View source for History of malaria

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[[File:"Keep out malaria mosquitoes repair your torn screen" - NARA - 514969.jpg|thumb|[[Second World War]] poster "Keep out malaria mosquitoes repair your torn screens". [[U.S. Public Health Service]], 1941–45]]

The '''history of malaria''' extends from its prehistoric origin as a [[zoonotic]] disease in the primates of Africa through to the 21st century. A widespread and potentially lethal human infectious disease, at its peak [[malaria]] infested every continent except [[Antarctica]].<ref>{{cite journal |vauthors=Carter R, Mendis KN | title = Evolutionary and historical aspects of the burden of malaria | journal = Clin Microbiol Rev | volume = 15 | issue = 4 | pages = 564–94 | year = 2002 | pmid = 12364370 | url = http://skishore.wikispaces.com/file/view/Evo-Historical+Aspects+of+Malaria.pdf | pmc = 126857 | doi = 10.1128/cmr.15.4.564-594.2002 | access-date = 4 August 2012 | archive-date = 10 January 2020 | archive-url = https://web.archive.org/web/20200110155522/https://skishore.wikispaces.com/file/view/Evo-Historical+Aspects+of+Malaria.pdf | url-status = dead }}</ref> Its prevention and treatment have been targeted in science and medicine for hundreds of years. Since the discovery of the ''[[Plasmodium]]'' [[parasite]]s which cause it, research attention has focused on their biology as well as that of the [[mosquitoe]]s which transmit the parasites.

References to its unique, periodic fevers are found throughout recorded history, beginning in the first millennium BC in Greece and China.<ref>{{cite journal |vauthors=Neghina R, Neghina AM, Marincu I, Iacobiciu I | title = Malaria, a Journey in Time: In Search of the Lost Myths and Forgotten Stories| journal = Am J Med Sci | issue =6| pages = 492–98| year =2010 | pmid = 20601857 | doi=10.1097/MAJ.0b013e3181e7fe6c | volume=340| s2cid = 205747078}}</ref><ref>[http://www.wdl.org/en/item/3044/ The Su Wen of the Huangdi Neijing (Inner Classic of the Yellow Emperor)]</ref>

For thousands of years, traditional [[Herbalism|herbal remedies]] have been used to treat malaria.<ref>{{cite journal | vauthors = Willcox ML, Bodeker G | title = Traditional herbal medicines for malaria | journal = BMJ | year = 2004 | volume = 329 | pages = 1156–59 | pmid = 15539672 | doi = 10.1136/bmj.329.7475.1156 | url = http://www.giftsofhealth.org/ritam/flyer/Willcox%26Bodeker2004.pdf | issue = 7475 | pmc = 527695 | access-date = 21 February 2010 | archive-date = 22 February 2022 | archive-url = https://web.archive.org/web/20220222135854/https://www.giftsofhealth.org/ritam/flyer/Willcox%26Bodeker2004.pdf | url-status = dead }}</ref> The first effective treatment for malaria came from the bark of the [[Cinchona|cinchona tree]], which contains [[quinine]]. After the link to mosquitos and their parasites was identified in the early 20th century, mosquito control measures such as widespread use of the insecticide [[Dichlorodiphenyltrichloroethane|DDT]], swamp drainage, covering or oiling the surface of open water sources, indoor residual spraying, and use of insecticide treated nets was initiated. Prophylactic quinine was prescribed in malaria endemic areas, and new therapeutic drugs, including [[chloroquine]] and [[artemisinin]]s, were used to resist the scourge. Today, artemisinin is present in every remedy applied in the treatment of malaria. After introducing artemisinin as a cure administered together with other remedies, malaria mortality in Africa decreased by half, though it later partially rebounded.<ref>{{Citation|first= Sergiusz|last= Prokurat|title= Economic outcomes of Malaria in South East Asia|publisher= Opportunities for cooperation between Europe and Asia|date= 2015|access-date= 5 August 2016|isbn= 978-83-62753-58-1|location= Józefów|pages= 157–74|url= http://www.proeconomics.pl/artykuly/Malaria.pdf|archive-url= https://web.archive.org/web/20161007121138/http://www.proeconomics.pl/artykuly/Malaria.pdf|archive-date= 7 October 2016|url-status= dead}}</ref>

Malaria researchers have won multiple Nobel Prizes for their achievements, although the disease continues to afflict some 200 million patients each year, killing more than 600,000.

Malaria was the most important health hazard encountered by U.S. troops in the South Pacific during [[World War II]], where about 500,000 men were infected.<ref name="Bray 2004">{{Cite book |author=Bray RS |title=Armies of Pestilence: The Effects of Pandemics on History |year=2004|publisher=James Clarke |isbn=978-0-227-17240-7 |page=102 |url=https://books.google.com/books?id=djPWGnvBm08C&pg=PA102}}</ref> 

At the close of the 20th century, malaria remained endemic in more than 100 countries throughout the tropical and subtropical zones, including large areas of Central and South America, [[Hispaniola]] ([[Haiti]] and the [[Dominican Republic]]), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania. Resistance of ''Plasmodium'' to anti-malaria drugs, as well as resistance of mosquitos to [[insecticide]]s and the discovery of [[Zoonosis|zoonotic]] species of the parasite have complicated control measures.

One estimate, which has been published in a 2002 ''[[Nature (journal)|Nature]]'' article, claims that malaria may have killed 50-60 billion people throughout history, or about half of all humans that have ever lived.<ref name="Whitfield2">{{cite journal |author=Whitfield, J. |year=2002 |title=Portrait of a serial killer |url=https://www.nature.com/articles/news021001-6 |journal=Nature |doi=10.1038/news021001-6|url-access=subscription }}</ref> However, speaking on the [[BBC]] podcast ''More or Less'', Emeritus Professor of Medical Statistics at Liverpool School of Tropical Medicine Brian Faragher voiced doubt about this estimate, noting that the ''Nature'' article in question did not reference the claim.<ref name=":0">{{Cite web |last=Pomeroy |first=Ross |date=3 October 2019 |title=Has Malaria Really Killed Half of Everyone Who Ever Lived? |url=https://www.realclearscience.com/blog/2019/10/03/has_malaria_really_killed_half_of_everyone_who_ever_lived.html |url-status=live |archive-url=https://web.archive.org/web/20230125151055/https://www.realclearscience.com/blog/2019/10/03/has_malaria_really_killed_half_of_everyone_who_ever_lived.html |archive-date=25 January 2023 |access-date=28 June 2023 |website=RealClear Science}}</ref><ref name=":1">{{cite podcast |host=Tim Harford |title=Have Mosquitoes Killed Half the World? |website=More or Less |publisher=[[BBC]] |date=5 October 2013 |url=https://www.bbc.co.uk/sounds/play/p01hnv98 |access-date=28 June 2023}}</ref> Faragher gave a tentative estimate of about 4-5% of deaths being caused by malaria, lower than the claimed 50%.<ref name=":0" /> ''More or Less'' were unable to find any source for the original figure aside from works which made the claim without reference.<ref name=":1" />
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== Origin and prehistoric period ==
{{see also|Genetic resistance to malaria|Plasmodium species infecting primates}}

[[File:Baltic Amber necklace with insects inclusions.jpg|thumb|right|The mosquito and the [[fly]] in this [[Baltic Sea|Baltic]] amber necklace are between 40 and 60 million years old.]]

The first evidence of malaria parasites was found in [[mosquito]]es preserved in [[amber]] from the [[Paleogene|Palaeogene period]] that are approximately 30 million years old.<ref>{{cite journal |author=Poinar G |title=Plasmodium dominicana n. sp. (Plasmodiidae: Haemospororida) from Tertiary Dominican amber |journal=Syst. Parasitol. |volume=61 |issue=1 |pages=47–52 |year=2005 |pmid=15928991 |doi=10.1007/s11230-004-6354-6|s2cid=22186899 }}</ref> Malaria protozoa are diversified into primate, rodent, bird, and reptile host lineages.<ref>{{cite journal |vauthors=Joy DA, Feng X, Mu J, Furuya T, Chotivanich K, Krettli AU, Ho M, Wang A, White NJ, Suh E, Beerli P, Su XZ | title = Early origin and recent expansion of Plasmodium falciparum | journal = Science | volume = 300 | issue = 5617 | pages = 318–21 | year = 2003 | pmid = 12690197 | doi = 10.1126/science.1081449| bibcode = 2003Sci...300..318J | s2cid = 20036560 }}</ref><ref>{{cite journal |vauthors=Hayakawa T, Culleton R, Otani H, Horii T, Tanabe K | title = Big bang in the evolution of extant malaria parasites | journal = Mol Biol Evol | volume = 25 | issue = 10 | pages = 2233–39| year = 2008 | pmid = 18687771 | doi = 10.1093/molbev/msn171 | doi-access = free }}</ref> The DNA of ''[[Plasmodium falciparum]]'' shows the same pattern of diversity as its human hosts, with greater diversity in Africa than in the rest of the world, showing that modern humans had had the disease before they left Africa.<ref>{{cite book|last=Higham |first=Tom |title=The World Before Us: How Science is Revealing a New Story of Our Human Origins|page= 12, note |publisher=Penguin Viking |year=2021|isbn=978-0-241-44067-4}}</ref> Humans may have originally caught ''P. falciparum'' from [[gorilla]]s.<ref>{{cite journal |author1=Liu W |author2=Li Y |author3=Learn GH |author4=Rudicell RS |author5=Robertson JD |author6=Keele BF |author7=Ndjango J-BN |author8=Sanz CM |author9=Morgan DB |author10=Locatelli S |author11=Gonder MK |author12=Kranzusch PJ |author13=Walsh PD |author14=Delaporte E |author15=Mpoudi-Ngole E |author16=Georgiev AV |author17=Muller MN |author18=Shaw GW |author19=Peeters M |author20=Sharp PM |author21=Julian C. Rayner JC |author22=Hahn BH |title= Origin of the human malaria parasite Plasmodium falciparum in gorillas|journal= Nature |volume=467 |issue=7314 |pages=420–25 |year=2010 |pmid=20864995 |doi=10.1038/nature09442 |pmc=2997044|bibcode= 2010Natur.467..420L}}</ref> ''[[Plasmodium vivax|P. vivax]]'', another malarial ''Plasmodium'' species among the six that infect humans, also likely originated in African [[gorilla]]s and [[Common chimpanzee|chimpanzees]].<ref>{{cite journal |vauthors=Liu W, etal |title=African origin of the malaria parasite Plasmodium vivax|journal=Nature Communications|date=21 February 2014|issue=5 |pages=3346|doi=10.1038/ncomms4346 |pmid=24557500|pmc=4089193|volume=5|bibcode=2014NatCo...5.3346L}}</ref> Another malarial species recently discovered to be transmissible to humans, ''[[Plasmodium knowlesi|P. knowlesi]]'', originated in Asian [[macaque monkey]]s.<ref>{{cite journal|vauthors=Lee KS, Divis PC, Zakaria SK, Matusop A, Julin RA, Conway DJ, Cox-Singh J, Singh B |title= Plasmodium knowlesi: reservoir hosts and tracking the emergence in humans and macaques. |journal = PLOS Pathog |year= 2011| issue=4 |pmc=3072369 |pmid=21490952 |doi=10.1371/journal.ppat.1002015 |volume=7 |pages=e1002015 |doi-access= free }}</ref> While ''[[Plasmodium malariae|P. malariae]]'' is highly host specific to humans, there is some evidence that low level non-symptomatic infection persists among wild chimpanzees.<ref>{{cite journal|last=Hayakawa|first=Toshiyuki|title=Identification of Plasmodium malariae, a human malaria parasite, in imported chimpanzees|date=2009|volume=4|issue=10|doi=10.1371/journal.pone.0007412|pmid=19823579|pmc=2756624|display-authors=etal|journal=PLOS ONE|pages=e7412|bibcode=2009PLoSO...4.7412H|doi-access=free}}</ref>

About 10,000 years ago, malaria started having a major impact on human survival, coinciding with the start of agriculture in the [[Neolithic Revolution]]. Consequences included [[natural selection]] for [[sickle-cell disease]], [[thalassaemias]], [[glucose-6-phosphate dehydrogenase deficiency]], [[Southeast Asian ovalocytosis]], [[elliptocytosis]] and loss of the Gerbich antigen ([[glycophorin C]]) and the [[Duffy antigen system|Duffy antigen]] on the [[red blood cells|erythrocytes]], because such [[blood disorders]] confer a selective advantage against malaria infection ([[balancing selection]]).<ref>{{cite journal | author = Canali S| title = Researches on thalassemia and malaria in Italy and the origins of the "Haldane hypothesis"| journal = Med Secoli| volume =20 | issue =3| pages = 827–46| year =2008 | pmid = 19848219 | url = https://www.researchgate.net/publication/38028954}}</ref> The three major types of inherited [[Genetic resistance to malaria|genetic resistance]] (sickle-cell disease, thalassaemias, and glucose-6-phosphate dehydrogenase deficiency) were present in the [[Mediterranean]] world by the time of the [[Roman Empire]], about 2000 years ago.<ref>{{cite journal |vauthors=Sallares R, Bouwman A, Anderung C | title = The Spread of Malaria to Southern Europe in Antiquity: New Approaches to Old Problems | journal = Med Hist| volume = 48 | issue = 3 | pages = 311–28| year = 2004 | pmid = 16021928 | pmc=547919 | doi=10.1017/s0025727300007651}}</ref>

Molecular methods have confirmed the high prevalence of ''[[Plasmodium falciparum|P. falciparum]]'' malaria in [[ancient Egypt]].<ref>{{cite journal | author = Brier B| title = Infectious diseases in ancient Egypt | journal = Infect Dis Clin North Am| year = 2004 | pmid = 15081501 | doi = 10.1016/S0891-5520(03)00097-7 | volume = 18 | pages = 17–27 | issue = 1}}<br />{{cite journal |vauthors=Nerlich AG, Schraut B, Dittrich S, Jelinek T, Zink AR | title = Plasmodium falciparum in Ancient Egypt| journal = Emerg Infect Dis | volume = 14 | pages =1317–19 | year = 2008 | pmid =18680669 | doi = 10.3201/eid1408.080235 | issue = 8 | pmc = 2600410 }}</ref> The [[Ancient Greek]] historian [[Herodotus]] wrote that the builders of the Egyptian [[pyramids]] ({{circa|2700}}–1700 BC) were given large amounts of [[garlic]],<ref>{{cite journal | author = Macaulay GC| title = The History of Herodotus, parallel English/Greek translation | year = 1890 | pages = Herodotus, 2.125| url = http://www.sacred-texts.com/cla/hh/hh2120.htm }}</ref> probably to protect them against malaria. The [[Pharaoh]] [[Sneferu]], the founder of the [[Fourth dynasty of Egypt]], who reigned from around 2613–2589 BC, used [[mosquito net|bed-nets]] as protection against mosquitoes. [[Cleopatra VII]], the last Pharaoh of [[Ancient Egypt]], similarly slept under a mosquito net.<ref name="malariasite">{{Cite web|url = http://www.malariasite.com/malaria/history_control.htm|title = History of Malaria Control|access-date = 2009-10-27|url-status = dead|archive-url = https://web.archive.org/web/20091111231452/http://www.malariasite.com/MALARIA/history_control.htm|archive-date = 11 November 2009}}</ref> However, whether the mosquito nets were used for the purpose of malaria prevention, or for more mundane purpose of avoiding the discomfort of mosquito bites, is unknown. The presence of malaria in [[Egypt]] from circa 800 BC onwards has been confirmed using [[DNA]]-based methods.<ref>{{cite journal |vauthors=Lalremruata A, Ball M, Bianucci R, Welte B, Nerlich AG, Kun JF, Pusch CM | title = Molecular identification of falciparum malaria and human tuberculosis co-infections in mummies from the Fayum depression (lower Egypt) | journal = PLOS ONE  | pmc=3614933 | pmid=23565222 | doi=10.1371/journal.pone.0060307 | volume=8 | issue=4 | year=2013 | pages=e60307| bibcode=2013PLoSO...860307L | doi-access = free }}</ref>

== Classical period ==

Malaria became widely recognized in [[ancient Greece]] by the 4th century BC and is implicated in the decline of many [[city-state]] populations. The term ''μίασμα'' (Greek for [[Miasma theory|miasma]]: "stain" or "pollution") was coined by [[Hippocrates]] of [[Kos]] who used it to describe dangerous fumes from the ground that are transported by winds and can cause serious illnesses. [[Hippocrates]] (460–370 BC), the "father of medicine", related the presence of intermittent [[fevers]] with [[Climate|climatic]] and [[Natural environment|environmental]] conditions and classified the fever according to periodicity: Gk.:''tritaios pyretos'' / L.:''febris tertiana'' (fever every third day), and Gk.:''tetartaios pyretos'' / L.:''febris quartana'' (fever every fourth day).<ref>{{cite book | author = Hippocrates| title = Of the epidemics | translator=Francis Adams |publisher=The Internet Classics Archive| url =http://classics.mit.edu//Hippocrates/epidemics.mb.txt }}</ref><ref>{{cite journal |vauthors=Pappas G, Kiriaze IJ, Falagas ME | title = Insights into infectious disease in the era of Hippocrates | journal = International Journal of Infectious Diseases | year = 2008 | pmid = 18178502 | doi = 10.1016/j.ijid.2007.11.003 | volume = 12 | pages = 347–50 | issue = 4| doi-access = free }}</ref>

The Chinese ''[[Huangdi Neijing]]'' (The Inner Canon of the Yellow Emperor) dating from ~300 BC – 200 AD apparently refers to repeated paroxysmal fevers associated with enlarged [[spleens]] and a tendency to epidemic occurrence.<ref>{{cite journal | author = Cox F | title = History of human parasitology | journal = Clinical Microbiology Reviews | volume = 15 | issue = 4 | pages = 595–612 | year = 2002 | pmid = 12364371 | doi = 10.1128/CMR.15.4.595-612.2002 | pmc = 126866 }}</ref>
Around 168 BC, the herbal remedy ''Qing-hao'' ([[:zh:青蒿素|青蒿]]) (''[[Artemisia annua]]'') came into use in China to treat female [[hemorrhoid]]s (''[[Wushi'er bingfang]]'' translated as "Recipes for 52 kinds of diseases" unearthed from the [[Mawangdui]]).<ref name=Li>{{cite journal |vauthors=Li Y, Wu YL | title = An over four millennium story behind qinghaosu (artemisinin) – a fantastic antimalarial drug from a traditional Chinese herb| journal = Current Medicinal Chemistry | volume = 10 | pages = 2197–230| year = 2003| pmid =14529339 | doi = 10.2174/0929867033456710 | issue = 21 }}</ref>
''Qing-hao'' was first recommended for acute intermittent fever episodes by [[Ge Hong]] as an effective medication in the 4th-century Chinese manuscript ''Zhou hou bei ji fang'', usually translated as "Emergency Prescriptions kept in one's Sleeve".<ref name="Wright2010"/> His recommendation was to soak fresh plants of the [[Artemisia (genus)|artemisia]] herb in cold water, wring them out, and ingest the expressed bitter juice in their raw state.<ref>{{cite journal | author = Hsu E | title = Reflections on the 'discovery' of the antimalarial qinghao| journal = British Journal of Clinical Pharmacology| volume = 61 | issue = 6 | pages = 666–70 | year = 2006 | pmid = 16722826 | doi = 10.1111/j.1365-2125.2006.02673.x |pmc=1885105}}</ref><ref>{{cite journal |vauthors=Li Y, Wu YL | title = How Chinese scientists discovered qinghaosu (artemisinin) and developed its derivatives? What are the future perspectives?| journal = Médecine Tropicale | volume = 58  | issue = Suppl. 3 | pages = 9–12 | year = 1998| pmid =10212890 | url = https://www.researchgate.net/publication/13085247}}</ref>

"Roman fever" refers to a particularly deadly strain of [[malaria]] that affected the Roman Campagna and the city of Rome throughout various epochs in history.<ref>{{Cite book |last1=North |first1=W. |url=https://archive.org/details/b24750025/ |title=Roman fever : the results of an enquiry during three years' residence on the spot into the origin, history, distribution and nature of the malarial fever of the Roman Campagna, with especial reference to their supposed connection with pathogenic organisms |last2=Royal College of Physicians of London |date=1896 |publisher=London : Sampson Low, Marston & Company |others=London Royal College of Physicians}}</ref> An epidemic of Roman fever during the 5th century AD may have contributed to the fall of the [[Roman Empire]].<ref>{{Cite book |last1=Jones |first1=W. H. S. (William Henry Samuel) |url=https://archive.org/details/cu31924012431700/ |title=Malaria, a neglected factor in the history of Greece and Rome |last2=Ross |first2=Ronald |last3=Ellett |first3=George Grigson |date=1907 |publisher=[[Cambridge University Press | Cambridge]]; [[Macmillan Publishers | Macmillan & Bowes]] |others=Cornell University Library |pages=85}}</ref> The many remedies to reduce the [[spleen]] in [[Pedanius Dioscorides]]'s ''[[De Materia Medica]]'' have been suggested to have been a response to chronic malaria in the Roman empire.<ref>{{cite book | url=http://www.ibidispress.scriptmania.com/box_widget.html | title=Dioscorides: De Materia Medica | publisher=Ibidis | author=Osbaldeston, Tess Anne | year=2000 | pages=Introduction, xxvi | url-status=dead | archive-url=https://web.archive.org/web/20140924062658/http://www.ibidispress.scriptmania.com/box_widget.html | archive-date=24 September 2014 }}</ref> Some so-called "[[vampire burial]]s" in [[late antiquity]] may have been performed in response to malaria epidemics. For example, some children who died of malaria were buried in the [[necropolis]] at [[Lugnano in Teverina]] using rituals meant to prevent them from [[Undead|returning from the dead]]. Modern scholars hypothesize that communities feared that the dead would return and spread disease.<ref>{{Cite news|url=https://www.washingtonpost.com/science/2018/10/15/archaeologists-find-vampire-burial-site-child-feared-capable-rising-dead|title=Archaeologists find 'vampire burial' site of a child feared capable of rising from the dead|last=Phillips|first=Kristine|date=2018-10-15|newspaper=The Washington Post|access-date=2018-10-15}}</ref>

In 835, the celebration of [[Hallowmas]] (All Saints Day) was moved from May to November at the behest of [[Pope Gregory IV]], on the "practical grounds that Rome in summer could not accommodate the great number of pilgrims who flocked to it", and perhaps because of [[public health]] considerations regarding Roman Fever, which claimed a number of lives of [[pilgrim]]s during the sultry summers of the region.<ref>Butler's Saint for the Day (Paul Burns), Liturgical Press, p. 516</ref>

[[File:Cinchona pubescens 1696.png|thumb|right|Cinchona tree by Theodor Zwinger, 1696]]

== Middle Ages ==

During the [[Middle Ages]], treatments for malaria (and other diseases) included blood-letting, inducing vomiting, limb amputations, and [[trepanning]]. Physicians and surgeons in the period used herbal medicines like [[Atropa belladonna|belladonna]] to bring about pain relief in affected patients.<ref name="medline">{{cite web|url=https://www.nlm.nih.gov/medlineplus/druginfo/natural/531.html|title=Belladonna|date=2009-12-16|website=Medline Plus|access-date=2010-11-29| archive-url= https://web.archive.org/web/20101220172635/http://www.nlm.nih.gov/medlineplus/druginfo/natural/531.html| archive-date= 20 December 2010 | url-status= live}}</ref><ref>{{Cite book|author=Ebadi, Manuchair|title=Pharmacodynamic Basis of Herbal Medicine|publisher=CRC Press|year=2007|isbn=9780849370502|page=203|url=https://books.google.com/books?id=CMJKgfhCKzIC&pg=PA203}}</ref>

=== European Renaissance ===

The name malaria is derived from {{lang|it|mal aria}} ('bad air' in [[Italian language#History|Medieval Italian]]). This idea came from the Ancient Romans, who thought that this disease came from pestilential fumes in the swamps. The word malaria has its roots in the [[miasma theory]], as described by historian and chancellor of Florence [[Leonardo Bruni]] in his {{lang|la|Historiarum Florentini populi libri XII}}, which was the first major example of Renaissance historical writing:<ref>{{cite journal |vauthors=Hempelmann E, Krafts K | title = Bad air, amulets and mosquitoes: 2,000 years of changing perspectives on malaria | journal = Malar. J. | volume = 12 | issue = 1| pages = 213 | year = 2013 | pmid = 23835014 | doi = 10.1186/1475-2875-12-232| url = http://www.malariajournal.com/content/pdf/1475-2875-12-232.pdf | pmc=3723432 | doi-access = free }}</ref>

{{blockquote|{{lang|it|Avuto i Fiorentini questo fortissimo castello e fornitolo di buone guardie, consigliavano fra loro medesimi fosse da fare. Erano alcuni a' quali pareva sommamente utile e necessario a ridurre lo esercito, e massimamente essendo affaticato per la infermità e per la {{strong|mala aria}}e per lungo e difficile campeggiare nel tempo dell'autunno e in luoghi infermi, e vedendo ancora ch'egli era diminuito assai per la licenza conceduta a molti pel capitano di potersi partire: perocchè, nel tempo che eglino erano stati lungamente a quello assedio, molti, o per disagio del campo o per paura d'infermità, avevano domandato e ottenuto licenza da lui}} (Acciajuoli 1476).

After the Florentines had conquered this stronghold, after putting good guardians on it they were discussing among themselves how to proceed. For some of them it appeared most useful and necessary to reduce the army, more so as it was extremely stressed by disease and {{strong|bad air}}, and due to the long-lasting and difficult camps in unhealthy places during the autumn. They (the Florentines) further considered that the army was reduced in numbers due to the leave permits granted to many soldiers by their officers. In fact, during the siege, many soldiers had asked and obtained leave permits due to the camp hardships and fear of illness [translated from medieval Italian, Toscanic dialect].
}}

The coastal plains of [[southern Italy]] fell from international prominence when malaria expanded in the 16th century. At roughly the same time, in the coastal marshes of England, mortality from "marsh fever" or "tertian ague" (''ague'': via French from medieval Latin {{lang|la|acuta}} (''febris''), acute fever) was comparable to that in [[sub-Saharan Africa]] today.<ref>{{cite journal | author = Dobson MJ | title = Malaria in England: a geographical and historical perspective| journal = Parassitologia | volume = 36| pages = 35–60| year = 1994 | pmid = 7898959 | issue = 1–2}}<br />{{cite journal | author = Knottnerus O S | title = Malaria Around the North Sea: A Survey | journal = Gerold Wefer, Wolfgang H. Berger, Karl-Ernst Behre, Eynstein Jansen (Ed.), Climatic Development and History of the North Atlantic Realm: Hanse Conference Report. Springer-Verlag | pages = 339–53| year = 2002| url = http://www.xs4all.nl/~ottoknot/werk/Malaria.html}}</ref> [[William Shakespeare]] was born at the start of the especially cold period that climatologists call the "[[Little Ice Age]]", yet he was aware enough of the ravages of the disease to mention it in eight of his plays.<ref>{{cite journal | author = Reiter P | title = From Shakespeare to Defoe: malaria in England in the Little Ice Age | journal =Emerg Infect Dis | volume = 6 | issue = 1 | pages = 1–11 | year = 2000 | pmid = 10653562| pmc = 2627969 | doi=10.3201/eid0601.000101}}</ref> Malaria was commonplace beside the [[Malaria in the River Thames|River Thames]] then and into the mid-Victorian era.<ref>{{cite journal|last=Dobson|first=Mary|year=1980|title="Marsh Fever" – the geography of malaria in England|journal=Journal of Historical Geography|volume=6|issue=4|pages=357–389|doi=10.1016/0305-7488(80)90145-0|pmid=11632265}}</ref>

Medical accounts and ancient autopsy reports state that tertian malarial fevers caused the death of four members of the prominent [[Medici]] family of [[Florence]].{{#tag:ref|[[Eleonora of Toledo]] (1522–1562), Cardinal Giovanni (1543–1562), Don Garzia (1547–1562) and [[Ferdinando I de' Medici, Grand Duke of Tuscany|Grand Duke Francesco I]] (1531–1587)|group=Note}} These claims have been confirmed with more modern methodologies.<ref>{{cite journal | doi = 10.1016/j.trstmh.2010.06.007 |vauthors=Fornaciari G, Giuffra V, Ferroglio E, Gino S, Bianucci R | title = Plasmodium falciparum immunodetection in bone remains of members of the Renaissance Medici family (Florence, Italy, sixteenth century)| journal = Trans R Soc Trop Med Hyg| volume = 104| issue = 9 | pages = 583–87 | year = 2010 | pmid = 20673935}}</ref>

== Spread to the Americas ==
Malaria was not referenced in the "medical books" of the [[Maya peoples|Mayans]] or [[Aztecs]]. Despite this, antibodies against malaria have been detected in some South American mummies, indicating that some malaria strains in the Americas might have a pre-Columbian origin.<ref>Rodrigues, Priscilla (et al.) (2018). Human Migration and the Spread of Malaria Parasites to the New World.</ref> European settlers and West African slaves could have brought other strains of malaria to the Americas in the 16th century.<ref>{{cite journal |vauthors=De Castro MC, Singer BH | title = Was malaria present in the Amazon before the European conquest? Available evidence and future research agenda| journal =J. Archaeol. Sci. | volume = 32| pages =337–40| year = 2005|doi = 10.1016/j.jas.2004.10.004 | issue = 3| bibcode = 2005JArSc..32..337D}}</ref><ref>{{Cite book |last=Ebron |first=Paulla A. |title=Feral Atlas: The More-Than-Human Anthropocene |publisher=Stanford University Press |year=2020 |isbn=9781503615045 |editor-last=Tsing |location=Stanford |language=EN |chapter=Slave ships were incubators for infectious diseases}}</ref><ref>{{cite journal |vauthors=Yalcindag E, Elguero E, Arnathau C, Durand P, Akiana J, Anderson TJ, Aubouy A, Balloux F, Besnard P, Bogreau H, Carnevale P, D'Alessandro U, Fontenille D, Gamboa D, Jombart T, Le Mire J, Leroy E, Maestre A, Mayxay M, Ménard D, Musset L, Newton PN, Nkoghé D, Noya O, Ollomo B, Rogier C, Veron V, Wide A, Zakeri S, Carme B, Legrand E, Chevillon C, Ayala FJ, Renaud F, Prugnolle F | title = Multiple independent introductions of Plasmodium falciparum in South America | journal =PNAS| year = 2011|doi = 10.1073/pnas.1119058109 | volume = 109 | issue = 2 | pages = 511–16 | pmid = 22203975 | pmc = 3258587| bibcode = 2012PNAS..109..511Y | doi-access = free }}</ref>

In his book ''[[1493: Uncovering the New World Columbus Created]]'', [[Charles C. Mann|Charles Mann]] cites sources that speculate that the reason African slaves were brought to the British Americas was because of their resistance to malaria. The colonies needed low-paid agricultural labor, and large numbers of poor British were ready to emigrate. North of the [[Mason–Dixon line]], where malaria-transmitting mosquitoes did not fare well, British [[Indentured servitude in British America|indentured servant]]s proved more profitable, as they would work toward their freedom. However, as malaria spread to places such as the tidewater of Virginia and South Carolina, the owners of large plantations came to rely on the enslavement of more malaria-resistant West Africans, while white small landholders risked ruin whenever they got sick. The disease also helped weaken the Native American population and made them more susceptible to other diseases. However, the theory that supposed resistance to Malaria is the reason for the use of Black labour on the plantation complexes, as opposed to economic or social reasons, has been questioned by historians of American and Caribbean slavery.

Malaria caused huge losses to British forces in the South during the Revolutionary War as well as to Union forces during the Civil War.

=== Cinchona tree ===
Spanish [[missionaries]] found that fever was treated by [[Amerindians]] near Loxa ([[Ecuador]]) with powder from [[Jesuit's bark|Peruvian bark]] (later established to be from any of several trees of genus ''[[Cinchona]]'').<ref>{{cite journal |vauthors=Butler AR, Khan S, Ferguson E | title = A brief history of malaria chemotherapy| journal = J R Coll Physicians Edinb | volume = 40| issue = 2| pages = 172–77 | year = 2010| pmid = 20695174| doi = 10.4997/JRCPE.2010.216| doi-access = free}}</ref> It was used by the [[Quechuas|Quechua]] Indians of Ecuador to reduce the shaking effects caused by severe chills.<ref>{{cite journal | author = Guerra F.| title = The introduction of Cinchona in the treatment of malaria | journal = J Trop Med Hyg| volume = 80 |issue = 6| pages = 112–18, 135–40| year = 1977 | pmid = 330870}}</ref> [[Jesuit]] Brother Agostino Salumbrino (1561–1642), who lived in [[Lima]] and was an [[apothecary]] by training, observed the Quechua using the bark of the [[cinchona]] tree for that purpose. While its effect in treating malaria (and hence malaria-induced shivering) was unrelated to its effect in controlling shivering from cold, it was nevertheless effective for malaria. The use of the "fever tree" bark was introduced into European medicine by Jesuit missionaries ([[Jesuit's bark]]).<ref>{{cite journal | author = Greenwood D.| title = The quinine connection| journal = J Antimicrob Chemother | volume = 30| issue = 4 | pages =417–27 | year = 1992 | pmid = 1490916 | doi = 10.1093/jac/30.4.417}}<br />{{cite journal |vauthors=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 | doi = 10.1002/anie.200400663}}</ref> Jesuit [[Bernabé Cobo|Bernabé de Cobo]] (1582–1657), who explored Mexico and Peru, is credited with taking cinchona bark to Europe. He brought the bark from Lima to Spain, and then to Rome and other parts of [[Italy]], in 1632. [[Francesco Torti]] wrote in 1712 that only "intermittent fever" was amenable to the fever tree bark.<ref>Torti, F. "Therapeutice Specialis ad Febres Periodicas Perniciosas", 1712 Modena</ref> This work finally established the specific nature of cinchona bark and brought about its general use in medicine.<ref name=Chwatt>{{cite journal |author=Bruce-Chwatt LJ |title=Three hundred and fifty years of the Peruvian fever bark |journal=British Medical Journal (Clinical Research Edition) |volume=296 |issue=6635 |pages=1486–87 |year=1988 |pmid=3134079 |pmc=2546010 |doi=10.1136/bmj.296.6635.1486 }}</ref>

It would be nearly 200 years before the active principles, quinine and other [[alkaloid]]s, of cinchona bark were isolated. [[Quinine]], a toxic plant alkaloid, is, in addition to its anti-malarial properties, moderately effective against nocturnal leg [[cramp]]s.<ref>{{cite journal | author = Guay DR| title = Are there alternatives to the use of quinine to treat nocturnal leg cramps?| journal = Consult Pharm | volume = 23 |issue = 2| pages =141–56 | year = 2008 | pmid = 18454580 | doi = 10.4140/TCP.n.2008.141}}</ref>

=== Clinical indications ===
In 1717, the dark pigmentation of a postmortem [[spleen]] and brain was published by the epidemiologist [[Giovanni Maria Lancisi]] in his malaria textbook ''De noxiis paludum effluviis eorumque remediis''.<ref>{{Cite web |date=2020-09-25 |title=Malariotherapy |url=https://factrepublic.com/facts/34907/ |access-date=2022-07-21 |website=FactRepublic.com}}</ref> This was one of the earliest reports of the characteristic enlargement of the spleen and dark color of the spleen and brain, which are the most constant post-mortem indications of chronic malaria infection. He related the prevalence of malaria in swampy areas to the presence of [[flies]] and recommended [[swamp]] [[drainage]] to prevent it.<ref>{{cite journal |vauthors=Cook GC, Webb AJ | title = Perceptions of malaria transmission before Ross' discovery in 1897| journal = Postgrad Med J |volume= 76 |issue= 901|pages= 738–40|year= 2000 | doi=10.1136/pmj.76.901.738 | pmid=11060174 | pmc=1741788}}</ref>

== 19th century ==
In the 19th century, the first drugs were developed to treat malaria, and parasites were first identified as its source.

=== Antimalarial drugs ===

==== Quinine ====
[[File:Original preparation of quinine acetate 2.jpeg|thumb|Original preparation of quinine acetate by Pelletier.  circa 1820.]]
French chemist [[Pierre Joseph Pelletier]] and French pharmacist [[Joseph Bienaimé Caventou]] separated in 1820 the alkaloids [[cinchonine]] and [[quinine]] from powdered fever tree bark, allowing for the creation of standardized doses of the active ingredients.<ref>Pelletier and Caventou (1820) [https://books.google.com/books?id=veE3AAAAMAAJ&pg=PA337 "Suite: Des recherches chimiques sur les quinquinas"] (Continuation: Chemical research on quinquinas), ''Annales de Chimie et de Physique'', vol. 15, pp. 337–65. The authors name quinine on p. 348: "..., nous avons cru devoir la nommer ''quinine'', pour la distinguer de la cinchonine par un nom qui indique également son origine." (..., we thought that we should name it "quinine" in order to distinguish it from cinchonine by means of a name that also indicates its origin.)<br />{{cite journal |vauthors=Kyle RA, Shampe MA |title=Discoverers of quinine |journal=JAMA |volume=229 |issue=4 |pages=462 |year=1974 |pmid=4600403 |doi=10.1001/jama.229.4.462 |doi-broken-date=5 December 2024 }}</ref> Prior to 1820, the bark was simply dried, ground to a fine powder and mixed into a liquid (commonly wine) for drinking.<ref>{{cite journal |vauthors=Siegel RE, Poynter FN |title= Robert Talbor, Charles II, and cinchona: a contemporary document|journal=Med Hist |volume=6 |issue=1|pages=82–85|year=1962 |pmid=16562233 |pmc=1034677 |doi=10.1017/s0025727300026892}}</ref>

[[Manuel Incra Mamani]] spent four years collecting cinchona seeds in the Andes in [[Bolivia]], highly prized for their quinine but whose export was prohibited.<ref>{{Cite web |last=Canales |first=Nataly Allasi |date=7 April 2022 |title=Hunting lost plants in botanical collections |url=https://wellcomecollection.org/articles/YjyPpREAAB8AhS-R |access-date=2022-05-09 |website=Wellcome Collection |language=en}}</ref> He provided them to an English trader, [[Charles Ledger]], who sent the seeds to his brother in England to sell.<ref name=":2">{{Cite web |date=2 April 2020 |title=The weird and wonderful world of the plant hunters - part 4: Quinine, the cinchona tree and empires in competition |url=https://treesforcities.org/stories/the-weird-and-wonderful-world-of-the-plant-hunters-part-4 |access-date=2022-05-09 |website=Trees for Cities |language=en}}</ref> They sold them to the Dutch government, who cultivated 20,000 trees of the ''[[Cinchona ledgeriana]]'' in Java (Indonesia). By the end of the 19th century, the Dutch had established a world monopoly over its supply.<ref>{{cite journal |author= Gramiccia G|title= Ledger's cinchona seeds: a composite of field experience, chance, and intuition|journal= Parassitologia |volume= 29 |issue= 2–3|pages= 207–20|year= 1987 |pmid=3334083}}</ref>

==== 'Warburg's Tincture' ====

In 1834, in [[British Guiana]], a German physician, [[Carl Warburg]], invented an [[antipyretic]] medicine: '[[Warburg's Tincture]]'. This secret, proprietary remedy contained quinine and other [[Herbalism|herbs]]. Trials were held in Europe in the 1840s and 1850s. It was officially adopted by the [[Austrian Empire]] in 1847. It was considered by many eminent medical professionals to be a more efficacious [[antimalarial]] than quinine. It was also more economical. The British government supplied Warburg's Tincture to troops in [[India]] and other colonies.<ref>{{cite journal |author= Maclean WC |title= Professor Maclean, C.B., on the true composition and therapeutic value of Warburg's Tincture |journal=Lancet |volume=106|pages=716–18 |year=1875|doi =10.1016/S0140-6736(02)30835-3 |issue= 2724|url= https://zenodo.org/record/1565450 }}<br />{{cite book |vauthors=Poser CM, Bruyn GW |title= An Illustrated History of Malaria | page= 87|location=New York|year=1999 |url=https://books.google.com/books?id=N4fyLSwLP3MC |publisher= Informa Health Care |isbn= 978-1-85070-068-5}}</ref>

==== Methylene blue ====

In 1876, [[methylene blue]] was synthesized by German chemist [[Heinrich Caro]].<ref>{{cite journal |vauthors=Krafts K, Hempelmann E, Oleksyn BJ |title=In search of the malarial parasite : Biographical sketches of the blood stain contributors|journal= Parasitol Research |volume= 109 |pages=521–29|year=2011|pmid=21660627 |doi=10.1007/s00436-011-2475-4 |issue=3 |s2cid=1823696}}</ref> [[Paul Ehrlich]] in 1880 described the use of "neutral" dyes—mixtures of [[acid]]ic and [[base (chemistry)|basic]] dyes—for the differentiation of cells in peripheral blood smears. In 1891, Ernst Malachowski<ref>{{cite journal |author=Malachowski E|title=Zur Morphologie des ''Plasmodium malariae''|journal= Centbl F Klin Med |volume=31 |pages=601–03|year=1891 }}</ref> and [[Romanowsky stain|Dmitri Leonidovich Romanowsky]]<ref>{{cite journal |author=Romanowsky D|title=Zur Frage der Parasitologie und Therapie der Malaria|journal= St Petersburg Med Wochenschr |volume=16 |pages=297–302, 307–15|year=1891}}</ref> independently developed techniques using a mixture of [[Eosin]] Y and modified methylene blue (methylene azure) that produced a surprising [[hue]] unattributable to either staining component: a shade of purple.<ref>{{cite journal |vauthors=Horobin RW, Walter KJ |title= Understanding Romanowsky staining. I: The Romanowsky-Giemsa effect in blood smears |journal= Histochemistry|volume= 86|issue= 3|pages=331–36|year= 1987|pmid=2437082 |url=https://www.researchgate.net/publication/20719192 |doi=10.1007/bf00490267|s2cid= 25723230 }}<br />{{cite journal |author=Woronzoff-Dashkoff KK.|title= The wright-giemsa stain. Secrets revealed |journal= Clin Lab Med. |volume= 22|issue= 1|pages=15–23|year= 2002|pmid=11933573 |doi=10.1016/S0272-2712(03)00065-9| url = https://www.researchgate.net/publication/11431311}}</ref> Malachowski used alkali-treated methylene blue solutions and Romanowsky used methylene blue solutions that were molded or aged. This new method differentiated [[blood cell]]s and demonstrated the nuclei of malarial parasites. Malachowski's staining technique was one of the most significant technical advances in the history of malaria.<ref>{{cite journal |vauthors=Krafts KP, Hempelmann E, Oleksyn B |title=The color purple: from royalty to laboratory, with apologies to Malachowski |journal= Biotech Histochem |volume=86 |pages=7–35|year=2011 |pmid= 21235291| doi = 10.3109/10520295.2010.515490 |issue=1|s2cid=19829220 |url=https://www.researchgate.net/publication/49755721}}</ref>

In 1891, [[Paul Guttmann]] and Ehrlich noted that [[methylene blue]] had a high affinity for some tissues and that this dye had a slight antimalarial property.<ref>{{cite journal|vauthors= Guttmann P, Ehrlich P|title= Ueber die Wirkung des Methylenblau bei Malaria|journal= Berliner Klinische Wochenschrift|volume= 28|pages= 953–56|year= 1891|url= http://www.pei.de/cln_092/nn_164284/SharedDocs/Downloads/institut/paul-ehrlich/1886-1896/1891-wirkung-methylenblau-malaria,templateId=raw,property=publicationFile.pdf/1891-wirkung-methylenblau-malaria.pdf|access-date= 24 July 2010|archive-url= https://web.archive.org/web/20120303121714/http://www.pei.de/cln_092/nn_164284/SharedDocs/Downloads/institut/paul-ehrlich/1886-1896/1891-wirkung-methylenblau-malaria,templateId=raw,property=publicationFile.pdf/1891-wirkung-methylenblau-malaria.pdf|archive-date= 3 March 2012|url-status= dead}}</ref> Methylene blue and its [[Congener (chemistry)|congeners]] may act by preventing the [[biocrystallization]] of [[heme]].<ref>{{cite journal |vauthors=Wainwright M, Amaral L |title= The phenothiazinium chromophore and the evolution of antimalarial drugs|journal= Trop Med Int Health|volume= 10|issue=6 |pages=501–11|year= 2005 |pmid=15941412 |doi=10.1111/j.1365-3156.2005.01417.x |doi-access=free }}{{cbignore|bot=medic}}</ref>

[[File:Laveran malaria drawings.png|thumb| In 1880, [[Charles Louis Alphonse Laveran]] observed pigmented parasites and the exflagellation of male gametocytes.<ref>{{cite journal |author=Laveran CLA |title=Note sur un nouveau parasite trouvé dans le sang de plusieurs malades atteints de fièvre palustres |journal=Bulletin de l'Académie de Médecine  |volume=9 |pages=1235–36 |year=1880 }}</ref>]]

=== Cause: Identification of ''Plasmodium'' and ''Anopheles'' ===

In 1848, German anatomist Johann Heinrich Meckel<ref>{{cite journal |vauthors=Lorber CG, Lorber CP, Schneider J |title=Die Medizinerfamilie Meckel aus Wetzlar |journal=Hess Aerzteblatt |volume=2 |pages=95–99 |year=2005 |url=http://www.laekh.de/upload/Hess._Aerzteblatt/2005/2005_02/2005_02_08.pdf |url-status=dead |archive-url=https://web.archive.org/web/20110719054014/http://www.laekh.de/upload/Hess._Aerzteblatt/2005/2005_02/2005_02_08.pdf |archive-date=19 July 2011 }}</ref> recorded [[hemozoin|black-brown pigment granules]] in the blood and [[spleen]] of a patient who had died in a mental hospital. Meckel was thought to have been looking at malaria [[parasitism|parasites]] without realizing it; he did not mention malaria in his report. He hypothesized that the pigment was [[melanin]].<ref>{{cite journal |author=Meckel H.|title= Ueber schwarzes Pigment in der Milz und dem Blute einer Geisteskranken|journal= Zeitschrift für Psychiatrie |volume= IV |pages= 198–226 |year= 1847 }}</ref> The causal relationship of pigment to the parasite was established in 1880, when French physician [[Charles Louis Alphonse Laveran]], working in the military hospital of [[Constantine, Algeria]], observed pigmented parasites inside the [[red blood cell]]s of people with malaria. He witnessed the events of exflagellation and became convinced that the moving [[Flagellum|flagella]] were [[parasitic]] [[microorganisms]]. He noted that quinine removed the parasites from the blood. Laveran called this microscopic organism ''Oscillaria malariae'' and proposed that malaria was caused by this [[protozoa]]n.<ref name=Cox >{{cite journal | author = Cox FE | title = History of the discovery of the malaria parasites and their vectors | journal = Parasites & Vectors | volume = 3 | pages = 5 | year = 2010 |doi = 10.1186/1756-3305-3-5 |url = http://www.parasitesandvectors.com/content/pdf/1756-3305-3-5.pdf | pmid = 20205846 | issue = 1 | pmc = 2825508 | doi-access = free }}</ref> This discovery remained controversial until the development of the [[oil immersion]] lens in 1884 and of superior staining methods in 1890–1891.

In 1885, [[Ettore Marchiafava]], [[Angelo Celli]] and [[Camillo Golgi]] studied the reproduction cycles in human blood (Golgi cycles). Golgi observed that all parasites present in the blood divided almost simultaneously at regular intervals and that division coincided with attacks of fever. In 1886 Golgi described the morphological differences that are still used to distinguish two malaria parasite species ''[[Plasmodium vivax]]'' and ''[[Plasmodium malariae]]''. Shortly after this Sakharov in 1889 and Marchiafava & Celli in 1890 independently identified ''[[Plasmodium falciparum]]'' as a species distinct from ''P. vivax'' and ''P. malariae''. In 1890, Grassi and Feletti reviewed the available information and named both ''P. malariae'' and ''P. vivax'' (although within the genus ''[[Haemamoeba]]''.)<ref name=Grassi1890>{{cite journal |last1=Grassi |first1=B |last2=Feletti |first2=R |year=1890 |title=Parasites malariques chez les oiseaux. |journal=Arch. Ital. Biol. |volume=13 |pages=297–300}}</ref> By 1890, Laveran's germ was generally accepted, but most of his initial ideas had been discarded in favor of the taxonomic work and clinical [[pathology]] of the Italian school. Marchiafava and Celli called the new microorganism ''[[Plasmodium]]''.<ref>{{cite journal |vauthors=Smith DC, Sanford LB |title= Laveran's germ: the reception and use of a medical discovery|journal= Am J Trop Med Hyg|volume= 34 |issue= 1|pages=2–20 |year= 1985 |pmid= 2578751|doi= 10.4269/ajtmh.1985.34.2}}</ref> ''H. vivax'' was soon renamed ''Plasmodium vivax''. In 1892, Marchiafava and Bignami proved that the multiple forms seen by Laveran were from a single species. This species was eventually named ''P. falciparum''. Laveran was awarded the 1907 [[Nobel Prize for Physiology or Medicine]] "in recognition of his work on the role played by protozoa in causing diseases".<ref>{{cite web | title = Biography of Alphonse Laveran | publisher = The Nobel Foundation | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1907/laveran-bio.html | access-date = 2007-06-15}}</ref>

Dutch physician [[Pieter Klazes Pel|Pieter Pel]] first proposed a tissue stage of the malaria parasite in 1886, presaging its discovery by over 50 years. This suggestion was reiterated in 1893 when Golgi suggested that the parasites might have an undiscovered tissue phase (this time in endothelial cells).<ref>{{cite journal |author= Golgi C |title= Sulle febbri malariche estivo-autumnali di Roma|journal= Gass Med di Pavia |volume= 2 |pages=481–93, 505–20, 529–44, 553–59 |year= 1893 }}</ref> Golgi's latent phase theory was supported by Pel in 1896.<ref>{{cite journal |author= Pel PK |title= Mededeelingen uit de Geneeskundige kliniek. Malaria infectie|journal= Ned Tijdschr Geneeskd |volume= 22 |pages=341–58 |year= 1886}}</ref>

[[File:Ross, 20.Aug.1897.jpg|thumb|right|220px| The notebook in which [[Ronald Ross]] first described pigmented malaria parasites in stomach tissues of an ''Anopheles'' mosquito, 20 and 21 August 1897]]

From about the mid-19th century, the establishment of the scientific method demanded testable hypotheses and verifiable phenomena for causation and transmission. Anecdotal reports{{refn|group=Note|[[Giovanni Maria Lancisi]], John Crawford,<ref>{{cite journal |author= Doetsch RN|title=John Crawford and his contribution to the doctrine of contagium vivum |journal= Bacteriol Rev|volume= 28 |pages= 87–96|year= 1964|pmid = 14130055 |pmc= 441211 |issue=1|doi=10.1128/MMBR.28.1.87-96.1964 }}</ref> [[Patrick Manson]],<ref>{{cite journal |author= Manson P|title= On the nature and significance of the crescentic and flagellated bodies in malarial blood |journal= Br Med J|volume= 2 |pages= 1306–08 |year= 1894 |doi= 10.1136/bmj.2.1771.1306 |pmid= 20755205 |issue= 4849 |pmc= 2405325}}</ref> [[Josiah C. Nott]], [[Albert Freeman Africanus King]]<ref>{{cite journal|author= King AFA|title= Insects and disease, mosquitoes and malaria|journal= Popular Sci. Monthly, Sep.|volume= 23|pages= 644–58|year= 1883|url= http://www.popsci.com/archive-viewer?id=6isDAAAAMBAJ&pg=644&query=insects+and+disease}}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> and Laveran developed theories that malaria was caused by mosquito bites, but little evidence supported this idea.}}, and the discovery in 1881 that mosquitoes were the vector of yellow fever,<ref>{{cite journal |author= WHO|title = Yellow fever |journal= Fact Sheet 2013|year= 2013|url=https://www.who.int/mediacentre/factsheets/fs100/en/}}</ref> eventually led to the investigation of mosquitoes in connection with malaria.

An early effort at malaria prevention occurred in 1896 in Massachusetts. An [[Uxbridge, MA|Uxbridge]] outbreak prompted health officer [[Leonard White (physician)|Dr. Leonard White]] to write a report to the State Board of Health, which led to a study of mosquito-malaria links and the first efforts for malaria prevention. Massachusetts state pathologist, Theobald Smith, asked that White's son collect mosquito specimens for further analysis, and that citizens add [[Window screen|screens]] to windows, and [[Drainage|drain]] collections of water.<ref name="malaria">{{cite web |title=A History of Mosquitoes in Massachusetts, by Curtis R. Best |publisher=Northeast Mosquito Control Association |url=http://www.nmca.org/Nmca93-4.htm |access-date=2008-03-31}}</ref>

Britain's [[Ronald Ross|Sir Ronald Ross]], an army surgeon working in [[Secunderabad]], [[India]], proved in 1897 that [[Mosquito-malaria theory|malaria is transmitted by mosquitoes]], an event now commemorated by [[World Mosquito Day]].<ref name="dfid">{{cite web|url=http://www.dfid.gov.uk/news/latest-news/2010/world-mosquito-day/ |title=World Mosquito Day 2010 |publisher=Department for International Development |date=20 August 2010 |access-date=21 November 2012 |archive-url=https://web.archive.org/web/20121031094341/http://www.dfid.gov.uk/News/Latest-news/2010/World-Mosquito-Day/ |archive-date=31 October 2012 |url-status=dead }}</ref> He was able to find pigmented malaria parasites in a mosquito that he artificially fed on a malaria patient who had crescents in his blood. He continued his research into malaria by showing that certain mosquito species (''[[Culex]] fatigans'') transmit malaria to [[Old World sparrow|sparrows]] and he isolated 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 | access-date = 2007-06-15}}</ref> He reported this to the [[British Medical Association]] in Edinburgh in 1898.

[[Giovanni Battista Grassi]], professor of [[Comparative Anatomy]] at Rome University, showed that human malaria could only be transmitted by ''[[Anopheles]]'' (Greek ''anofelís'': good-for-nothing) mosquitoes.<ref>{{cite journal |author= Capanna E |title= Grassi versus Ross: who solved the riddle of malaria? | journal= International Microbiology |volume= 9 |issue= 1 |pages= 69–74|year= 2006|pmid=16636993 |url = http://www.im.microbios.org/0901/0901069.pdf }}</ref> Grassi, along with coworkers [[Amico Bignami]], [[Giuseppe Bastianelli]] and Ettore Marchiafava, announced at the session of the [[Accademia dei Lincei]] on 4 December 1898 that a healthy man in a non-malarial zone had contracted tertian malaria after being bitten by an experimentally infected ''Anopheles claviger'' specimen.

In 1898–1899, Bastianelli, Bignami and Grassi were the first to observe the complete transmission cycle of ''P. falciparum'', ''P. vivax'' and ''P. malaria'' from mosquito to human and back in ''A. claviger''.<ref>{{cite journal|vauthors=Grassi B, Bignami A, Bastianelli G |title=Ulteriore ricerche sul ciclo dei parassiti malarici umani sul corpo del zanzarone|journal= Accad Lincei|year=1899|issue=8|pages=21–28}}</ref>

A dispute broke out between the British and Italian schools of malariology over priority, but Ross received the 1902 Nobel Prize for Physiology or Medicine for "his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it."<ref>{{cite web | title = Ross and the Discovery that Mosquitoes Transmit Malaria Parasites| work = CDC Malaria website | url = https://www.cdc.gov/malaria/history/ross.htm | access-date = 2007-06-15 |archive-url = https://web.archive.org/web/20070602185153/http://www.cdc.gov/malaria/history/ross.htm |archive-date = 2 June 2007}}</ref>

=== Synthesis of quinine ===

[[William Henry Perkin]], a student of [[August Wilhelm von Hofmann]] at the [[Royal College of Chemistry]] in London, unsuccessfully tried in the 1850s to synthesize quinine in a commercial process. The idea was to take two equivalents of N-allyltoluidine ({{chem|C|10|H || 13|N}}) and three atoms of oxygen to produce quinine ({{chem|C|20|H|24|N|2|O|2}}) and water. Instead, [[Perkin's mauve]] was produced when attempting [[quinine total synthesis]] via the oxidation of N-allyltoluidine.<ref>{{cite journal |author= Seeman JI|title= The Woodward-Doering/Rabe-Kindler total synthesis of quinine: setting the record straight|journal= Angewandte Chemie International Edition |volume= 46 |issue= 9 |pages=1378–413 |year= 2007 |pmid= 17294412 |doi= 10.1002/anie.200601551|doi-access= free }}</ref> Before Perkin's discovery, all [[dye]]s and pigments were derived from roots, leaves, insects, or, in the case of [[Tyrian purple]], [[Mollusca|molluscs]].

Quinine wouldn't be successfully synthesized until 1918. Synthesis remains elaborate, expensive and low yield, with the additional problem of separation of the [[Stereoisomerism|stereoisomers]]. Though quinine is not one of the major drugs used in treatment, modern production still relies on extraction from the cinchona tree.

== 20th century ==
[[File:Sir_Patrick_Hehir%2C_Malaria_in_India_Wellcome_L0026242.jpg|thumb|Malaria map of [[British India]], 1927]]

=== Etiology: Plasmodium tissue stage and reproduction ===

Relapses were first noted in 1897 by William S. Thayer, who recounted the experiences of a physician who relapsed 21 months after leaving an endemic area.<ref>{{cite book |author= Thayer W. |title=Lectures on the malarial fevers |url = https://books.google.com/books?id=Woqcfoq5dwoC | publisher=D.Appleton & Co., New York|year= 1898 |isbn= 978-0-543-91236-7}}</ref> He proposed the existence of a tissue stage. Relapses were confirmed by Patrick Manson, who allowed infected ''Anopheles'' mosquitoes to feed on his eldest son.<ref>{{cite journal | author = Manson P | title=Experimental proof of the mosquito-malaria theory. 1900. | journal=Yale J Biol Med | year=2002 | volume=75 | issue=2 | pages=107–112 | pmc=2588736 | pmid = 12230309 }}</ref> The younger Manson then described a relapse nine months after his apparent cure with quinine.<ref>{{cite journal | author = Manson PT | title =Experimental Malaria: Recurrence after Nine Months | journal = Br Med J |volume = 2| pages = 77 | year = 1901 | pmc=2505910 | doi = 10.1136/bmj.2.2115.77 | pmid=20759742 | issue = 2115}}</ref>

Also, in 1900 Amico Bignami and Giuseppe Bastianelli found that they could not infect an individual with blood containing only [[gametocyte]]s.<ref>{{cite journal |vauthors=Bignami A, Bastianelli G |title =Sulla inoculazione delle sangue di semiluna malariche d'uomo | journal = Atti Soc Studi Malar |volume = 1| pages = 15–20 | year = 1900 }}</ref> The possibility of the existence of a chronic blood stage infection was proposed by Ronald Ross and David Thompson in 1910.<ref>{{cite journal |vauthors=Ross R, Thompson D | title =Some enumeration studies on malarial fever | url=https://archive.org/stream/philtrans04341040/04341040_djvu.txt |journal = Ann Trop Med Parasitol |volume = 4| issue =562 | pages = 267–306 | year = 1910 | bibcode =1910RSPSB..83..159R | doi =10.1080/00034983.1910.11685718 | s2cid =86898611 }}</ref>

The existence of asexually-reproducing avian malaria parasites in cells of the internal organs was first demonstrated by Henrique de Beaurepaire Aragão in 1908.<ref>{{cite journal |vauthors=James SP, Tate P | title = Exo-erythrocytic schizogony in Plasmodium gallinaceum Brumpt, 1935 | journal = Parasitology |volume = 30| pages = 128–38| year = 1938 | doi =10.1017/S0031182000010891| s2cid = 86462883 }}</ref>

Three possible mechanisms of relapse were proposed by [[Émile Marchoux|Marchoux]] in 1926 (<code>i</code>) [[parthenogenesis]] of macro[[gametocyte]]s: (<code>ii</code>) persistence of [[schizont]]s in small numbers in the blood where immunity inhibits multiplication, but later disappears and/or (<code>iii</code>) reactivation of an encysted body in the blood.<ref>{{cite journal | author = Marchoux E | title =Paludisme| journal = J. B. Bailliere, Paris. | year = 1926 }}</ref> James in 1931 proposed that [[Apicomplexan life cycle|sporozoites]] are carried to internal organs, where they enter [[Mononuclear phagocyte system|reticuloendothelial]] cells and undergo a cycle of development, based on quinine's lack of activity on them.<ref>{{cite journal | author = James SP | title =The use of plasmoquine in the prevention of malarial infections | journal = Proc R Acad Sci Amst |volume = 34| pages = 1424–25 | year = 1931}}</ref> Huff and Bloom in 1935 demonstrated stages of avian malaria that transpire outside blood cells (exoerythrocytic).<ref>{{cite journal |vauthors=Huff CG, Bloom W | title =A Malarial Parasite Infecting All Blood and Blood-Forming Cells of Birds | journal = J Infect Dis |volume = 57| pages = 315–36 | year = 1935 | issue = 3 | jstor = 30088998 | doi = 10.1093/infdis/57.3.315}}</ref> In 1945 Fairley ''et al.'' reported that inoculation of blood from a patient with ''P. vivax'' may fail to induce malaria, although the donor may subsequently exhibit the condition. Sporozoites disappeared from the blood stream within one hour and reappeared eight days later. This suggests the presence of forms that persist in tissues.<ref>{{cite journal | author = Fairley NH | title =Chemotherapeutic suppression and prophylaxis in malaria | journal = Trans R Soc Trop Med Hyg |volume = 38| pages = 311–65 | year = 1945 | pmid = 20293965 | issue = 5 | doi = 10.1016/0035-9203(45)90038-1}}</ref> Using mosquitoes rather than blood, in 1946 [[Percy George Shute|Shute]] described a similar phenomenon and proposed the existence of an 'x-body' or resting form.<ref>{{cite journal | author = Shute PG | title = Latency and long-term relapses in benign tertian malaria | journal = Trans R Soc Trop Med Hyg | volume = 40 | pages = 189–200 | year = 1946 | url = https://academic.oup.com/trstmh/article-abstract/40/2/189/1855586?redirectedFrom=fulltext | doi = 10.1016/0035-9203(46)90056-9 | pmid = 20275230 | issue = 2 | url-access = subscription }}</ref> The following year Sapero proposed a link between relapse and a tissue stage not yet discovered.<ref>{{cite journal | author = Sapero JJ | title = New Concepts in the Treatment of Relapsing Malaria| journal = Am J Trop Med Hyg|volume = 27 | issue = 3| pages = 271–83 | year = 1947 | doi = 10.4269/ajtmh.1947.s1-27.271}}</ref> Garnham in 1947 described exoerythrocytic [[schizogony]] in ''[[Hepatocystis]] (Plasmodium) kochi''.<ref>{{cite journal | author = Garnham PCC | title = Exoerythrocytic schizogony in Plasmodium kochi laveran. A preliminary note| journal = Trans R Soc Trop Med Hyg |volume = 40| pages = 719–22| year = 1947 | doi = 10.1016/0035-9203(47)90029-1 | pmid = 20243887 | issue = 5 }}</ref> In the following year, British biologists [[Henry Edward Shortt]] and [[Cyril Garnham]] described the liver stages of ''P. cynomolgi'' in monkeys.<ref name="Shortt HE, Garnham PCC">{{cite journal |vauthors=Shortt HE, Garnham PC |title= Pre-erythrocytic stage in mammalian malaria parasites|journal=Nature |volume= 161|issue=4082 |pages=126 |year=1948 |pmid=18900752 |doi=10.1038/161126a0 |bibcode= 1948Natur.161..126S|s2cid= 4105546|doi-access=free }}</ref> In the same year, a human volunteer consented to receive a massive dose of infected sporozoites of ''[[Plasmodium vivax|P. vivax]]'' and undergo a liver biopsy three months later, thus allowing Shortt ''et al.'' to demonstrate the tissue stage.<ref>{{cite journal |vauthors=Shortt HE, Fairley NH, Covell G, Shute PG, Garnham PC | title = Pre-erythrocytic Stage of Plasmodium Falciparum | journal = Br Med J |volume = 2| pages = 1006–08, illust| year = 1948| pmid = 15393036 |pmc=2051640 | doi = 10.1136/bmj.2.3282.1006-c | issue = 4635}}</ref> The tissue form of ''[[Plasmodium ovale]]'' was described in 1954 and that of ''P. malariae'' in 1960 in experimentally infected chimpanzees.

The latent or dormant liver form of the parasite ([[hypnozoite]]), apparently responsible for the relapses characteristic of ''P. vivax'' and ''P. ovale'' infections,<ref>{{cite journal |author=Cogswell FB |title=The hypnozoite and relapse in primate malaria |journal=Clin. Microbiol. Rev. |volume=5 |issue=1 |pages=26–35 |year=1992|pmid=1735093 |pmc=358221 |doi=10.1128/CMR.5.1.26 }}</ref><ref>{{cite journal |author= Markus MB |title= Do hypnozoites cause relapse in malaria?. |journal= Trends Parasitol |volume=31 |issue=6 |pages=239–45 |year= 2015|pmid=25816801 |doi=10.1016/j.pt.2015.02.003}}</ref> was first observed in the 1980s.<ref name="Cox"/><ref name=kro>{{cite journal |vauthors=Krotoski WA, Collins WE, Bray RS, Garnham PC, Cogswell FB, Gwadz RW, Killick-Kendrick R, Wolf R, Sinden R, Koontz LC, Stanfill PS | title = Demonstration of hypnozoites in sporozoite-transmitted Plasmodium vivax infection | journal = Am J Trop Med Hyg | volume = 31 | issue = 6 | pages = 1291–93 | year = 1982 | pmid = 6816080 | doi = 10.4269/ajtmh.1982.31.1291 }}</ref> The term ''hypnozoite'' was coined by Miles B. Markus while a student. In 1976, he speculated: "If sporozoites of ''[[Isospora]]'' can behave in this fashion, then those of related Sporozoa, like malaria parasites, may have the ability to survive in the tissues in a similar way."<ref>{{cite journal | author = Markus MB| title = Malaria: Origin of the Term "Hypnozoite" | journal = J Hist Biol | year = 2011| pmid = 20665090| doi = 10.1007/s10739-010-9239-3| volume = 44 | issue = 4 | pages = 781–86| s2cid = 1727294 }}</ref> In 1982, Krotoski ''et al'' reported identification of ''P. vivax'' hypnozoites in liver cells of infected chimpanzees.<ref name=kro/>

From 1980 onwards and until recently (even in 2022), recurrences of ''P. vivax'' malaria have been thought to be mostly hypnozoite-mediated. Between 2018 and 2021, however, it was reported that vast numbers of non-circulating, non-hypnozoite parasites occur unobtrusively in tissues of ''P. vivax''-infected people, with only a small proportion of the total parasite biomass present in the peripheral bloodstream. This finding supports an intellectually insightful paradigm-shifting viewpoint, which has prevailed since 2011 (albeit not believed between 2011 and 2018 or later by most malariologists), that an unknown percentage of ''P. vivax'' recurrences are recrudescences (having a non-circulating or sequestered merozoite origin), and not relapses (which have a hypnozoite source). The recent discoveries did not give rise to this new theory, which was pre-existing.<ref>{{cite journal |last1=Markus |first1=MB. |title=Theoretical origin of genetically homologous ''Plasmodium vivax'' malarial recurrences |journal=Southern African Journal of Infectious Diseases |date=2022 |volume=37 |issue=1 |page=369 |doi=10.4102/sajid.v37i1.369 |pmid=35399558 |pmc=8991251}}</ref> They merely confirmed the validity thereof.<ref>{{cite journal |last1=Markus |first1=MB |title=How does primaquine prevent ''Plasmodium vivax'' malarial recurrences? |journal=Trends in Parasitology |date=2022 |volume=38 |issue=11 |pages=924–925 |doi=10.1016/j.pt.2022.09.006 |pmid=36180306|s2cid=252579139 }}</ref>

=== Malariotherapy ===
{{see also|Pyrotherapy|Helminthic therapy}}

In the early 20th century, before [[antibiotics]], patients with tertiary [[syphilis]] were intentionally infected with malaria to induce a fever; this was called malariotherapy. In 1917, [[Julius Wagner-Jauregg]], a Viennese [[psychiatrist]], began to treat neurosyphilitics with induced ''[[Plasmodium vivax]]'' malaria.<ref>{{cite journal | journal = Science | author = Vogel G | title = Malaria as a Lifesaving Therapy | volume = 342 | page = 686 | year = 2013 | pmid = 24202157 | doi=10.1126/science.342.6159.686 | issue=6159| bibcode = 2013Sci...342..686V }}</ref> Three or four bouts of fever were enough to kill the temperature-sensitive syphilis bacteria (''Spirochaeta pallida'' also known as ''[[Treponema pallidum]]''). ''P. vivax'' infections were then terminated by quinine. By accurately controlling the fever with quinine, the effects of both syphilis and malaria could be minimized. While about 15% of patients died from malaria, this was preferable to the almost-certain death from syphilis.<ref>{{cite journal | author = Wagner-Jauregg J. | title = Verhütung und Behandlung der Progressiven Paralyse durch Impfmalaria | journal = Handbuch der Experimentellen Therapie, Ergänzungsband München | year = 1931 }}</ref> [[Malaria therapy|Therapeutic malaria]] opened up a wide field of [[chemotherapeutic]] research and was practiced until 1950.<ref>{{cite journal |vauthors=Frankenburg FR, Baldessarini RJ | title = Neurosyphilis, malaria, and the discovery of antipsychotic agents| journal = Harv Rev Psychiatry | volume = 16 | issue =5 | pages = 299–307| year = 2008 | pmid =18803105 | doi = 10.1080/10673220802432350 | s2cid = 20786200}}</ref> Wagner-Jauregg was awarded the 1927 Nobel Prize in Physiology or Medicine for his discovery of the therapeutic value of malaria inoculation in the treatment of [[dementia paralytica]].<ref name="nobel-1927">{{cite web | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1927/index.html | title = The Nobel Prize in Physiology or Medicine 1927 | access-date = 2007-07-28 | publisher = The Nobel Foundation}}</ref>

[[Henry Heimlich]] advocated malariotherapy as a treatment for [[AIDS]],<ref>{{cite web|url=https://abcnews.go.com/blogs/headlines/2007/06/dr_heimlichs_ne/|title=Dr. Heimlich's New 'Maneuver': Cure AIDS With Malaria|publisher=ABC News|author=Brian Ross And Joseph Rhee|date=8 June 2007}}</ref> and some studies of malariotherapy for HIV infection have been performed in China.<ref name=lancetNierengarten2003>{{Cite journal | doi = 10.1016/S1473-3099(03)00642-X| title = Malariotherapy to treat HIV patients?| journal = The Lancet Infectious Diseases| volume = 3| issue = 6| pages = 321| year = 2003| last1 = Nierengarten | first1 = M. B. | pmid=12781493}}</ref> The United States [[Centers for Disease Control and Prevention]] does not recommend the use of malariotherapy for HIV.<ref name=lancetNierengarten2003/>

=== Panama Canal and vector control ===
{{main|Health measures during the construction of the Panama Canal}}

In 1881, Dr. [[Carlos Finlay]], a Cuban-born physician of Scottish ancestry, theorized that [[yellow fever]] was transmitted by a specific mosquito, later designated ''[[Aedes aegypti]]''.<ref>{{cite journal|author=Finlay CJ.|title=El mosquito hipotéticamente considerado como agent de transmision de la fiebre amarilla|journal=Anales de la Real Academia de Ciencias Médicas Físicas y Naturales de la Habana|date=1881|issue=18|pages=147–69}}</ref> The theory remained controversial for twenty years until it was confirmed in 1901 by [[Walter Reed]].<ref>{{cite journal |vauthors=Reed W, Carroll J, Agramonte A |title= The Etiology of Yellow Fever|journal= JAMA|volume= 36|issue= 7|pages= 431–40 |year= 1901|doi=10.1001/jama.1901.52470070017001f|url= https://zenodo.org/record/1447271}}</ref> This was the first scientific proof of a disease being transmitted exclusively by an insect vector, and demonstrated that control of such diseases necessarily entailed control or eradication of their insect vector.

Yellow fever and malaria among workers had seriously delayed construction of the [[Panama Canal]]. Mosquito control instituted by [[William C. Gorgas]] dramatically reduced this problem.<ref>{{cite journal |author= Sutter PS|title= Nature's agents or agents of empire? Entomological workers and environmental change during the construction of the Panama Canal|journal= Isis|volume= 98 |issue= 4|pages= 724–54 |year= 2007 |pmid=18314643 |doi= 10.1086/529265|s2cid= 24222445}}</ref>

=== Antimalarial drugs ===

==== Chloroquine ====

[[File:Andersag Resochin 17.7.1934.png|thumb|left| Protocol for the synthesis of Resochin, Hans Andersag 1934]]

[[Hans Andersag|Johann "Hans" Andersag]]<ref>{{cite journal |vauthors=Krafts K, Hempelmann E, Skórska-Stania A | title=From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy| journal= Parasitol Res| volume =  111| issue = 1 | pages = 1–6 | year=2012| doi= 10.1007/s00436-012-2886-x| pmid= 22411634| s2cid=54526057|url = https://www.researchgate.net/publication/221697452}}</ref> and colleagues synthesized and tested some 12,000 compounds, eventually producing Resochin as a substitute for quinine in the 1930s.<ref>{{cite journal | author = Hempelmann E.| title = Hemozoin biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors| journal = Parasitol Res | volume = 100 | issue = 4 | pages = 671–76 | year = 2007 | pmid = 17111179 | doi = 10.1007/s00436-006-0313-x| s2cid = 30446678|url =https://www.researchgate.net/publication/6687081}}</ref><ref>{{cite journal |vauthors=Jensen M, Mehlhorn H | title = Seventy-five years of Resochin in the fight against malaria| journal = Parasitol Res | volume = 105 | issue = 3 | pages = 609–27| year = 2009 | pmid = 19593586 | doi = 10.1007/s00436-009-1524-8| s2cid = 8037461}}</ref> It is chemically related to quinine through the possession of a [[quinoline]] nucleus and the dialkylaminoalkylamino side chain. Resochin (7-chloro-4- 4- (diethylamino) – 1 – methylbutyl amino quinoline) and a similar compound Sontochin (3-methyl Resochin) were synthesized in 1934.<ref>{{cite journal | author = Coatney GR | title = Pitfalls in a Discovery: The Chronicle of Chloroquine | journal = Am J Trop Med Hyg | volume = 12 | issue = 2 | pages = 121–28 | year = 1963 | pmid = 14021822| doi=10.4269/ajtmh.1963.12.121}}</ref> In March 1946, the drug was officially named [[Chloroquine]].<ref>{{cite journal |vauthors=Loeb RF, Clark WM, Coatney GR, Coggeshall LT, Dieuaide FR, Dochez AR, Hakansson EG, Marshall EK, Marvel SC, McCoy OR, Sapero JJ, Sebrell WH, Shannon JA, Carden GA | title = Activity of a new antimalarial agent, chloroquine (SN 7618) | journal = J. Am. Med. Assoc.| volume = 130 | pages = 1069–70| year = 1946| url = http://jama.ama-assn.org/cgi/content/summary/130/16/1069 | doi = 10.1001/jama.1946.02870160015006 | issue=16| pmid = 21019115 }}</ref> Chloroquine is an inhibitor of [[hemozoin]] production through [[biocrystallization]]. Quinine and chloroquine affect malarial parasites only at life stages when the parasites are forming hematin-pigment (hemozoin) as a byproduct of [[hemoglobin]] degradation.
Chloroquine-resistant forms of ''P. falciparum'' emerged only 19 years later.<ref>{{cite journal |vauthors=Wellems TE, Plowe CV |title=Chloroquine-resistant malaria |journal=J. Infect. Dis. |volume=184 |issue=6 |pages=770–76 |year=2001 |pmid=11517439 |doi=10.1086/322858|doi-access= |s2cid=11343688 }}</ref> The first resistant strains were detected around the [[Cambodia]]‐[[Thailand]] border and in [[Colombia]], in the 1950s.<ref>{{cite journal |author=Payne D |title=Spread of chloroquine resistance in Plasmodium falciparum |journal=Parasitol. Today (Regul. Ed.) |volume=3 |issue=8 |pages=241–46 |year=1987 |pmid=15462966 |doi= 10.1016/0169-4758(87)90147-5}}</ref> In 1989, chloroquine resistance in ''P. vivax'' was reported in Papua New Guinea. These resistant strains spread rapidly, producing a large mortality increase, particularly in Africa during the 1990s.<ref>{{cite journal |vauthors=Snow RW, Trape JF, Marsh K |title=The past, present and future of childhood malaria mortality in Africa |journal=Trends Parasitol. |volume=17 |issue=12 |pages=593–97 |year=2001 |pmid=11756044 |doi=10.1016/S1471-4922(01)02031-1}}</ref>

==== Artemisinins ====
Systematic screening of [[Chinese herbology|traditional Chinese medical herbs]] was carried out by Chinese research teams, consisting of hundreds of scientists in the 1960s and 1970s.<ref>{{cite journal |vauthors=Li Y, Wu Y | title = A golden phoenix arising from the herbal nest – A review and reflection on the study of antimalarial drug Qinghaosu | journal = Frontiers of Chemistry in China | volume = 5 | issue = 4 | pages = 357–422 | year = 2010 | doi = 10.1007/s11458-010-0214-5| s2cid = 73573938 }}</ref> Qinghaosu, later named [[artemisinin]], was cold-extracted in a neutral milieu (pH 7.0) from the dried leaves of ''[[Artemisia annua]]''.<ref name="Wright2010">{{cite journal |vauthors=Wright CW, Linley PA, Brun R, Wittlin S, Hsu E | title = Ancient Chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of qing hao with potent antimalarial activity | journal = Molecules| volume = 15 | pages = 804–12| year = 2010 |pmid =20335947 | pmc = 6257115 | doi = 10.3390/molecules15020804 | issue = 2| doi-access = free }}</ref><ref>{{cite journal | author = Liao F| title = Discovery of Artemisinin (Qinghaosu) | journal = Molecules| volume = 14 | pages = 5362–66| year = 2009 | doi =10.3390/molecules14125362 | issue = 12| pmc = 6254926 | doi-access = free }}</ref>

Artemisinin was isolated by pharmacologist [[Tu Youyou]] ([[Nobel Prize in Physiology or Medicine]], 2015). Tu headed a team tasked by the Chinese government with finding a treatment for chloroquine-resistant malaria. Their work was known as [[Project 523]], named after the date it was announced – 23 May 1967. The team investigated more than 2000 Chinese herb preparations and by 1971 had made 380 extracts from 200 herbs. An extract from qinghao (''[[Artemisia annua]]'') was effective, but the results were variable. Tu reviewed the literature, including ''Zhou hou bei ji fang'' (A handbook of prescriptions for emergencies) written in 340 BC by Chinese physician Ge Hong. This book contained the only useful reference to the herb: "A handful of qinghao immersed in two litres of water, wring out the juice and drink it all." Tu's team subsequently isolated a nontoxic, neutral extract that was 100% effective against parasitemia in animals. The first successful trials of artemisinin were in 1979.<ref>{{cite journal |vauthors=Miller LH, Su X | title = Artemisinin: Discovery from the Chinese Herbal Garden| journal = Cell | volume = 146 | issue = 6 | pages = 855–58 | year = 2011 | doi=10.1016/j.cell.2011.08.024 | pmc=3414217 | pmid=21907397}}</ref>

[[File:Artemisia annua West Virginia.jpg|thumb|upright=1.3|''[[Artemisia annua]]'' being grown as a field crop in [[West Virginia]] for the production of artemisinin, 2005]]

Artemisinin is a sesquiterpene [[lactone]] containing a [[peroxide]] group, which is believed to be essential for its anti-malarial activity. Its derivatives, [[artesunate]] and [[artemether]], have been used in clinics since 1987 for the treatment of drug-resistant and drug-sensitive malaria, especially cerebral malaria. These drugs are characterized by fast action, high efficacy, and good tolerance. They kill the asexual forms of ''[[Plasmodium berghei|P. berghei]]'' and ''P. cynomolgi'' and have transmission-blocking activity.<ref>{{cite journal |vauthors=Chotivanich K, Sattabongkot J, Udomsangpetch R, Looareesuwan S, Day NP, Coleman RE, White NJ | title = Transmission-Blocking Activities of Quinine, Primaquine, and Artesunate| journal = Antimicrob Agents Chemother| volume = 50| issue = 6| pages = 1927–30| year = 2006| pmid = 16723547| doi =10.1128/AAC.01472-05 | pmc = 1479118}}</ref> In 1985, [[Zhou Yiqing]] and his team combined artemether and [[lumefantrine]] into a single tablet, which was registered as a medicine in China in 1992. Later, it became known as [[Artemether/lumefantrine|"Coartem"]].<ref>{{cite journal | author = Weiyuan C| title = Ancient Chinese anti-fever cure becomes panacea for malaria| journal =Bull World Health Organ| volume = 87| issue = 10| pages = 743–44| year = 2009| pmid = 19876540| pmc=2755319| doi = 10.2471/BLT.09.051009}}</ref> Artemisinin combination treatments (ACTs) are now widely used to treat uncomplicated ''falciparum'' malaria, but access to ACTs is still limited in most malaria-endemic countries, and only a minority of the patients who need artemisinin-based combination treatments receive them.<ref>{{cite journal |vauthors=Nosten F, White NJ | title = Artemisinin-based combination treatment of falciparum malaria| journal = Am J Trop Med Hyg | volume = 77 | issue = 6 | pages = 181–92 | year = 2007 | pmid = 18165491| doi = 10.4269/ajtmh.2007.77.181| doi-access = free }}</ref>

In 2008, White predicted that improved agricultural practices, selection of high-yielding hybrids, [[Microorganism|microbial]] production, and the development of synthetic peroxides would lower prices.<ref name=White2008>{{cite journal | author = White NJ | title = Qinghaosu (artemisinin): the price of success| journal = Science| volume = 320 | issue = 5874 | pages = 330–34| year = 2008 | pmid = 18420924 | doi = 10.1126/science.1155165| bibcode = 2008Sci...320..330W| s2cid = 39014319}}</ref><ref>{{cite journal |vauthors=Hale V, Keasling JD, Renninger N, Diagana TT | title = Microbially derived artemisinin: a biotechnology solution to the global problem of access to affordable antimalarial drugs | journal = Am J Trop Med Hyg | volume = 77 | issue = 6 Suppl | pages = 198–202 | year = 2007 | pmid = 18165493 | doi = 10.4269/ajtmh.2007.77.198 | doi-access = free }}</ref>

=== Insecticides ===

Efforts to control the spread of malaria had a major setback in 1930: [[Entomology|entomologist]] [[Raymond Corbett Shannon]] discovered imported disease-bearing ''[[Anopheles gambiae]]'' mosquitoes living in [[Brazil]] (DNA analysis later revealed the actual species to be ''A. arabiensis'').<ref>{{Cite book|title=Mosquito: The Story of Man's Deadliest foe | year=2002 | publisher=Hyperion | page=131 | first1=Andrew | last1=Spielman | first2=Michael | last2=D'Antonio | isbn=978-0-7868-8667-8}}.</ref> This species of mosquito is a particularly efficient vector for malaria and is native to Africa.<ref>{{cite journal |vauthors=Parmakelis A, Russello MA, Caccone A, Marcondes CB, Costa J, Forattini OP, Sallum MA, Wilkerson RC, Powell JR |title=Historical analysis of a near disaster: Anopheles gambiae in Brazil |journal=American Journal of Tropical Medicine and Hygiene |volume=78 |issue=1 |pages=176–78 |year=2008 |pmid=18187802 |doi=10.4269/ajtmh.2008.78.176 |doi-access=free }}</ref> In 1938, the introduction of this vector caused the greatest epidemic of malaria ever seen in the [[New World]]. However, complete eradication of ''A. gambiae'' from northeast Brazil and thus from the New World was achieved in 1940 by the systematic application of the [[arsenic]]-containing compound [[Paris green]] to breeding places, and of [[pyrethrum]] spray-killing to adult resting places.<ref>{{cite book|vauthors=Russell PF, West LS, Manwell RD, MacDonald G | title = Practical Malariology 2nd ed | publisher = Oxford University Press, London, New York, Toronto| year = 1963 }}</ref>

==== DDT ====

The Austrian chemist [[Othmar Zeidler]] is credited with the first synthesis of [[DDT]] ('''D'''ichloro'''D'''iphenyl'''T'''richloroethane) in 1874.<ref>{{cite journal | author = Zeidler O| title = Verbindungen von Chloral mit Brom- und Chlorbenzol| journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 7 | issue = 2| pages = 1180–81 | year = 1874 |doi = 10.1002/cber.18740070278 | url = https://zenodo.org/record/1425070}}</ref> The insecticidal properties of DDT were identified in 1939 by chemist [[Paul Hermann Müller]] of [[Novartis|Geigy Pharmaceutical]]. For his discovery of DDT as a contact [[poison]] against several [[arthropod]]s, he was awarded the 1948 Nobel Prize in Physiology or Medicine.<ref name="nobel-1948">
{{cite web | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1948/index.html | title = The Nobel Prize in Physiology or Medicine 1948 | access-date = 2007-07-28 | publisher = The Nobel Foundation}}</ref> In the fall of 1942, samples of the chemical were acquired by the United States, Britain and Germany. Laboratory tests demonstrated that it was highly effective against many insects.

[[Rockefeller Foundation]] studies showed in [[Mexico]] that DDT remained effective for six to eight weeks if sprayed on the inside walls and ceilings of houses and other buildings.<ref>{{cite journal | author = The Rockefeller Foundation | title = Annual Report | year = 1944 | url = http://www.rockefellerfoundation.org/uploads/files/d336704a-253d-45da-8572-5c98bcd65801-1944.pdf | journal =  | access-date = 25 March 2014 | archive-date = 10 April 2013 | archive-url = https://web.archive.org/web/20130410170432/http://www.rockefellerfoundation.org/uploads/files/d336704a-253d-45da-8572-5c98bcd65801-1944.pdf | url-status = dead }}</ref> The first field test in which residual DDT was applied to the interior surfaces of all habitations and outbuildings was carried out in central [[Italy]] in the spring of 1944. The objective was to determine the residual effect of the spray on anopheline density in the absence of other control measures. Spraying began in [[Castel Volturno]] and, after a few months, in the delta of the [[Tiber]]. The unprecedented effectiveness of the chemical was confirmed: the new [[insecticide]] was able to eradicate malaria by eradicating mosquitoes.<ref>{{cite journal |vauthors=Soper FL, Knipe FW, Casini G, Riehl LA, Rubino A | title = Reduction of Anopheles Density Effected by the Preseason Spraying of Building Interiors with DDT in Kerosene, at Castel Volturno, Italy, in 1944–1945 and in the Tiber Delta in 1945 | volume = 27 | issue = 1 | pages = 177–200 | year = 1947 | pmid = 20292226 | journal=American Journal of Tropical Medicine and Hygiene| doi = 10.4269/ajtmh.1947.s1-27.177 }}</ref> At the end of World War II, a massive malaria control program based on DDT spraying was carried out in Italy. In [[Sardinia]] – the second largest island in the Mediterranean – between 1946 and 1951, the Rockefeller Foundation conducted a large-scale experiment to test the feasibility of the strategy of "species eradication" in an endemic malaria vector.<ref>{{cite journal | author = Tognotti E| title = Program to Eradicate Malaria in Sardinia, 1946–1950| journal = Emerging Infectious Diseases | volume = 15 | issue = 9 | pages = 1460–66 | year = 2009 | pmid = 19788815 | pmc = 2819864 | doi = 10.3201/eid1509.081317 }}</ref> Malaria was effectively eliminated in the United States by the use of DDT in the [[National Malaria Eradication Program]] (1947–52). The concept of eradication prevailed in 1955 in the Eighth [[World Health Assembly]]: DDT was adopted as a primary tool in the fight against malaria.

In 1953, the [[World Health Organization]] (WHO) launched an antimalarial program in parts of Liberia as a pilot project to determine the feasibility of malaria eradication in tropical Africa. However, these projects encountered difficulties that foreshadowed the general retreat from malaria eradication efforts across tropical Africa by the mid-1960s.<ref>{{cite journal | author = Webb James L. A. | year = 2011 | title = The First Large-Scale Use of Synthetic Insecticide for Malaria Control in Tropical Africa: Lessons from Liberia, 1945–1962 | url = http://muse.jhu.edu/journals/journal_of_the_history_of_medicine_and_allied_sciences/v066/66.3.webb.html | journal = Journal of the History of Medicine and Allied Sciences | volume = 66 | issue = 3| pages = 347–76 | doi=10.1093/jhmas/jrq046| pmid = 20624820 | s2cid = 23161797 }}</ref>

DDT was banned for agricultural uses in the US in 1972 (DDT has never been banned for non-agricultural uses such as malaria control<ref>Michael Palmer, [http://www.science.uwaterloo.ca/~mpalmer/stuff/DDT-myth.pdf The ban of DDT did not cause millions to die from malaria]</ref>) after the discussion opened in 1962 by ''[[Silent Spring]]'', written by American biologist [[Rachel Carson]], which launched the [[Environmental science|environmental]] movement in the West. The book catalogued the environmental impacts of indiscriminate DDT spraying and suggested that DDT and other [[pesticide]]s cause cancer and that their agricultural use was a threat to [[wildlife]]. The [[United States Agency for International Development|U.S. Agency for International Development]] supports [[Indoor residual spraying|indoor DDT spraying]] as a vital component of malaria control programs and has initiated DDT and other insecticide spraying programs in tropical countries.<ref>{{cite journal |vauthors=Sadasivaiah S, Tozan Y, Breman JG | title = Dichlorodiphenyltrichloroethane (DDT) for indoor residual spraying in Africa: how can it be used for malaria control? | journal = American Journal of Tropical Medicine and Hygiene | volume = 77 | issue = 6 | pages = 249–63 | year = 2007 | pmid = 18165500 | doi = 10.4269/ajtmh.2007.77.249 | doi-access = free }}</ref>

[[File:Fields of white daisies (Chrysanthemum cinerariaefolium ).JPG|thumb|left| [[Pyrethrum]] field (''[[Chrysanthemum]] cinerariaefolium'') Lari Hills, Nairobi, Kenya, in 2010]]

==== Pyrethrum ====

Other [[insecticide]]s are available for mosquito control, as well as physical measures, such as draining the [[wetland]] breeding grounds and the provision of better [[sanitation]]. [[Pyrethrum]] (from the flowering plant ''[[Chrysanthemum]]'' [or ''[[Tanacetum]]''] ''cinerariaefolium'') is an economically important source of natural insecticide. [[Pyrethrin]]s attack the [[nervous system]]s of all insects. A few minutes after application, the insect cannot move or fly, while female mosquitoes are inhibited from biting.<ref>{{cite journal |vauthors=Duchon S, Bonnet J, Marcombe S, Zaim M, Corbel V | title = Pyrethrum: a mixture of natural pyrethrins has potential for malaria vector control | journal = Journal of Medical Entomology | volume = 46 | issue = 3 | pages = 516–22 | year = 2009 | pmid = 19496422 | doi = 10.1603/033.046.0316 | doi-access = free }}</ref> The use of pyrethrum in insecticide preparations dates to about 400 [[Common Era|BCE]]. Pyrethrins are [[Biodegradation|biodegradable]] and break down easily on exposure to light. The majority of the world's supply of pyrethrin and ''Chrysanthemum cinerariaefolium'' comes from [[Kenya]]. The flower was first introduced into Kenya and the highlands of [[East Africa|Eastern Africa]] during the late 1920s. The flowers of the plant are harvested shortly after blooming; they are either dried and powdered, or the oils within the flowers are extracted with [[solvent]]s.

=== Research ===

==== Avian, mouse and monkey models ====
Until the 1950s, screening of anti-malarial drugs was carried out on avian malaria. Avian malaria species differ from those that infect humans. The discovery in 1948 of ''[[Plasmodium berghei]]'' in wild rodents in the [[Belgian Congo|Congo]]<ref>{{cite journal |vauthors=Vincke IH, Lips M |title= Un nouveau plasmodium d'un rongeur sauvage du Congo: ''Plasmodium berghei'' n.sp |journal= Annales de la Société Belge de Médecine Tropicale |volume= 28 |pages= 97–104|year=1948}}</ref> and later other rodent species that could infect laboratory rats transformed drug development. The short hepatic phase and life cycle of these parasites made them useful as animal models, a status they still retain.<ref name="Cox " /> ''Plasmodium cynomolgi'' in rhesus monkeys (''[[Macaca mulatta]]'') was used in the 1960s to test drugs active against ''P. vivax''.

Growth of the liver stages in animal-free systems was achieved in the 1980s when pre-erythrocytic ''P. berghei'' stages were grown in wI38, a human [[embryonic cell|embryonic lung cell]] line (cells cultured from one specimen).<ref>{{cite journal |title=The Influence of Cell Type and Culture Medium on the {{nat|In vitro}} Cultivation of Exoerythrocytic Stages of Plasmodium berghei |first1=Michael R. |last1=Hollingdale |first2=Pamela |last2=Leland |first3=James L. |last3=Leef |first4=Richard L. |last4=Beaudoin |journal=The Journal of Parasitology |volume= 69 |issue= 2 |date=April 1983 |pages= 346–52 |doi=10.2307/3281232 |jstor=3281232|pmid=6343574 }}</ref> This was followed by their growth in the human hepatoma line HepG2.<ref>{{Cite journal | pmid = 2489396| year = 1989| last1 = Davies| first1 = C. S.| title = Improved techniques for the culture of the liver stages of Plasmodium berghei and their relevance to the study of causal prophylactic drugs| journal = Acta Leidensia| volume = 58| issue = 2| pages = 97–113| last2 = Suhrbier| first2 = A. S.| last3 = Winger| first3 = L. A.| last4 = Sinden| first4 = R. E.}}</ref> Both ''P. falciparum'' and ''P. vivax'' have been grown in human liver cells; partial development of ''P. ovale'' in human liver cells was achieved; and ''P. malariae'' was grown in chimpanzee and ''[[Night monkey|monkey]]'' liver cells.<ref>{{Cite journal | doi = 10.1128/CMR.15.3.355-364.2002| pmid = 12097244| title = Cultivation of ''Plasmodium'' spp.| journal = Clinical Microbiology Reviews| volume = 15| issue = 3| pages = 355–64| year = 2002| last1 = Schuster | first1 = F. L.| pmc = 118084}}</ref>

The first successful continuous [[malaria culture]] was established in 1976 by William Trager and James B. Jensen, which facilitated research into the molecular biology of the parasite and the development of new drugs. By using increasing volumes of culture medium, ''P.falciparum'' was grown to higher [[parasitemia]] levels (above 10%).<ref>{{cite journal |vauthors=Trager W, Jensen JB | title = Human malaria parasites in continuous culture| journal = Science| volume = 193 | issue = 4254 | pages = 673–75 | year = 1976 | pmid = 781840| doi=10.1126/science.781840| bibcode = 1976Sci...193..673T}}<br />{{cite journal | author = Schuster FL | title = Cultivation of Plasmodium spp | journal = Clin Microbiol Rev| volume = 15 | issue = 3 | pages = 355–64 | year = 2002 | pmid = 12097244 | doi = 10.1128/CMR.15.3.355-364.2002 | pmc = 118084 }}</ref>

==== Diagnostics ====

The use of antigen-based [[Malaria antigen detection tests|malaria rapid diagnostic tests (RDTs)]] emerged in the 1980s.<ref>{{cite journal |vauthors=Ling IT, Cooksley S, Bates PA, Hempelmann E, Wilson RJ | title=Antibodies to the glutamate dehydrogenase of Plasmodium falciparum| journal=Parasitology | year=1986 | volume=92 | pages=313–24 | pmid=3086819 | doi=10.1017/S0031182000064088 | issue=2 | s2cid=16953840| url=https://eprints.lancs.ac.uk/id/eprint/56298/1/download6.pdf}}</ref> In the 21st century, [[Giemsa stain|Giemsa]] [[microscopy]] and RDTs became the two preferred [[Medical diagnosis|diagnostic]] techniques. Malaria RDTs do not require special equipment and offer the potential to extend accurate malaria diagnosis to areas lacking microscopy services.<ref>{{cite journal |vauthors=Makler MT, Piper RC | title=Rapid malaria tests: where do we go after 20 years?| journal=Am J Trop Med Hyg| year=2009| volume=81 | pages=921–26 | pmid=19996417| doi=10.4269/ajtmh.2009.09-0202 | issue=6 | doi-access=free }}<br />{{cite journal |vauthors=Bisoffi Z, Gobbi F, Angheben A, Van den Ende J | title=The Role of Rapid Diagnostic Tests in Managing Malaria| journal=PLOS Medicine| year=2009| volume=6 | pages=e1000063 | pmid=19399160| doi=10.1371/journal.pmed.1000063 | issue=4 | pmc=2667642| doi-access=free}}</ref>

=== A zoonotic malarial parasite ===

''Plasmodium knowlesi'' has been known since the 1930s in Asian [[macaque]] monkeys and as experimentally capable of infecting humans. In 1965, a natural human infection was reported in a U.S. soldier returning from the Pahang Jungle of the [[Malaysia]]n peninsula.<ref>{{cite journal|vauthors=Antinori S, Galimberti L, Milazzo L, Corbellino M|title=Plasmodium knowlesi: The emerging zoonotic malaria parasite|journal=Acta Tropica|year=2013|volume=125|issue=2|pages=191–201|url=http://www.malarianexus.com/_common/updateable/files/articles/634941176681754741.pdf|doi=10.1016/j.actatropica.2012.10.008|pmid=23088834|access-date=23 March 2014|archive-url=https://web.archive.org/web/20160303235913/http://www.malarianexus.com/_common/updateable/files/articles/634941176681754741.pdf|archive-date=3 March 2016|url-status=dead}}</ref>

==See also==
* [[Malaria in the River Thames]]
* [[Malaria in Mandatory Palestine]]

== Notes ==
{{reflist|group=Note}}

== References ==
{{reflist}}

==Further reading==
* {{Cite book |author=Packard RM |title=The Making of a Tropical Disease: A Short History of Malaria |url=https://books.google.com/books?id=B_V1Xj6wH7IC |year=2007 |publisher=JHU Press |isbn=978-0-8018-8712-3 |series=Johns Hopkins Biographies of Disease}}
* {{Cite book |author=Shah S |title=The Fever: How Malaria Has Ruled Humankind for 500,000 Years |url=https://books.google.com/books?id=4jUjPh64X9UC |year=2010 |publisher=Macmillan |isbn=978-0-374-23001-2}} [https://www.amazon.com/Fever-Malaria-Ruled-Humankind-Years/dp/0374230013/ excerpt and text search]

== External links ==
* [http://nobelprize.org/nobel_prizes/medicine/laureates/1907/laveran-lecture.html Alphonse Laveran Nobel Lecture: Protozoa as causes of disease]
* [http://nobelprize.org/nobel_prizes/medicine/laureates/1948/muller-lecture.pdf Paul H Müller Nobel Lecture 1948: Dichloro-diphenyl-trichloroethane and newer insecticides]
* [http://nobelprize.org/nobel_prizes/medicine/laureates/1902/ross-lecture.pdf Ronald Ross Nobel Lecture]
* [http://nobelprize.org/nobel_prizes/medicine/laureates/1927/wagner-jauregg-lecture.html Julius Wagner-Jauregg Nobel Lecture: The Treatment of Dementia Paralytica by Malaria Inoculation]
* [http://www.im.microbios.org/0901/0901069.pdf Grassi versus Ross: Who solved the riddle of malaria?]
* [https://www.bbc.co.uk/history/ancient/romans/malaria_01.shtml Malaria and the Fall of Rome]
* [http://www.xs4all.nl/~ottoknot/werk/Malaria.html Malaria Around the North Sea]
* [https://web.archive.org/web/20140619212323/http://www.malariasite.com/malaria/History.htm Malariasite: History]
* [https://www.cdc.gov/malaria/about/history/ Centers for Disease Control: History of Malaria]

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