After seventy years of commitment and some very significant results since the early 21st century, the combat against malaria has reached a crossroads. Progress has slowed down in recent years, but new research tools, strategies and avenues have come to light. In addition, global health stakeholders have rallied around the target to reduce mortality rates associated with the disease by 90% by 2030. IRD’s experts and their partners are committed on all fronts to defeating malaria: screening and treating patients, protecting exposed populations, reducing transmission and factoring in the various changes liable to abate disease dynamics.
Malaria is an infectious disease caused by a parasite known as Plasmodium (see section: Plasmodium – Plasmodia). The parasite is transmitted through bites from a vector mosquito, the female Anopheles. Formerly widespread across the world, the disease is now mainly endemic in tropical regions, given the favourable environmental conditions for the parasite and for disease transmission.
In 2020, WHO reported an estimated 241 million cases of malaria – 90% of which were in Africa – and 627,000 deaths. Naturally, most research and control measures focus on the parasite Plasmodium falciparum, which is predominant on the African continent and responsible for almost all fatalities.
Malaria causes multiple symptoms comparable to those of influenza, often accompanied by gastrointestinal symptoms. However, severe forms can also occur, from the time of disease onset or following failure to treat the disease, characterised by potentially life-threatening vital organ failure. Populations living in areas where malaria is endemic can be reinfected several times, and, over time, develop partial immunity, which limits the symptoms. Young children, whose immune system is still naïveWhich has never been in contact with a foreign antigen, and pregnant women whose defences are temporarily modified, pay the heaviest price in terms of morbidity and mortality. 96% of casualties from malaria are under five years of age.
Malaria is a multifactorial problem, linked to the level of development of the countries affected and involving problems of access to diagnostics and care, poor awareness of the disease among exposed populations, various obstacles to the implementation of prevention or treatment, and vector control measures.
Screening and treating patients
Unsurprisingly, one of the first stages of intervention to combat malaria consists in diagnosing and treating infections from the time of onset. This is a prerequisite for reducing the number of patients, preventing severe forms of the disease, and fatalities. In the case of gestational malaria, early diagnosis is key to preventing severe anaemia, or even death, during pregnancy, in mothers, and also underweight infants. Low birth weight is one of the main causes of infant mortality in Africa. Screening for malaria infection from the time of onset of the first clinical signs is key, as the disease has symptoms common to many other diseases. Finally, to facilitate their practical use, screening tests and treatments must be readily available and accessible free of charge, as close as possible to the exposed populations. Scientists are working with national malaria control programmes to assess strategies employed to achieve these aims. They are also helping to monitor treatment efficacy, and to improve and diversify treatments.
Rapid diagnostic test
“The development and distribution of malaria rapid diagnostic tests, in recent years, are a substantial advance in combatting the disease”, reckons Jean Gaudart, Public Health Physician and Statistician in the Joint Research Unit for Economic & Social Health Science & Medical Information Processing (SESSTIM). “These tests just need one drop of blood on a strip coated with an ad hoc reagent, and can be performed and interpreted by practically anyone, making diagnosis more accessible and making it possible to initiate early treatment.” Similar to COVID-19 rapid antigen tests, these easy-to-interpret tools contain a line indicating whether or not the subject is infected. Before these tests, cases were diagnosed using blood samples which needed to be examined by a laboratory technician under a microscope, in a healthcare facility, containing the necessary equipment, which was a substantially more burdensome process...
In concrete terms, these tests represent the first stage of integrated disease management strategiesProvision of rapid diagnostic tests and treatment of uncomplicated forms at local level, designed to reach patients as quickly as possible. This approach enables community health workers to learn how to administer these tests in a few hours. Several trials have demonstrated the effectiveness of this strategy, in Mali and Senegal in particular, where community health workers visited their village’s households regularly in order to test symptomatic subjects, and, if malaria infection was confirmed, to supply the medication required immediately. This approach is particularly effective for controlling uncomplicated forms of the disease, and transferring patients with more severe forms to specialist wards. It was previously effective in South-East Asia, and is now being used to eradicate nearly all cases of the disease in some regions of Western Africa. (see section: The amazing story of Dielmo-Ndiop).
“Incidentally, by ruling out some suspected cases of malaria following bouts of fever or gastrointestinal problems in endemic areas, these tests have revealed, and subsequently made it possible to treat and prevent, other endemic diseases, like borreliosis”, says Cheikh Sokhna, biologist with the Joint Research Unit for Vectors – Tropical and Mediterranean Infections (VITROME).
Most treatments aim to neutralise the parasite when it produces symptoms, i.e. in the blood phase of its cycle in humans (see section: The highly complex Plasmodium cycle). To prevent severe forms of the disease, which are frequently associated with a lack of care or delayed care, treatments must be administered as soon as possible. Since the 2000s, and following the emergence of parasite resistance to previous treatments, the main drugs are derivatives of artemisinin, obtained from a Chinese plant whose effects have been known for many years. These active ingredients are easy to use, administered by injection or by the oral route, and quickly eliminate the parasites present in the blood. Inexpensive and widely distributed thanks to support from the Global Fund to Fight AIDS, Tuberculosis and Malaria, artemisinin derivatives are primarily used in association with other “partner” drugs, such as amodiaquine, lumefantrine, piperaquine, and pyronaridine. The aim of these bitherapies, known as artemisinin-based combination therapies (ACTs), is to supplement the activity of the artemisinin derivatives and reduce the risk of resistance.
To detect the emergence of resistances, scientists regularly study the efficacy of recommended treatments. “Clinical data from treated patients are analysed, along with blood samples, by sequencing some or all of the parasite’s genome to detect any previously identified or hitherto unknown resistance genes”, explains Jérôme Clain, a biologist at the Mother and Child in Tropical Regions Joint Research Unit: pathogens, healthcare system and epidemiological transition (MERIT).
Finally, some parasite species, Plasmodium vivax and Plasmodium ovale (see section: Plasmodium – Plasmodia), can persist in dormant form in the liver for extended periods of time. A specific treatment, based on primaquine, is required to prevent recurrence, which can even occur several years after the first bout of malaria.
Besides monitoring the efficacy of existing treatments, scientists are working on improving therapies. “In Benin, we have identified a specific profile associated with cerebral malaria and death”adjuvant therapyA substance added to the primary treatment in order to enhance or boost its action to the artesunateArtemisinin derivative that is used to treat these cases, with the aim of aiding the innate immune response to resolve the brain inflammation.”, reveals Agnès Aubouy, a biologist in the Joint Research Unit for Pharmacochemistry and Biology for Development (PHARMA-DEV). “This severe clinical form of the disease is manifested as a deep coma and affects children in particular, with a 30% mortality rate among patients from two to six years of age. The ultimate aim of our research is to propose an
Scientists at PHARMA-DEV are also working on expanding the therapeutic arsenal against malaria by researching new treatments. In this way, ethno-pharmacological surveys conducted on populations and traditional medicine practitioners are aiming to identify plants used as antimalarials. For example, they have identified the plants Terminalia albida in Guinea and Terminalia macroptera in Mali, whose bark, leaf or root extracts have displayed very interesting antimalarial activities both in vitro and in vivo on mouse infection models. “This type of approach can either help us identify new antimalarial drugs, which might give us the drugs of the future, or validate the use of traditional herbal medicine”, explains the specialist (see section: Artemisia, the plant everybody is talking about). “The use of antimalarial plants in the form of herbal teas is of particular interest, as it has already been adopted by populations living in areas where malaria is endemic.” However, the disadvantage of this type of herbal product is the variability of the constituents, associated with cultivation (soil composition, climate, etc.), harvesting (plant age, parts collected), drying, and preparation conditions: aspects which are all liable to modify efficacy and may adversely affect reliability.
In contrast to the symptomatic blood phase of the disease, which can be treated with numerous drugs, up to now, there have been few treatments for the liver and transmissible phases (see section: The highly complex Plasmodium cycle). Yet it is crucial to be able to target the parasite at these stages of its cycle, in order to prevent the onset of disease from the liver stage onwards, and to block transmission to a healthy mosquito in the case of gametocyte stages. To this end, scientists are analysing many drugs used in all kinds of indications in order to identify those with similar chemical structures to the rare treatments that are effective in combating these two stages. This is known as drug repurposing. “We look for drugs which have similar structural units to conventional antimalarials or which can be converted in situ by the human liver, which is an important agent in the metabolism of antimalarial drugs”, explains Romain Duval, a chemist at MERIT. “And we have already obtained very encouraging in vitro results, for example establishing the activity of a cough suppressant and antidepressant against the liver and gametocyte stages of the parasite, respectively.” The next stage in the potential therapeutic repurposing of these drugs against malaria will be to confirm their efficacy on mouse models infected with a rodent parasite.
“We monitor the epidemic dynamics of the disease closely, using information systems now in place in a growing number of countries in endemic areas”, points out Jean Gaudart. “Where does peak transmission occur, at what time of the year, under which environmental and societal conditions? The answer to these questions helps fine-tune the control strategies used by national malaria control programmes to contextualise interventions, and determine whether there are any factors that can be adjusted in a public health initiative.”
In this way, this research has revealed the emergence of a transmission hot spot following substantial economic investment in agricultural development, in the Diré district of Northern Mali. In this region of the Sahel with seasonal malaria transmission, involving control measures which essentially focus on the wet season, the implementation of irrigation schemes has led to an explosion in the Anopheles population. Rather than the rain, the main driver of the malaria epidemic has become the water throughout the irrigated area, and the control strategy has had to be adapted. Similarly, research has demonstrated that in South Africa, where malaria has virtually been eradicated due to the continued use of the insecticide DDT, the final stumbling block concerns cases imported from neighbouring Zimbabwe which replenish the human reservoir. “Therefore, to succeed, the control strategy needs to account for the economic and social conditions of the poor migrant workers, who cross the Limpopo to find work and do not seek treatment or are afraid to seek medical care because their status is not necessarily legal”, explains the public health physician and statistician Jean Gaudart.
To defeat malaria, the researchers involved in these diagnostic, treatment and strategy issues are in agreement on the importance of monitoring the efficacy of treatments and screening tests in each region – by enhancing knowledge about the parasites present – and of improving access to care and education on the disease among exposed populations.
Artemisia, the plant everybody is talking about
Artemisia annua and Artemisia afra, two species of the plant used to extract artemisininactive ingredient forming the basis of first-line malaria drugs, obtained through extraction or hemisynthesis, are used extensively in popular medicine and traditional malaria treatments in endemic regions. According to the promoters of these plants, including highly active NGOs, they are effective in preventing and treating the disease, are well-tolerated, are an alternative to the numerous counterfeit malaria drugs and pharmaceutical industry monopolies, and can be grown and used in remote rural regions denied access to conventional treatments. For their detractors, their use involves many risks: their potential toxicity is unclear, the use of plants with insufficient artemisinin doses exposes the patient to potential therapeutic failures and might induce artemisinin resistance.
“Our in vitro studies have demonstrated that infusions of these two plants strongly inhibit malaria parasites, in particular their liver and blood stages, which could explain their preventive and curative effects among populations”, explains Romain Duval, a chemist at MERIT. “Even more surprisingly, the efficacy of Artemisia afra, the African species containing low or extremely low levels of artemisinin, seems to indicate the presence in this species of as yet unknown active compounds or combinations of active compounds, justifying the therapeutic interest.” An analysis of uses and phytochemical prospection of these plants could be a promising avenue leading to the discovery of new malaria treatments.
The amazing story of Dielmo-Ndiop
Formerly decimated by malaria, the two Senegalese villages of Dielmo and Ndiop are now virtually malaria-free. “There is no need for preventive treatment when visiting the area”, reckons Cheikh Sokhna, a biologist with the VITROME Joint Research Unit. “The infection risk is now non-existent.” This is a complete turnaround for these two rural villages, where mosquitoes used to proliferate – particularly due to the immediate proximity of a river in in the case of Dielmo. With one thousand malaria infections each year, malaria used to take a heavy toll in these villages, as reflected by the mortality of young children prior to the 1990s. Chosen by scientists from IRD and Institut Pasteur in Dakar and Paris to study the disease and trial control strategies, the villages are now no longer experiencing any mortality from the disease. The experts rolled out the resources required to ensure timely diagnosis and treatment, and promoted the use of insecticide-impregnated mosquito nets to keep people safe from nocturnal bites while sleeping. Naturally, they have been monitoring the impact of these measures on the populations’ health ever since. As testing grounds for control strategies and observatories of health and social impacts, the two villages are living proof of the effectiveness of local, integrated malaria control.
Protecting exposed populations
The old saying that prevention is better than cure is particularly relevant to malaria. A varied arsenal of tools designed to prevent disease onset is used with the aim of eliminating the parasite in exposed subjects’ bodies prior to symptom onset, limiting human-vector contact, and preparing the immune system to better resist uncomplicated and severe forms of the disease. These different approaches to prevention can be used on their own, or combined, depending on the conditions. They are primarily aimed at people at the greatest risk from malaria, young children and pregnant women in regions where the disease is endemic.
Seasonal or intermittent chemoprevention
Administering medication even before malaria infection occurs, based on drugs which are toxic to Plasmodium in its blood stage in humans, provides effective protection against uncomplicated and severe forms of the disease. These chemoprevention strategies target young children, who have not yet acquired immunity against the parasite, and pregnant women whose immune system undergoes temporary vulnerabilities in order to tolerate the foetus. In the latter, prevention is based on intermittent preventive treatment during pregnancy (IPTp), i.e. administering at least three doses of a drug (sulfadoxine/pyrimethamine) during pregnancy, during antenatal check-ups at maternity clinics. “However, this strategy, which has been scientifically proven to be effective, continues to be underused in Sub-Saharan Africa, where under 40% of women actually receive the three doses”, explains Valérie Briand, a medical epidemiologist for the Global Health in the Global South (GHiGS) joint research team, part of the Bordeaux Population Health Joint Research Unit. “To increase IPT uptake, in Mali and Burkina Faso, we are assessing a home medical administration system, alongside maternity clinic administration. This is an integrated strategy, as IPTp is administered by a community health worker at the same time as seasonal malaria chemoprevention (PMC) aimed at protecting children under five years of age.”
In these regions of the Sahel, where malaria transmission only occurs during the rainy season, the preventive treatment for young children – a combination of sulfadoxine/pyrimethamine and amodiaquine – is administered on three consecutive days during the critical period by a community health worker visiting households. In humid equatorial and subequatorial areas of Africa where transmission occurs year-round, the protection of children is based on intermittent preventive treatment.
Indeed, for infants, WHO recommends administering an IPTi – three doses of sulfadoxine/pyrimethamine during the first year, administered during immunisation sessions under the Expanded Programme on Immunisation (EPI) – but this programme has not been rolled out in any countries other than Sierra Leone. “We are assessing the implementation, efficacy and acceptability/feasibility of the IPTi programme and its extension to the second year of a child’s life in Togo, Sierra Leone and Mozambique”, points out the specialist. If the efficacy and acceptability of these interventions are also established for the second year of a child’s life, as we hope, they could soon be included in WHO guidelines.”
For people travelling to areas in which malaria is endemic, and therefore have no acquired immunisation, a preventive regimen covering the time of their stay followed by the end of the cycle of a potential parasite in the body, is required.
Impregnated mosquito nets and home spraying
Reducing the number of mosquito bites is a simple and effective way to prevent infection linked to transmission of the parasite from an infected host to a healthy subject. With this in mind, vector control enables the reduction of direct contact between humans and vectors, mosquito population density and mosquito longevity, as older females are the most dangerous in terms of contamination. Indeed, around ten days after they have been infected by biting a Plasmodium carrier, the parasite will have grown in their digestive system and will be capable of contaminating a new host. The primary vector prevention method currently recommended is the use of insecticide-impregnated mosquito nets to protect bedding. This is because Anopheles gambiae, the main vector of Plasmodium falciparum, prefers to bite at night and indoors. Developed by an IRD team in Burkina Faso in 1983, adopted by WHO and widely distributed worldwide with support from the Global Fund to Fight AIDS, Tuberculosis and Malaria, these household protection aids have proven to be highly effective. One study has established that 68% of the reduction in malaria infections could be attributed to these aids, corresponding to a significant drop in mortality associated with the disease, from 1.8 million deaths per year at the turn of the century to 400,000, subsequently rising to over 600,000 recently.
“Like indoor spraying – the second vector prevention method recommended by WHO – the insecticides used are pyrethrinoids, which have the advantage of not building up in the environment”, explains Fabrice Chandre, a medical entomologist at the Joint Research Unit for Infectious diseases and vectors: ecology, genetics, evolution and control (MIVEGEC). This intervention consists in applying insecticide on interior walls in homes in order to poison the mosquitoes that land there, before or after feeding on blood. The method has been highly effective and has helped to eradicate malaria in some countries, but not in Africa.
Other methods are available or are in the pipeline in order to reduce vector pressure near homes and protect exposed populations: breeding-ground clearance, use of repellents or, conversely, trapping using attractants such as carbon dioxide (CO2) or lactic acid.
“Finally, we are conducting ethnobotanical research in Côte d’Ivoire, to assess the benefits of plant-based substances used locally to repel mosquitoes”, notes the scientist. “This knowledge may help us get the better of this vector!”
As most subjects living in endemic areas acquire some immunity before adulthood – protecting them against frequent bouts and against the severe form of the disease – the idea of stimulating immune processes to protect children and pregnant women is an attractive one. “The interactions between the human host and the parasite must be understood in order to develop a vaccine. However, this is a highly complex problem”, warns Adrian Luty, a parasitologist and a specialist in infectious disease immunology at the Mother and Child in Tropical Regions: pathogens, healthcare system and epidemiological transition (MERIT) Joint Research Unit. “Because, unlike viruses or bacteria which only have a few genes and, as such, vaccine targets, Plasmodium is a single-cell eukaryote, with a nucleus containing all the genetic information in DNA form. It can code over 5,000 proteins, which may be involved in infecting humans. Therefore, there are potentially more than 5,000 targets, leaving aside the fact the parasite transitions through four stages (see the Parasite cycle) in the human host’s body, with different proteins expressed at each stage.”
Polymorphisms, i.e. varied parasite strains which do not always express the same variants of different molecules, also exist, thus complicating the problem even further. It is precisely this variety that is mostly responsible for the low level of protection from the vaccines developed to date, including the renowned RTS,S vaccine recently recommended by WHO, which only protects 30 to 40% of vaccinated children for a relatively short period.
With a view to developing effective vaccines, scientists have started working on a long-term project aiming to identify target antigens among the 5,000 proteins expressed by Plasmodium. These molecules produced by the parasite are likely to trigger an immune system response particularly in the form of antibodies capable of blocking the invasion of host cells (hepatocytes or erythrocytes) by parasites. The antibodies produced against vaccine candidate antigens can also help to control Plasmodium by interacting with immune cells such as monocytes and neutrophils.
Setting up cohortsgroups formed for an epidemiological study of individuals naturally exposed to malaria makes it possible to observe the onset of malaria infections in the participants over time and study the risk and protective factors for malaria. The cohorts established by MERIT in Senegal and Benin incorporating very detailed parasitological and clinical follow-up of children constitute a key tool for studying the protective role of specific antibodies against malaria antigens and identifying the most promising vaccine candidate antigens under natural exposure conditions. “The GLURP (glutamate-rich protein), MSP (merozoite surface protein), MSP2, MSP3 and AMA (Apical Membrane Antigen) proteins, which are involved in the blood stage of the parasite’s human cycle, are promising targets”, points out David Courtin, a molecular biologist at MERIT. “We already have evidence of their efficacy in vitro, and they have passed the preclinical stages, with some having reached the clinical trial phase.” Despite the obstacles, the quest for vaccines to protect the young continues. Furthermore, thanks to their cohort study, the scientists have established the negative impact of coinfections with other tropical parasites – particularly schistosomiasisthe second-biggest tropical parasitic endemic after malaria, causing 280,000 annual deaths – which lower specific antibody responses against vaccine-candidate antigens and could increase children’s vulnerability to malaria. Guidelines may be issued recommending deworming treatment to combat helminth infections prior to administering malaria vaccine in order to improve its efficacy.
Vaccination against the gestational form
In addition to being a danger to pregnant women, the gestational form of the disease is also a major healthcare challenge in neonatal medicine and paediatrics. This form of the disease is linked to interactions between red blood cells infested with Plasmodium and a specific placental protein. It often goes unnoticed because it is asymptomatic, but placental infection with the parasite causes delayed foetal development, restricting exchanges with the mother during the intrauterine period, and results in low birth weight. In Sub-Saharan Africa, low birth weight is the primary risk factor for mortality during the first year of a child’s life. Furthermore, in utero exposure to malaria may affect the child’s future immune potential against the disease. “After deciphering the molecular mechanisms at play and isolating a protein inducing an immune response, we have developed a vaccine specifically for the gestational form of malaria”, reports Adrian Luty, who is involved in the venture as part of a scientific consortium including teams from Benin, France, Germany, and Denmark. “When administered to young girls who have not previously given birth, it will protect their first pregnancy, when the time comes.”
This is because malaria in pregnancy essentially affects first-time mothers, as women acquire specific immunity in subsequent pregnancies. The vaccine, for which clinical trials have commenced in Germany and Benin, is producing promising results. “However, once again, as for the RTS,S vaccine, we will definitely need to look at developing a second multivalent version, incorporating polymorphisms of the target protein, induced by parasite variability”, reckons the specialist. Once fully developed and distributed, each year, this vaccine could prevent 50 million cases of gestational malaria and save many babies’ lives.
Scientists are in agreement on the importance of developing effective vaccines, incorporating an array of polymorphisms of the parasite, and of improving the knowledge, strategy and tools to control the vector, and fine-tuning chemoprevention methods to defeat malaria.
The highly complex Plasmodium cycle
The life cycle of the parasite responsible for malaria requires two successive hosts: a human and a mosquito from the family Culicidae, subfamily Anophelinae.
The human contracts malaria when bitten by an infected female Anopheles, feeding on the human’s blood . The mosquito injects the parasites in sporozoite form with its saliva. These sporozoites remain in the bloodstream for about a half an hour, before reaching the liver and entering the hepatocytes. Once there, the sporozoites grow and divide by mitosis to form a schizont containing several thousand nuclei. After one week, the schizont bursts, releasing several thousand merozoites into the bloodstream. They enter red blood cells, are transformed into trophozoites, and then grow and divide to form a schizont, which, when it bursts, releases more merozoites which will undergo further erythrocyticinside red blood cells cycles lasting from 24 to 72 hours depending on the Plasmodium species. The bursting of the schizonts corresponds to the outbreaks of fever characteristic of the disease.
After several erythrocytic cycles, the schizonts spawn male and female gametocytes, initiating the sexual cycle. From that moment on, a female Anopheles which bites our human will absorb gametocytes. These turn into gametes in the mosquito’s stomach. Fertilisation between gametes then spawns a motile egg which turns into an oocyst whose nucleus divides and, after bursting, releases a large number of sporozoites which reach the saliva glands, ready to infect a human. This sexual cycle lasts from 10 to 40 days depending on the temperature and Plasmodium species, e.g. 12 days for P. falciparum in tropical Africa .
Finally, Plasmodium vivax and Plasmodium ovale are capable of remaining in hepatocytes in dormant form, and of causing resurgence of the disease months or years later.
Plasmodium – Plasmodia
Plasmodium, the parasite responsible for malaria is not a single species… Among this genus of protozoans, five different species, differentiated by their geographic area and their symptomatic profile, are capable of infecting humans:
Plasmodium falciparum, is the most widespread and the most dangerous species, causing the most fatalities. It is predominant in Africa, where it accounts for the vast majority of illnesses. However, its preponderance could cause the contributions of other species that are not quite so spectacularly pathogenic to be underestimated or ignored. In Asia, it represents under half of all malaria cases.
Plasmodium vivax is highly active in Central and South America, where it causes three-quarters of the malaria cases. Not as virulent as P. falciparum, it can nonetheless be life-threatening. It can remain in the liver for years after the first bout of malaria, in dormant form, before resurging and causing a recurrence of symptoms.
Plasmodium ovale is rife in Western Africa. It causes moderate forms of malaria, and, like P vivax, has a dormant form.
Plasmodium malariae is present throughout the world, but only causes mild bouts of malaria.
Plasmodium knowlesi is quite commonly found in macaques in South-East Asia. It has been infecting humans in recent decades. Also transmitted by Anopheles, it causes potentially severe malaria and is responsible for up to 70% of cases in some areas.
In the absence of an effective vaccine, which could help prevent malaria infection, and alongside such a vaccine when it eventually emerges, there are two possible pathways to impeding malaria transmission and eradicating the disease: eliminating the vector and purging human parasite reservoirs. Entomological research, vector control strategies and large-scale or targeted local malaria treatment campaigns offer promising prospects in this regard. Combined with initiatives designed to protect and treat exposed populations, some of these interventions have already helped eradicate malaria in certain regions of the world where it was still claiming casualties only a few years ago. For example, Argentina, China, and Algeria have recently overcome the disease. Initiatives rolled out in Africa with this in mind are seeing encouraging results, in Senegal and Uganda in particular.
Pursuit of the mosquito
“Vector control is an effective means of restricting, or even halting the number of infecting bites, and therefore the transmission of malaria from an infected subject to a healthy person”, explains Fabrice Chandre, an entomologist at MIVEGEC. “It involves not only reducing vector density, and contact between humans and vectors, but also shortening the vectors’ lives.” Indeed, older females are the most dangerous Anopheles, as the parasite needs around ten days to grow in the mosquito before it can be transmitted as a result of a feed on blood (see section: Parasite cycle).
Many techniques are employed with the aim of eradicating malaria vectors. Some Northern countries succeeded over a century ago by implementing sanitation measures in marshy areas that were conducive to mosquito development. Eradication has also been obtained through the roll-out of protective measures, chemical mosquito extermination campaigns, and biological control measures using larva-eating fish in permanent or semi-permanent breeding grounds. Very recently, genetic control measures, aimed at releasing male Anopheles modified with a gene causing sterile offspring, have been envisaged, but have yet to overcome certain ethical obstacles.
In areas where malaria is endemic, the increasingly widespread use of impregnated mosquito nets over the last twenty years should have a major influence on the vector mosquito population. By preventing mosquitoes from feeding on blood – essential for females to produce their eggs – these tools have the potential to restrict their density sufficiently to endanger their population. However, this has not happened. Mosquitoes are incredibly adaptable and are maintaining their numbers, despite the pressures applied by vector control measures around human hosts, by modifying their behaviours.
Promise of endectocides
“Key vector species display considerable flexibility in terms of their choice of host for their feeds on blood, in that they are capable of gorging on the blood of animals when they are unable to bite humans who are safe underneath their mosquito nets”, explains Karine Mouline, an entomologist at MIVEGEC. In this way, in some regions, such as South-West Burkina Faso, more than 50% of malaria vectors captured in homes have also fed on cattle, pigs, sheep or goats, but especially on bovines. To target these ubiquist mosquitoes, vector control experts have looked into treating cattle with ivermectin.
This drug is widely used in veterinary medicine to kill all types of parasites, particularly gastrointestinal roundworms. It has also been used in human medicine for over thirty years to treat populations affected by lymphatic filariasis and onchocerciasis: parasitic diseases found in tropical regions. Ivermectin’s endectocide actionproperty of an antiparasitic treatment active both on internal parasites and on external parasites against the vector of malaria has been demonstrated. “When we administered it to bovines, we demonstrated that the blood feed taken by Anopheles significantly affects their survival for three weeks”, she explains. “In the field, this measure could help reduce vector populations. However, this reduction would only be temporary, and would not have an impact in epidemiological terms.” In association with a specialist firm, scientists have subsequently developed a biopolymer-based, long-acting injectable ivermectin formulation. The ivermectin concentration released and the duration of action can be modulated. In this way, trials have been conducted using formulations for six or more months. In addition, although malaria does not affect bovines, farmers also benefit, as animals receiving long-term antiparasitic treatment gain more weight and breed more.
Naturally, scientists are now working on developing a long-acting endectocide formulation for humans, also based on biopolymers and ivermectin. The first are already being used for other drugs currently undergoing Phase 3 trialsconducted on a large number of patient volunteers, the objective of phase 3 trials is to prove the therapeutic efficacy of a new treatment, identify adverse effects, and assess the short- and medium-term benefit-risk ratio., and ivermectin has been and continues to be distributed on a large-scale in many human medicine campaigns. Phase 1 trials, establishing the safety of the formulation will take place in Europe soon. Subsequent trials aimed at confirming its efficacy against the wild malaria vector will be conducted in endemic areas in Africa.
“With this formulation, there is great hope of being able to radically reduce Anopheles densities, and hence Plasmodium transmission. Several successive treatment campaigns could be implemented where needed according to the epidemiological profile”, reckons Karine Mouline.
According to experts, eradicating the malaria vector, which is key if we are to halt transmission of the disease, is unlikely to have disastrous environmental consequences. “There are 3,600 mosquito species, only 100 to 200 of which are capable of transmitting pathogens to humans – parasites or viruses”, states Fabrice Chandre. “They only represent a fraction of mosquito diversity, and the gap left in ecosystems by vector species eradicated through vector control measures might in some cases be filled quickly by non-vector species.”
Flushing out the parasite
To halt transmission, another alternative is to deplete parasite reservoirs. This might even be necessary to make headway in disease control. “In the last four of five years, WHO reports have shown that we are no longer gaining ground in the fight against malaria. This standstill, if not regression, is evidence that current control measures are not sufficient”, confirms Gilles Cottrell, an epidemiologist at MERIT. “The methods, essentially based on treating cases, diagnostics and prevention with impregnated mosquito nets and indoor insecticides, have paid off, but they are now confronted by the presence of a reservoir of asymptomatic carriers.”
New Plasmodium PCR detection tools have indeed demonstrated that some of the population in endemic regions are infected with the parasite without showing any clinical symptoms. As they are not affected by the disease, these healthy carriers naturally do not seek screening or treatment. However, despite their low parasite load, they can infect mosquitoes that bite them and thus help spread malaria in spite of the control strategies in place. “Even now, we know that diagnosed symptomatic cases are the tip of the iceberg”, he says. “Depending on the epidemiological profiles – seasonal or non-seasonal malaria, high- or low-transmission regions – studies have shown that 60 to 90% of those infected develop asymptomatic forms.”
For all that, the role of these healthy carriers in disease transmission continues to be under review. In Benin, a cohort of asymptomatic infected subjects is followed up each month. By measuring the subjects’ parasite load and testing the infecting parasite strain, scientists at MERIT, the Clinical Research Institute of Benin, the University of Abomey-Calavi, and the Entomological Research Centre in Cotonou are developing a better understanding of the duration of their asymptomatic infection. “The studies conducted to date show that although healthy carriers are less contagious due to their low parasite load in the blood, they have a significant impact in global transmission due to their large numbers”, considers Gilles Cottrell. This could be the case in Eastern Senegal, in the triangle located between the cities of Tambacounda, Kedougou, and Kolda. “Despite the intensive use of control strategies that have proven to be effective in the region, malaria is strongly persistent”, explains Elhadji Bâ, an epidemiologist at VITROME. “Our work on monitoring the population is intended to assess the place and role of asymptomatic carriers in epidemiological dynamics in this red transmission zone.”
The evidence of this “invisible human reservoir” in populations raises questions about technical issues and public awareness. The roll-out of highly sensitive molecular tests is required to detect parasite levels that are infinitesimally small in some cases. It will also be necessary to persuade healthy subjects to undergo screening and testing for the benefit of all.
Targeting the invisible reservoir
To reduce the proportion of asymptomatic carriers in the population – in the hope that this will have a significant impact on transmission, scientists are trying out drug-based interventions designed to kill the parasite. “Two strategies can be envisaged, either mass screening of the population with tests that are sensitive enough to detect asymptomatic carriers and treat them specifically, or mass treatment of the entire exposed population”, explains Jordi Landier, an epidemiologist at SESSTIM. A pilot trial is currently underway based on the second model in the Tambacounda region, in Senegal with the University of Thiès and the national malaria control programme in Senegal.
“In June, August, and September 2018, we administered a curative treatment providing protection against malaria to the entire population of 30 villages”, reports Elhadji Bâ, of VITROME, an investigator in this trial. “It consisted in extending a form of seasonal chemoprevention (SCP) usually reserved for children to all the inhabitants. This is known as mass drug administration (MDA). Other control localities only received the usual chemoprevention, namely SCP targeted at children.” The objective of this trial which was implemented prior to the resumption of transmission (end of dry season) is to reduce the number of carriers, and above all eradicate gametocytes – the form of the parasite that can be transmitted to mosquitoes – in order to prevent transmission during the rainy season, when the vectors proliferate due to puddles of water which are conducive to egg-laying.
Seasonal window of opportunity
Besides lowering transmission in the wet season in regions where the epidemiology fits into a seasonal pattern as in this trial, scientists are also working on another approach. “During the dry season, the parasite takes refuge in asymptomatic human carriers, while awaiting the season when vectors will allow it to enter other hosts”, says Jordi Landier. “This creates a choke point, a period of vulnerability in the parasite cycle: Plasmodium is present at low levels in much fewer hosts than in other seasons, and its circulation is restricted by the low number of mosquitoes.” This window of opportunity could help to eradicate it in a given area, either by treating everyone, or by screening and treating healthy carriers, at the right time.
However, these efforts to purge the human reservoir are not intended to be carried out independently of the other control measures: “It is absolutely essential to accompany these interventions with long-term community-wide access to malaria diagnostics and treatment, close to populations”, adds Jordi Landier. “After the intervention, we need to do everything we can to treat cases who are reinfected despite these measures – when travelling for example – immediately, so that the reservoir does not build up again.”
Finally, a treatment is available that blocks parasite transmission from an infected subject to a vector mosquito. This drug, called primaquine, does not treat malaria symptoms. However, WHO recommends that it be prescribed in association with other treatments, in order to impede disease transmission as much as possible.
Highly practical tools and strategies can therefore be used to combat the vector and the parasite. Progress in this area means that we can reasonably hope to take control of disease transmission in the medium term, but only if the investments are not solely focused on immunological approaches.
History of malaria treatments
At a time when clinical trials are being conducted on tritherapies, in order to replace bitherapies which may eventually become obsolete, malaria treatments already have a long history. Quinine, extracted from a type of tree bark chewed by Amerindians to treat fever, has been known for many generations in South America. Brought to Europe by Jesuit missionaries in 1660, it was sold at incredibly high prices in Europe where malaria was still rife. In 1870, its active ingredient was identified by two French pharmacists, Joseph Pelletier and Joseph Bienaimé Caventou. In Java, the Dutch started cultivating the cinchona, the tree whose bark contains quinine, and this production was sufficient to meet the growing needs, until the island fell into the hands of the Japanese. The pharmaceutical sector then focused on developing a synthetic antimalarial drug, successively formulating, from 1930 to 1950, pamaquine, quinacrine, chloroquine, amodiaquine, primaquine, pyrimethamine, chlorproguanil, and proguanil. Chloroquine, effective as a curative and preventive treatment, inexpensive and with few adverse effects, ultimately became the most frequently used treatment. However, resistances emerged during the first years of use, first in the Amazon and Asia, and then later in Africa. As an alternative, the sulfadoxine – pyrimethamine combination (marketed under the trade name Fansidar®) was then used. The 1980s saw the introduction of two other synthetic drugs similar to quinine, mefloquine (Lariam®), and halofantrine (Halfan®), but their efficacy quickly declined. In 1973, a new drug was isolated from qinghao (the Chinese vernacular namename commonly given to a species, and generally only used in its country of origin for Artemisia annua), a plant used in China for over 1,500 years. Its active ingredient, artemisinin (also known as qinghaosu) enabled the development of several derivatives in the 1990s, such as artesunate, dihydroartemisinin, artemether, which are highly effective against malaria, and especially severe forms of the disease. These drugs are now used in combination with one or two other antimalarial drugs with different modes of action, in order to restrict resistant parasite selection. They currently represent the only therapeutic solutions against P. falciparum infection in most endemic areas.
Malaria control, like many other modern-day scientific challenges, is part of a context profoundly marked by change. The experts striving to defeat this epidemic are required to deal with ever-changing data, conditions, and research endpoints. Due to anthropic activity, environmental effects or the high degree of genetic plasticity of the parasite and its vector – and the vector’s incredible behavioural adaptability – the circumstances are rarely stable. Therefore, it is necessary to devise solutions and approaches which are capable of accounting for, and often anticipating, what is currently happening or about to happen, in a truly agile approach to science.
Epidemiological seasonality and climate
Water plays a major role in the epidemiological dynamics of malaria, as it affects the breeding of the vector mosquito. Depending on the specific climatic and environmental conditions of each region, the vector finds breeding-grounds conducive to egg-laying in temporary rain puddles or in perennial watering places. Therefore, humidity determines the seasonal or, conversely, continuous nature of transmission in an area. Climate change, and the rainfall variations associated with it, will naturally affect epidemiology, and should guide disease control strategies. “In this way, Lake Agofou, in Northern Mali, is a typical example of the impact of climate change on malaria”, reports Jean Gaudart, a public health physician and statistician at SESSTIM. “Once temporary, filled with rainfall and dried out due to seepage to groundwater tables, its dynamics have changed profoundly. The drought and violent rains experienced in this region in recent years have eroded the soils down to impermeable clays. Water has built up, creating a permanent lake, providing year-round mosquito breeding grounds and radically changing the local epidemiological characteristics of malaria.”
Elsewhere, floods, also linked to the disruption of rainfall patterns, which are characteristic features of climate change, are upsetting the dynamics of malaria. This is seen in South Africa, for example, where the increase in extreme rainfall events, creating large amounts of stagnant water, is accompanied by malaria epidemic peaks.
Plasmodium fights back
Unlike climate change whose effects have become apparent only in the last few decades, the emergence of drug resistance in the parasite causing malaria is far from new. The occurrence mechanism should be considered in the context of the broad genetic variability of Plasmodium falciparum and the widespread use of treatments: only a few parasites – carrying specific mutation(s) – need to survive the treatment intended to kill them, and be subsequently transmitted by vectors... Cases of P. falciparum resistance detected in Africa, such as resistances to chloroquine or to pyrimethamine, have either occurred in South-East Asia from where they have spread to Africa, or have occurred locally as in the recent case of artemisinin derivatives.
In South and Central America, Oceania and India, these resistances are essentially the result of native phenomena. In fact, many of the treatments developed over the last 150 years to treat malaria have successively declined in efficacybecause they have encountered parasite strains that had become resistant. Given this continuous threat, scientific studies are being conducted on an ongoing basis to monitor the efficacy of the treatments used.
These resistances might have remained confined to their original region. However, people now travel for a few hours or days, to work, do business, study or simply as tourists, carrying resistant strains in their bodies. At the new destination, the parasite will spread through bites by local mosquitoes. In this way, chloroquine- and pyrimethamine-resistant P. falciparum strains have been imported into Africa as a result of intercontinental travel.
However, the experts have no intention of being caught off-guard: “We are already testing tritherapies in anticipation of the time when current bitherapies are no longer sufficiently effective”, explains Jérôme Clain, a biologist at MERIT. “This involves adding, to the bitherapies currently in use, another drug or product that has already been proven to be effective against the parasite .” The aim of the clinical trial,4 which has commenced in Gabon and Mali and is soon to begin in Ghana and Benin, is not to discover a revolutionary treatment, but simply to gain a few years in the long-running battle against parasite drug resistance. Motivated by the same pragmatic goal, other teams across the world are also currently assessing alternative tritherapies in Asia and Africa, while others are assessing new bitherapies.
According to the same selection mechanisms that apply to survival characteristics, the malaria vector develops resistances to the insecticides that are used to kill it. “Anopheles have a genome that is constantly evolving, particularly through the existence of chromosomal inversion mechanisms which give them high levels of genetic polymorphism. In this way, each generation produces extensive potential to adapt to changes, and to resist control tools”, explains Karine Mouline, an entomologist at MIVEGEC. Various modes of insecticide resistance are reported: physiological (detoxication enzyme overexpression, insecticide target molecule mutations, thickening of the cuticlesurface part of arthropod exoskeletons, etc.) and behavioural (modification of biting periods and locations to reach humans when they are not protected by their mosquito netting, phenotypic plasticity allowing them to feed on alternative hosts to humans such as livestock, etc.).” »
In fact, the African Anopheles genome displays twice as much genetic polymorphism as the continent’s fruit fly populations, and ten times more than Homo sapiens! However, some genes also exhibit some permeability between diverse Anopheles populations. This allows characteristics to pass from one to the other, during breeding encounters between their members. This explains how mutations imparting resistance to certain chemical molecules used to control this vector can spread among separate groups of insects, and rapidly from one end of the continent to the other, etc. If chemical vector control measures fail to continually adapt to the evolution underway in the field, resistances emerge after two or three years. This requires scientists to constantly study the emergence of mosquito adaptations.
However, the behaviour of Anopheles never ceases to surprise the experts. This wild mosquito, which was formerly rural, confined to marshes, clearings and the outskirts of fields and villages, is no longer only infesting the countryside. It is now present in African cities such as Lagos, Kinshasa, or Bangui. Drawing on its tremendous genetic variety, the malaria vector has successfully adapted to humans’ new living conditions: it now breeds in polluted water, typical of stagnant city puddles, whereas it was previously only able to lay its eggs in clean water. In addition to this spatial adaptation, which allows the mosquito to feed on city-dwellers’ blood, chronological changes to its habits have occurred. In this way, research has shown that it has extended its predation period to circumvent household prevention measures. It no longer only bites at night, when people are protected by their mosquito netting, but also in the evening and early morning. This makes protecting populations particularly complicated. Recent studies, in Libreville and Bangui, have even established that the vector Anopheles is quite active in the daytime.
“While most bites take place between dusk and dawn inside homes, 20 to 30% occur in the daytime, also indoors”, explains Diego Ayala, a medical entomologist and an evolutionary biology specialist at MIIVEGEC. “And diurnal mosquitoes have comparable Plasmodium falciparum infection rates to those active at night.” This suggests that daytime bites could represent a substantial proportion of malaria infections. Scientists are already considering extending protection measures against vectors: “Indoor spraying, which consists in applying long-acting insecticides to the interior walls of homes, could be extended to schools to improve the protection of children, who are the main victims of malaria”, states the researcher.
Malaria control also needs to account for the direct impact of human activities, behaviours in response to the risk, and lifestyle changes among exposed populations. In this way, the efforts made to feed ever greater numbers of inhabitants or produce products for export have effects on the dynamics of the disease. Irrigated agricultural developments, rice cultivation, and cash crop plantations entail profound changes to landscapes and the hydrological context. As such, by creating year-round breeding grounds for Anopheles, they often disrupt the local epidemiological characteristics of the disease and require appropriate accompanying control and prevention measures. Similarly, the introduction of market gardening in urban areas, to feed city-dwellers, has helped to sustain some urban pressure from the vector, which must be taken into account.
In addition, the behaviours of exposed populations can also have a significant impact on malaria transmission. As such, protective measures against vectors must be adopted and used regularly in order to be effective. Research has shown that the use of impregnated mosquito nets, even when distributed free of charge as is mostly the case, is not necessarily guaranteed. Even for the majority who have adopted these nets, there are some circumstances in which they do not follow the rules despite the infection risks involved, especially when it is too hot to sleep in their beds.
Some research is also examining the social and economic changes that play a role in the epidemiology of the disease. “Sudden population movements due to turmoil, such as those experienced in the countries of the Sahel with the politico-military crisis of recent years, frequently modify the epidemiological map, and malaria control stakeholders need to be prepared for this”, explains Jean Gaudart. Similarly, researchers are taking a close interest in the growth in intraregional migrations, from one village to another, for work, to do business or for family reasons, while adopting lifestyles that are less constrained by agriculture. “The question is how they contribute to the spread of the parasite, and whether they could replenish the reservoir in an area where the disease is under control”, he explains. These human factors make the case for greater involvement of populations in control measures: “One of the key aspects in the future, to ultimately defeat malaria, is to listen to the people living with it day-to-day”, considers the expert. “Not only must we take their opinions on-board, we must also educate them on this subject, and develop educational initiatives on the disease and its prevention.”
Finally, for IRD’s experts and their partners, malaria is a multifactorial health issue that will never be overcome by relying on a single mechanism. On the contrary, all tools and approaches that have proven to be effective should be implemented. This entails developing healthcare systems in the affected countries, and ramping up access to diagnostics, local care and community healthcare for populations exposed to the parasite, with particular reliance on national malaria control programmes.
Similarly, infection prevention, through household vector control measures – which are highly effective – and improved distribution of preventive treatment, must be continued and ramped up. On the scientific level, a great deal of work still needs to be done. On the local level, we need to gain a better understanding of the epidemiology of the disease, document the awareness levels of populations, ensure that current curative treatments continue to be effective in the area and that diagnostics are sufficiently sensitive and tailored to the parasitic context, while developing and funding effective customised prevention protocols targeting groups exposed to severe forms and factoring in acceptance among populations, etc. On a larger scale, treatments and vector control tools need to be improved and effective vaccines need to be distributed.
Most of these experts believe that defeating malaria is an attainable goal, but much progress needs to be made before this ambition can be realised.
Longevity, transmission and cutting-edge technology
Assessing mosquito longevity in their natural habitat is no easy matter. However, this factor is key to their ability to transmit malaria. A female mosquito only becomes a disease vector after it has actually bitten an infected person and the parasite has completed part of its life cycle inside the mosquito before reaching its saliva glands. This process takes some time, a matter of days or even weeks, meaning that older female Anopheles are the most dangerous. To determine the lifetime of mosquitoes, and hence the potential danger of vector populations, scientists are developing high-tech methods as part of the MoVe-ADAPT project environmental DNATechnique allowing the census of individuals or species from the collection of their DNA in the environment to track these females in breeding grounds and natural habitats, using methods somewhat similar to those used by police forensic departments to pursue criminals.” The data collected on vector longevity will help us gain an understanding of the transmission pressure that they represent, and, if their life expectancy is showing signs of increasing or decreasing, of how mosquitoes are adapting to global changes.: “Our aim is to monitor the individual outcomes of mosquitos captured as larvae in the field, genetically characterised for identification purposes, and subsequently released and recaptured at other stages of their lifetimes, explains Carlo Costantini, a biologist at MIVEGEC. For this purpose, we will be using