Malaria

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Malaria, derived from male aria (Italian for "bad air") and formerly called ague or marsh fever in English, is an infectious disease which causes about 350-500 million infections with humans and approximately 1.3 - 3 million deaths annually<ref>Campbell, Neil A. et al. "Biology" Seventh edition. Menlo Park, CA: Addison Wesley Longman, Inc. 2005</ref>, mainly in the tropics. Sub-Saharan Africa accounts for 85-90% of these fatalities.<ref>Scott P. Layne, M.D. UCLA Department of Epidemiology, "Principles of Infectious Disease Epidemiology / EPI 220"</ref> The death rate is expected to double in the next 20 years.<ref>Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary</ref> The exact statistics are unknown because many cases occur in rural areas where people do not have access to hospitals and/or the means to afford health care. Consequently, many cases are treated at home and are undocumented.<ref>Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary</ref>

Malaria is caused by the protozoan parasites of the genus Plasmodium (of the phylum Apicomplexa), and the transmission vector for human malarial parasite is the female Anopheles mosquito. The P. falciparum variety of the parasite accounts for 80% of cases and 90% of deaths. Children under the age of five and pregnant women are the most vulnerable to the severe forms of malaria.

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History

For his discovery of the cause of malaria, the French army doctor Charles Louis Alphonse Laveran was awarded the Nobel Prize for Physiology or Medicine in 1907. Britain's Sir Ronald Ross also received a Nobel prize (in 1902) for describing the life cycle stages of the malaria parasite that develop within the mosquito host.

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Symptoms

Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anaemia caused by haemolysis, haemoglobinuria, and convulsions. There may be the feeling of tingling in the skin, particularly with malaria caused by P. falciparum. Complications of malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia and hemoglobinuria with renal failure may occur.

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Mechanisms of the disease

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Mosquitoes

It is the nature of mosquitoes that only the females feed on blood, thus males do not transmit the disease. The Anopheles species prefer to feed at night. They usually start searching for a meal at dusk, and will continue throughout the night until taking a meal. Young mosquitoes first ingest the malaria parasite by feeding on a human carrier. Infected female Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands.

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The malarial parasite

When an infected mosquito pierces a person's skin to take a blood meal, the sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver. There they hide within hepatic liver cells and multiply asexually. Development in the hepatic cell takes 6 to 15 days depending on the species. Within hepatic cells the parasite mutates to produce hundreds or thousands of merozoites which, following rupture of the hepatic cell, are released into the blood stream and invade red blood cells.

Within the red blood cells they multiply further, again asexually, periodically breaking out of the exploited red blood cells to invade fresh red blood cells and start the amplification cycle anew. The classical description of waves of fever coming every two (Plasmodium falciparum) or three days (Plasmodium vivax) arises from simultaneous waves of merozoites breaking out of red blood cells during the same day.

Some of the sporozoites in vivax and ovale malaria do not develop into hepatic stage merozoites immediately, but produce hypnozoites that remain dormant for several months (typically, from 6 to 12 months, but sometimes up to 3 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. About a half of the cases of vivax infection in temperate areas start after having overwintered, i.e. during the next year after the mosquito bite.

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.

Although the red blood cell surface adhesive proteins (called PfEMP1) are exposed to the immune system they do not serve as good immune targets because of their extreme diversity; there are at least 50 variations of PfEMP1 within a single parasite and perhaps limitless versions within parasite populations. Like a thief changing disguises or a spy with multiple passports, the parasite switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step ahead of the pursuing immune system.

By the time the human immune system learns to recognize the protein and starts making antibodies against it, the parasite has switched to another form of the protein, making it difficult for the immune system to keep up.

The stickiness of the red blood cells is particularly pronounced in Plasmodium falciparum malaria and this is the main factor giving rise to hemorrhagic complications of malaria.

High endothelial venules (the smallest branches of the circulatory system) can be occluded by the infected red blood cells, such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells affect the integrity of the blood brain barrier possibly leading to reversible coma. Even when treated, serious neurological consequences may result from cerebral malaria, especially in children.

Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes with the blood, fertilization occurs in the mosquito's gut which means the mosquito is 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.

The recognized species causing disease in humans are P. falciparum (which alone accounts for 80% of the recognized cases and ~90% of the deaths), P. vivax, P. ovale, and P. malariae. Infections with P. knowlesi and P. semiovale are also known to cause malaria but are of limited public health importance.

Other mammals (bats, rodents, non-human primates) as well as birds and reptiles also suffer from malaria. However, the species of malaria found in animals is rarely infectious in humans. Three human forms (which account for most malaria cases) are completely exclusive to humans. Only one form, P. malariae, can cause malaria in both humans and other higher primates. Other animal forms of malaria do not infect humans at all.

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Diagnosis

The gold standard for the diagnosis of malaria is microscopic examination of blood films, because each of the four major parasite species has distinguishing physical characteristics visible under a microscope. Two sorts of blood films are traditionally used. Thin films are similar to usual blood films and allow the microscopist to tell what species the malaria is, because the appearance of the parasite 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 nd therefore distinguishing between the different species can be much more difficult.<ref name="warhurst1996">Template:Cite journal</ref> From the thick film, an experienced microscopist can detect parasite levels down to as low as 0.0000001%. Microscopic diagnosis 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. Please refer to the chapters on each parasite for a description of their microscopic appearances: P. falciparum, P. vivax, P. ovale, P. malariae.

The biggest pitfall in most laboratories in developed countries is leaving too great a delay between taking the blood sample and making the blood films. As blood cools to room temperature, male gametocytes will divide and release microgametes: these are long sinuous filamentous structures that can be mistaken for organisms such as Borrelia. If the blood is kept at warmer temperatures, schizonts will rupture and merozoites invading erythrocytes will mistakenly give the appreance of the accolé form of P. falciparum. If P. vivax or P. ovale is left for several hours in EDTA, the build up of acid in the sample will cause the parasitised erythrocytes to shrink and the parasite will roll up, simulating the appearance of P. malariae. This problem is made worse if anticoagulants such as heparin or citrate are used. The anticoagulant that causes the least problems is EDTA. Romanovski's stain or a variant stain is usually used. Some laboratories mistakenly use the same stain as they do for routine haematology blood films (pH 7.2): malaria blood films must be stained at pH 6.8, or Schüffner's dots and James's dots will not be seen.

In areas where microscopy is not available, there are antigen detection tests that require only a drop of blood. <ref>Template:Cite journal</ref> OptiMAL-IT® will reliably detect falciparum down to 0.01% parasitaemia and non-falciparum down to 0.1%. Paracheck-Pf® will detect parasitaemias down to 0.002% but will not distinguish between falciparum and non-falciparum malaria. Parasite nucleic acids are detected using polymerase chain reaction. This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory.

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Treatment

There are several families of drugs used to treat malaria. Chloroquine was the antimalarial drug of choice for many years in most parts of the world. However, resistance of Plasmodium falciparum to chloroquine has spread recently from Asia to Africa, making the drug ineffective against the most dangerous Plasmodium strain in many affected regions of the world.

There are several other substances which are used for treatment and, partially, for prevention (prophylaxis). Many drugs can be used for both purposes; larger doses are used to treat cases of malaria. Their deployment depends mainly on the frequency of resistant parasites in the area where the drug is used.

Currently available anti-malarial drugs include:

Extracts of the plant Artemisia annua, containing the compound artemisinin or semi-synthetic derivatives (a substance unrelated to quinine), offer over 90% efficacy rates, but their supply is not meeting demand. A 2005 study published in Nature Structural And Molecular Biology (NSMB) described possible drug resistance, although the finding could help the development of other drugs.<ref>"Malaria drug resistance warning", BBC News, 2005-06-06</ref>. These findings contradict other findings published at Plos Genetics which suggest the mitochondria as the major target of action of artemisinin and its analogs. The paper published at NSMB is under heavy criticism since they did not perform obvious experiments to conclude to their findings (They did not actually create resistant parasites).

In February 2002, the journal Science and other press outlets<ref name="bbcnewdrug2002">Malaria drug offers new hope. BBC News 2002-02-15.</ref> announced progress on a new treatment for infected individuals. A team of French and South African researchers had identified a new drug they were calling "G25."<ref>One step closer to conquering malaria</ref> It cured malaria in test primates by blocking the ability of the parasite to copy itself within the red blood cells of its victims. In 2005 the same team of researchers published their research on achieving an oral form, which they refer to as "TE3" or "te3."<ref>Salom-Roig, X. et al. (2005) Dual molecules as new antimalarials. Combinatorial Chemistry & High Throughput Screening 8:49-62.</ref> As of early 2006, there is no information in the mainstream press as to when this family of drugs will become commercially available.

Although effective anti-malarial drugs are on the market, the disease remains a threat to people living in endemic areas who have no proper and prompt access to effective drugs. Access to pharmacies and health facilities, as well as drug costs, are major obstacles. Médecins Sans Frontières estimates that the cost to treat a malaria-infected person in an endemic country is between US$0.25 and $2.40. <ref name="msf">Medecins Sans Frontieres, "What is the Cost and Who Will Pay?"</ref>

There is a problem of availability of effective malaria treatments in the United States. Most hospitals in the United States do not stock intravenous quinine, and with the reduced use of quinidine by cardiologists, many hospitals have no access to intravenous anti-malarial drugs at all.

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Prevention and disease control

Image:Malaria map.PNG

Methods used to prevent the spread of disease, or to protect individuals in areas where malaria is endemic, include prophylactic drugs, mosquito eradication, and the prevention of mosquito bites. There is currently no vaccine that will prevent malaria, but this is an active field of research.

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Prophylactic drugs

Several drugs, most of which are also used for treatment of malaria, can be taken preventatively. 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 travellers to malarial regions. This is due to the potentially high cost of purchasing the drugs, because long-term use of some drugs may have negative side effects, and because some effective anti-malarial drugs are difficult to obtain outside of wealthy nations.

Quinine was used starting in the seventeenth century as a prophylactic against malaria. The development of more effective alternatives such as quinacrine, chloroquine, and primaquine in the twentieth 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 for malaria prophylaxis.

Modern drugs used preventatively include mefloquine (Lariam®), doxycycline (available generically), and atovaquone proguanil hydrochloride (Malarone®). The choice of which drug to use is usually driven by what 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 continue taking them for a similar amount of time after leaving.

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Mosquito eradication

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 the draining of wetland breeding grounds and better sanitation, in conjunction with the monitoring and treatment of infected humans, eliminated it from affluent regions. In 2002, there were 1,059 cases of malaria reported in the US, including eight deaths. In five of those cases, the disease was contracted in the United States. Malaria was eliminated from the northern parts of the USA in the early twentieth century, and the use of the pesticide DDT eliminated it from the South by 1951. 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.<ref>Gladwell, Malcolm. (2001) "The Mosquito Killer", The New Yorker, 2001-07-02.</ref> However, these efforts have so far failed to eradicate malaria in many parts of the developing world - the problem is most prevalent in Africa. The United States itself may face the spread of malaria in the future as climate change (warming) leads to an expansion of the areas in which mosquitoes are active.

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DDT Insecticide

DDT was developed as the first of the modern insecticides early in World War II. While it was initially used with great effect to combat mosquitoes spreading malaria, it was banned for use in many countries in the 1970s due to its negative ecological impact. There is great controversy regarding this impact and the use of DDT to fight human diseases. Some claim that the ban is responsible for tens of millions of deaths in tropical countries where previously, DDT was effective in controlling malaria.

Before the environmental problems of DDT were known, this powerful and inexpensive insecticide was widely used. It played a major role in helping to eradicating malaria in many parts of the world. In the 1970s, the ecological disaster resulting from its use halted the use of this chemical; however, for many applications it remains an inexpensive and effective insecticide. Given the severity of the malaria epidemic, there is renewed interest in the measured use of DDT. Spraying interior walls, where mosquitos land, with DDT is effective in areas where the mosquitoes are not DDT-resistant. 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 for large-scale field spraying. However many developed countries heavily discourage DDT use even in small amounts.<ref>The Stockholm Convention on persistent organic pollutants</ref>

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Economics

The World Bank estimates that malaria costs Africa US$12 billion a year in lost productivity. Economic advisor Jeffrey Sachs estimates that malaria can be controlled for $3 billion a year. In 2004, the US gave $500 Million in anti-malaria aid.<ref>Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary</ref> It has been argued that, in order to meet the Millennium Development Goals, money should be redirected from HIV/AIDS treatment to malaria prevention, which for the same amount of money would provide greater benefit to African economies.<ref>Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary</ref>

In the long run, it seems that disease prevention is likely to be more cost-effective than disease treatment; however, disease prevention programs typically require funding for capital costs. The World Bank estimates that malaria costs Africa millions of lives a year, and $12 billion in lost productivity. A simple mosquito net costing US$2-$5 is effective in preventing malaria for a household; however, this capital cost is often considered unaffordable by a subsistence farmer who may earn ~US$250 per year. In cases where preventative measures exist, appropriate financing may assist in making these solutions more affordable to all.

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Mosquito Nets and Prevention of mosquito bites

Mosquito nets help keep mosquitos away from people, and thus greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier, so 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.<ref>Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary</ref> 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 insecticide (often permethrin) 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 US$2.50 - $3.50 (2-3 euros) from the United Nations, The World Health Organization, and others.

For maximum effectiveness, the nets should be re-impregnated with incesticide every six months. This process poses a significant logistical problem in rural areas. A new type of impregnated net, called Olyset, releases insecticide for approximately 5 years<ref>New Mosquito Nets Could Help Fight Malaria in Africa</ref>, and costs about US$5.50. ITN's have the advantage of protecting people sleeping under the net and simultaneously killing mosquitoes that contact the net. This has the effect of killing the most dangerous mosquitoes. Some protection is also provided to others, including people sleeping in the same room but not under the net.

Unfortuantely, the cost of treating malaria is high relative to income, and the illness results in lost wages. Consequently, the financial burden means that the cost of a mosquito net is 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.<ref>Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary</ref>

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.<ref>Permethrin-treated chaddars and top-sheets: appropriate technology for protection against malaria in Afghanistan and other complex emergencies.</ref>

A new approach, announced in Science on June 10, 2005, uses inert 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.<ref name="bbcfungus">"Fungus 'may help malaria fight'", BBC News, 2005-06-09</ref>

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Vaccination

Vaccines for malaria are under development, with no completely effective vaccine yet available (as of January 2006). A team backed by the Gates Foundation and the pharma giant GlaxoSmithKline have announced results of a Phase IIb trial for RTS,S/AS02A, a vaccine which reduces infection risk by approximately 30% and severity of infection by over 50%. The study looked at over 2000 Mozambican children.<ref>Malaria Vaccine Initiative</ref> Further research will delay this vaccine from commercial release until around 2010.

In January 2005, University of Edinburgh scientists announced the discovery of an antibody which protects against the disease. The scientists will lead a £17m European consortium of malaria researchers.<ref>MacGregor, Fiona. (2005) Scots scientists boost malaria vaccine quest. The Scotsman, 2005-01-16.</ref> It is hoped that the genome sequence of the most deadly agent of malaria, Plasmodium falciparum, which was completed in 2002, will provide targets for new drugs or vaccines. <ref name="ito2002">Ito J, Ghosh A, Moreira LA, Wimmer EA, Jacobs-Lorena M. (2002) Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite. Nature 417:387-8. PMID 12024215</ref>

Sterile insect technique is emerging as a potential method to control malaria-carrying mosquitoes. 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,<ref>Imperial College, London, "Scientists create first transgenic malaria mosquito", 2000-06-22.</ref> with the first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002. <ref>Jacobs-Lorena et al, "Researchers genetically alter mosquitoes to impair malaria transmission", Case-Western, 2002.</ref>

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Social and economic impacts of malaria

The geographic distribution of malaria is complex, and malarial and malaria-free areas are often found very close to each other.<ref name="greenwood2002">Greenwood, B. and Mutabingwa, T. (2002) Malaria in 2002. Nature 415:670-672.</ref> In general, though, malaria is more common in rural areas than in cities; this is in contrast to dengue fever where urban areas present the greater risk. For example, the capital cities of the Philippines, Thailand and Sri Lanka are essentially malaria-free, but the disease is present in many rural parts of those nations. By contrast, in West Africa, Ghana and Nigeria have malaria throughout the entire country, though the risk is lower in the larger cities.

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Evolutionary Pressure of Malaria on Human Genes

Malaria is thought to have been the greatest selective pressure on the human genome in recent history <ref>Kwiatkowski, D.P. (2005) How Malaria Has Affected the Human Genome and What Human Genetics Can Teach Us about Malaria. American Journal of Human Genetics 77:171-192.</ref>. This is due to the high levels of mortality and morbidity caused by malaria, especially the falciparum form.

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Sickle-Cell Anaemia

The best-studied influence of the malaria parasite upon the human genome is the blood disease, sickle-cell anaemia. In sickle-cell anaemia, there is a mutation in the HBB gene which codes for a haemoglobin subunit. The normal allele is HbA, but the sickle-cell allele, HbS, has a mutation from Glutamic Acid to Valine at amino acid 6. This change from a hydrophilic to a hydrophobic residue encourages binding between haemoglobin molecules, with polymerisation of haemoglobin deforming red blood cells into a sickle shape.

Individuals homozygous for HbS have full sickle-cell anaemia and rarely live beyond αadolescence. However, this allele has sustained gene frequencies in populations where malaria is endemic of around 10%. This is because individuals heterozygous for the mutated allele (HbA/HbS) have a low level of anaemia but also have a greatly reduced chance of malaria infection. The existence of four haplotypes of HbS suggests that this mutation has emerged independently at least four times in malaria-endemic areas, further demonstrating its evolutionary advantage in such affected regions.

There are also other mutations of the HBB gene which appear to confer similar resistance to malaria infection. These are HbE and HbC which are common in Southeast Asia and Western Africa respectively.

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Thalassaemias

Another well documented set of mutations found in the human genome associated with malaria are those involved in causing blood disorders known as thalassaemias. Studies in Sardinia and Papua New Guinea have found that the gene frequency of β-thalassaemias is related to the level of endemicity in a given population. A study on more than 500 children in Liberia found that those with β-thalassaemia had a 50% decreased chance of getting clinical malaria. Similar studies have found links between gene frequency and malaria endemicity in the α+ form of α-thalassaemia.

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Duffy Antigens

The Duffy antigens are antigens expressed on red blood cells and other cells in the body acting as a chemokine receptor. The expression of Duffy antigens on blood cells is encoded by Fy genes (Fya, Fyb, Fyc etc.). Plasmodium vivax malaria uses the Duffy antigen to enter blood cells. However, it is possible to express no Duffy antigen on red blood cells (Fy-/Fy-). This genotype confers complete resistance to P. vivax infection. The genotype has not been found in Chinese populations, has rarely been found in white populations, but is found in 68% of black people. This is thought to be due to very high exposure ot P. vivax in Africa in the past.

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G6PD

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme which normally protects from the effects of oxidative stress in red blood cells. However, a genetic deficiency in this enzyme results in increased protection against severe malaria.

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References

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External links

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Vaccine and other research

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DDT

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Animations, images and photos

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