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{{further|[[Jesuit's bark]]}}
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Malaria has infected humans for over 50,000 years, and may have been a human [[pathogen]] for the entire history of our species.<ref>{{cite journal | author = Joy D, Feng X, Mu J, ''et al'' | title = Early origin and recent expansion of Plasmodium falciparum. | journal = Science | volume = 300 | issue = 5617 | pages = 318-21 | year = 2003 | pmid = 12690197}}</ref> Indeed, close relatives of the human malaria parasites remain common in chimpanzees, our closest relatives.<ref>{{cite journal | author = Escalante A, Freeland D, Collins W, Lal A | title = The evolution of primate malaria parasites based on the gene encoding cytochrome b from the linear mitochondrial genome. | url=http://www.pnas.org/cgi/content/full/95/14/8124 | journal = Proc Natl Acad Sci U S A | volume = 95 | issue = 14 | pages = 8124-9 | year = 1998 | pmid = 9653151}}</ref> References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China.<ref>{{cite journal | author = Cox F | title = History of human parasitology. | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12364371 | journal = Clin Microbiol Rev | volume = 15 | issue = 4 | pages = 595-612 | year = 2002 | pmid = 12364371}}</ref> The term malaria originates from Medieval [[Italian language|Italian]]: ''mala aria'' &mdash; "[[miasma theory of disease|bad air]]"; and the disease was formerly called '''ague''' or '''marsh fever''' due to its association with swamps.
{{Malaria}}
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{{CMG}}; '''Associate Editor(s)-In-Chief:''' [[User:YazanDaaboul|Yazan Daaboul]], [[User:Sergekorjian|Serge Korjian]], {{AJL}}, {{Marjan}}
Scientific studies on malaria made their first significant advance in 1880, when a French army doctor working in Algeria named [[Charles Louis Alphonse Laveran]] observed parasites inside the [[red blood cell]]s of people suffering from malaria. He therefore proposed that malaria was caused by this [[protozoa]]n, the first time protozoa were identified as causing disease.<ref>{{cite web | title = Biography of Alphonse Laveran | publisher = The Nobel Foundation | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1907/laveran-bio.html | accessdate = 2007-06-15}} ] Nobel foundation. Accessed 25 Oct 2006</ref> For this and later discoveries, he was awarded the 1907 [[Nobel Prize for Physiology or Medicine]]. The protozoan was called ''Plasmodium'' by the Italian scientists Ettore Marchiafava and Angelo Celli.<ref>{{cite web | title =  Ettore Marchiafava| work = | url = http://www.whonamedit.com/doctor.cfm/2478.html | accessdate = 2007-06-15}}</ref> A year later, Carlos Finlay, a Cuban doctor treating patients with [[yellow fever]] in Havana, first suggested that mosquitoes were transmitting disease to and from humans.  However, it was Britain's Sir Ronald Ross working in India who finally proved in 1898 that malaria is transmitted by mosquitoes. He did this by showing that certain mosquito species transmit malaria to birds and isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds.<ref>{{cite web | title = Biography of Ronald Ross | publisher = The Nobel Foundation | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1902/ross-bio.html | accessdate = 2007-06-15}}</ref> For this work Ross received the 1902 Nobel Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly-established [[Liverpool School of Tropical Medicine]] and directed malaria-control efforts in Egypt, Panama, Greece and Mauritius.<ref>{{cite web | title = Ross and the Discovery that Mosquitoes Transmit Malaria Parasites| work = CDC Malaria website | url = http://www.cdc.gov/malaria/history/ross.htm | accessdate = 2007-06-15}}</ref> The findings of Finlay and Ross were later confirmed by a medical board headed by Walter Reed in 1900, and its recommendations implemented by William C. Gorgas in [[Health measures during the construction of the Panama Canal|the health measures undertaken]] during construction of the Panama Canal. This public-health work saved the lives of thousands of workers and helped develop the methods used in future public-health campaigns against this disease.


The first effective treatment for malaria was the bark of [[Cinchona|cinchona tree]], which contains [[quinine]]. This tree grows on the slopes of the Andes, mainly in Peru. This natural product was used by the inhabitants of Peru to control malaria, and the Jesuits introduced this practice to Europe during the 1640s where it was rapidly accepted.<ref>{{cite journal | author = Kaufman T, Rúveda E | title = The quest for quinine: those who won the battles and those who won the war. | journal = Angew Chem Int Ed Engl | volume = 44 | issue = 6 | pages = 854-85 | year = 2005 | pmid = 15669029}}</ref> However, it was not until 1820 that the active ingredient quinine was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Jean Bienaime Caventou.<ref>{{cite journal |author=Kyle R, Shampe M |title=Discoverers of quinine |journal=JAMA |volume=229 |issue=4 |pages=462 |year=1974 |pmid=4600403}}</ref>
==Overview==
The symptoms of malaria, one of the oldest known infections, were initially believed to be caused by noxious elements. In 1880 Charles Louis Alphone Laveran discovered the ''[[Plasmodium]]'' parasite in blood smears of patients with malaria. The role of mosquitos in the transmission of malaria to humans was discovered a few years later. The entire life cycle of the ''[[Plasmodium]]'' parasite remained enigmatic until 1982.Although malaria has historically been treated using [[quinine]], an alkaloid derived from barks of cinchona, the first synthetic quinine was produced in 1948.In 2014, the first candidate for anti-malarial vaccine was developed.


In the early twentieth century, before [[antibiotics]], patients with [[syphilis]] were intentionally [[infected]] with malaria to create a [[fever]], following the work of [[Julius Wagner-Jauregg]]. By accurately controlling the fever with [[quinine]], the effects of both syphilis and malaria could be minimized. Although some patients died from malaria, this was preferable than the almost-certain death from syphilis.<ref>{{cite journal | author = Raju T | title = Hot brains: manipulating body heat to save the brain. | url=http://pediatrics.aappublications.org/cgi/content/full/117/2/e320 | journal = Pediatrics | volume = 117 | issue = 2 | pages = e320-1 | year = 2006 | pmid = 16452338}}</ref>
==Historical Perspective==
===Discovery===
====Ancient History====
*Malaria is one of the earliest discovered global diseases, which continues to infect hundreds of million people worldwide. Frequently, it has been regarded as the most significant disease over the past three thousand years. Since antiquity, the malarial syndrome has been described in ancient China, India, Greece, and Egypt.<ref name="pmid20205846">{{cite journal| author=Cox FE| title=History of the discovery of the malaria parasites and their vectors. | journal=Parasit Vectors | year= 2010 | volume= 3 | issue= 1 | pages= 5 | pmid=20205846 | doi=10.1186/1756-3305-3-5 | pmc=PMC2825508 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20205846  }} </ref>
*Hippocrates, Homer, and other Greek and Roman physicians often referred to malaria as the “marsh fever”, “intermittent fever”, and “ague”.<ref name="pmid20205846">{{cite journal| author=Cox FE| title=History of the discovery of the malaria parasites and their vectors. | journal=Parasit Vectors | year= 2010 | volume= 3 | issue= 1 | pages= 5 | pmid=20205846 | doi=10.1186/1756-3305-3-5 | pmc=PMC2825508 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20205846  }} </ref><ref name="pmid7021827">{{cite journal| author=Bruce-Chwatt LJ| title=Alphonse Laveran's discovery 100 years ago and today's global fight against malaria. | journal=J R Soc Med | year= 1981 | volume= 74 | issue= 7 | pages= 531-6 | pmid=7021827 | doi= | pmc=PMC1439072 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7021827  }} </ref>
*The name “malaria” was only coined in the mid-eighteenth century, derived from two Latin words that collectively translate to “bad air”.<ref name="pmid81525">{{cite journal| author=Dutta HM, Dutt AK| title=Malarial ecology: a global perspective. | journal=Soc Sci Med | year= 1978 | volume= 12 | issue= 2D | pages= 69-84 | pmid=81525 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=81525  }} </ref>  


Although the blood stage and mosquito stages of the malaria life cycle were established in the 19<sup>th</sup> and early 20<sup>th</sup> centuries, it was not until the 1980s that the latent liver form of the parasite was observed.<ref>{{cite journal | author = Krotoski W, Collins W, Bray R, ''et al'' | title = Demonstration of hypnozoites in sporozoite-transmitted Plasmodium vivax infection. | journal = Am J Trop Med Hyg | volume = 31 | issue = 6 | pages = 1291-3 | year = 1982 | pmid = 6816080}}</ref><ref>{{cite journal | author = Meis J, Verhave J, Jap P, Sinden R, Meuwissen J | title = Malaria parasites--discovery of the early liver form. | journal = Nature | volume = 302 | issue = 5907 | pages = 424-6 | year =1983 | pmid = 6339945}}</ref> The discovery of this latent form of the parasite finally explained why people could appear to be cured of malaria but still relapse years after the parasite had disappeared from their bloodstreams.
====Discovery and Differentiation of the Malaria Parasite====
*Malaria was originally believed to be an airborne noxious element or miasma from swamps. It was not until 1880, when Charles Louis Alphone Laveran, a French military physician, discovered an infectious parasite when he microscopically examined blood smears of 44 malaria patients and “noticed among the red corpuscles elements that seemed to be parasites”.<ref name="pmid6750753">{{cite journal| author=Laveran CL| title=Classics in infectious diseases: A newly discovered parasite in the blood of patients suffering from malaria. Parasitic etiology of attacks of malaria: Charles Louis Alphonse Laveran (1845-1922). | journal=Rev Infect Dis | year= 1982 | volume= 4 | issue= 4 | pages= 908-11 | pmid=6750753 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6750753  }} </ref>
**He was eventually rewarded the Nobel Prize for Physiology or Medicine in 1907 for his overall research on malaria.<ref name="pmid20205846">{{cite journal| author=Cox FE| title=History of the discovery of the malaria parasites and their vectors. | journal=Parasit Vectors | year= 2010 | volume= 3 | issue= 1 | pages= 5 | pmid=20205846 | doi=10.1186/1756-3305-3-5 | pmc=PMC2825508 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20205846  }} </ref>
**In 1883, it was hypothesized that malarial transmission is by mosquito.<ref name="pmid81525">{{cite journal| author=Dutta HM, Dutt AK| title=Malarial ecology: a global perspective. | journal=Soc Sci Med | year= 1978 | volume= 12 | issue= 2D | pages= 69-84 | pmid=81525 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=81525  }} </ref>
*Fourteen years later in 1897, Sir Ronald Ross, an Indian-born British bacteriologist, isolated malarial oocysts in Anopheles mosquitos and was able to prove that the culcine mosquito is the malarial vector for avian malaria.<ref name="pmid20756775">{{cite journal| author=Ross R| title=Observations on a Condition Necessary to the Transformation of the Malaria Crescent. | journal=Br Med J | year= 1897 | volume= 1 | issue= 1883 | pages= 251-5 | pmid=20756775 | doi= | pmc=PMC2432879 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20756775  }} </ref>
**Consequently, he also won the Nobel Prize for Physiology or Medicine in 1902 for his research on malarial transmission and life cycle.<ref name="pmid81525">{{cite journal| author=Dutta HM, Dutt AK| title=Malarial ecology: a global perspective. | journal=Soc Sci Med | year= 1978 | volume= 12 | issue= 2D | pages= 69-84 | pmid=81525 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=81525  }} </ref>
**Ross’s discovery was then followed by a similar discovery one year later for Anopheles mosquito and human malaria by Italian researchers Giovanni Battista Grassi, Amico Bignami, Giuseppe Bastianelli, Angelo Celli, Camillo Golgi, and Ettore Marchiafava.<ref name="pmid20205846">{{cite journal| author=Cox FE| title=History of the discovery of the malaria parasites and their vectors. | journal=Parasit Vectors | year= 2010 | volume= 3 | issue= 1 | pages= 5 | pmid=20205846 | doi=10.1186/1756-3305-3-5 | pmc=PMC2825508 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20205846  }} </ref>
 
==Outbreaks==
===Malaria in the United States===
* Malaria was mostly eliminated from the United States in the early 1950s.<ref name="CDC">Malaria Facts. CDC.gov accessed on 07/24/2014 [http://www.cdc.gov/malaria/about/facts.html]</ref>
 
* Between 1957 and 2011, in the United States, 63 outbreaks of locally transmitted mosquito-borne malaria occurred. In such outbreaks, local mosquitoes become infected by biting individuals carrying malaria parasites (acquired in endemic areas), subsequently transmitting malaria to local residents.<ref name="CDC">Malaria Facts. CDC.gov accessed on 07/24/2014 [http://www.cdc.gov/malaria/about/facts.html]</ref>
 
* Between 1963 and 2011, 97 cases of '''[[blood transfusion|transfusion]]-transmitted malaria''' were reported in the United States. Approximately two thirds of these cases could have been prevented if the implicated donors had been deferred according to established guidelines.<ref name="CDC">Malaria Facts. CDC.gov accessed on 07/24/2014 [http://www.cdc.gov/malaria/about/facts.html]</ref>
 
==Landmark Events in the Development of Treatment Strategies==
===Synthetic Quinine===
*Robert Woodward and William vonEggers Doering developed the total synthesis of quinine in 1944.
*Paul Rabe and Karl Kindler’s report on converting d-quinotoxine into quinine in 1918.<ref name="pmid17294412">{{cite journal| author=Seeman JI| title=The Woodward-Doering/Rabe-Kindler total synthesis of quinine: setting the record straight. | journal=Angew Chem Int Ed Engl | year= 2007 | volume= 46 | issue= 9 | pages= 1378-413 | pmid=17294412 | doi=10.1002/anie.200601551 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17294412  }} </ref><ref name="pmid15669029">{{cite journal| author=Kaufman TS, Rúveda EA| title=The quest for quinine: those who won the battles and those who won the war. | journal=Angew Chem Int Ed Engl | year= 2005 | volume= 44 | issue= 6 | pages= 854-85 | pmid=15669029 | doi=10.1002/anie.200400663 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15669029  }} </ref>
*Originally, quinine is an alkaloid derived from barks of cinchona and Remijia tree species that were proven to be effective in the treatment of malaria.
*With Woodward and Doering’s discovery of the first artificial quinine, the first synthetic pharmacological agent to treat malaria was produced.<ref name="pmid15669029">{{cite journal| author=Kaufman TS, Rúveda EA| title=The quest for quinine: those who won the battles and those who won the war. | journal=Angew Chem Int Ed Engl | year= 2005 | volume= 44 | issue= 6 | pages= 854-85 | pmid=15669029 | doi=10.1002/anie.200400663 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15669029  }} </ref>
 
===Chloroquine===
*In 1934, chloroquine (Resochin) was synthesized followed by Sontochin.<ref name="urlA Brief History of Malaria - Saving Lives, Buying Time - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK215638/ |title=A Brief History of Malaria - Saving Lives, Buying Time - NCBI Bookshelf |format= |work= |accessdate=}}</ref>
*These compounds belonged to a new class of antimalarials known as four-amino quinolines.
*Following World War II, chloroquine emerged as the principal weapons in the WHO's ambitious “global eradication” malaria campaign.
*Chloroquine-resistant P. falciparum (CRPF) probably arose de novo from four independent geographic locations:
#The Thai-Cambodian border around 1957.
#Venezuela and the nearby Magdalena Valley of Colombia around 1960.
#Port Moresby, Papua New Guinea, in the mid-1970s.
#In Africa, CRPF was first found in 1978, spreading next to inland coastal areas and by 1983, to Sudan, Uganda, Zambia, and Malawi.
===Sulfadoxine-Pyrimethamine===
* Sulfadoxine-pyrimethamine (SP),the most widely used antifolate antimalarial combination today, was introduced in Thailand in 1967. Resistance to SP was reported in Thailand later that year.<ref name="urlA Brief History of Malaria - Saving Lives, Buying Time - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK215638/ |title=A Brief History of Malaria - Saving Lives, Buying Time - NCBI Bookshelf |format= |work= |accessdate=}}</ref>
*The pyrimidine derivative, proguanil, emerged from the antimalarial pipeline during World War II. it stimulated further study for making agents that block folate synthesis in parasites and bacteria, and resulted in the development of pyrimethamine.
*It became apparent that malaria parasites could quickly alter the target enzyme of the two drugs, leading to resistance.
*sulfonamides were then combined with proguanil or pyrimethamine for increasing efficacy, and forestalling or preventing the development of resistance.
===Mefloquine===
*[[Mefloquine]] was a collaborative achievement of the U.S. Army Medical Research and Development Command, the World Health Organization (WHO/TDR), and Hoffman-La Roche.<ref name="urlA Brief History of Malaria - Saving Lives, Buying Time - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK215638/ |title=A Brief History of Malaria - Saving Lives, Buying Time - NCBI Bookshelf |format= |work= |accessdate=}}</ref>
*Mefloquine's efficacy in preventing falciparum malaria was acknowledged in 1974.
*[[Mefloquine]] resistance began to appear in Asia around the time of the drug's availability in 1985.
===Artemisinin===
*[[Artemisinin]] is the antimalarial isolated by Chinese scientists in 1972 from Artemisia annua (sweet wormwood).<ref name="urlA Brief History of Malaria - Saving Lives, Buying Time - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK215638/ |title=A Brief History of Malaria - Saving Lives, Buying Time - NCBI Bookshelf |format= |work= |accessdate=}}</ref>
*The earliest report of its use appears in a Chinese book found in the Mawanhgolui Han dynasty tombs dating to 168 BC.
*[[Artemisinin]] and other Artemether-group drugs are the main line of treatment against drug-resistant malaria in many areas of southeast Asia.
*The number of Artemisinin-based combination therapy treatment courses procured from manufacturers increased globally from 187 million in 2010 to 409 million in 2016.<ref name="urlWHO | Q&A on artemisinin resistance, SYSTEM DO NOT MOVE OR EDIT">{{cite web |url=http://www.who.int/malaria/media/artemisinin_resistance_qa/en/ |title=WHO &#124; Q&A on artemisinin resistance, SYSTEM DO NOT MOVE OR EDIT |format= |work= |accessdate=}}</ref>
*Artemisinin partial resistance likely emerged prior to 2001.To date, it has been confirmed in 5 countries: Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Viet Nam.<ref name="urlWHO | Q&A on artemisinin resistance, SYSTEM DO NOT MOVE OR EDIT">{{cite web |url=http://www.who.int/malaria/media/artemisinin_resistance_qa/en/ |title=WHO &#124; Q&A on artemisinin resistance, SYSTEM DO NOT MOVE OR EDIT |format= |work= |accessdate=}}</ref>
===Partial Eradication of Malaria===
*Upon the understanding of malaria's mode of transmission and mechanisms of disease, mosquito control and prompt diagnosis and treatment, allowed most European countries to eliminate malaria before the Second World War.<ref name="pmid19497083">{{cite journal| author=Mendis K, Rietveld A, Warsame M, Bosman A, Greenwood B, Wernsdorfer WH| title=From malaria control to eradication: The WHO perspective. | journal=Trop Med Int Health | year= 2009 | volume= 14 | issue= 7 | pages= 802-9 | pmid=19497083 | doi=10.1111/j.1365-3156.2009.02287.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19497083  }} </ref>  
*In 1955, the Global Malaria Eradication Program was established in an effort to control and eliminate malaria, as well as to reduce the malarial burden in regions of moderate prevalence outside tropical Africa.
*The financial coverage and expertise to fight malaria further expanded to include global efforts, such as "Global Fund to Fight HIV, TB, and Malaria", "U.S. President's Malaria Initiative", and "World Bank's Booster Program".<ref name="pmid19497083">{{cite journal| author=Mendis K, Rietveld A, Warsame M, Bosman A, Greenwood B, Wernsdorfer WH| title=From malaria control to eradication: The WHO perspective. | journal=Trop Med Int Health | year= 2009 | volume= 14 | issue= 7 | pages= 802-9 | pmid=19497083 | doi=10.1111/j.1365-3156.2009.02287.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19497083  }} </ref>
*In 2008, the World Health Organization (WHO) announced a multibillion-dollar initiative to eradicate malaria, partially funded by international donors.<ref name="pmid18525039">{{cite journal| author=Okie S| title=A new attack on malaria. | journal=N Engl J Med | year= 2008 | volume= 358 | issue= 23 | pages= 2425-8 | pmid=18525039 | doi=10.1056/NEJMp0803483 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18525039  }} </ref>
 
*In 2005, with a grant funding from the Bill and Melinda Gates Foundation, PATH Malaria Vaccine Initiative (MVI), a non-profit organization, collaborated with Glaxosmithkline, to develop an anti-malarial vaccine. The vaccine has been administered, alongside other infant vaccines, through the Expanded Program on Immunization (EPI).
*In 2011, the first co-primary end point from the phase 3 trial of RTS, S/AS01 malaria vaccine was published, followed by a second co-primary end point in 2012.<ref name="pmid23136909">{{cite journal| author=RTS,S Clinical Trials Partnership. Agnandji ST, Lell B, Fernandes JF, Abossolo BP, Methogo BG et al.| title=A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. | journal=N Engl J Med | year= 2012 | volume= 367 | issue= 24 | pages= 2284-95 | pmid=23136909 | doi=10.1056/NEJMoa1208394 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23136909  }} </ref>  
*The vaccine was used to protect against uncomplicated and severe malaria in infants. In July 2014, Glaxosmithkline applied for approval to be the world's first anti-malarial vaccine. Other malarial vaccines are currently being developed, but still require further validation of their clinical efficacy.


==References==
==References==
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Latest revision as of 20:10, 20 November 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Alison Leibowitz [3], Marjan Khan M.B.B.S.[4]

Overview

The symptoms of malaria, one of the oldest known infections, were initially believed to be caused by noxious elements. In 1880 Charles Louis Alphone Laveran discovered the Plasmodium parasite in blood smears of patients with malaria. The role of mosquitos in the transmission of malaria to humans was discovered a few years later. The entire life cycle of the Plasmodium parasite remained enigmatic until 1982.Although malaria has historically been treated using quinine, an alkaloid derived from barks of cinchona, the first synthetic quinine was produced in 1948.In 2014, the first candidate for anti-malarial vaccine was developed.

Historical Perspective

Discovery

Ancient History

  • Malaria is one of the earliest discovered global diseases, which continues to infect hundreds of million people worldwide. Frequently, it has been regarded as the most significant disease over the past three thousand years. Since antiquity, the malarial syndrome has been described in ancient China, India, Greece, and Egypt.[1]
  • Hippocrates, Homer, and other Greek and Roman physicians often referred to malaria as the “marsh fever”, “intermittent fever”, and “ague”.[1][2]
  • The name “malaria” was only coined in the mid-eighteenth century, derived from two Latin words that collectively translate to “bad air”.[3]

Discovery and Differentiation of the Malaria Parasite

  • Malaria was originally believed to be an airborne noxious element or miasma from swamps. It was not until 1880, when Charles Louis Alphone Laveran, a French military physician, discovered an infectious parasite when he microscopically examined blood smears of 44 malaria patients and “noticed among the red corpuscles elements that seemed to be parasites”.[4]
    • He was eventually rewarded the Nobel Prize for Physiology or Medicine in 1907 for his overall research on malaria.[1]
    • In 1883, it was hypothesized that malarial transmission is by mosquito.[3]
  • Fourteen years later in 1897, Sir Ronald Ross, an Indian-born British bacteriologist, isolated malarial oocysts in Anopheles mosquitos and was able to prove that the culcine mosquito is the malarial vector for avian malaria.[5]
    • Consequently, he also won the Nobel Prize for Physiology or Medicine in 1902 for his research on malarial transmission and life cycle.[3]
    • Ross’s discovery was then followed by a similar discovery one year later for Anopheles mosquito and human malaria by Italian researchers Giovanni Battista Grassi, Amico Bignami, Giuseppe Bastianelli, Angelo Celli, Camillo Golgi, and Ettore Marchiafava.[1]

Outbreaks

Malaria in the United States

  • Malaria was mostly eliminated from the United States in the early 1950s.[6]
  • Between 1957 and 2011, in the United States, 63 outbreaks of locally transmitted mosquito-borne malaria occurred. In such outbreaks, local mosquitoes become infected by biting individuals carrying malaria parasites (acquired in endemic areas), subsequently transmitting malaria to local residents.[6]
  • Between 1963 and 2011, 97 cases of transfusion-transmitted malaria were reported in the United States. Approximately two thirds of these cases could have been prevented if the implicated donors had been deferred according to established guidelines.[6]

Landmark Events in the Development of Treatment Strategies

Synthetic Quinine

  • Robert Woodward and William vonEggers Doering developed the total synthesis of quinine in 1944.
  • Paul Rabe and Karl Kindler’s report on converting d-quinotoxine into quinine in 1918.[7][8]
  • Originally, quinine is an alkaloid derived from barks of cinchona and Remijia tree species that were proven to be effective in the treatment of malaria.
  • With Woodward and Doering’s discovery of the first artificial quinine, the first synthetic pharmacological agent to treat malaria was produced.[8]

Chloroquine

  • In 1934, chloroquine (Resochin) was synthesized followed by Sontochin.[9]
  • These compounds belonged to a new class of antimalarials known as four-amino quinolines.
  • Following World War II, chloroquine emerged as the principal weapons in the WHO's ambitious “global eradication” malaria campaign.
  • Chloroquine-resistant P. falciparum (CRPF) probably arose de novo from four independent geographic locations:
  1. The Thai-Cambodian border around 1957.
  2. Venezuela and the nearby Magdalena Valley of Colombia around 1960.
  3. Port Moresby, Papua New Guinea, in the mid-1970s.
  4. In Africa, CRPF was first found in 1978, spreading next to inland coastal areas and by 1983, to Sudan, Uganda, Zambia, and Malawi.

Sulfadoxine-Pyrimethamine

  • Sulfadoxine-pyrimethamine (SP),the most widely used antifolate antimalarial combination today, was introduced in Thailand in 1967. Resistance to SP was reported in Thailand later that year.[9]
  • The pyrimidine derivative, proguanil, emerged from the antimalarial pipeline during World War II. it stimulated further study for making agents that block folate synthesis in parasites and bacteria, and resulted in the development of pyrimethamine.
  • It became apparent that malaria parasites could quickly alter the target enzyme of the two drugs, leading to resistance.
  • sulfonamides were then combined with proguanil or pyrimethamine for increasing efficacy, and forestalling or preventing the development of resistance.

Mefloquine

  • Mefloquine was a collaborative achievement of the U.S. Army Medical Research and Development Command, the World Health Organization (WHO/TDR), and Hoffman-La Roche.[9]
  • Mefloquine's efficacy in preventing falciparum malaria was acknowledged in 1974.
  • Mefloquine resistance began to appear in Asia around the time of the drug's availability in 1985.

Artemisinin

  • Artemisinin is the antimalarial isolated by Chinese scientists in 1972 from Artemisia annua (sweet wormwood).[9]
  • The earliest report of its use appears in a Chinese book found in the Mawanhgolui Han dynasty tombs dating to 168 BC.
  • Artemisinin and other Artemether-group drugs are the main line of treatment against drug-resistant malaria in many areas of southeast Asia.
  • The number of Artemisinin-based combination therapy treatment courses procured from manufacturers increased globally from 187 million in 2010 to 409 million in 2016.[10]
  • Artemisinin partial resistance likely emerged prior to 2001.To date, it has been confirmed in 5 countries: Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Viet Nam.[10]

Partial Eradication of Malaria

  • Upon the understanding of malaria's mode of transmission and mechanisms of disease, mosquito control and prompt diagnosis and treatment, allowed most European countries to eliminate malaria before the Second World War.[11]
  • In 1955, the Global Malaria Eradication Program was established in an effort to control and eliminate malaria, as well as to reduce the malarial burden in regions of moderate prevalence outside tropical Africa.
  • The financial coverage and expertise to fight malaria further expanded to include global efforts, such as "Global Fund to Fight HIV, TB, and Malaria", "U.S. President's Malaria Initiative", and "World Bank's Booster Program".[11]
  • In 2008, the World Health Organization (WHO) announced a multibillion-dollar initiative to eradicate malaria, partially funded by international donors.[12]
  • In 2005, with a grant funding from the Bill and Melinda Gates Foundation, PATH Malaria Vaccine Initiative (MVI), a non-profit organization, collaborated with Glaxosmithkline, to develop an anti-malarial vaccine. The vaccine has been administered, alongside other infant vaccines, through the Expanded Program on Immunization (EPI).
  • In 2011, the first co-primary end point from the phase 3 trial of RTS, S/AS01 malaria vaccine was published, followed by a second co-primary end point in 2012.[13]
  • The vaccine was used to protect against uncomplicated and severe malaria in infants. In July 2014, Glaxosmithkline applied for approval to be the world's first anti-malarial vaccine. Other malarial vaccines are currently being developed, but still require further validation of their clinical efficacy.

References

  1. ↑ 1.0 1.1 1.2 1.3 Cox FE (2010). "History of the discovery of the malaria parasites and their vectors". Parasit Vectors. 3 (1): 5. doi:10.1186/1756-3305-3-5. PMC 2825508. PMID 20205846.
  2. ↑ Bruce-Chwatt LJ (1981). "Alphonse Laveran's discovery 100 years ago and today's global fight against malaria". J R Soc Med. 74 (7): 531–6. PMC 1439072. PMID 7021827.
  3. ↑ 3.0 3.1 3.2 Dutta HM, Dutt AK (1978). "Malarial ecology: a global perspective". Soc Sci Med. 12 (2D): 69–84. PMID 81525.
  4. ↑ Laveran CL (1982). "Classics in infectious diseases: A newly discovered parasite in the blood of patients suffering from malaria. Parasitic etiology of attacks of malaria: Charles Louis Alphonse Laveran (1845-1922)". Rev Infect Dis. 4 (4): 908–11. PMID 6750753.
  5. ↑ Ross R (1897). "Observations on a Condition Necessary to the Transformation of the Malaria Crescent". Br Med J. 1 (1883): 251–5. PMC 2432879. PMID 20756775.
  6. ↑ 6.0 6.1 6.2 Malaria Facts. CDC.gov accessed on 07/24/2014 [1]
  7. ↑ Seeman JI (2007). "The Woodward-Doering/Rabe-Kindler total synthesis of quinine: setting the record straight". Angew Chem Int Ed Engl. 46 (9): 1378–413. doi:10.1002/anie.200601551. PMID 17294412.
  8. ↑ 8.0 8.1 Kaufman TS, Rúveda EA (2005). "The quest for quinine: those who won the battles and those who won the war". Angew Chem Int Ed Engl. 44 (6): 854–85. doi:10.1002/anie.200400663. PMID 15669029.
  9. ↑ 9.0 9.1 9.2 9.3 "A Brief History of Malaria - Saving Lives, Buying Time - NCBI Bookshelf".
  10. ↑ 10.0 10.1 "WHO | Q&A on artemisinin resistance, SYSTEM DO NOT MOVE OR EDIT".
  11. ↑ 11.0 11.1 Mendis K, Rietveld A, Warsame M, Bosman A, Greenwood B, Wernsdorfer WH (2009). "From malaria control to eradication: The WHO perspective". Trop Med Int Health. 14 (7): 802–9. doi:10.1111/j.1365-3156.2009.02287.x. PMID 19497083.
  12. ↑ Okie S (2008). "A new attack on malaria". N Engl J Med. 358 (23): 2425–8. doi:10.1056/NEJMp0803483. PMID 18525039.
  13. ↑ RTS,S Clinical Trials Partnership. Agnandji ST, Lell B, Fernandes JF, Abossolo BP, Methogo BG; et al. (2012). "A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants". N Engl J Med. 367 (24): 2284–95. doi:10.1056/NEJMoa1208394. PMID 23136909.


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