infants. However, a notable finding from these trials is the relatively short duration of protection, highlighting the need to investigate the underlying reasons [39].

Known also as Mosquirix, the RTS,S/AS01 vaccine is a ground-breaking weapon in the fight against malaria. It is intended to prevent Plasmodium falciparum malaria, the most dangerous form of the illness, and is the first malaria vaccine in the entire world to receive regulatory approval. The PATH Malaria Vaccine Initiative and other partners assisted GlaxoSmithKline (GSK) in developing the vaccine.

Vaccine Composition and Mechanism of Action: Recombinant proteins are the basis of the RTS,S/AS01 vaccine. It combines a portion of the hepatitis B surface antigen with the circumsporozoite protein (CSP) of Plasmodium falciparum. The 3-O-desacyl-4′-monophosphoryl lipid A (MPL) and QS-21, a saponin derivative, are two immunostimulants that are included in the AS01E adjuvant, a liposome-based formulation that is part of the adjuvant system used in the vaccine formulation. The effectiveness of the vaccine is increased by the adjuvant system, which improves the immune response.

The CSP found on the sporozoite stage of the malaria parasite is the target of the vaccine’s immune response, which is how it works. Following vaccination, a person’s immune system responds to the CSP antigen by recognizing it. In order to stop the parasites from progressing to the blood stage of infection and causing clinical malaria, this immune response aims to neutralize the sporozoites and infected liver cells.

Clinical Trials and Efficacy: The RTS,S/AS01 vaccine was developed after extensive clinical trials were carried out in several malaria-endemic African nations. The efficacy of the vaccine in lowering the incidence of malaria in young children and infants was demonstrated in the Phase 3 clinical trial, also known as the RTS,S Clinical Trials Partnership [31, 32, 33].

The trial’s findings showed that the vaccine only partially protected against malaria. The vaccine demonstrated efficacy against clinical malaria and severe malaria anemia in infants, and it significantly decreased the number of severe malaria cases in young children. However, the vaccine’s efficacy gradually decreased, necessitating booster doses to continue providing protection [31, 32, 33].

Implementation and Ongoing Research: The World Health Organization (WHO) advised the use of the RTS,S/AS01 vaccine in pilot implementation programmes in a few African nations with high malaria burdens after regulatory approval. These pilot projects aimed to assess the vaccine’s practical application, viability, and efficacy in a larger population [31, 32, 33].

Over the next 2 years, the first-ever malaria vaccine will be administered to 18 million people in 12 different African countries and regions. The rollout represents a significant advance in the fight against one of the continent’s leading causes of death [40].

The doses have been prioritized to areas with the greatest need, where the risk of malaria illness and death among children is highest, using the principles outlined in the Framework for allocation of limited malaria vaccine supply [40].

The Malaria Vaccine Implementation Programme (MVIP), coordinated by WHO and funded by Gavi, the Vaccine Alliance, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and Unitaid, has been providing the malaria vaccine to Ghana, Kenya, and Malawi since 2019. Since its administration to more than 1.7 million kids in Ghana, Kenya, and Malawi in 2019, the RTS,S/AS01 vaccine has been proven to be both safe and effective, leading to a significant decline in both severe malaria and child mortality. The malaria vaccine has attracted interest from at least 28 African nations [40].

Nine additional nations, including Benin, Burkina Faso, Burundi, Cameroon, the Democratic Republic of the Congo, Liberia, Niger, Sierra Leone, and Uganda, will be able to incorporate the vaccine into their routine immunization programmes for the first time thanks to the initial 18 million dose allocation, in addition to Ghana, Kenya, and Malawi. This distribution round makes use of the vaccine doses that Gavi, Vaccine Alliance has access to through UNICEF. The first doses of the vaccine should arrive in countries in the final quarter of 2023, and they should begin to be distributed by early 2024 [40].

Research is still being conducted to evaluate the vaccine’s long-term effects, ideal dosing regimens, and potential integration into current malaria control strategies as a result of its use in real-world settings. Additionally, researchers are examining how well the vaccine works in various age groups and how it interacts with other malaria interventions like insecticide-treated bed nets and antimalarial drugs.

A thorough investigation of the interactions between malaria parasites and the human immune system, as well as their co-evolution, is urgently needed in order to develop better vaccine strategies. Additionally, early-stage clinical trials of a radiation-attenuated whole-cell sporozoite vaccine (PfSPZ) have demonstrated promise in offering sterile protection against homologous challenge. The lack of demonstrated heterologous (cross-strain) protection, the need for a large number of parasites and intravenous administration to induce anti-sporozoite immunity, and the logistical difficulty of preserving the vaccine’s viability with a liquid nitrogen cold chain are just a few of this vaccine’s significant drawbacks. The fundamental problem of inducing strain-transcendent protection, which remains a top priority in vaccine development, is still present in other live-cell sporozoite vaccine approaches, such as genetically attenuated parasites and chemoprophylaxis with sporozoites [14]. These approaches may offer incremental improvements over PfSPZ.

3. Conclusion

The majority of malaria cases and deaths are concentrated in sub-Saharan African and south/southeast Asian countries. However, there are instances of imported malaria cases in regions considered malaria-free or that have recently achieved malaria eradication through dedicated efforts. This emergence of imported malaria cases in non-endemic areas poses a new public health challenge. Particularly, imported cases from South Asia, where P. vivax infections are prevalent, can lead to the persistence of dormant liver-stage hypnozoites, causing recurrent episodes of malaria in non-endemic settings. If suitable breeding environments for mosquito vectors, such as construction sites with artificial water reservoirs, are present, imported P. vivax infections can result in local outbreaks.

Factors like global warming, increased travel for business or leisure purposes, migration due to employment opportunities or geopolitical conflicts, and changes in land use (such as plantation drives in previously barren areas) have altered the epidemiological characteristics of imported malaria in various countries. If not managed properly, these conditions can elevate vector density levels to the point where local transmission of the disease may occur following imported malaria cases. The rise of drug-resistant malaria, particularly drug-resistant strains of P. vivax, poses a significant threat to malaria control efforts in malaria-free countries with a substantial number of expatriates originating from P. vivax-endemic regions. Therefore, regular monitoring of imported malaria cases is essential in such settings.

To maintain malaria-free status, non-endemic countries must adhere to measures such as early diagnosis, appropriate treatment, integrated mosquito control programs, and consistent monitoring of drug resistance in Plasmodium species. Additionally, the adoption of efficient and effective vector control measures is crucial in preventing imported malaria cases from leading to indigenous transmission in many countries. Continuous efforts and vigilance are necessary to sustain the status of being malaria-free in these regions.