Malaria

Malaria is a mosquito-borne infectious disease caused by a eukaryotic protist of the genus Plasmodium. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, there are approximately 350–500 million cases of malaria, killing between one and three million people, the majority of whom are young children in sub-Saharan Africa. Ninety percent of malaria-related deaths occur in sub-Saharan Africa. Malaria is commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development.

Five species of the plasmodium parasite can infect humans; the most serious forms of the disease are caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae causes milder disease in humans that is not generally fatal. A fifth species, Plasmodium knowlesi, is a zoonosis that causes malaria in macaques but can also infect humans.

Malaria is naturally transmitted by the bite of a female Anopheles mosquito. When a mosquito bites an infected person, a small amount of blood is taken, which contains malaria parasites. These develop within the mosquito, and about one week later, when the mosquito takes its next blood meal, the parasites are injected with the mosquito's saliva into the person being bitten. After a period of between two weeks and several months (occasionally years) spent in the liver, the malaria parasites start to multiply within red blood cells, causing symptoms that include fever and headache. In severe cases, the disease worsens, leading to coma and death.

A wide variety of antimalarial drugs are available to treat malaria. In the last 5 years, treatment of P. falciparum infections in endemic countries has been transformed by the use of combinations of drugs containing an artemisinin derivative. Severe malaria is treated with intravenous or intramuscular quinine or, increasingly, the artemisinin derivative artesunate. Several drugs are also available to prevent malaria in travellers to malaria-endemic countries (prophylaxis). Resistance has developed to several antimalarial drugs, most notably chloroquine.

Malaria transmission can be reduced by preventing mosquito bites by distribution of inexpensive mosquito nets and insect repellents, or by mosquito-control measures such as spraying insecticides inside houses and draining standing water where mosquitoes lay their eggs.

Although many are under development, the challenge of producing a widely available vaccine that provides a high level of protection for a sustained period is still to be met.

Signs and symptoms

Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia (caused by hemolysis), hemoglobinuria, retinal damage, and convulsions. The classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting four to six hours, occurring every two days in P. vivax and P. ovale infections, while every three for P. malariae. P. falciparum can have recurrent fever every 36–48 hours or a less pronounced and almost continuous fever. For reasons that are poorly understood, but that may be related to high intracranial pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage. Malaria has been found to cause cognitive impairments, especially in children. It causes widespread anemia during a period of rapid brain development and also direct brain damage. This neurologic damage results from cerebral malaria to which children are more vulnerable. Cerebral malaria is associated with retinal whitening, which may be a useful clinical sign in distinguishing malaria from other causes of fever.

Severe malaria is almost exclusively caused by P. falciparum infection, and usually arises 6–14 days after infection. Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure may cause blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death within hours or days. In the most severe cases of the disease, fatality rates can exceed 20%, even with intensive care and treatment. In endemic areas, treatment is often less satisfactory and the overall fatality rate for all cases of malaria can be as high as one in ten. Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.

Chronic malaria is seen in both P. vivax and P. ovale, but not in P. falciparum. Here, the disease can relapse months or years after exposure, due to the presence of latent parasites in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can, therefore, be deceptive. The longest incubation period reported for a P. vivax infection is 30 years. Approximately one in five of P. vivax malaria cases in temperate areas involve overwintering by hypnozoites (i.e., relapses begin the year after the mosquito bite).

Causes

Malaria parasites

Malaria parasites are members of the genus Plasmodium (phylum Apicomplexa). In humans malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi. P. falciparum is the most common cause of infection and is responsible for about 80% of all malaria cases, and is also responsible for about 90% of the deaths from malaria. Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents. There have been documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi,  P. simiovale, P. brazilianum, P. schwetzi and P. simium; however, with the exception of P. knowlesi, these are mostly of limited public health importance.

Mosquito vectors and the Plasmodium life cycle

The parasite's primary (definitive) hosts and transmission vectors are female mosquitoes of the Anopheles genus, while humans and other vertebrates are secondary hosts. Young mosquitoes first ingest the malaria parasite by feeding on an infected human carrier and the infected Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, the parasite gametocytes taken up in the blood will further differentiate into male or female gametes and then fuse in the mosquito gut. This produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall. When the oocyst ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, where they are then ready to infect a new human host. This type of transmission is occasionally referred to as anterior station transfer. The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal.

Only female mosquitoes feed on blood, thus males do not transmit the disease. The females of the Anopheles genus of mosquito prefer to feed at night. They usually start searching for a meal at dusk, and will continue throughout the night until taking a meal. Malaria parasites can also be transmitted by blood transfusions, although this is rare.

Pathogenesis

A mosquito infects a person by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, then trophozoites (a feeding stage), then schizonts (a reproduction stage), then back into merozoites. Sexual forms called gametocytes are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.Malaria in humans develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase involves infection of the hepatic system, or liver, whereas the erythrocytic phase involves infection of the erythrocytes, or red blood cells. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver. Within 30 minutes of being introduced into the human host, the sporozoites infect hepatocytes, multiplying asexually and asymptomatically for a period of 6–15 days. Once in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells, thus beginning the erythrocytic stage of the life cycle. The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.

Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their hosts to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.

Some P. vivax and P. ovale sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several months (6–12 months is typical) to as long as three years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in these two species of malaria.

The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the P. falciparum parasite displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen. This "stickiness" is the main factor giving rise to hemorrhagic complications of malaria. High endothelial venules (the smallest branches of the circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The blockage of these vessels causes symptoms such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells can breach the blood brain barrier possibly leading to coma.

Although the red blood cell surface adhesive proteins (called PfEMP1, for Plasmodium falciparum erythrocyte membrane protein 1) are exposed to the immune system, they do not serve as good immune targets, because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and effectively limitless versions within parasite populations. The parasite switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step ahead of the pursuing immune system.

Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut, thereby defining the mosquito as the definitive host of the disease. New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes, and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight, particularly in P. falciparum infection, but also in other species infection, such as P. vivax.

Diagnosis

Since Charles Laveran first visualised the malaria parasite in blood in 1880, the mainstay of malaria diagnosis has been the microscopic examination of blood.

Fever and septic shock are commonly misdiagnosed as severe malaria in Africa, leading to a failure to treat other life-threatening illnesses. In malaria-endemic areas, parasitemia does not ensure a diagnosis of severe malaria, because parasitemia can be incidental to other concurrent disease. Recent investigations suggest that malarial retinopathy is better (collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma.

Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been investigated as alternative, less invasive specimens.

Symptomatic diagnosis

Areas that cannot afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than using only a history of subjective fevers, a correct diagnosis increased from 21% to 41% of cases, and unnecessary treatment for malaria was significantly decreased.

Microscopic examination of blood films

The most economic, preferred, and reliable diagnosis of malaria is microscopic examination of blood films because each of the four major parasite species has distinguishing characteristics. Two sorts of blood film are traditionally used. Thin films are similar to usual blood films and allow species identification because the parasite's appearance is best preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult. With the pros and cons of both thick and thin smears taken into consideration, it is imperative to utilize both smears while attempting to make a definitive diagnosis.

From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) down to as low as 0.0000001% of red blood cells. Diagnosis of species can be difficult because the early trophozoites ("ring form") of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites.

One important thing to note is that P. malariae and P. knowlesi (which is the most common cause of malaria in South-east Asia) look very similar under the microscope. However, P. knowlesi parasitemia increases very fast and causes more severe disease than P. malariae, so it is important to identify and treat infections quickly. Therefore modern methods such as PCR  or monoclonal antibody panels that can distinguish between the two should be used in this part of the world.

Antigen tests

For areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, there are commercial antigen detection tests that require only a drop of blood. Immunochromatographic tests (also called: Malaria Rapid Diagnostic Tests, Antigen-Capture Assay or "Dipsticks") been developed, distributed and fieldtested. These tests use finger-stick or venous blood, the completed test takes a total of 15–20 minutes, and the results are read visually as the presence or absence of colored stripes on the dipstick, so they are suitable for use in the field. The threshold of detection by these rapid diagnostic tests is in the range of 100 parasites/µl of blood (commercial kits can range from about 0.002% to 0.1% parasitemia) compared to 5 by thick film microscopy. One disadvantage is that dipstick tests are qualitative but not quantitative – they can determine if parasites are present in the blood, but not how many.

The first rapid diagnostic tests were using P. falciparum glutamate dehydrogenase as antigen. PGluDH was soon replaced by P.falciparum lactate dehydrogenase, a 33 kDa oxidoreductase. It is the last enzyme of the glycolytic pathway, essential for ATP generation and one of the most abundant enzymes expressed by P.falciparum. PLDH does not persist in the blood but clears about the same time as the parasites following successful treatment. The lack of antigen persistence after treatment makes the pLDH test useful in predicting treatment failure. In this respect, pLDH is similar to pGluDH. Depending on which monoclonal antibodies are used, this type of assay can distinguish between all five different species of human malaria parasites, because of antigenic differences between their pLDH isoenzymes.

Molecular methods

Molecular methods are available in some clinical laboratories and rapid real-time assays (for example, QT-NASBA based on the polymerase chain reaction) are being developed with the hope of being able to deploy them in endemic areas.

PCR (and other molecular methods) is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitemia in the field.

Prevention

Many researchers argue that prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the capital costs required are out of reach of many of the world's poorest people. Economic adviser Jeffrey Sachs estimates that malaria can be controlled for US$3 billion in aid per year.

The distribution of funding varies among countries. Countries with large populations do not receive the same amount of support. The 34 countries that received a per capita annual support of less than $1 included some of the poorest countries in Africa.

Brazil, Eritrea, India, and Vietnam have, unlike many other developing nations, successfully reduced the malaria burden. Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.

Vector control

Efforts to eradicate malaria by eliminating mosquitoes have been successful in some areas. Malaria was once common in the United States and southern Europe, but vector control programs, in conjunction with the monitoring and treatment of infected humans, eliminated it from those regions. In some areas, the draining of wetland breeding grounds and better sanitation were adequate. Malaria was eliminated from the northern parts of the USA in the early 20th century by such methods, and the use of the pesticide DDT eliminated it from the South by 1951. In 2002, there were 1,059 cases of malaria reported in the US, including eight deaths, but in only five of those cases was the disease contracted in the United States.

Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by filling or applying oil to places with standing water. These methods have seen little application in Africa for more than half a century. In the 1950s and 1960s, there was a major public health effort to eradicate malaria worldwide by selectively targeting mosquitoes in areas where malaria was rampant. However, these efforts have so far failed to eradicate malaria in many parts of the developing world—the problem is most prevalent in Africa.

Sterile insect technique is emerging as a potential mosquito control method. Progress towards transgenic, or genetically modified, insects suggest that wild mosquito populations could be made malaria-resistant. Researchers at Imperial College London created the world's first transgenic malaria mosquito, with the first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002. Successful replacement of current populations with a new genetically modified population, relies upon a drive mechanism, such as transposable elements to allow for non-Mendelian inheritance of the gene of interest. However, this approach contains many difficulties and success is a distant prospect. An even more futuristic method of vector control is the idea that lasers could be used to kill flying mosquitoes.

Prophylactic drugs

Several drugs, most of which are also used for treatment of malaria, can be taken preventively. Generally, these drugs are taken daily or weekly, at a lower dose than would be used for treatment of a person who had actually contracted the disease. Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the cost of purchasing the drugs, negative side effects from long-term use, and because some effective anti-malarial drugs are difficult to obtain outside of wealthy nations.

Quinine was used starting in the 17th century as a prophylactic against malaria. The development of more effective alternatives such as quinacrine, chloroquine, and primaquine in the 20th century reduced the reliance on quinine. Today, quinine is still used to treat chloroquine resistant Plasmodium falciparum, as well as severe and cerebral stages of malaria, but is not generally used for prophylaxis.

Modern drugs used preventively include mefloquine (Lariam), doxycycline (available generically), and the combination of atovaquone and proguanil hydrochloride (Malarone). The choice of which drug to use depends on which drugs the parasites in the area are resistant to, as well as side-effects and other considerations. The prophylactic effect does not begin immediately upon starting taking the drugs, so people temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving (with the exception of atovaquone proguanil that only needs be started 2 days prior and continued for 7 days afterwards).

The use of prophylactic drugs where malaria-bearing mosquitoes are present may encourage the development of partial immunity.

Indoor residual spraying

Indoor residual spraying (IRS) is the practice of spraying insecticides on the interior walls of homes in malaria affected areas. After feeding, many mosquito species rest on a nearby surface while digesting the bloodmeal, so if the walls of dwellings have been coated with insecticides, the resting mosquitos will be killed before they can bite another victim, transferring the malaria parasite.

The first pesticide used for IRS was DDT. Although it was initially used exclusively to combat malaria, its use quickly spread to agriculture. In time, pest-control, rather than disease-control, came to dominate DDT use, and this large-scale agricultural use led to the evolution of resistant mosquitoes in many regions. The DDT resistance shown by Anopheles mosquitoes can be compared to antibiotic resistance shown by bacteria. The overuse of anti-bacterial soaps and antibiotics led to antibiotic resistance in bacteria, similar to how overspraying of DDT on crops led to DDT resistance in Anopheles mosquitoes. During the 1960s, awareness of the negative consequences of its indiscriminate use increased, ultimately leading to bans on agricultural applications of DDT in many countries in the 1970s. Since the use of DDT has been limited or banned for agricultural use for some time, DDT may now be more effective as a method of disease-control.

Although DDT has never been banned for use in malaria control and there are several other insecticides suitable for IRS, some advocates have claimed that bans are responsible for tens of millions of deaths in tropical countries where DDT had once been effective in controlling malaria. Furthermore, most of the problems associated with DDT use stem specifically from its industrial-scale application in agriculture, rather than its use in public health.

The World Health Organization (WHO) currently advises the use of 12 different insecticides in IRS operations. These include DDT and a series of alternative insecticides (such as the pyrethroids permethrin and deltamethrin), to combat malaria in areas where mosquitoes are DDT-resistant and to slow the evolution of resistance. This public health use of small amounts of DDT is permitted under the Stockholm Convention on Persistent Organic Pollutants (POPs), which prohibits the agricultural use of DDT. However, because of its legacy, many developed countries discourage DDT use even in small quantities.

One problem with all forms of Indoor Residual Spraying is insecticide resistance via evolution of mosquitos. According to a study published on Mosquito Behavior and Vector Control, mosquito species that are affected by IRS are endophilic species (species that tend to rest and live indoors), and due to the irritation caused by spraying, their evolutionary descendants are trending towards becoming exophilic (species that tend to rest and live out of doors), meaning that they are not as affected—if affected at all—by the IRS, rendering it somewhat useless as a defense mechanism.

Mosquito nets and bedclothes

Mosquito nets help keep mosquitoes away from people and greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier and they are often treated with an insecticide designed to kill the mosquito before it has time to search for a way past the net. Insecticide-treated nets (ITN) are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net. Although ITN are proven to be very effective against malaria, less than 2% of children in urban areas in Sub-Saharan Africa are protected by ITNs. Since the Anopheles mosquitoes feed at night, the preferred method is to hang a large "bed net" above the center of a bed such that it drapes down and covers the bed completely.

The distribution of mosquito nets impregnated with insecticides such as permethrin or deltamethrin has been shown to be an extremely effective method of malaria prevention, and it is also one of the most cost-effective methods of prevention. These nets can often be obtained for around $2.50–$3.50 (2–3 euros) from the United Nations, the World Health Organization (WHO), and others. ITNs have been shown to be the most cost-effective prevention method against malaria and are part of WHO’s Millennium Development Goals (MDGs).

While some experts argue that international organizations should distribute ITNs and LLINs to people for free in order to maximize coverage (since such a policy would reduces price barriers), others insist that cost-sharing between the international organization and recipients would led to greater usage of the net (arguing that people will value a good more if they pay for it). Additionally, proponents of cost-sharing argue that such a policy ensures that nets are efficiently allocated to those people who most need them (or are most vulnerable to infection). Through a "selection effect", they argue, those people who most need the bed nets will choose to purchase them, while those less in need will opt out.

However, a randomized controlled trial study of ITNs uptake among pregnant women in Kenya, conducted by economists Pascaline Dupas and Jessica Cohen, found that cost-sharing does not necessarily increase the usage intensity of ITNs nor does it induce uptake by those most vulnerable to infection, as compared to a policy of free distribution. In some cases, cost-sharing can actually decrease demand for mosquito nets by erecting a price barrier. Dupas and Cohen’s findings support the argument that free distribution of ITNs can be more effective than cost-sharing in both increasing coverage and saving lives. In a cost-effectiveness analysis, Dupas and Cohen note that “cost-sharing is at best marginally more cost-effective than free distribution, but free distribution leads to many more lives saved.”

The researchers base their conclusions about the cost-effectiveness of free distribution on the proven spillover benefits of increased ITN usage. When a large number of nets are distributed in one residential area, their chemical additives help reduce the number of mosquitoes in the environment. With fewer mosquitoes in the environment, the chances of malaria infection for recipients and non-recipients are significantly reduced. (In other words, the importance of the physical barrier effect of ITNs decreases relative to the positive externality effect of the nets in creating a mosquito-free environment when ITNs are highly concentrated in one residential cluster or community.)

For maximum effectiveness, the nets should be re-impregnated with insecticide every six months. This process poses a significant logistical problem in rural areas. New technologies like Olyset or DawaPlus allow for production of long-lasting insecticidal mosquito nets (LLINs), which release insecticide for approximately 5 years, and cost about US$5.50. ITNs protect people sleeping under the net and simultaneously kill mosquitoes that contact the net. Some protection is also provided to others by this method, including people sleeping in the same room but not under the net.

While distributing mosquito nets is a major component of malaria prevention, community education and awareness on the dangers of malaria are associated with distribution campaigns to make sure people who receive a net know how to use it. "Hang Up" campaigns such as the ones conducted by volunteers of the International Red Cross and Red Crescent Movement consist of visiting households that received a net at the end of the campaign or just before the rainy season, ensuring that the net is being used properly and that the people most vulnerable to malaria, such as young children and the elderly, sleep under it. A study conducted by the CDC in Sierra Leone showed a 22 percent increase in net utilization following a personal visit from a volunteer living in the same community promoting net usage. A study in Togo showed similar improvements.

Mosquito nets are often unaffordable to people in developing countries, especially for those most at risk. Only 1 out of 20 people in Africa own a bed net. Nets are also often distributed though vaccine campaigns using voucher subsidies, such as the measles campaign for children. A study among Afghan refugees in Pakistan found that treating top-sheets and chaddars (head coverings) with permethrin has similar effectiveness to using a treated net, but is much cheaper. Another alternative approach uses spores of the fungus Beauveria bassiana, sprayed on walls and bed nets, to kill mosquitoes. While some mosquitoes have developed resistance to chemicals, they have not been found to develop a resistance to fungal infections.

Vaccination

Immunity (or, more accurately, tolerance) does occur naturally, but only in response to repeated infection with multiple strains of malaria.

Vaccines for malaria are under development, with no completely effective vaccine yet available. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live, radiation-attenuated sporozoites, providing protection to about 60% of the mice upon subsequent injection with normal, viable sporozoites. Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans. It was determined that an individual can be protected from a P. falciparum infection if they receive over 1,000 bites from infected, irradiated mosquitoes.

It has been generally accepted that it is impractical to provide at-risk individuals with this vaccination strategy, but that has been recently challenged with work being done by Dr. Stephen Hoffman, one of the key researchers who originally sequenced the genome of Plasmodium falciparum. His work most recently has revolved around solving the logistical problem of isolating and preparing the parasites equivalent to 1000 irradiated mosquitoes for mass storage and inoculation of human beings. The company has recently received several multi-million dollar grants from the Bill & Melinda Gates Foundation and the U.S. government to begin early clinical studies in 2007 and 2008. The Seattle Biomedical Research Institute (SBRI), funded by the Malaria Vaccine Initiative, assures potential volunteers that "the [2009] clinical trials won't be a life-threatening experience. While many volunteers [in Seattle] will actually contract malaria, the cloned strain used in the experiments can be quickly cured, and does not cause a recurring form of the disease." "Some participants will get experimental drugs or vaccines, while others will get placebo."

Instead, much work has been performed to try and understand the immunological processes that provide protection after immunization with irradiated sporozoites. After the mouse vaccination study in 1967, it was hypothesized that the injected sporozoites themselves were being recognized by the immune system, which was in turn creating antibodies against the parasite. It was determined that the immune system was creating antibodies against the circumsporozoite protein (CSP) which coated the sporozoite. Moreover, antibodies against CSP prevented the sporozoite from invading hepatocytes. CSP was therefore chosen as the most promising protein on which to develop a vaccine against the malaria sporozoite. It is for these historical reasons that vaccines based on CSP are the most numerous of all malaria vaccines.

Presently, there is a huge variety of vaccine candidates on the table. Pre-erythrocytic vaccines (vaccines that target the parasite before it reaches the blood), in particular vaccines based on CSP, make up the largest group of research for the malaria vaccine. Other vaccine candidates include: those that seek to induce immunity to the blood stages of the infection; those that seek to avoid more severe pathologies of malaria by preventing adherence of the parasite to blood venules and placenta; and transmission-blocking vaccines that would stop the development of the parasite in the mosquito right after the mosquito has taken a bloodmeal from an infected person. It is hoped that the knowledge of the P. falciparum genome, the sequencing of which was completed in 2002, will provide targets for new drugs or vaccines.

The first vaccine developed that has undergone field trials, is the SPf66, developed by Manuel Elkin Patarroyo in 1987. It presents a combination of antigens from the sporozoite (using CS repeats) and merozoite parasites. During phase I trials a 75% efficacy rate was demonstrated and the vaccine appeared to be well tolerated by subjects and immunogenic. The phase IIb and III trials were less promising, with the efficacy falling to between 38.8% and 60.2%. A trial was carried out in Tanzania in 1993 demonstrating the efficacy to be 31% after a years follow up, however the most recent (though controversial) study in The Gambia did not show any effect. Despite the relatively long trial periods and the number of studies carried out, it is still not known how the SPf66 vaccine confers immunity; it therefore remains an unlikely solution to malaria. The CSP was the next vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporoziote protein, but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). However at an early stage a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed.

The efficacy of Patarroyo's vaccine has been disputed with some US scientists concluding in The Lancet (1997) that "the vaccine was not effective and should be dropped" while the Colombian accused them of "arrogance" putting down their assertions to the fact that he came from a developing country.

The RTS,S/AS02A vaccine is the candidate furthest along in vaccine trials. It is being developed by a partnership between the PATH Malaria Vaccine Initiative (a grantee of the Gates Foundation), the pharmaceutical company, GlaxoSmithKline, and the Walter Reed Army Institute of Research. In the vaccine, a portion of CSP has been fused to the immunogenic "S antigen" of the hepatitis B virus; this recombinant protein is injected alongside the potent AS02A adjuvant. In October 2004, the RTS,S/AS02A researchers announced results of a Phase IIb trial, indicating the vaccine reduced infection risk by approximately 30% and severity of infection by over 50%. The study looked at over 2,000 Mozambican children. More recent testing of the RTS,S/AS02A vaccine has focused on the safety and efficacy of administering it earlier in infancy: In October 2007, the researchers announced results of a phase I/IIb trial conducted on 214 Mozambican infants between the ages of 10 and 18 months in which the full three-dose course of the vaccine led to a 62% reduction of infection with no serious side-effects save some pain at the point of injection. Further research will delay this vaccine from commercial release until around 2011.

Other methods

Education in recognizing the symptoms of malaria has reduced the number of cases in some areas of the developing world by as much as 20%. Recognizing the disease in the early stages can also stop the disease from becoming a killer. Education can also inform people to cover over areas of stagnant, still water e.g. Water Tanks which are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people. This is most put in practice in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas.

The Malaria Control Project is currently using downtime computing power donated by individual volunteers around the world (see Volunteer computing and BOINC) to simulate models of the health effects and transmission dynamics in order to find the best method or combination of methods for malaria control. This modeling is extremely computer intensive due to the simulations of large human populations with a vast range of parameters related to biological and social factors that influence the spread of the disease. It is expected to take a few months using volunteered computing power compared to the 40 years it would have taken with the current resources available to the scientists who developed the program.

An example of the importance of computer modeling in planning malaria eradication programs is shown in the paper by Águas and others. They showed that eradication of malaria is crucially dependent on finding and treating the large number of people in endemic areas with asymptomatic malaria, who act as a reservoir for infection. The malaria parasites do not affect animal species and therefore eradication of the disease from the human population would be expected to be effective.

Other interventions for the control of malaria include mass drug administrations and intermittent preventive therapy.

Treatment

Active malaria infection with P. falciparum is a medical emergency requiring hospitalization. Infection with P. vivax, P. ovale or P. malariae can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. Most antimalarial drugs are produced industrially and are sold at pharmacies. However, as the cost of such medicines are often too high for most people in the developing world, some herbal remedies (such as Artemisia annua tea) have also been developed, and have gained support from international organisations such as Médicins Sans Frontières. When properly treated, someone with malaria can expect a complete recovery.

Counterfeit drugs

Sophisticated counterfeits have been found in several Asian countries such as Cambodia, China, Indonesia, Laos, Thailand, Vietnam and are an important cause of avoidable death in those countries. WHO have said that studies indicate that up to 40% of artesunate based malaria medications are counterfeit, especially in the Greater Mekong region and have established a rapid alert system to enable information about counterfeit drugs to be rapidly reported to the relevant authorities in participating countries. There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.