Malaria is a serious and potentially life-threatening disease caused by protozoan parasites of the genus Plasmodium. It is transmitted by female Anopheles mosquito vectors (a biting arthropod that transmits pathogens from an infected animal to an uninfected animal or human).
Generally, malaria is a preventable and curable disease, but in 2019, there were 229 million cases and 409,000 deaths. This disease is mainly found in tropical and subtropical regions of Africa, Central and South America, and Asia, with Africa carrying a disproportionately high disease burden. Children under five years old are at the highest risk of contracting this disease, with 67% of malaria-related deaths reported to be within this age group in 2019.
Nonetheless, implementing treatments and control measures can lead to the eradication of the disease. Proof of this can be seen in Europe, where malaria was once a major health issue until it was declared malaria-free in 1975. Henceforth, successful malaria control programmes are needed in regions where the disease is still found so we can continue our efforts in reducing the huge cost malaria has on human life.
Malaria isn’t just responsible for significant mortality, but it also has a serious impact on people living with the disease (because not everyone who gets infected will die) and subsequently the economy of countries with high disease burden.
DALYs (Disability Adjusted Life Years) measures the loss of health due to premature death, disease or disability, where one DALY equates to the loss of one year of a healthy life. In 2017, 45 million DALYs were lost due to malaria. And when infected individuals become ill, there is a loss of income and worker productivity.
To help you better visualise the problem - since children are at greater risk of contracting malaria, there are high rates of school absenteeism. Meanwhile, the excessive premature mortality and susceptibility of pregnant women mean malaria has a significant effect on population growth. Additionally, the economic cost of treating and controlling the disease is huge. In fact, did you know that 40% of Africa’s public health care spending goes towards malaria?
All in all, it is clear that malaria presents the capability to amplify the other challenges facing developing countries and this thereby leads to a vicious cycle where already disadvantaged countries continue to suffer.
In this article, we shall explore the transmission, epidemiology, and consequences of this devastating disease as well as current methods to treat and control malaria.
Malaria across the globe
Infectious diseases are described as ‘endemic’ in a region if they are always present. So, if there are lots of cases in a certain region, then that region is described as having ‘high endemicity’.
Malaria is endemic in around 100 countries, as seen in Figure 1a, with almost half of the world’s population at risk of contracting the disease. This disease is found in sub-Saharan Africa, South East Asia, Eastern Mediterranean, Western Pacific, and the Americas.
However, it is important to note that malaria is not a tropical disease. Over the last century, the disease has been eradicated in regions (and even countries) where it was once historically common.
Let’s take a look at Figure 1b, which illustrates how widespread malaria once was.
Figure 1: (a) This map shows an approximation of where malaria transmission is known to occur across the globe. This map was adapted from the CDC, “Where Malaria Occurs”. (b) It is important to note that malaria is not a tropical disease. This map illustrates that malaria was once common across Europe, the Caribbean, and parts of North America. However, successful control measures led to eradication of the disease here and in numerous other countries across the globe. This map was obtained from ourworldindata.org.
Within malaria-endemic countries, there is significant variation in the infection and mortality rates, as reflected by the fact that 94% of the malaria cases and deaths occur in Africa, with over half of the deaths taking place in six countries there. Factors such as socio-economic conditions, environmental and climatic conditions, infrastructure, and the state of the healthcare system can all affect the transmission of this disease, meaning that countries can have some areas with high endemicity whilst others could be malaria-free.
On the other hand, in countries such as the UK and US, malaria cases are imported into the country when infected travellers return from malaria-endemic regions. In particular, imported cases account for a minority of total malaria cases across the globe - in 2018, there were 1,683 cases in the UK, all of which were imported with a death toll of 6 people.
The parasite
Malaria is caused by Plasmodium parasites, which is a genus of protozoans (i.e. single-celled eukaryotic organisms).
Overall, there are 156 Plasmodium species that infect a range of vertebrates, including non-human primates, birds, and humans. However, only four of those species are capable of infecting humans- these are Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.
P. falciparum is the most common and fatal species, whilst P. vivax is the predominant species in Central America, South America, and India. In contrast, P. knowlesi is also capable of infecting humans, however, its natural intermediate host is macaque monkeys rather than humans, unlike the other four Plasmodium species. Given that it is transmitted from monkeys to humans (via mosquitoes) and it hasn’t yet been confirmed whether this species can be transmitted between humans if monkeys were not in the equation, it is zoonotic malaria.
Interestingly, the first zoonotic malaria infection was only identified in 2004, in Borneo and has since been reported in Thailand, the Philippines, Singapore, Vietnam, and Myanmar. However, it is important to highlight that infection by this simian malaria is often misdiagnosed, so it is likely that there are more unreported cases.
Transmission: the vector and the host
So, now that we know what the causative agent of malaria is in humans, let’s have a look at how it is spread.
Malaria is an example of a vector-borne disease. In general, vector-borne diseases are spread when a haematophagous (blood-feeding) arthropod takes a blood meal from an infected individual and then moves on to feed on an uninfected individual, who subsequently becomes infected as a result of this. In the case of malaria, the female Anopheles mosquitoes transmit the pathogen when it bites humans (or other animals).
You might be wondering why it is the females specifically that transmit malaria? Well, females need the nutrients from the blood for egg development while male mosquitoes don’t, so males aren’t actually capable of biting.
Around 60 Anopheles mosquitoes are major malaria vectors. Meanwhile, other vector-borne protozoan parasites include Leishmania (which is transmitted by sandflies) and Trypanosoma brucei (which causes the African sleeping sickness and is transmitted by the tsetse fly). In addition, the mosquito Aedes aegypti is a vector for numerous viral diseases such as the yellow fever virus, dengue virus, and Zika virus.
The epidemiological triad
Interactions between the parasite, vector, human host, and the environment all affect the distribution of malaria and the intensity of its transmission. This model of infectious disease is known as the epidemiological triad, as seen in Figure 2. For example, some mosquitoes are anthropophagic (i.e. bite humans) rather than zoophagic (i.e. bite animals) and have a longer lifespan, meaning the parasite is more likely to be able to complete its development in the mosquito. Reasons like these thus explain why certain Anopheles mosquitoes, such as many African species, are better at vectoring malaria and therefore why Africa carries a disproportionate disease burden.
Besides that, there is a range of other behavioural features which differ between Anopheles species that can also affect the epidemiology (control and distribution) of malaria. For example, does the mosquito prefer feeding and resting inside or outside, and during the day or late at night?
Furthermore, mosquito breeding sites and the habitats of larvae (the early aquatic stage of mosquitoes) also need to be considered. These locations can vary from species-to-species, with some species preferring freshwater, whilst others being more enthusiastic about breeding in man-made pools. In addition to that, the amount of shade or sun also influences whether an environment is suitable or not.
The malaria vector Anopheles dirus (An. dirus) is an example that illustrates the significance of various characteristics on disease transmission. This malarial vector lives in the forests of Southeast Asia, so those who enter are at a much higher risk of infection compared to others who stay at home. Conversely, An. gambiae is the primary vector in Subsaharan Africa - it is anthropophagic, feeds at night, and can breed in small, temporary water pools such as hoofprints.
Vector range is not the only determinant of malaria transmission. Anopheles atroparvus is found across Europe and the UK and was historically an important malarial vector. Although the vector is present, malarial transmission can’t occur here because Plasmodium needs certain temperature and humidity levels to survive. However, with global warming leading to temperatures rising across the globe, it is becoming increasingly likely that when infected travellers return to their home countries from malaria-endemic regions, malaria transmission may be established (transmission can’t occur in the UK currently).
Figure 2: The epidemiological triad is a model of infectious disease causation. It consists of the causative agent, the environment, the host, and, in the case of vector-borne diseases, the vector. Disease is a result of interaction between these factors. Five Plasmodium species can cause malaria in humans, although P. knowlesi is a zoonotic pathogen whose natural host is macaque monkeys. The image of an erythrocyte infected with Plasmodium falciparum was obtained from the CDC DPDx.
Why do all these matter?
Given that mosquito vectors are a key determinant of where malaria transmission occurs and who is most at risk, understanding their traits, such as the behavioural features that were previously discussed, is essential. This information can be used to enhance the effectiveness of malaria control programmes and make them more specific to different regions depending on which Anopheles species is present.
The life cycle
Given this disease’s mode of transmission, the malaria parasite needs to be capable of surviving in two hosts. The first is the definitive host (mosquitoes) - this is the host where the sexual stage of the parasite’s life cycle occurs. Meanwhile, the second is the intermediate host (humans), where the asexual phase occurs.
The parasite survives in each host by differentiating into various stages depending on its location. These specific forms can differentially express genes that, in turn, allow them to invade cells and tissues, replicate, as well as evade immune defences.
Figure 3 shows the life cycle of Plasmodium falciparum and its different stages in the mosquito and human host.
Figure 3: The life cycle of Plasmodium falciparum. This figure was produced using BioRender.
Pre-erythrocytic stage (liver stage)
When an infected female Anopheles bites an uninfected human, the most common method of transmission would be the mosquito injecting its sporozoites into the bloodstream. But on rare occasions, the parasite can spread in utero (from mother to foetus) via blood transfusions or needle sharing.
Within a few hours, these sporozoites reach the liver and infect hepatocytes (liver cells), where they undergo asexual replication (mitosis) and mature. After six days, tens of thousands of merozoites burst from the infected hepatocyte into the blood.
Bloodstream stage
These merozoites go on to infect erythrocytes (red blood cells) and, again, they undergo asexual replication. The infected erythrocyte eventually bursts, releasing more merozoites into the blood to infect more erythrocytes. Overall, these blood-stage parasites are the key culprits responsible for clinical symptoms displayed by infected individuals.
Photo: Thin blood smear showing red blood cells infected by Plasmodium falciparum. This photo was obtained from the CDC DPDx.
Throughout this stage of the cycle, some merozoites will become male or female gametocytes (germ cells).
Mosquito stage
When a mosquito bites an infected individual and takes up their blood, it ingests these gametocytes (which then divide to form gametes). Sexual reproduction occurs when male and female gametes fuse to form a zygote, similar to when sperm swims to an egg and fuses with it in human sexual reproduction.
This zygote becomes a motile ookinete which invades the mosquito’s midgut wall and develops into an oocyst, whereby being ‘motile’ means the ookinete is capable of actively moving. The midgut is a layer of cells within the mosquito that is involved in digesting food and absorbing nutrients. Division in the oocyst produces sporozoites that are released when the oocyst bursts.
After that, the new sporozoites migrate to the salivary gland, thereby making the mosquito infectious. So, when it next bites a human, the sporozoites will enter the bloodstream and the cycle will be repeated.
The illness: from silent to severe
Cytoadherence and its consequences
When bitten by an Anopheles mosquito carrying human-specific Plasmodium, around seven to 30 days pass before symptoms are displayed. This is known as the incubation period.
Plasmodium falciparum-infected individuals can have ‘uncomplicated malaria’, where they display mild symptoms, such as fever, chills, headaches, and diarrhoea. Given that these symptoms are associated with other diseases such as influenza, the common cold, or COVID-19, there is a possibility for malaria to be misdiagnosed, especially in areas where the disease is less common and therefore not expected.
This can be a problem because if malaria is untreated, some individuals will develop severe malaria. This form of malaria occurs when Plasmodium falciparum infects erythrocytes and forces its host cell to adhere to the endothelium of blood vessels to facilitate its own survival - this is illustrated in Figure 4. The resulting sequestration of infected erythrocytes in the vessels causes cell damage, microvascular obstruction, and organ failure.
Furthermore, the location of this ‘cytoadherence’ determines the nature of severe malaria. For example, adhesion to cerebral blood vessels will result in cerebral malaria, which is characterised by seizures and comas. In pregnant women, adherence to the placental endothelium causes pregnancy-associated malaria. This serious disease can lead to low birth weight, stillbirth, or even abortion. Not to mention, since erythrocytes are targeted by the parasite, anaemia can also be observed amongst severe malaria patients, and this is a particularly serious threat to children as it can lead to developmental impairment. The ability of P. falciparum to cause cytoadherence and the sequestration of infected erythrocytes in blood vessels explains why it is the deadliest species.
Conversely, a unique feature of P. vivax and P. ovale is their ability to form ‘hypnozoites’, which remain in the infected patient’s liver. Hypnozoites are the dormant versions of the parasite in the life cycle of some Plasmodium species, and they can persist for long periods of time. As a result, the reactivation of these parasites often leads to relapses of the disease years after the initial infection.
Figure 4: Plasmodium falciparum can force the erythrocyte (red blood cell) it has infected to bind to endothelial cells lining blood vessels. This is known as cytoadherence and leads to sequestration of infected erythrocytes in microvessels. The diagram shows that sequestration in different organs, such as the brain, placenta and lung, is responsible for the different types of severe malaria, such as cerebral malaria, seen in some infected individuals. This figure was adapted from Aird et al. (2019), Plasmodium falciparum picks (on) EPCR and was made using BioRender.
Immunity
Nonetheless, people living in malaria-endemic regions are continuously exposed to the pathogen throughout their lifetime and they, therefore, acquire natural immunity to it. This means that they are better able to fight infection and often only develop asymptomatic malaria rather than the clinical or severe malaria described above.
In these regions with stable malaria, children under five years are particularly vulnerable. Although they are protected in the first few months of life by maternal antibodies that cross the placenta, these antibodies are quickly lost over time, thereby leaving the child with no acquired immunity.
Similarly, malaria epidemics (outbreaks) often occur because the population is not normally exposed to the pathogen and therefore aren’t immune.
Treatments: past, present, and future
Drugs throughout the ages
Looking at the potentially life-threatening symptoms malaria can cause, one would hope that the disease is treatable.
Fortunately, it is! So, we will now explore some of the available treatments for malaria.
Malaria has plagued human populations for centuries; in fact, a malarial antigen was recently discovered in 3000-year-old Egyptian remains whilst the disease is also known to have affected the early Chinese, Greeks, and Romans.
Throughout this time, a range of antimalarial treatments has been discovered. The bark of Cinchona trees has been used since the 1600s to treat malarial fever. Meanwhile, quinine, which was isolated from this bark in the 19th century, is still used today.
More recently, a new antimalarial drug class called chloroquine was synthesised in 1934 and was one of the main contributors to malaria eradication in numerous regions throughout the 20th century.
Next, in 1972, artemisinin was isolated from Artemisia annua, a plant used by Chinese herbalists for over 2000 years. This highly effective antimalarial drug can be taken alongside another drug to improve its efficacy and prevent resistance occurring - this is known as an artemisinin-based combination therapy (ACT). ACT has been an essential tool in the fight against malaria throughout the 21st century and is the first-line treatment in a huge number of countries.
If malaria is suspected, a rapid diagnostic (RDT) is taken. Patients found to be infected with P. falciparum will begin ACT treatment to hopefully prevent the development of fatal complications and cure them.
Medication can also be given to people travelling to malaria-endemic regions to prevent the disease - this preventative treatment is called prophylaxis. Similarly, in some regions of Africa chemopreventive medication is given to children under five years of age to reduce child mortality.
The parasite strikes back
Whilst it may seem like we have a range of antimalarial drugs available, Plasmodium parasites, like many pathogens, are unfortunately capable of evolving resistance to drugs. When these parasites replicate, a random mutation that confers drug resistance may occur. This mutant would have a selective advantage over other parasites in the population - this basically means that other parasites will be killed by the drug, whilst the mutant will persist and replicate. The result is a drug-resistant parasite population which can now be spread to others.
By the 1960s, the heavy use of chloroquine led to widespread resistance against it in P. falciparum. Combining drugs, like in ACT, is commonly used to prevent resistance occurring in pathogens - if a pathogen develops resistance against one drug, it will still be killed by another. In fact, combination therapy is used successfully to treat HIV and Hepatitis C virus, whilst combinations of antibiotics can be administered together to prevent bacterial resistance. Despite this, ACT resistance was discovered in 2009 and is spreading across Southeast Asia.
Vaccines: the future
The growing issue of drug resistance means preventative measures are the best way to reduce malaria mortality and are essential when it comes to disease elimination.
Vaccines are an example of such measures. Whilst there aren’t currently any malaria vaccines commercially available, this is a huge field of research which is making significant progress. There are three types of malarial vaccines, each of which targets a different stage of the malaria life cycle, as seen in Figure 5.
Figure 5: The three types of malaria vaccines. Pre-erythrocytic vaccines target the pre-erythrocytic stages of Plasmodium falciparum, whilst blood-stage vaccines target the blood stage. In contrast, transmission-blocking vaccines are altruistic vaccines which target the sexual parasite stages in the mosquito. This figure was adapted from Arama and Troye-Blomberg (2014), The path of malaria vaccine development: challenges and perspectives and made using BioRender.
The first targets the liver stage of the parasite to prevent the initial infection being established and therefore preventing clinical disease and transmission of the parasite. These are called pre-erythrocytic vaccines.
Meanwhile, the second type, known as blood-stage vaccines, targets merozoites as this stage of the parasite is responsible for symptoms associated with malaria so blocking it prevents clinical illness.
And lastly, the final type aims to block transmission and are therefore known as transmission-blocking vaccines. This is done by inducing antibodies (proteins which target foreign antigens for killing) against antigens (molecules which stimulate the immune response) which are found on the parasite when it is in the mosquito. These antibodies, therefore, help target the sexual stages of the parasite. Additionally, transmission-blocking vaccines are examples of ‘altruistic vaccines’ as they don’t protect the vaccinee from infection, but instead help prevent future transmission.
Controlling the vector
Whilst treatment, and potentially vaccines in the future, are important for reducing malaria prevalence, we can take advantage of the fact the Plasmodium is a vector-borne species to further control the disease.
In essence, targeting Anopheles mosquitoes is an integral component of malaria control programmes because these vectors are essential for Plasmodium to complete its full life cycle and be transmitted to its next host.
The not-so-good old days
Historically and presently, insecticides have been the main method of reducing the vector population. Past malaria control is mainly attributed to the success of DDT, an insecticide developed in the 1940s. The chemical was used as part of the Global Malaria Eradication Programme across the globe, which led to the eradication of the disease in numerous countries. However, DDT was later found to be having a significant effect on ecosystems and was potentially harmful to human health, so its extensive usage was subsequently cancelled. In particular, Rachel Carson’s publication “Silent Spring” (1962) warned against the dangers of insecticides and is widely credited with starting the modern environmental movement. As a matter of fact, the name “Silent Spring” was derived from the finding that birds which ingest DDT lay thin-shelled eggs which break prematurely, leading to a decline in bird populations.
Today’s ‘legalised’ weapons
There are currently four classes of approved insecticides - pyrethroids, organophosphates, organochlorines (e.g. DDT) and carbamates, all of which can be used to target adult mosquitoes. These insecticides are essentially nerve agents, meaning that they interfere with the central nervous system of insects. These thereby result in paralysis, spasms and rapid death.
Various methods using these insect-killing chemicals can be incorporated into malaria control programmes, each with their own advantages and limitations.
Space spraying, which involves the release of a ‘liquid fog’ of insecticide, is used for a short-term and rapid reduction in the adult mosquito population, often in response to a malaria epidemic.
Meanwhile, insecticide-treated bed nets (ITNs) are one of the main contributors to the recent reduction in child mortality, particularly across Africa. To showcase the effectiveness of these, Figure 6 shows how the proportion of children sleeping under nets has increased, whilst malaria mortality has decreased. Essentially, these nets prevent the individual being bitten by mosquitoes and kill any mosquitoes which try to bite. Also, nets are logistically easy to distribute and cost effective, though it is important to highlight that they need to be constantly re-treated with insecticide. Henceforth, long-lasting insecticidal nets (LLINs) are a solution to this as they don’t require respraying. So overall, these nets can reduce uncomplicated malaria incidence by 50% in regions where malaria is stable.
Figure 6: (a) The share of children <5 years old sleeping under insecticide-treated nets has increased from 1999 to 2008 to 2017. (b) Deaths from malaria across the world, from 1990 to 2017, differentiated by age groups. The correlation between increasing proportion of children sleeping under nets and significant reduction in malaria-associated deaths suggests the insecticide-treated nets have contributed to reducing malaria mortality. These maps were obtained from ourworldindata.org.
Moreover, another strategy would be to conduct indoor residual spraying (IRS), which basically involves spraying insecticides on indoor walls of houses once or twice a year in order to kill mosquitoes that rest on sprayed walls. Nevertheless, LLINs and IRS are currently the most important mosquito control strategy because of their cost-effectiveness and potential to be scaled up.
Ah, of course this would happen
Similar to drug resistance in Plasmodium, Anopheles resistance to insecticides is a growing problem that threatens to reverse the gains made in reducing malaria prevalence.
73 countries have reported mosquito resistance to at least one insecticide class, with 26 of this reporting resistance to all four classes. Meanwhile, scientists are struggling to develop new insecticides which could replace the current classes, so vector control research is increasingly focusing on alternative approaches.
One example of genetic control is a gene drive - in which the aim of this is to introduce genetically modified mosquitoes into a population. This modification targets female mosquitoes as they are the ones that bite and whose numbers determine the future population size. In addition, the genetic modification is self-sustaining, which means it can rapidly spread itself without human intervention and hopefully reduce the mosquito population, leading to a reduction in malaria transmission.
Why is all this important?
Since the 19th century, we have made huge progress in eradicating the disease in many countries and reducing malaria-associated mortality. However, many countries - particularly those in sub-Saharan Africa - continue to be crippled by the mortality and economic consequences of malaria endemicity.
What can we do to control and eradicate malaria in these areas?
Firstly, understanding the Plasmodium parasite and its life cycle is essential in determining how it causes disease, which leads to the development of methods to cure it with drugs or prevent it with chemoprophylaxis or vaccinations.
Secondly, as a vector-borne disease, we also need to know about the biology and ecology of Anopheles mosquitoes as they are essential for sustaining malaria transmission. Understanding factors such as where the mosquitoes feed and breed allows us to target vector control programmes, such as IRS and LLINs, and make sure they are as efficient as possible. This information is also used by researchers for the development of new ways to kill mosquitoes as insecticide resistance spreads and threatens to increase malaria mortality.
Author
Ambar Khan
BSc Biological Sciences
Imperial College London
Disclaimer: All figures created using BioRender are intended solely for educational purposes and not for profit.