View source for Yellow fever

{{Short description|Viral disease}}
{{Redirect2|American Plague|Yellow plague|the rock band|The American Plague|the Yellow Plague of Rhos in medieval Wales|Maelgwn Gwynedd|other uses|Yellow fever (disambiguation)}}
{{Use dmy dates|date=September 2023}}
{{Infobox medical condition (new)
| name = Yellow fever
| image = YellowFeverVirus.jpg
| caption = A [[Transmission electron microscope|TEM]] [[micrograph]] of Yellow fever virus (234,000× magnification)
| image_size = 250px
| field = [[Infectious disease (medical specialty)|Infectious disease]]
| synonyms = Yellow jack, yellow plague,<ref name=Old2009/> bronze john<ref>{{cite book | vauthors = Bazin H |title=Vaccination: a history from Lady Montagu to genetic engineering |date=2011 |publisher=J. Libbey Eurotext |location=Montrouge |isbn=978-2-7420-0775-2 |page=407 |url=https://books.google.com/books?id=orjaA_7sYZQC&pg=PA407 |url-status=live |archive-url=https://web.archive.org/web/20170223042240/https://books.google.com/books?id=orjaA_7sYZQC&pg=PA407 |archive-date=2017-02-23}}</ref>
| symptoms = [[Fever]], [[chills]], [[muscle pain]], [[headache]], [[Nausea]], [[Vomiting]], [[Fatigue]], [[loss of appetite]], [[Jaundice|yellow skin]]<ref name=WHO2014/>
| complications = [[Liver failure]], [[bleeding]]<ref name=WHO2014/>
| onset = 3–6 days post exposure<ref name=WHO2014/>
| duration = 3–4 days<ref name=WHO2014/>
| causes = Yellow fever virus spread by [[mosquitoes]]<ref name=WHO2014/>
| risks = 
| diagnosis = [[Blood test]]<ref name=Toll2009/>
| differential = 
| prevention = [[Yellow fever vaccine]]<ref name=WHO2014/>
| treatment = [[Supportive care]]<ref name=WHO2014/>
| medication = 
| prognosis = 
| frequency = ≈130,000 severe cases in Africa alone (2013)<ref name=WHO2014/><ref name=garskeetal2014>{{cite journal|vauthors=Garske T, Van Kerkhove MD, Yactayo S, Ronveaux O, Lewis RF, Staples JE, Perea W, Ferguson NM, ((Yellow Fever Expert Committee))|title=Yellow Fever in Africa: Estimating the Burden of Disease and Impact of Mass Vaccination from Outbreak and Serological Data|journal=PLOS Medicine|volume=11|issue=5|id=e1001638|doi=10.1371/journal.pmed.1001638|doi-access=free|year=2014|article-number=e1001638 |pmid=24800812|pmc=4011853}}</ref>
| deaths = ≈78,000 in Africa alone (2013)<ref name=WHO2014/><ref name=garskeetal2014/>
}}

'''Yellow fever''' is a [[Virus|viral]] [[disease]] of typically [[acute (medicine)|short duration]].<ref name=WHO2014>{{cite web |title=Yellow fever Fact sheet N°100 |url=https://www.who.int/mediacentre/factsheets/fs100/en/ |work=World Health Organization |access-date=23 February 2014 |date=May 2013 |url-status=live |archive-url=https://web.archive.org/web/20140219011908/http://www.who.int/mediacentre/factsheets/fs100/en/ |archive-date=19 February 2014}}</ref> In most cases, symptoms include [[fever]], [[chills]], [[Anorexia (symptom)|loss of appetite]], [[nausea]], muscle pains—particularly in the back—and [[headache]]s.<ref name=WHO2014/> Symptoms typically improve within five days.<ref name=WHO2014/> In about 15% of people, within a day of improving the fever recurs, abdominal pain occurs and [[liver]] damage begins, causing [[jaundice|yellow skin]].<ref name=WHO2014/><ref>{{cite book | vauthors = Scully C |title=Scully's Medical Problems in Dentistry |date=2014 |publisher=Elsevier Health Sciences |isbn=978-0-7020-5963-6 |page=572 |url=https://books.google.com/books?id=OZXdAwAAQBAJ&pg=PA572 |language=en }}</ref> If this occurs, the risk of bleeding and [[kidney failure|kidney problems]] is increased.<ref name=WHO2014/><ref>{{Cite web |title=Yellow fever |url=https://www.who.int/news-room/fact-sheets/detail/yellow-fever |access-date=2022-04-30 |website=World Health Organization |language=en}}</ref>

The disease is caused by the yellow fever virus and is spread by the bite of an infected [[mosquito]].<ref name=WHO2014/><ref name="mayoclinic">{{Cite web |title=Yellow fever - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/yellow-fever/symptoms-causes/syc-20353045 |access-date=2022-04-27 |website=Mayo Clinic |language=en |archive-url=https://web.archive.org/web/20220424083736/https://www.mayoclinic.org/diseases-conditions/yellow-fever/symptoms-causes/syc-20353045 |archive-date=Apr 24, 2022 }}</ref> It infects humans, other [[primate]]s,<ref>{{Cite journal |last1=Goes de Jesus |first1=Jaqueline |last2=Gräf |first2=Tiago |last3=Giovanetti |first3=Marta |last4=Mares-Guia |first4=Maria Angélica |last5=Xavier |first5=Joilson |last6=Lima Maia |first6=Maricelia |last7=Fonseca |first7=Vagner |last8=Fabri |first8=Allison |last9=dos Santos |first9=Roberto Fonseca |last10=Mota Pereira |first10=Felicidade |last11=Ferraz Oliveira Santos |first11=Leandro |date=2020-08-11 |title=Yellow fever transmission in non-human primates, Bahia, Northeastern Brazil |journal=PLOS Neglected Tropical Diseases |volume=14 |issue=8 |article-number=e0008405 |doi=10.1371/journal.pntd.0008405 |pmc=7418952 |pmid=32780745 |doi-access=free }}</ref> and several types of mosquitoes.<ref name=WHO2014/> In cities, it is spread primarily by ''[[Aedes aegypti]]'', a type of mosquito found throughout the [[tropics]] and [[subtropics]].<ref name=WHO2014/> The virus is an [[RNA virus]] of the genus ''[[Orthoflavivirus]],'' with a full scientific name ''Orthoflavivirus flavi.''<ref>{{Cite journal |last=Postler |first=Thomas S. |last2=Beer |first2=Martin |last3=Blitvich |first3=Bradley J. |last4=Bukh |first4=Jens |last5=de Lamballerie |first5=Xavier |last6=Drexler |first6=J. Felix |last7=Imrie |first7=Allison |last8=Kapoor |first8=Amit |last9=Karganova |first9=Galina G. |last10=Lemey |first10=Philippe |last11=Lohmann |first11=Volker |last12=Simmonds |first12=Peter |last13=Smith |first13=Donald B. |last14=Stapleton |first14=Jack T. |last15=Kuhn |first15=Jens H. |date=2023 |title=Renaming of the genus Flavivirus to Orthoflavivirus and extension of binomial species names within the family Flaviviridae |url=https://link.springer.com/10.1007/s00705-023-05835-1 |journal=Archives of Virology |language=en |volume=168 |issue=9 |doi=10.1007/s00705-023-05835-1 |pmid=37561168|url-access=subscription }}</ref> The disease may be difficult to tell apart from other illnesses, especially in the early stages.<ref name=WHO2014/> To confirm a suspected case, blood-sample testing with a [[polymerase chain reaction]] is required.<ref name=Toll2009>{{cite journal | vauthors = Tolle MA | title = Mosquito-borne diseases | journal = Current Problems in Pediatric and Adolescent Health Care | volume = 39 | issue = 4 | pages = 97–140 | date = April 2009 | pmid = 19327647 | doi = 10.1016/j.cppeds.2009.01.001 }}</ref>

A safe and effective [[yellow fever vaccine|vaccine against yellow fever]] exists, and some countries require vaccinations for travelers.<ref name=WHO2014/> Other efforts to prevent infection include reducing the population of the transmitting mosquitoes.<ref name=WHO2014/> In areas where yellow fever is common, early diagnosis of cases and immunization of large parts of the population are important to prevent [[outbreak]]s.<ref name=WHO2014/> Once a person is infected, management is symptomatic; no specific measures are effective against the virus.<ref name=WHO2014/> Death occurs in up to half of those who get severe disease.<ref name=WHO2014/><ref>{{cite web |title=Frequently Asked Questions About Yellow Fever |url=https://www.cdc.gov/yellowfever/qa/ |website=CDC |access-date=18 March 2016 |date=August 21, 2015 |url-status=live |archive-url=https://web.archive.org/web/20160323210418/http://www.cdc.gov/yellowfever/qa/ |archive-date=23 March 2016}}</ref>

In 2013, yellow fever was estimated to have caused 130,000 severe infections and 78,000 deaths in Africa.<ref name=WHO2014/><ref name=garskeetal2014/> Approximately 90 percent of an estimated 200,000 cases of yellow fever per year occur in Africa.<ref name="pmid17304460">{{cite journal |last=Barnett |first=Elizabeth D. |title=Yellow Fever: Epidemiology and Prevention |journal=Clinical Infectious Diseases |volume=44 |issue=6 |pages=850–856 |year=2007 |doi=10.1086/511869 |doi-access=free |pmid=17304460}}</ref> Nearly a billion people live in an area of the world where the disease is common.<ref name=WHO2014/> It is common in tropical areas of the continents of South America and Africa,<ref>{{cite journal |last1=Lataillade |first1=Lucy de Guilhem de |last2=Vazeille |first2=Marie |last3=Obadia |first3=Thomas |last4=Madec |first4=Yoann |last5=Mousson |first5=Laurence |last6=Kamgang |first6=Basile |last7=Chen |first7=Chun-Hong |last8=Failloux |first8=Anna-Bella |last9=Yen |first9=Pei-Shi |title=Risk of yellow fever virus transmission in the Asia-Pacific region |journal=Nature Communications |date=16 November 2020 |volume=11 |issue=1 |page=5801 |doi=10.1038/s41467-020-19625-9 |pmid=33199712 |pmc=7669885 |bibcode=2020NatCo..11.5801L }}</ref> but not in Asia.<ref name=WHO2014/><ref name=CDC2011>{{cite web |url=https://www.cdc.gov/yellowfever/ |title=CDC Yellow Fever |access-date=2012-12-12 |url-status=live |archive-url=https://web.archive.org/web/20121221085711/http://www.cdc.gov/yellowfever/ |archive-date=2012-12-21}}</ref> Since the 1980s, the number of cases of yellow fever has been increasing.<ref name=WHO2014/><ref name=Barr2007>{{cite journal | vauthors = Barrett AD, Higgs S | title = Yellow fever: a disease that has yet to be conquered | journal = Annual Review of Entomology | volume = 52 | pages = 209–229 | year = 2007 | pmid = 16913829 | doi = 10.1146/annurev.ento.52.110405.091454 }}</ref> This is believed to be due to fewer people being immune, more people living in cities, people moving frequently, and [[climate change|changing climate]] increasing the habitat for mosquitoes.<ref name=WHO2014/>

The disease originated in Africa and spread to the Americas starting in the 17th century with the European trafficking of [[Atlantic slave trade|enslaved Africans]] from sub-Saharan Africa.<ref name=Old2009>{{cite book |doi=10.1093/oso/9780190056780.003.0005 |chapter=Yellow Fever |title=Viruses, Plagues, and History |date=2020 |last1=Oldstone |first1=Michael B. A. |pages=89–122 |isbn=978-0-19-005678-0 }}</ref><ref>{{Cite web |title=History of Yellow Fever in the U.S. |url=https://asm.org/Articles/2021/May/History-of-Yellow-Fever-in-the-U-S |access-date=2022-04-27 |website=ASM.org |language=en}}</ref> Since the 17th century, several major [[List of epidemics|outbreaks]] of the disease have occurred in the Americas, Africa, and Europe.<ref name=Old2009/> In the 18th and 19th centuries, yellow fever was considered one of the most dangerous [[infectious disease]]s; numerous epidemics swept through major cities of the US and in other parts of the world.<ref name=Old2009/>

In 1927, the yellow fever virus became the first human virus to be isolated.<ref name="lindenbach2007">{{cite book |title=Fields Virology |edition=5th |publisher=Lippincott Williams & Wilkins | vauthors = Lindenbach BD, Rice CM | veditors = Knipe DM, Howley PM |year=2007 |location=Philadelphia, PA |page=1101 |isbn=978-0-7817-6060-7 |chapter=Flaviviridae: The Viruses and Their Replication }}</ref><ref>{{cite book |url=https://books.google.com/books?id=wpDaaFcFA3kC&pg=PA17 |title=West Nile Virus | vauthors = Sfakianos J, Hecht A |date=2009 |publisher=Chelsea House |others=Foreword by David Heymann |isbn=978-1-60413-254-0 | veditors = Babcock H |edition=2nd |series=Deadly Diseases & Epidemics |location=New York |page=17 |type=Curriculum-based juvenile nonfiction |quote=The yellow fever virus was isolated in 1927}}</ref>

==Signs and symptoms==
Yellow fever begins after an incubation period of three to six days.<ref name="urlFact Sheet | CDC Yellow Fever">{{cite web |url=https://www.cdc.gov/yellowfever/symptoms/index.html |title=CDC: Yellow fever—Symptoms and treatment |access-date=2010-11-10 |url-status=live |archive-url=https://web.archive.org/web/20120321164313/http://www.cdc.gov/yellowfever/symptoms/index.html |archive-date=2012-03-21 }}</ref> Most cases cause only mild infection with fever, headache, chills, back pain, fatigue, loss of appetite, muscle pain, nausea, and vomiting.<ref name="urlWHO | Yellow fever">{{cite web |url=https://www.who.int/mediacentre/factsheets/fs100/en/ |title=Yellow fever |publisher=WHO |access-date=2009-08-13 |url-status=live |archive-url=https://web.archive.org/web/20090817074958/http://www.who.int/mediacentre/factsheets/fs100/en/ |archive-date=2009-08-17 }}</ref> In these cases, the infection lasts only three to six days.<ref>{{Cite web|title=Yellow fever|url=https://www.who.int/news-room/fact-sheets/detail/yellow-fever|access-date=2021-07-11|website=World Health Organization|language=en}}</ref>

In 15% of cases, the disease enters  a second, toxic phase, characterized by recurring fever, accompanied by [[jaundice]] caused by [[hepatitis|liver damage]], as well as [[abdominal pain]].<ref>{{cite book |title=Control of Communicable Diseases Manual |publisher=Amer Public Health Assn |isbn=978-0-87553-018-5 |edition=20th |year=2015}}</ref> Bleeding in the mouth, nose, eyes and [[Human gastrointestinal tract|gastrointestinal tract]] causes [[hematemesis|vomit containing blood]], hence one of the names in Spanish for yellow fever, {{lang|es|vómito negro}} ("black vomit").<ref name="pmid14582304">{{cite journal | vauthors = Chastel C | title = [Centenary of the discovery of yellow fever virus and its transmission by a mosquito (Cuba 1900-1901)] | language = fr | journal = Bulletin de la Socitété de Pathologie Exotique | volume = 96 | issue = 3 | pages = 250–256 | date = August 2003 | pmid = 14582304 }}</ref> There may also be kidney failure, hiccups, and delirium.<ref>Dr. [[Irwin Sherman]], ''Twelve Diseases that Changed Our World''. p. 144. ASM Press. 2007. {{ISBN|978-1-55581-466-3}}. {{OCLC|141178241}}.</ref><ref>Franklin, Jon; Sutherland, John. ''[[Guinea Pig]] Doctors: The Drama of Medical Research Through Self-Experimentation'', New York: William Morrow & Co (March 1984) {{ISBN|0-688-02666-4}}</ref>

Among those who develop jaundice, the fatality rate is 20 to 50%, while the overall [[case fatality rate|fatality rate]] is about 3 to 7.5%.<ref name="pmid18061688">{{cite journal | vauthors = Monath TP | title = Treatment of yellow fever | journal = Antiviral Research | volume = 78 | issue = 1 | pages = 116–124 | date = April 2008 | pmid = 18061688 | doi = 10.1016/j.antiviral.2007.10.009 }}</ref> Severe cases may have a mortality rate greater than 50%.<ref name=Tomori2004>{{cite journal | vauthors = Tomori O | title = Yellow fever: the recurring plague | journal = Critical Reviews in Clinical Laboratory Sciences | volume = 41 | issue = 4 | pages = 391–427 | year = 2004 | pmid = 15487593 | doi = 10.1080/10408360490497474 }}</ref>

Surviving the infection provides lifelong [[Immunity (medical)|immunity]],<ref>{{cite book | vauthors = Modrow S, Falke D, Truyen U |title=Molekulare Virologie – Eine Einführung für Biologen und Mediziner |publisher=Spektrum Akademischer Verlag |year=2002 |isbn=978-3-8274-1086-3 |page=182 |edition=2nd }}</ref> generally with no permanent organ damage.<ref name="pmid16647971">{{cite book | vauthors = Rogers DJ, Wilson AJ, Hay SI, Graham AJ | title = Global Mapping of Infectious Diseases: Methods, Examples and Emerging Applications | chapter = The global distribution of yellow fever and dengue | volume = 62 | pages = 181–220 | year = 2006 | pmid = 16647971 | pmc = 3164798 | doi = 10.1016/S0065-308X(05)62006-4 | isbn = 978-0-12-031762-2 | series = Advances in Parasitology }}</ref><ref>{{Cite web |date=2020-02-26 |title=Symptoms, Diagnosis, & Treatment |url=https://www.cdc.gov/yellowfever/symptoms/index.html |access-date=2022-04-30 |website=www.cdc.gov |language=en-us}}</ref>

=== Complication ===
Yellow fever can lead to death for 20% to 50% of those who develop severe disease. Jaundice, fatigue, heart rhythm problems, seizures and internal bleeding may also appear as complications of yellow fever during recovery time.<ref name="mayoclinic"/><ref>{{Cite web |title=Yellow Fever: Symptoms, Complications, and Treatment |url=https://www.practo.com/health-wiki/yellow-fever-symptoms-complications-and-treatment/67/article |access-date=2022-03-31 |website=Practo}}</ref>

==Cause==
{{Virusbox
| name = Yellow fever virus
| image = Ijms-20-04657-g002.webp
| image_alt =
| image_caption = Flavivirus structure and genome
| parent = Flavivirus
| species = Orthoflavivirus flavi
| synonyms =
| synonyms_ref =
| subdivision_ranks =
| subdivision =
}}

Yellow fever is caused by Yellow fever virus (YFV), an enveloped [[RNA virus]] 40–50 {{abbr|nm|nanometer}} in width, the type species and namesake of the family ''[[Flaviviridae]]''.<ref name="lindenbach2007"/> It was the first illness shown to be transmissible by filtered human serum and transmitted by mosquitoes, by American doctor [[Walter Reed]] around 1900.<ref name="staples2008">{{cite journal | vauthors = Staples JE, Monath TP | title = Yellow fever: 100 years of discovery | journal = JAMA | volume = 300 | issue = 8 | pages = 960–962 | date = August 2008 | pmid = 18728272 | doi = 10.1001/jama.300.8.960 | doi-access = free }}</ref> The positive-[[Sense (molecular biology)|sense]], single-stranded [[RNA]] is around 10,862 [[nucleotide]]s long and has a single [[open reading frame]] encoding a [[polyprotein]].<ref>{{cite book | vauthors = Modrow S, Falke D, Truyen U, Schätzl H | title = Molecular Virology | chapter = Viruses with Single-Stranded, Positive-Sense RNA Genomes |pages=185–349 | date = April 2013 | doi = 10.1007/978-3-642-20718-1_14 | isbn = 978-3-642-20717-4 }}</ref> [[Host (biology)|Host]] [[protease]]s cut this polyprotein into three structural (C, prM, E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration corresponds to the arrangement of the protein coding [[gene]]s in the [[genome]].<ref name="pmid18796313">{{cite journal | vauthors = Sampath A, Padmanabhan R | title = Molecular targets for flavivirus drug discovery | journal = Antiviral Research | volume = 81 | issue = 1 | pages = 6–15 | date = January 2009 | pmid = 18796313 | pmc = 2647018 | doi = 10.1016/j.antiviral.2008.08.004 }}</ref> Minimal YFV 3{{prime}}UTR region is required for stalling of the host 5{{prime}}-3{{prime}} exonuclease XRN1.<ref>{{cite journal | vauthors = Roby JA, Pijlman GP, Wilusz J, Khromykh AA | title = Noncoding subgenomic flavivirus RNA: multiple functions in West Nile virus pathogenesis and modulation of host responses | journal = Viruses | volume = 6 | issue = 2 | pages = 404–427 | date = January 2014 | pmid = 24473339 | pmc = 3939463 | doi = 10.3390/v6020404 | doi-access = free }}</ref> The UTR contains PKS3 pseudoknot structure, which serves as a molecular signal to stall the exonuclease and is the only viral requirement for subgenomic flavivirus RNA (sfRNA) production.<ref>{{cite journal | vauthors = Funk A, Truong K, Nagasaki T, Torres S, Floden N, Balmori Melian E, Edmonds J, Dong H, Shi PY, Khromykh AA | display-authors = 6 | title = RNA structures required for production of subgenomic flavivirus RNA | journal = Journal of Virology | volume = 84 | issue = 21 | pages = 11407–11417 | date = November 2010 | pmid = 20719943 | pmc = 2953152 | doi = 10.1128/JVI.01159-10 }}</ref> The sfRNAs are a result of incomplete degradation of the viral genome by the exonuclease and are important for viral pathogenicity.<ref>{{cite journal | vauthors = Silva PA, Pereira CF, Dalebout TJ, Spaan WJ, Bredenbeek PJ | title = An RNA pseudoknot is required for production of yellow fever virus subgenomic RNA by the host nuclease XRN1 | journal = Journal of Virology | volume = 84 | issue = 21 | pages = 11395–11406 | date = November 2010 | pmid = 20739539 | pmc = 2953177 | doi = 10.1128/jvi.01047-10 }}</ref> Yellow fever belongs to the group of [[Viral hemorrhagic fever|hemorrhagic fevers]].<ref>{{Cite web |title=Hemorrhagic Fevers |url=https://medlineplus.gov/hemorrhagicfevers.html |access-date=2022-04-24 |website=medlineplus.gov}}</ref>

The viruses infect, amongst others, [[monocyte]]s, [[macrophage]]s, [[Schwann cells]], and [[dendritic cell]]s. They attach to the cell surfaces via specific [[receptor (biochemistry)|receptors]] and are taken up by an endosomal [[Vesicle (biology)|vesicle]].<ref>{{cite journal | vauthors = Vercammen E, Staal J, Beyaert R | title = Sensing of viral infection and activation of innate immunity by toll-like receptor 3 | journal = Clinical Microbiology Reviews | volume = 21 | issue = 1 | pages = 13–25 | date = January 2008 | pmid = 18202435 | pmc = 2223843 | doi = 10.1128/CMR.00022-07 }}</ref> Inside the [[endosome]], the decreased pH induces the fusion of the endosomal membrane with the [[virus envelope]].<ref>{{cite journal |last1=Zhang |first1=Xingwang |last2=Wu |first2=Wei |title=Ligand-mediated active targeting for enhanced oral absorption |journal=Drug Discovery Today |date=July 2014 |volume=19 |issue=7 |pages=898–904 |doi=10.1016/j.drudis.2014.03.001 |pmid=24631680 }}</ref> The [[capsid]] enters the [[cytosol]], decays, and releases the genome.<ref>{{cite journal | vauthors = Mudhakir D, Harashima H | title = Learning from the viral journey: how to enter cells and how to overcome intracellular barriers to reach the nucleus | journal = The AAPS Journal | volume = 11 | issue = 1 | pages = 65–77 | date = March 2009 | pmid = 19194803 | pmc = 2664881 | doi = 10.1208/s12248-009-9080-9 }}</ref> Receptor binding, as well as membrane fusion, are [[catalysis|catalyzed]] by the protein E, which changes its conformation at low pH, causing a rearrangement of the 90 homo[[protein dimer|dimer]]s to 60 homo[[protein trimer|trimer]]s.<ref name="pmid18796313"/><ref>{{cite journal | vauthors = Dhiman G, Abraham R, Griffin DE | title = Human Schwann cells are susceptible to infection with Zika and yellow fever viruses, but not dengue virus | journal = Scientific Reports | volume = 9 | issue = 1 | page = 9951 | date = July 2019 | pmid = 31289325 | pmc = 6616448 | doi = 10.1038/s41598-019-46389-0 | bibcode = 2019NatSR...9.9951D }}</ref>

After entering the host cell, the viral genome is replicated in the rough [[endoplasmic reticulum]] (ER) and in the so-called vesicle packets.<ref>{{cite journal | vauthors = Inoue T, Tsai B | title = How viruses use the endoplasmic reticulum for entry, replication, and assembly | journal = Cold Spring Harbor Perspectives in Biology | volume = 5 | issue = 1 | article-number = a013250 | date = January 2013 | pmid = 23284050 | pmc = 3579393 | doi = 10.1101/cshperspect.a013250 }}</ref> At first, an immature form of the virus particle is produced inside the ER, whose M-protein is not yet cleaved to its mature form, so is denoted as precursor M (prM) and forms a complex with protein E.<ref>{{cite journal | vauthors = Veesler D, Johnson JE | title = Virus maturation | journal = Annual Review of Biophysics | volume = 41 | pages = 473–496 | date = 2012 | pmid = 22404678 | pmc = 3607295 | doi = 10.1146/annurev-biophys-042910-155407 }}</ref> The immature particles are processed in the [[Golgi apparatus]] by the host protein [[furin]], which cleaves prM to M.<ref>{{cite journal | vauthors = Op De Beeck A, Molenkamp R, Caron M, Ben Younes A, Bredenbeek P, Dubuisson J | title = Role of the transmembrane domains of prM and E proteins in the formation of yellow fever virus envelope | journal = Journal of Virology | volume = 77 | issue = 2 | pages = 813–820 | date = January 2003 | pmid = 12502797 | pmc = 140810 | doi = 10.1128/JVI.77.2.813-820.2003 }}</ref> This releases E from the complex, which can now take its place in the mature, infectious [[virion]].<ref name="pmid18796313"/>

===Transmission===
[[File:Aedes aegypti bloodfeeding CDC Gathany.jpg|thumb|''Aedes aegypti'' feeding]]
[[File:Aedes aegypti E-A-Goeldi 1905.jpg|thumb|Adults of the yellow fever mosquito ''A. aegypti'': The male is on the left, females are on the right. Only the female mosquito bites humans to transmit the disease.]]

Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito ''Aedes aegypti'', but other mostly ''[[Aedes]]'' mosquitoes such as the tiger mosquito (''[[Aedes albopictus]]'') can also serve as a [[vector (epidemiology)|vector]] for this virus.<ref name="Yellow fever">{{Cite web |title=Yellow fever |url=https://www.who.int/news-room/fact-sheets/detail/yellow-fever |access-date=2022-04-24 |website=World Health Organization |language=en}}</ref> Like other [[arbovirus]]es, which are transmitted by mosquitoes, Yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or another primate.<ref name="who.int">{{Cite web |title=Yellow fever |url=https://www.who.int/health-topics/yellow-fever |access-date=2022-04-24 |website=World Health Organization |language=en}}</ref> Viruses reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect [[epithelial cell]]s and replicate there. From there, they reach the [[haemocoel]] (the blood system of mosquitoes) and from there the [[salivary gland]]s.<ref>{{cite journal | vauthors = Kumar A, Srivastava P, Sirisena P, Dubey SK, Kumar R, Shrinet J, Sunil S | title = Mosquito Innate Immunity | journal = Insects | volume = 9 | issue = 3 | page = 95 | date = August 2018 | pmid = 30096752 | pmc = 6165528 | doi = 10.3390/insects9030095 | doi-access = free }}</ref> When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person.<ref name="Monath Encyclopedia of Insects Yellow Fever">{{cite book |doi=10.1016/B978-0-12-374144-8.00279-4 |chapter=Yellow Fever |title=Encyclopedia of Insects |date=2009 |last1=Monath |first1=Thomas P. |pages=1064–1065 |isbn=978-0-12-374144-8 }}</ref> Transovarial transmissionial and [[transstadial transmission]] of yellow fever virus within ''A. aegypti'', that is, the transmission from a female mosquito to its eggs and then larvae, are indicated.<ref>{{cite journal | vauthors = Nag DK, Payne AF, Dieme C, Ciota AT, Kramer LD | title = Zika virus infects Aedes aegypti ovaries | journal = Virology | volume = 561 | pages = 58–64 | date = September 2021 | pmid = 34147955 | doi = 10.1016/j.virol.2021.06.002 | pmc = 10117528 | doi-access = free }}</ref> This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease.<ref>{{cite journal | vauthors = Fontenille D, Diallo M, Mondo M, Ndiaye M, Thonnon J | title = First evidence of natural vertical transmission of yellow fever virus in Aedes aegypti, its epidemic vector | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 91 | issue = 5 | pages = 533–535 | year = 1997 | pmid = 9463659 | doi = 10.1016/S0035-9203(97)90013-4 }}</ref>

Three epidemiologically different infectious cycles occur<ref name=Barr2007/> in which the virus is transmitted from mosquitoes to humans or other primates.<ref>{{cite web |title=Infectious Diseases Related to Travel |url=http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/yellow-fever |website=Yellow Book |publisher=Centers for Disease Control and Prevention |access-date=20 March 2016 |url-status=live |archive-url=https://web.archive.org/web/20160320215700/http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/yellow-fever |archive-date=20 March 2016}}</ref> In the "urban cycle", only the yellow fever mosquito ''A. aegypti'' is involved. It is well adapted to urban areas, and can also transmit other diseases, including [[Zika fever]], [[dengue fever]], and [[chikungunya]].<ref>{{cite journal |last1=Zerbo |first1=Alexandre |last2=Castro Delgado |first2=Rafael |last3=Arcos González |first3=Pedro |title=Aedes-borne viral infections and risk of emergence/resurgence in Sub-Saharan African urban areas |journal=Journal of Biosafety and Biosecurity |date=December 2020 |volume=2 |issue=2 |pages=58–63 |doi=10.1016/j.jobb.2020.10.002 |doi-access=free }}</ref> The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except for an outbreak in Bolivia in 1999, this urban cycle no longer exists in South America.<ref>{{Cite book | vauthors = Kotar SL, Gessler JE |url= https://books.google.com/books?id=odYBDgAAQBAJ&pg=PA7 |title=Yellow Fever: A Worldwide History |date=2017-02-03 |publisher=McFarland |isbn=978-1-4766-2628-4 |language=en}}</ref>

Besides the urban cycle, both in Africa and South America, a [[sylvatic cycle]] (forest or jungle cycle) is present, where ''[[Aedes africanus]]'' (in Africa) or mosquitoes of the genus ''[[Haemagogus]]'' and ''[[Sabethes]]'' (in South America) serve as vectors.<ref>{{cite book |doi=10.1016/B978-012373960-5.00385-3 |chapter=Yellow Fever, Historical |title=International Encyclopedia of Public Health |date=2008 |last1=Chastel |first1=C. |pages=665–675 |isbn=978-0-12-373960-5 }}</ref> In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates.<ref name="Monath Encyclopedia of Insects Yellow Fever"/> In South America, the sylvatic cycle is currently the only way unvaccinated humans can become infected, which explains the low incidence of yellow fever cases on the continent.<ref name="Yellow fever"/> People who become infected in the jungle can carry the virus to urban areas, where ''A. aegypti'' acts as a vector. Because of this sylvatic cycle, yellow fever cannot be eradicated except by completely eradicating the mosquitoes that serve as vectors.<ref name=Barr2007/>

In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles.<ref>{{EMedicine|article|232244|Yellow Fever}}</ref> Different mosquitoes of the genus ''Aedes'' are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa.<ref name="WHO_2001">{{cite web |title=Yellow fever fact sheet |work=WHO—Yellow fever |url=https://www.who.int/mediacentre/factsheets/fs100/en/ |access-date=2006-04-18 |url-status=live |archive-url=https://web.archive.org/web/20060418004055/http://www.who.int/mediacentre/factsheets/fs100/en/ |archive-date=2006-04-18 }}</ref>

Concern exists about yellow fever spreading to southeast Asia, where its vector ''A. aegypti'' already occurs.<ref>{{cite web |title=Ebola outbreak Alert and response operations Diseases Biorisk reduction Yellow fever: a current threat |url=https://www.who.int/csr/disease/yellowfev/impact1/en/ |website=WHO |access-date=4 August 2016 |archive-url=https://web.archive.org/web/20160808215707/http://www.who.int/csr/disease/yellowfev/impact1/en/ |archive-date=8 August 2016}}</ref>

==Pathogenesis==
After transmission from a mosquito, the viruses replicate in the [[lymph node]]s and infect [[dendritic cell]]s in particular. From there, they reach the liver and infect [[hepatocyte]]s (probably indirectly via [[Kupffer cell]]s), which leads to [[Eosinophil granulocyte|eosinophilic degradation]] of these cells and to the release of [[cytokine]]s. Apoptotic masses known as [[Councilman body|Councilman bodies]] appear in the [[cytoplasm]] of hepatocytes.<ref name=Sherris>{{cite book | veditors = Ryan KJ, Ray CG |title=Sherris Medical Microbiology |edition=4th |publisher=McGraw Hill |year=2004 |isbn=978-0-8385-8529-0 }}</ref><ref name="Quaresma_2006">{{cite journal | vauthors = Quaresma JA, Barros VL, Pagliari C, Fernandes ER, Guedes F, Takakura CF, Andrade HF, Vasconcelos PF, Duarte MI | display-authors = 6 | title = Revisiting the liver in human yellow fever: virus-induced apoptosis in hepatocytes associated with TGF-beta, TNF-alpha and NK cells activity | journal = Virology | volume = 345 | issue = 1 | pages = 22–30 | date = February 2006 | pmid = 16278000 | doi = 10.1016/j.virol.2005.09.058 | doi-access = free }}</ref>

Fatality may occur when [[cytokine storm]], [[Shock (circulatory)|shock]], and [[Multiple organ dysfunction syndrome|multiple organ failure]] follow.<ref name="pmid18061688"/>

==Diagnosis==
Yellow fever is most frequently a clinical [[diagnosis]], based on [[symptomatology]] and travel history. Mild cases of the disease can only be confirmed virologically.<ref name="who.int"/> Since mild cases of yellow fever can also contribute significantly to regional outbreaks, every suspected case of yellow fever (involving symptoms of fever, pain, nausea, and vomiting 6–10 days after leaving the affected area) is treated seriously.<ref name="who.int"/>

If yellow fever is suspected, the virus cannot be confirmed until 6–10 days following the illness. A direct confirmation can be obtained by [[reverse transcription polymerase chain reaction]], where the genome of the virus is amplified.<ref name=Toll2009/> Another direct approach is the isolation of the virus and its growth in cell culture using [[blood plasma]]; this can take 1–4 weeks.<ref>{{cite journal | vauthors = Leland DS, Ginocchio CC | title = Role of cell culture for virus detection in the age of technology | journal = Clinical Microbiology Reviews | volume = 20 | issue = 1 | pages = 49–78 | date = January 2007 | pmid = 17223623 | pmc = 1797634 | doi = 10.1128/CMR.00002-06 }}</ref><ref name="pmid17304460"/>

Serologically, an [[ELISA|enzyme-linked immunosorbent assay]] during the acute phase of the disease using specific [[IgM]] against yellow fever or an increase in specific [[Immunoglobulin G|IgG]] [[titer]] (compared to an earlier sample) can confirm yellow fever.<ref>{{cite journal | vauthors = Falconar AK, de Plata E, Romero-Vivas CM | title = Altered enzyme-linked immunosorbent assay immunoglobulin M (IgM)/IgG optical density ratios can correctly classify all primary or secondary dengue virus infections 1 day after the onset of symptoms, when all of the viruses can be isolated | journal = Clinical and Vaccine Immunology | volume = 13 | issue = 9 | pages = 1044–1051 | date = September 2006 | pmid = 16960117 | pmc = 1563575 | doi = 10.1128/CVI.00105-06 }}</ref> Together with clinical symptoms, the detection of IgM or a four-fold increase in IgG titer is considered sufficient indication for yellow fever. As these tests can cross-react with other flaviviruses, such as [[dengue virus]], these indirect methods cannot conclusively prove yellow fever infection.<ref>{{cite journal | vauthors = Houghton-Triviño N, Montaña D, Castellanos J | title = Dengue-yellow fever sera cross-reactivity; challenges for diagnosis | journal = Revista de Salud Publica | volume = 10 | issue = 2 | pages = 299–307 | date = March 2008 | pmid = 19039426 | doi = 10.1590/s0124-00642008000200010 | doi-access = free }}</ref>

Liver [[biopsy]] can verify [[inflammation]] and [[necrosis]] of hepatocytes and detect viral [[antigen]]s. Because of the bleeding tendency of yellow fever patients, a biopsy is only advisable ''post mortem'' to confirm the cause of death.<ref>{{cite journal | vauthors = Talwani R, Gilliam BL, Howell C | title = Infectious diseases and the liver | journal = Clinics in Liver Disease | volume = 15 | issue = 1 | pages = 111–130 | date = February 2011 | pmid = 21111996 | pmc = 3660095 | doi = 10.1016/j.cld.2010.09.002 }}</ref>

In a [[differential diagnosis]], infections with yellow fever must be distinguished from other feverish illnesses such as [[malaria]]. Other [[viral hemorrhagic fever]]s, such as [[Ebola virus]], [[Lassa virus]], [[Marburg virus]], and [[Junin virus]], must be excluded as the cause.<ref>{{cite journal | vauthors = Cleri DJ, Ricketti AJ, Porwancher RB, Ramos-Bonner LS, Vernaleo JR | title = Viral hemorrhagic fevers: current status of endemic disease and strategies for control | journal = Infectious Disease Clinics of North America | volume = 20 | issue = 2 | pages = 359–93, x | date = June 2006 | pmid = 16762743 | pmc = 7135140 | doi = 10.1016/j.idc.2006.02.001 }}</ref>

==Prevention==
Personal prevention of yellow fever includes vaccination and avoidance of mosquito bites in areas where yellow fever is endemic.<ref name="Yellow fever"/> Institutional measures for the prevention of yellow fever include vaccination programmes and measures to control mosquitoes. Programmes for distribution of mosquito nets for use in homes produce reductions in malaria and yellow fever. EPA-registered insect repellent is recommended when outdoors. Exposure for even a short time is enough for a potential mosquito bite. Long-sleeved clothing, long pants, and socks are useful for prevention. Applying larvicides to water-storage containers can help eliminate potential mosquito breeding sites. EPA-registered insecticide spray decreases the transmission of yellow fever.<ref>{{Cite web |url=https://www.cdc.gov/yellowfever/prevention/ |title=Prevention {{!}} Yellow Fever {{!}} CDC |website=www.cdc.gov |access-date=2016-10-26 |url-status=live |archive-url=https://web.archive.org/web/20161026165250/http://www.cdc.gov/yellowfever/prevention/ |archive-date=2016-10-26}}</ref>
* Use insect repellent when outdoors such as those containing [[DEET]], [[picaridin]], [[ethyl butylacetylaminopropionate]] (IR3535), or [[oil of lemon eucalyptus]] on exposed skin.<ref>{{Cite journal | vauthors = Lo WL, Mok KL, Yu Pui Ming SD |date=September 2018 |title=Which insect repellents should we choose? Implications from results of local market survey and review of current guidelines |journal=Hong Kong Journal of Emergency Medicine |volume=25 |issue=5 |pages=272–280 |doi=10.1177/1024907918773630 |doi-access=free }}</ref>
* Mosquitoes may bite through thin clothing, so spraying clothes with repellent containing [[permethrin]] or another EPA-registered repellent gives extra protection.<ref>{{Cite book | vauthors = Shmaefsky BR |url= https://books.google.com/books?id=9k2Z3UlFeZQC&pg=PA62 |title=Yellow Fever |date= November 2009 |publisher=Infobase Publishing |isbn=978-1-60413-231-1 |language=en}}</ref> Clothing treated with permethrin is commercially available. Mosquito repellents containing permethrin are not approved for application directly to the skin.<ref>{{Cite web |last=US EPA |first=OCSPP |date=2013-07-15 |title=Repellent-Treated Clothing |url=https://www.epa.gov/insect-repellents/repellent-treated-clothing |access-date=2022-04-25 |website=[[United States Environmental Protection Agency]] |language=en}}</ref>
* The peak biting times for many mosquito species are dusk to dawn. However, ''A. aegypti'', one of the mosquitoes that transmit yellow fever virus, feeds during the daytime.<ref name="Frequently Asked Questions">{{Cite web |date=2020-02-26 |title=Frequently Asked Questions |url=https://www.cdc.gov/yellowfever/qa/index.html |access-date=2022-04-25 |website=www.cdc.gov |language=en-us}}</ref> Staying in accommodations with screened or air-conditioned rooms, particularly during peak biting times, also reduces the risk of mosquito bites.<ref name="Frequently Asked Questions"/>

===Vaccination===
{{Main|Yellow fever vaccine}}
[[File:Yellow fever certificate.JPG|thumb|The [[Carte Jaune|cover of a certificate]] that confirms the holder has been vaccinated against yellow fever|upright]]
[[File:Yellow fever vaccination travel requirements map.svg|thumb|400px|[[Yellow fever vaccine|Vaccination against yellow fever]] 10 days before entering this country/territory is required for travellers coming from...<ref name="WHO country list">{{Cite web |url=https://www.who.int/publications/m/item/countries-with-risk-of-yellow-fever-transmission-and-countries-requiring-yellow-fever-vaccination-(may-2021) |title=Countries with risk of yellow fever transmission and countries requiring yellow fever vaccination (May 2021) |work=World Health Organization |publisher=United Nations |date=26 May 2021 |access-date=16 January 2022}}</ref>
{{Legend|#008000|All countries}}
{{Legend|#00FF00|Risk countries (including airport transfers){{refn|group=note|name=transit explanation|Also required for travellers having transited (more than 12 hours) through a risk country's airport.}}}}
{{Legend|#FFFF00|Risk countries (excluding airport transfers){{refn|group=note|name=no transit|Not required for travellers having transited through a risk country's airport.}}}}
{{Legend|#D35F5F|No requirement (risk country){{refn|group=note|name=ArBrPe|The WHO has designated (parts of) Argentina, Brazil, and Peru as risk countries, but these countries do not require incoming travellers to vaccinate against yellow fever.}}}}
{{Legend|#C0C0C0|No requirement (non-risk country)}}]]

[[Vaccination]] is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people,<ref name="pmid19520559">{{cite journal | vauthors = Barrett AD, Teuwen DE | title = Yellow fever vaccine - how does it work and why do rare cases of serious adverse events take place? | journal = Current Opinion in Immunology | volume = 21 | issue = 3 | pages = 308–313 | date = June 2009 | pmid = 19520559 | doi = 10.1016/j.coi.2009.05.018 }}</ref> and had been reported to last for at least 10 years. The [[World Health Organization]] (WHO) now states that a single dose of vaccine is sufficient to confer lifelong immunity against yellow fever disease.<ref>[https://www.who.int/mediacentre/news/releases/2013/yellow_fever_20130517/en/ WHO | Yellow fever vaccination booster not needed] {{webarchive|url=https://web.archive.org/web/20130609154615/http://www.who.int/mediacentre/news/releases/2013/yellow_fever_20130517/en/ |date=2013-06-09 }}. Who.int (2013-05-17). Retrieved on 2014-05-12.</ref> The attenuated live vaccine stem 17D was developed in 1937 by [[Max Theiler]].<ref name="pmid19520559"/> The WHO recommends routine vaccination for people living in affected areas between the 9th and 12th month after birth.<ref name=Toll2009/>

Up to one in four people experience fever, aches, local soreness, and redness at the injection site.<ref>[https://www.cdc.gov/vaccines/hcp/vis/vis-statements/yf.html Yellow Fever Vaccine Information Statement.] {{webarchive|url=https://web.archive.org/web/20130921061606/http://www.cdc.gov/vaccines/hcp/vis/vis-statements/yf.html |date=2013-09-21 }} Centers for Disease Control and Prevention. March 30, 2011.</ref> In rare cases (less than one in 200,000 to 300,000),<ref name="pmid19520559"/> the vaccination can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to [[meningoencephalitis]] and is fatal in less than 5%<ref name="pmid19520559"/> of cases.<ref name=Toll2009/><ref name="pmid18061688"/>

The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105&nbsp;million people in 14 countries in West Africa.<ref>{{cite web |title=Yellow fever |url=https://www.who.int/mediacentre/factsheets/fs100/en/ |website=World Health Organization |access-date=2 April 2017 |url-status=live |archive-url=https://web.archive.org/web/20170418024142/http://www.who.int/mediacentre/factsheets/fs100/en/ |archive-date=18 April 2017}}</ref> No outbreaks were reported during 2015. The campaign was supported by the [[GAVI]] alliance and governmental organizations in Europe and Africa.<ref>{{Cite web |title=Measles vaccination has saved an estimated 17.1 million lives since 2000 |url=https://www.who.int/news/item/12-11-2015-measles-vaccination-has-saved-an-estimated-17-1-million-lives-since-2000 |access-date=2022-04-25 |website=World Health Organization |language=en}}</ref> According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected.<ref name=BBC_vaccination>{{cite news |url=https://news.bbc.co.uk/2/hi/africa/8373960.stm |title=Twelve million West Africans get yellow fever vaccines |date=23 November 2009 |work=BBC News |access-date=23 November 2009 |url-status=live |archive-url=https://web.archive.org/web/20170908222719/http://news.bbc.co.uk/1/hi/world/africa/8373960.stm |archive-date=8 September 2017}}</ref>

Demand for yellow fever vaccines has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes.<ref name=WHO2016>{{cite web |title=Fractional Dose Yellow Fever Vaccine as a Dose-sparing Option for Outbreak Response. WHO Secretariat Information Paper. Department of Immunization, Vaccines and Biologicals. WHO reference number: WHO/YF/SAGE/16.1. |url=http://apps.who.int/iris/bitstream/handle/10665/246236/WHO-YF-SAGE-16.1-eng.pdf;jsessionid=F4BD11CEBB8426D52C781267F9795A8A?sequence=1 |date=20 July 2016 |publisher=World Health Organization |access-date=2 September 2018}}</ref> Recent upsurges in yellow fever outbreaks in Angola (2015), the Democratic Republic of Congo (2016), Uganda (2016), and more recently in Nigeria and Brazil in 2017 have further increased demand, while straining global vaccine supply.<ref name=WHO2016 /><ref>{{cite web |title=WHO supports the immunization of 874,000 people against yellow fever in Nigeria. News Release. |url=https://www.who.int/mediacentre/news/releases/2017/immunization-yellowfever-nigeria/en/ |date=16 October 2017 |publisher=World Health Organization |access-date=2 September 2018}}</ref> Therefore, to vaccinate susceptible populations in preventive mass immunization campaigns during outbreaks, [[Fractional dose vaccination|fractional dosing]] of the vaccine is being considered as a dose-sparing strategy to maximize limited vaccine supplies.<ref name=WHO2016 /> Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations.<ref name=WHO2016 /><ref name="pmid28596091">{{cite journal | author = World Health Organization | title = Human papillomavirus vaccines: WHO position paper, May 2017-Recommendations | journal = Vaccine | volume = 35 | issue = 43 | pages = 5753–5755 | date = October 2017 | pmid = 28596091 | doi = 10.1016/j.vaccine.2017.05.069 }}</ref> The first practical use of fractional dose yellow fever vaccination was in response to a large yellow fever outbreak in the Democratic Republic of the Congo in mid-2016.<ref name=WHO2016 /> Available evidence shows that fractional dose yellow fever vaccination induces a level of immune response similar to that of the standard full dose.<ref name="pmid31859201">{{cite journal |vauthors=Nnaji CA, Shey MS, Adetokunboh OO, Wiysonge CS | title = Immunogenicity and safety of fractional dose yellow fever vaccination: A systematic review and meta-analysis | journal = Vaccine | volume = 38 | issue = 6 | pages = 1291–1301 | date = February 2020 | pmid = 31859201 | doi = 10.1016/j.vaccine.2019.12.018 }}</ref>

In March 2017, the WHO launched a vaccination campaign in Brazil with 3.5&nbsp;million doses from an emergency stockpile.<ref>{{cite web |title=WHO dispatched 3.5 million doses of yellow fever vaccine for outbreak response in Brazil |url=https://www.who.int/csr/disease/yellowfev/vaccination-in-Brazil/en/ |website=World Health Organization |access-date=2 April 2017 |url-status=live |archive-url=https://web.archive.org/web/20170401134133/http://www.who.int/csr/disease/yellowfev/vaccination-in-Brazil/en/ |archive-date=1 April 2017}}</ref> In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil.<ref name="Yellow fever – Brazil">{{cite journal |title=Yellow fever – Brazil |journal=Nature |volume=150 |issue=3811 |page=573 |bibcode=1942Natur.150T.573. |year=1942 |doi=10.1038/150573d0 |doi-access=free}}</ref> In March 2018, Brazil shifted its policy and announced it planned to vaccinate all 77.5&nbsp;million currently unvaccinated citizens by April 2019.<ref>{{cite news | vauthors = Darlington S |title=Fearing New Outbreaks, Brazil Will Vaccinate Country Against Yellow Fever |url=https://www.nytimes.com/2018/03/20/world/americas/yellow-fever-brazil-vaccinate.html |access-date=21 March 2018 |work=The New York Times |date=20 March 2018}}</ref>

====Compulsory vaccination====
Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present.<ref>{{cite journal | vauthors = Kuno G | title = The Absence of Yellow Fever in Asia: History, Hypotheses, Vector Dispersal, Possibility of YF in Asia, and Other Enigmas | journal = Viruses | volume = 12 | issue = 12 | page = 1349 | date = November 2020 | pmid = 33255615 | pmc = 7759908 | doi = 10.3390/v12121349 | doi-access = free }}</ref> The disease does not yet occur in Asia. To prevent the introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas.<ref>{{cite journal | vauthors = Wasserman S, Tambyah PA, Lim PL | title = Yellow fever cases in Asia: primed for an epidemic | journal = International Journal of Infectious Diseases | volume = 48 | pages = 98–103 | date = July 2016 | pmid = 27156836 | doi = 10.1016/j.ijid.2016.04.025 | doi-access = free | hdl = 10220/47081 | hdl-access = free }}</ref> Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO.<ref name="WHO country list"/> If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated.<ref name=Toll2009/>

===Vector control===
[[File:Luchemos todos contra el dengue.jpg|thumb|left|Information campaign for prevention of [[dengue]] and yellow fever in [[Paraguay]]]]

Control of the yellow fever mosquito ''A. aegypti'' is of major importance, especially because the same mosquito can also transmit [[dengue]] fever and [[chikungunya]] disease.<ref>{{Cite web |title=Vector-borne diseases |url=https://www.who.int/news-room/fact-sheets/detail/vector-borne-diseases |access-date=2022-04-25 |website=World Health Organization |language=en}}</ref> ''A. aegypti'' breeds preferentially in water, for example, in installations by inhabitants of areas with precarious drinking water supplies, or in domestic refuse, especially tires, cans, and plastic bottles. These conditions are common in urban areas in developing countries.<ref>{{Cite web |title=Humanitarian emergencies |url=https://www.who.int/teams/environment-climate-change-and-health/water-sanitation-and-health/environmental-health-in-emergencies/humanitarian-emergencies |access-date=2022-04-25 |website=World Health Organization |language=en}}</ref>

Two main strategies are employed to reduce ''A. aegypti'' populations.<ref>{{cite journal | vauthors = Singh RK, Dhama K, Khandia R, Munjal A, Karthik K, Tiwari R, Chakraborty S, Malik YS, Bueno-Marí R | display-authors = 6 | title = Prevention and Control Strategies to Counter Zika Virus, a Special Focus on Intervention Approaches against Vector Mosquitoes-Current Updates | journal = Frontiers in Microbiology | volume = 9 | page = 87 | date = 2018 | pmid = 29472902 | doi = 10.3389/fmicb.2018.00087 | pmc = 5809424 | doi-access = free }}</ref> One approach is to kill the developing larvae. Measures are taken to reduce the water accumulations in which the larvae develop. [[Larvicide]]s are used, along with larvae-eating fish and [[copepod]]s, which reduce the number of larvae.<ref>{{Cite web |last=US EPA |first=OCSPP |date=2013-02-21 |title=Controlling Mosquitoes at the Larval Stage |url=https://www.epa.gov/mosquitocontrol/controlling-mosquitoes-larval-stage |access-date=2022-04-25 |website=[[United States Environmental Protection Agency]] |language=en}}</ref> For many years, copepods of the genus ''[[Mesocyclops]]'' have been used in [[Vietnam]] for preventing dengue fever.<ref>{{cite journal | vauthors = Tran TT, Olsen A, Viennet E, Sleigh A | title = Social sustainability of Mesocyclops biological control for dengue in South Vietnam | journal = Acta Tropica | volume = 141 | issue = Pt A | pages = 54–59 | date = January 2015 | pmid = 25312335 | doi = 10.1016/j.actatropica.2014.10.006 | doi-access = free }}</ref> This eradicated the mosquito vector in several areas. Similar efforts may prove effective against yellow fever. [[Pyriproxyfen]] is recommended as a chemical larvicide, mainly because it is safe for humans and effective in small doses.<ref name=Toll2009/>

The second strategy is to reduce populations of the adult yellow fever mosquito. [[Lethal ovitrap]]s can reduce ''Aedes'' populations, using lesser amounts of pesticide because it targets the pest directly.<ref>{{cite journal | vauthors = Hustedt JC, Boyce R, Bradley J, Hii J, Alexander N | title = Use of pyriproxyfen in control of Aedes mosquitoes: A systematic review | journal = PLOS Neglected Tropical Diseases | volume = 14 | issue = 6 | article-number = e0008205 | date = June 2020 | pmid = 32530915 | pmc = 7314096 | doi = 10.1371/journal.pntd.0008205 | doi-access = free }}</ref> Curtains and lids of water tanks can be sprayed with [[insecticide]]s, but application inside houses is not recommended by the WHO.<ref>{{cite journal | vauthors = Pérez D, Van der Stuyft P, Toledo ME, Ceballos E, Fabré F, Lefèvre P | title = Insecticide treated curtains and residual insecticide treatment to control Aedes aegypti: An acceptability study in Santiago de Cuba | journal = PLOS Neglected Tropical Diseases | volume = 12 | issue = 1 | article-number = e0006115 | date = January 2018 | pmid = 29293501 | pmc = 5766245 | doi = 10.1371/journal.pntd.0006115 | doi-access = free }}</ref> Insecticide-treated [[mosquito net]]s are effective, just as they are against the ''[[Anopheles]]'' mosquito that carries malaria.<ref name=Toll2009/>

==Treatment==
As with other ''Flavivirus'' infections, no cure is known for yellow fever. Hospitalization is advisable and intensive care may be necessary because of rapid deterioration in some cases. Certain acute treatment methods lack efficacy: [[passive immunization]] after the emergence of symptoms is probably without effect; [[ribavirin]] and other [[antiviral drug]]s, as well as treatment with [[interferon]]s, are ineffective in yellow fever patients.<ref name="pmid18061688"/> Symptomatic treatment includes rehydration and pain relief with drugs such as [[paracetamol]] (acetaminophen). However, [[Acetylsalicylic acid|aspirin]] and other [[Nonsteroidal anti-inflammatory drug|non-steroidal anti-inflammatory drugs]] (NSAIDs) are often avoided because of an increased risk of gastrointestinal bleeding due to their anticoagulant effects.<ref>{{Cite web|vauthors=Sterk E|date=January 2013|title=Yellow Fever Case Management|url=https://bibop.ocg.msf.org/docs/3/L003YEFM03E-E_YellowFeverMFS2013.pdf|access-date=6 May 2021|website=OCG BibOp|publisher=Médecins Sans Frontières|quote=NSAIDS need to be avoided because of the risk of gastrointestinal bleeding and the anti-platelet effect (aspirin).|archive-date=6 May 2021|archive-url=https://web.archive.org/web/20210506164323/https://bibop.ocg.msf.org/docs/3/L003YEFM03E-E_YellowFeverMFS2013.pdf}}</ref>

==Epidemiology==
Yellow fever is [[Endemic (epidemiology)|common]] in tropical and subtropical areas of South America and Africa.<ref>{{cite book | vauthors = Simon LV, Hashmi MF, Torp KD | chapter = Yellow Fever |date=2022 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK470425/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29262028 |access-date=2022-04-25 }}</ref> Worldwide, about 600 million people live in endemic areas. The WHO estimates 200,000 cases of yellow fever worldwide each year.<ref>{{Cite web |date=2019-02-19 |title=Global Health - Newsroom - Yellow Fever |url=https://www.cdc.gov/globalhealth/newsroom/topics/yellowfever/index.html |access-date=2022-04-25 |website=www.cdc.gov |language=en-us}}</ref> About 15% of people infected with yellow fever progress to a severe form of the illness, and up to half of those will die, as there is no cure for yellow fever.<ref>{{Cite web|title=Yellow fever vaccination booster not needed|url=https://www.who.int/news/item/17-05-2013-yellow-fever-vaccination-booster-not-needed|access-date=2021-10-09|website=World Health Organization|language=en}}</ref>

===Africa===
[[File:Yellow fever Africa 2009.jpeg|thumb|upright=1.2|Areas with risk of yellow fever in Africa (2017)]]

An estimated 90% of yellow fever infections occur on the African continent.<ref name=Toll2009/> In 2016, [[2016 Angola and DR Congo yellow fever outbreak|a large outbreak originated in Angola]] and spread to neighboring countries before being contained by a massive vaccination campaign.<ref>{{Cite web |title=Mass vaccination campaign to protect millions against yellow fever in Angola and the Democratic Republic of the Congo |url=https://www.who.int/news-room/feature-stories/detail/mass-vaccination-campaign-to-protect-millions-against-yellow-fever-in-angola-and-democratic-republic-of-the-congo |access-date=2022-04-25 |website=World Health Organization |language=en}}</ref> In March and April 2016, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first appearance of the disease in Asia in recorded history.<ref>{{cite web |title=Yellow Fever – China |url=https://www.who.int/csr/don/22-april-2016-yellow-fever-china/en/ |website=World Health Organization |access-date=9 February 2017 |archive-url=https://web.archive.org/web/20170319162041/http://who.int/csr/don/22-april-2016-yellow-fever-china/en/ |archive-date=19 March 2017}}</ref><ref>{{cite journal | vauthors = Woodall JP, Yuill TM | title = Why is the yellow fever outbreak in Angola a 'threat to the entire world'? | journal = International Journal of Infectious Diseases | volume = 48 | pages = 96–97 | date = July 2016 | pmid = 27163382 | doi = 10.1016/j.ijid.2016.05.001 | doi-access = free }}</ref>

[[Phylogenetic]] analysis has identified seven [[genotype]]s of yellow fever viruses, and they are assumed to be differently adapted to humans and to the vector ''A. aegypti''. Five genotypes (Angola, Central/East Africa, East Africa, West Africa I, and West Africa II) occur only in Africa. West Africa genotype I is found in [[Nigeria]] and the surrounding region.<ref name=Mutebi2002>{{cite journal | vauthors = Mutebi JP, Barrett AD | title = The epidemiology of yellow fever in Africa | journal = Microbes and Infection | volume = 4 | issue = 14 | pages = 1459–1468 | date = November 2002 | pmid = 12475636 | doi = 10.1016/S1286-4579(02)00028-X }}</ref> West Africa genotype I appears to be especially infectious, as it is often associated with major outbreaks. The three genotypes found outside of Nigeria and Angola occur in areas where outbreaks are rare. Two outbreaks, in Kenya (1992–1993) and Sudan (2003 and 2005), involved the East African genotype, which had remained undetected in the previous 40 years.<ref name=Ellis2008>{{cite journal | vauthors = Ellis BR, Barrett AD | title = The enigma of yellow fever in East Africa | journal = Reviews in Medical Virology | volume = 18 | issue = 5 | pages = 331–346 | year = 2008 | pmid = 18615782 | doi = 10.1002/rmv.584 }}</ref>

===South America===
[[File:Yellow fever South America 2009.jpeg|thumb|upright=1.2|Areas with risk of yellow fever in South America (2018)]]

In South America, two genotypes have been identified (South American genotypes I and II).<ref name=Barr2007/> Based on phylogenetic analysis these two genotypes appear to have originated in West Africa<ref name="Mutebi2004">{{cite journal | vauthors = Mutebi JP, Rijnbrand RC, Wang H, Ryman KD, Wang E, Fulop LD, Titball R, Barrett AD | display-authors = 6 | title = Genetic relationships and evolution of genotypes of yellow fever virus and other members of the yellow fever virus group within the Flavivirus genus based on the 3' noncoding region | journal = Journal of Virology | volume = 78 | issue = 18 | pages = 9652–9665 | date = September 2004 | pmid = 15331698 | pmc = 515011 | doi = 10.1128/JVI.78.18.9652-9665.2004 }}</ref> and were first introduced into Brazil.<ref name="Auguste2010">{{cite journal | vauthors = Auguste AJ, Lemey P, Pybus OG, Suchard MA, Salas RA, Adesiyun AA, Barrett AD, Tesh RB, Weaver SC, Carrington CV | display-authors = 6 | title = Yellow fever virus maintenance in Trinidad and its dispersal throughout the Americas | journal = Journal of Virology | volume = 84 | issue = 19 | pages = 9967–9977 | date = October 2010 | pmid = 20631128 | pmc = 2937779 | doi = 10.1128/JVI.00588-10 }}</ref> The date of introduction of the predecessor African genotype which gave rise to the South American genotypes appears to be 1822 (95% confidence interval 1701 to 1911).<ref name="Auguste2010"/> The historical record shows an outbreak of yellow fever occurred in Recife, Brazil, between 1685 and 1690. The disease seems to have disappeared, with the next outbreak occurring in 1849.<ref>{{Cite book | vauthors = Bhattacharya A |url=https://books.google.com/books?id=b6ynBQAAQBAJ&pg=PA92 |title=A REVIEW ON VIRAL HEMORRHAGIC FEVER | date=7 June 2013 |publisher=Lulu.com |isbn=978-1-304-11397-9 |language=en}}</ref> It was likely introduced with the trafficking of slaves through the [[Atlantic slave trade|slave trade]] from Africa. Genotype I has been divided into five subclades, A through E.<ref name=deSouza2010>{{cite journal | vauthors = de Souza RP, Foster PG, Sallum MA, Coimbra TL, Maeda AY, Silveira VR, Moreno ES, da Silva FG, Rocco IM, Ferreira IB, Suzuki A, Oshiro FM, Petrella SM, Pereira LE, Katz G, Tengan CH, Siciliano MM, Dos Santos CL | display-authors = 6 | title = Detection of a new yellow fever virus lineage within the South American genotype I in Brazil | journal = Journal of Medical Virology | volume = 82 | issue = 1 | pages = 175–185 | date = January 2010 | pmid = 19950229 | doi = 10.1002/jmv.21606 }}</ref>

In late 2016, a large outbreak began in [[Minas Gerais]] state of Brazil that was characterized as a sylvatic or jungle [[epizootic]].<ref name="Faria2017">{{cite web |vauthors = Faria NR | title = Real-time Genomic Surveillance of the Yellow Fever Virus Outbreak in Brazil, 2017 |website=Virological | date = May 2017 |url=https://virological.org/t/real-time-genomic-surveillance-of-the-yellow-fever-virus-outbreak-in-brazil-2017/182}}</ref>  Real-time phylogenetic investigations at the epicentre of the outbreak revealed that the outbreak was caused by the introduction of a virus lineage from the Amazon region into the southeast region around July 2016,<ref name="Faria2018">{{cite journal |vauthors = Faria NR, Kraemer MU, Hill SH, Goes de Jesus J, Aguiar RS, Iani FC, etal | title = Genomic and epidemiological monitoring of yellow fever virus transmission potential | journal = Science | volume = 361 | issue = 6405 | pages = 894–899 | date = August 2018 | pmid = 30139911 | pmc = 6874500 | doi =  10.1126/science.aat7115| bibcode = 2018Sci...361..894F }}</ref> spreading rapidly across several neotropical monkey species, including [[brown howler]] monkeys,<ref>{{cite web |title=Yellow fever killing thousands of monkeys in Brazil |url=https://www.sciencedaily.com/releases/2017/03/170322155611.htm |website=www.sciencedaily.com |access-date=24 March 2017 |url-status=live |archive-url=https://web.archive.org/web/20170324174443/https://www.sciencedaily.com/releases/2017/03/170322155611.htm |archive-date=24 March 2017}}</ref> which serve as a [[sentinel species]] for yellow fever. No cases had been transmitted between humans by the ''A. aegypti'' mosquito, which can sustain urban outbreaks that can spread rapidly. In April 2017, the sylvatic outbreak continued moving toward the Brazilian coast, where most people were unvaccinated.<ref name="Yellow fever – Brazil"/> By the end of May the outbreak appeared to be declining after more than 3,000 suspected cases, 758 confirmed and 264 deaths confirmed to be yellow fever.<ref>{{cite web |title=ProMED-mail post Yellow fever - Americas (47): Brazil, PAHO/WHO |url=http://www.promedmail.org/post/5071826 |website=www.promedmail.org |publisher=International Society for Infectious Diseases |access-date=1 June 2017 |language=en |url-status=live |archive-url=https://web.archive.org/web/20170908222719/http://www.promedmail.org/post/5071826 |archive-date=8 September 2017}}</ref> The Health Ministry launched a vaccination campaign and was concerned about spread during the [[Carnival]] season in February and March.<ref>{{Cite web |title=Yellow fever cases continue to rise {{!}} Pulse Nigeria |url=https://www.pulse.ng/articles/news/local/in-brazil-yellow-fever-cases-continue-to-rise-2024080219533133916 |access-date=2025-11-08 |website=www.pulse.ng |language=en}}</ref> The CDC issued a [[Centers for Disease Control and Prevention#Travelers' Health|Level 2 alert (practice enhanced precautions.)]]<ref>{{cite web |title=Yellow Fever in Brazil – Alert – Level 2, Practice Enhanced Precautions – Travel Health Notices {{!}} Travelers' Health {{!}} CDC |url=https://wwwnc.cdc.gov/travel/notices/alert/yellow-fever-brazil |website=wwwnc.cdc.gov |access-date=1 June 2017 |language=en-us |url-status=live |archive-url=https://web.archive.org/web/20170525133831/https://wwwnc.cdc.gov/travel/notices/alert/yellow-fever-brazil |archive-date=25 May 2017}}</ref>

A Bayesian analysis of genotypes I and II has shown that genotype I accounts for virtually all the current infections in [[Brazil]], [[Colombia]], [[Venezuela]], and [[Trinidad]] and [[Tobago]], while genotype II accounted for all cases in [[Peru]].<ref name="Mir2017">{{cite journal | vauthors = Mir D, Delatorre E, Bonaldo M, Lourenço-de-Oliveira R, Vicente AC, Bello G | title = Phylodynamics of Yellow Fever Virus in the Americas: new insights into the origin of the 2017 Brazilian outbreak | journal = Scientific Reports | volume = 7 | issue = 1 | page = 7385 | date = August 2017 | pmid = 28785067 | pmc = 5547128 | doi = 10.1038/s41598-017-07873-7 | bibcode = 2017NatSR...7.7385M }}</ref> Genotype I originated in the northern Brazilian region around 1908 (95% highest posterior density interval [HPD]: 1870–1936). Genotype II originated in Peru in 1920 (95% HPD: 1867–1958).<ref name="Mir2017"/> The estimated rate of mutation for both genotypes was about 5 × 10<sup>−4</sup> substitutions/site/year, similar to that of other RNA viruses.<ref name="Mir2017"/>

===Asia===
The main vector (''A. aegypti'') also occurs in tropical and subtropical regions of Asia, the Pacific, and Australia, but yellow fever had never occurred there until jet travel introduced 11 cases from the [[2016 Angola and DR Congo yellow fever outbreak]] in Africa. Proposed explanations include:<ref>{{cite journal | vauthors = Lataillade LG, Vazeille M, Obadia T, Madec Y, Mousson L, Kamgang B, Chen CH, Failloux AB, Yen PS | display-authors = 6 | title = Risk of yellow fever virus transmission in the Asia-Pacific region | journal = Nature Communications | volume = 11 | issue = 1 | page = 5801 | date = November 2020 | pmid = 33199712 | pmc = 7669885 | doi = 10.1038/s41467-020-19625-9 | bibcode = 2020NatCo..11.5801L }}</ref>
* That the strains of the mosquito in the east are less able to transmit Yellow fever virus.{{citation needed|date=November 2024}}
* That immunity is present in the populations because of other diseases caused by related viruses (for example, [[dengue]]).<ref>{{Cite web |title=Dengue and severe dengue |url=https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue |access-date=2022-04-25 |website=World Health Organization |language=en}}</ref>
* That the disease was never introduced because the shipping trade was insufficient.

But none is considered satisfactory.<ref>{{cite book | veditors = Vainio J, Cutts F |title=Yellow Fever |publisher=WHO Division of Emerging and other Communicable Diseases Surveillance and Control |year=1998  }}</ref><ref>{{cite journal | vauthors = Monath TP |title= The absence of yellow fever in Asia: hypotheses. A cause for concern? |journal= Virus Inf Exch Newslett |pages=106–7 |date= 1989 }}</ref> Another proposal is the absence of a slave trade to Asia on the scale of that to the Americas.<ref name="Cathey2014">{{cite journal | vauthors = Cathey JT, Marr JS | title = Yellow fever, Asia and the East African slave trade | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 108 | issue = 5 | pages = 252–257 | date = May 2014 | pmid = 24743951 | doi = 10.1093/trstmh/tru043 }}</ref> The [[trans-Atlantic slave trade]] probably introduced yellow fever into the Western Hemisphere from Africa.<ref name="Bryant2007">{{cite journal | vauthors = Bryant JE, Holmes EC, Barrett AD | title = Out of Africa: a molecular perspective on the introduction of yellow fever virus into the Americas | journal = PLOS Pathogens | volume = 3 | issue = 5 | page = e75 | date = May 2007 | pmid = 17511518 | pmc = 1868956 | doi = 10.1371/journal.ppat.0030075 | doi-access = free }}</ref>

==History==
{{Main|History of yellow fever}}

===Early history===
[[File:Affinerie des sucres (1).JPG|thumb|Sugar curing house, 1762: Sugar pots and jars on sugar plantations served as breeding place for larvae of ''A. aegypti'', the vector of yellow fever.]]
[[File:Yellow Fever Deaths Lafayette Cemetery 1 New Orleans.jpg|thumb|Headstones of people who died in the [[History of yellow fever#Lower Mississippi Valley: 1878|yellow fever epidemic of 1878]] can be found in New Orleans' cemeteries.]]
[[File:James Biddle to Sec Nav Thompson re deaths aboard USS Macedonian 3 August 1822 p 1.jpg|thumb|upright|A page from Commodore James Biddle's list of the 76 dead (74 of yellow fever) aboard the USS ''Macedonian'', dated 3 August 1822]]

The evolutionary origins of yellow fever most likely lie in Africa, with transmission of the disease from nonhuman primates to humans.<ref name="pmid14696332">{{cite book |vauthors=Gould EA, de Lamballerie X, Zanotto PM, Holmes EC |title=Origins, evolution, coadaptations within the genus Flavivirus |series=Advances in Virus Research |volume=59 |pages=277–314 |year=2003 |pmid=14696332 |doi=10.1016/S0065-3527(03)59008-X |isbn=978-0-12-039859-1 }}</ref><ref name="Bryant2007"/> The virus is thought to have originated in East or Central Africa and spread from there to West Africa. As it was endemic in Africa, local populations had developed some immunity to it. When an outbreak of yellow fever would occur in an African community where colonists resided, most Europeans died, while the indigenous Africans usually developed nonlethal symptoms resembling [[influenza]].<ref name=Old2009/> This phenomenon, in which certain populations develop immunity to yellow fever due to prolonged exposure in their childhood, is known as [[acquired immunity]].<ref>{{cite book | vauthors = McNeill JR |title=Mosquito Empires: Ecology and war in the greater Caribbean, 1620–1914 |url=https://archive.org/details/mosquitoempirese00mcne |url-access=limited |year=2010 |publisher=Cambridge University Press |location=NY |pages=[https://archive.org/details/mosquitoempirese00mcne/page/n63 44]–45}}</ref> The virus, as well as the vector ''A. aegypti,'' were probably transferred to North and South America with the trafficking of [[Atlantic slave trade|slaves]] from Africa, part of the [[Columbian exchange]] following European exploration and colonization.<ref name="pmid30158957">{{cite journal | vauthors = Chippaux JP, Chippaux A | title = Yellow fever in Africa and the Americas: a historical and epidemiological perspective | journal = The Journal of Venomous Animals and Toxins Including Tropical Diseases | volume = 24 | issue = | page = 20 | date = 2018 | pmid = 30158957 | pmc = 6109282 | doi = 10.1186/s40409-018-0162-y | doi-access = free }}</ref> However, some researchers have argued that yellow fever might have existed in the Americas during the pre-Columbian period as mosquitoes of the genus ''Haemagogus'', which is indigenous to the Americas, have been known to carry the disease.<ref>{{cite journal |last1=Wilkinson |first1=Robert L. |title=Yellow fever: Ecology, epidemiology, and role in the collapse of the Classic lowland Maya civilization |journal=Medical Anthropology |date=November 1994 |volume=16 |issue=1–4 |pages=269–294 |doi=10.1080/01459740.1994.9966118 |pmid=8643025 }}</ref>

The first definitive outbreak of yellow fever in the New World was in 1647 on the island of [[Barbados]].<ref name=mcneill>{{cite journal |last1=McNeill |first1=J. R. |title=Yellow Jack and Geopolitics: Environment, Epidemics, and the Struggles for Empire in the American Tropics, 1650-1825 |journal=OAH Magazine of History |date=April 2004 |volume=18 |issue=3 |pages=9–13 |doi=10.1093/maghis/18.3.9 }}</ref> An outbreak was recorded by Spanish colonists in 1648 in the [[Yucatán Peninsula]], where the [[indigenous peoples|indigenous]] [[Mayan people]] called the illness ''xekik'' ("blood vomit"). In 1685, Brazil suffered its first epidemic in [[Recife]]. [[John Mitchell (geographer)|Dr. John Mitchell]] of Virginia made the first recorded mention of a disease by the name "yellow fever" in 1744.<ref>The earliest mention of "yellow fever" appears in a manuscript of 1744 by [[John Mitchell (geographer)|Dr. John Mitchell]] of Virginia; copies of the manuscript were sent to Mr. [[Cadwallader Colden]], a physician in New York, and to Dr. [[Benjamin Rush]] of Philadelphia; the manuscript was eventually printed (in large part) in 1805 and reprinted in 1814.  See:
* {{cite journal | vauthors = | title = Dr. John Mitchell's Account of the Yellow Fever in Virginia in 1741-42, Written in 1748 | journal = Annals of Medical History | volume = 6 | issue = 1 | pages = 91–92 | date = January 1934 | pmid = 33944007 | pmc = 7943142 | doi = | url = }}</ref><ref>(John Mitchell) (1805) [https://books.google.com/books?id=kJ21Uy4-lb0C&pg=PA1 (Mitchell's account of the Yellow Fever in Virginia in 1741–2)] {{webarchive|url=https://web.archive.org/web/20170223052443/https://books.google.com/books?id=kJ21Uy4-lb0C&pg=PA1|date=2017-02-23}}, ''The Philadelphia Medical Museum,'' 1 (1) : 1–20.</ref><ref>(John Mitchell) (1814) [https://books.google.com/books?id=_EZJAAAAYAAJ&pg=PA181 "Account of the Yellow fever which prevailed in Virginia in the years 1737, 1741, and 1742, in a letter to the late Cadwallader Colden, Esq. of New York, from the late John Mitchell, M.D.F.R.S. of Virginia,"] {{webarchive|url=https://web.archive.org/web/20170223052456/https://books.google.com/books?id=_EZJAAAAYAAJ&pg=PA181|date=2017-02-23}} ''American Medical and Philosophical Register'', '''4''' : 181–215. The term ''yellow fever'' appears on p.&nbsp;186. On p.&nbsp;188, Mitchell mentions "... the distemper was what is generally called yellow fever in America." However, on pages 191–192, he states "... I shall consider the cause of the yellowness which is so remarkable in this distemper, as to have given it the name of the Yellow Fever." Unfortunately, Mitchell misidentified the cause of yellow fever, believing it was transmitted through '"putrid miasma" in the air.'{{citation needed|date=June 2021}}</ref> However, Mitchell misdiagnosed the disease that he observed and treated, which was probably [[Weil's disease]] or [[hepatitis]].<ref>{{cite journal | vauthors = Jarcho S | title = John Mitchell, Benjamin Rush, and yellow fever | journal = Bulletin of the History of Medicine | volume = 31 | issue = 2 | pages = 132–136 | year = 1957 | pmid = 13426674 }}</ref>

McNeill argues that the environmental and ecological disruption caused by the introduction of [[History of sugar|sugar plantations]] created the conditions for mosquito and viral reproduction, and subsequent outbreaks of yellow fever.<ref>{{cite book | vauthors = McNeill J |title=Mosquito Empires: Ecology and War in the Greater Caribbean, 1620–1914 |date=2010 |publisher=Cambridge University Press |location=New York, NY |isbn=978-0-511-67268-2}}</ref> Deforestation reduced populations of insectivorous birds and other creatures that fed on mosquitoes and their eggs.<ref>{{cite journal | vauthors = Burkett-Cadena ND, Vittor AY | title = Deforestation and vector-borne disease: Forest conversion favors important mosquito vectors of human pathogens | journal = Basic and Applied Ecology | volume = 26 | pages = 101–110 | date = February 2018 | pmid = 34290566 | pmc = 8290921 | doi = 10.1016/j.baae.2017.09.012 | bibcode = 2018BApEc..26..101B }}</ref>

In [[British America|Colonial times]] and during the [[Napoleonic Wars]], the West Indies were known as a particularly dangerous posting for soldiers due to yellow fever being endemic in the area.<ref>{{Cite journal | vauthors = Buckley RN |date=1978 |title=The Destruction of the British Army in the West Indies 1793-1815: A Medical History |journal=Journal of the Society for Army Historical Research |volume=56 |issue=226 |pages=79–92 |jstor=44224266 |pmid=11614813 }}</ref> The mortality rate in British garrisons in [[Jamaica]] was seven times that of garrisons in Canada, mostly because of yellow fever and other tropical diseases.<ref>{{cite journal | vauthors = McNeill JR | title = Yellow fever and geopolitics: environment, epidemics, and the struggles for empire in the American tropics, 1650-1900 | journal = History Now | volume = 8 | issue = 2 | pages = 10–16 | date = 2002 | pmid = 20690235 }}</ref> Both English and French forces posted there were seriously affected by the "yellow jack".<ref>{{Cite journal | vauthors = McNeill JR |date=2004 |title=Yellow Jack and Geopolitics: Environment, Epidemics, and the Struggles for Empire in the American Tropics, 1640-1830 |journal=Review (Fernand Braudel Center) |volume=27 |issue=4 |pages=343–364 |jstor=40241611 }}</ref> Wanting to regain control of the highly profitable sugar trade on Hispaniola, and rejuvenate France's New World empire, Napoleon sent an army under the command of his brother-in-law General [[Charles Leclerc (general, born 1772)|Charles Leclerc]] to Saint-Domingue to seize control after a slave revolt.<ref>{{Cite web | vauthors = Marshall A |date=2020-11-18 |title=What was the Haitian Revolution (1791-1804)? |url=https://bootcampmilitaryfitnessinstitute.com/2020/11/18/what-was-the-haitian-revolution-1791-1804/ |access-date=2022-04-25 |website=Boot Camp & Military Fitness Institute |language=en-GB}}</ref> The historian J. R. McNeill asserts that yellow fever inflicted between 35,000 and 45,000 casualties on French army,<ref>{{cite book | vauthors = McNeill JR |title=Mosquito Empires: Ecology and War in the Greater Caribbean, 1620–1914 |year=2010 |publisher=Cambridge University Press |page=259}}</ref> which was forced to withdraw, with only one-third surviving to return to France. Consequently, Napoleon abandoned his plans for North America and sold [[Louisiana Purchase|Louisiana]] to the US in 1803. In 1804, [[Haiti]] proclaimed its independence as the second republic in the Western Hemisphere.<ref>{{Cite news |date=2019-02-11 |title=Haiti profile - Timeline |language=en-GB |work=BBC News |url=https://www.bbc.com/news/world-latin-america-19548814 |access-date=2022-04-25}}</ref> Considerable debate exists over whether the number of deaths caused by disease in the [[Haitian Revolution]] was exaggerated.<ref>{{cite book | vauthors = Girard PR |title=The Slaves Who Defeated Napoleon: Toussaint Louverture and the Haitian War of Independence, 1801–1804 |url=https://books.google.com/books?id=03XSP22p3kgC&pg=PA179 |year=2011 |publisher=University of Alabama Press |pages=179–80 |url-status=live |archive-url=https://web.archive.org/web/20160911094340/https://books.google.com/books?id=03XSP22p3kgC&pg=PA179 |archive-date=2016-09-11 |isbn=978-0-8173-1732-4}}</ref>

Although yellow fever is most prevalent in tropical-like climates, the northern United States was not exempt from the fever. The first outbreak in English-speaking North America occurred in [[New York City]] in 1668.<ref>{{Cite book | vauthors = Kotar SL, Gessler JE |url=https://books.google.com/books?id=odYBDgAAQBAJ&pg=PA12 |title=Yellow Fever: A Worldwide History |date=2017-02-03 |publisher=McFarland |isbn=978-1-4766-2628-4 |language=en}}</ref> English colonists in [[Philadelphia]] and the French in the [[Mississippi River Valley]] recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia, [[Baltimore]], and New York City in the 18th and 19th centuries. The disease traveled along [[steamboat]] routes from New Orleans, causing some 100,000–150,000 deaths in total.<ref>{{cite journal | vauthors = Patterson KD | title = Yellow fever epidemics and mortality in the United States, 1693-1905 | journal = Social Science & Medicine | volume = 34 | issue = 8 | pages = 855–865 | date = April 1992 | pmid = 1604377 | doi = 10.1016/0277-9536(92)90255-O }}</ref> The [[Yellow Fever Epidemic of 1793]] in Philadelphia, which was then the capital of the United States, caused thousands of deaths totaling over 9% of the city's population,<ref>{{cite journal | vauthors = Miller JC |title=The Wages of Blackness: African American Workers and the Meanings of Race during Philadelphia's 1793 Yellow Fever Epidemic |journal=The Pennsylvania Magazine of History and Biography |year=2005 |volume=129 |issue=2 |pages=163–194}}</ref> including [[James Hutchinson (physician)|James Hutchinson]], a physician helping to treat the population of the city. As the outbreak escalated organs of the federal government fled piecemeal to the city to Trenton, New Jersey, eventually being joined by President [[George Washington]].<ref>{{cite web |title=Yellow Fever Attacks Philadelphia, 1793 |work=EyeWitness to History |url=http://www.eyewitnesstohistory.com/yellowfever.htm |access-date=2009-08-14 |url-status=live |archive-url=https://web.archive.org/web/20070607233805/http://www.eyewitnesstohistory.com/yellowfever.htm |archive-date=2007-06-07 }}</ref> This was done with little coordination or formal sanction and at times was carried out in great haste. All entities of the federal government including Congress and President soon returned to resume operations in Philadelphia as the epidemic subsided. However, another severe outbreak in 1799 culminated in an official decision to [[Relocation of the United States Government to Trenton|relocate the national government]] to the city of Trenton, where it remained for the next six months. 

The southern city of [[New Orleans]] was plagued with major epidemics during the 19th century, most notably in 1833 and 1853.<ref>{{Cite news |title=How Yellow Fever Turned New Orleans Into The 'City Of The Dead' |language=en |work=Codeswitch |publisher=NPR |url=https://www.npr.org/sections/codeswitch/2018/10/31/415535913/how-yellow-fever-turned-new-orleans-into-the-city-of-the-dead |access-date=2022-04-25}}</ref> A major epidemic occurred in both New Orleans and [[Shreveport, Louisiana]], in 1873. Its residents called the disease "yellow jack". Urban epidemics continued in the United States until 1905, with the last outbreak affecting New Orleans.<ref>{{cite book | vauthors = Pierce J, Writer J  |title=Yellow Jack: How Yellow Fever ravaged America and Walter Reed Discovered Its Deadly Secrets |url=https://archive.org/details/yellowjackhowyel0000pier |url-access=registration |year=2005 |publisher=John Wiley & Sons |location=Hoboken |page=[https://archive.org/details/yellowjackhowyel0000pier/page/3 3]}}</ref><ref name="Barr2007" /><ref>{{cite web |url=http://tennesseeencyclopedia.net/entry.php?rec=1545 |title=The Tennessee Encyclopedia of History and Culture:Yellow Fever Epidemics |publisher=Tennessee Historical Society |archive-url=https://web.archive.org/web/20131212071247/http://tennesseeencyclopedia.net/entry.php?rec=1545 |archive-date=December 12, 2013 |url-status=live |access-date=June 20, 2013}}</ref>

At least 25 major outbreaks took place in the Americas during the 18th and 19th centuries, including particularly serious ones in [[Cartagena, Chile]], in 1741; Cuba in 1762 and 1900; [[Santo Domingo]] in 1803; and [[Memphis, Tennessee]], in 1878.<ref>John S. Marr, and John T. Cathey. "The 1802 Saint-Domingue yellow fever epidemic and the Louisiana Purchase." ''Journal of Public Health Management and Practice'' 19#.1 (2013): 77–82. [http://s2.medicina.uady.mx/observatorio/docs/er/ac/RE2013_Ac_Marr.pdf online] {{webarchive|url=https://web.archive.org/web/20160204181607/http://s2.medicina.uady.mx/observatorio/docs/er/ac/RE2013_Ac_Marr.pdf |date=2016-02-04 }}</ref>

In the early 19th century, the prevalence of yellow fever in the Caribbean "led to serious health problems" and alarmed the [[United States Navy]] as numerous deaths and sickness curtailed naval operations and destroyed morale.<ref>Langley, Harold D. ''A History of Medicine in the Early U.S. Navy'' (Johns Hopkins Press: Baltimore 1995), 274-275</ref> One episode began in April 1822 when the frigate [[HMS Macedonian|USS ''Macedonian'']] left [[Boston]] and became part of Commodore James Biddle's West India Squadron. Unbeknownst to all, they were about to embark on an assignment that "would prove a cruise through hell".<ref name="Sharp The Disastrous Voyage">{{cite web | vauthors = Sharp JG | title = The Disastrous Voyage: Yellow Fever aboard the USS Macedonian & USS Peacock, 1822 | access-date = 15 August 2020 | url = http://www.usgwarchives.net/va/portsmouth/shipyard/yf1822.html | archive-url = https://web.archive.org/web/20191025010821/http://www.usgwarchives.net/va/portsmouth/shipyard/yf1822.html | archive-date = 25 October 2019 }}</ref> Secretary of the Navy [[Smith Thompson]] had assigned the squadron to guard American merchant shipping and suppress piracy.<ref>{{Cite web |title=Annual Report of the Secretary of the Navy - 1823 |url=https://www.history.navy.mil/content/history/nhhc/research/library/online-reading-room/title-list-alphabetically/a/secnav-reports/1823.html |access-date=2022-04-25 |website=NHHC |language=en-US }}</ref> From 26 May to 3 August 1822, 76 of the ''Macedonian''{{'}}s officers and men died, including John Cadle, surgeon USN. 74 of these deaths were attributed to yellow fever. Biddle reported that another 52 of his crew were on the sick list. In their report to the secretary of the Navy, Biddle and Surgeon's Mate Charles Chase stated the cause as "fever". As a consequence of this loss, Biddle noted that his squadron was forced to return to Norfolk Navy Yard early. Upon arrival, the ''Macedonian''{{'}}s crew were provided medical care and quarantined at [[Craney Island (Virginia)|Craney Island, Virginia]].<ref>{{cite journal | journal = Nara M125 | volume = 79 | id = letter no. 15 | title = Captains Letters | author = James Biddle to Smith Thompson | date = 3 August 1822 }}</ref><ref>{{cite news | title = The Macedonian a list of the deaths | work = Connecticut Herald | date = 20 August 1822 | page = 2 }}</ref><ref name="Sharp The Disastrous Voyage"/>

In 1853, [[Cloutierville, Louisiana]], had a late-summer outbreak of yellow fever that quickly killed 68 of the 91 inhabitants. A local doctor concluded that some unspecified infectious agent had arrived in a package from New Orleans.<ref>{{cite journal |journal=The Transactions of the American Medical Association |volume=9 |date=1856 |page=704 |title=Yellow Fever at the Village of Cloutierville, La, in the Years 1853 and 1854 |first1=Samuel O. |last1=Scruggs }}</ref><ref>{{cite journal |last1=D' Antoni |first1=Blaise C. |title=Cloutierville Yellow Fever Deaths, 1853 |journal=New Orleans Genesis |volume=9 |issue=35 |date=June 1970 |pages=261–262 }}</ref> In 1854, 650 residents of [[Savannah, Georgia]], died from yellow fever.<ref>{{cite journal | vauthors = Lockley T  |title='Like a clap of thunder in a clear sky': differential mortality during Savannah's yellow fever epidemic of 1854 |journal=Social History |date=2012 |volume=37 |issue=2 |pages=166–186 |doi=10.1080/03071022.2012.675657 |url=http://wrap.warwick.ac.uk/49566/1/WRAP_Lockley_9670721-hi-160114-like_a_clap_of_thunder_in_a_clear_sky.pdf }}</ref> In 1858, [[St. Matthew's German Evangelical Lutheran Church]] in [[Charleston, South Carolina]], had 308 yellow fever deaths, reducing the congregation by half.<ref>St. Matthew's Evangelical Lutheran Church: 125 Years of Christian Service, 1967.</ref> A ship carrying persons infected with the virus arrived in [[Hampton Roads]] in southeastern [[Virginia]] in June 1855.<ref name="Virginia">{{cite web |url=http://etext.lib.virginia.edu/etcbin/fever-browse?id=N2659002 |archive-url=https://archive.today/20121212204518/http://etext.lib.virginia.edu/etcbin/fever-browse?id=N2659002 |archive-date=2012-12-12 |title=Mosquito control ends fatal plague of yellow fever |access-date=2007-06-11 | vauthors = Mauer HB |publisher=etext.lib.virginia.edu }} (undated newspaper clipping).</ref> The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of Norfolk and [[Portsmouth, Virginia|Portsmouth]].<ref>{{cite web |title=Yellow Fever |url=http://www.usgwarchives.net/va/yellow-fever/yftoc.html |website=www.usgwarchives.net |access-date=30 September 2019}}</ref> In 1873, Shreveport lost 759 citizens in an 80-day period to a yellow fever epidemic that began in August, by November over 400 additional victims succumbed for a total death toll of approximately 1,200.<ref>{{Cite web|url=http://ldh.la.gov/assets/oph/Center-PHCH/Center-CH/infectious-epi/Annuals/LaIDAnnual_YellowFever.pdf|title=Louisiana Office of Public Health Statistics, page 6|access-date=28 September 2018|archive-date=4 February 2019|archive-url=https://web.archive.org/web/20190204032113/http://ldh.la.gov/assets/oph/Center-PHCH/Center-CH/infectious-epi/Annuals/LaIDAnnual_YellowFever.pdf|url-status=dead}}</ref><ref>{{Cite web|url=http://www.oaklandcemeteryla.org/Tour/Tour-Stop-1.aspx|title=Tour Stop 1 - Yellow Fever Victims - Tour - Oakland Cemetery - Shreveport - Louisiana - Founded 1847|website=www.oaklandcemeteryla.org|access-date=2018-09-28|archive-date=2018-09-28|archive-url=https://web.archive.org/web/20180928202518/http://www.oaklandcemeteryla.org/Tour/Tour-Stop-1.aspx}}</ref>

The widespread [[Lower Mississippi Valley yellow fever epidemic of 1878]] caused an estimated 20,000 fatalities.<ref>{{cite book | vauthors = Crosby MC |title=The American Plague |year=2006 |publisher=Berkley Publishing Group |location=New York |page=75}}</ref> That year, Memphis had an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge epidemic of yellow fever.<ref>{{cite web |title=Yellow Fever — the plague of Memphis |url=http://historic-memphis.com/memphis-historic/yellow-fever/yellow-fever.html |publisher=HistoricMemphis.com |access-date=August 20, 2014 |url-status=live |archive-url=https://web.archive.org/web/20140821093209/http://historic-memphis.com/memphis-historic/yellow-fever/yellow-fever.html |archive-date=August 21, 2014}}</ref> The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but passengers were not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi River for the next two months before unloading her passengers.<ref>{{cite book | vauthors = Barnes E |year=2005 |title=Diseases and Human Evolution |url=https://archive.org/details/diseaseshumanevo0000barn |url-access=registration |location=Albuquerque |publisher=University of New Mexico |isbn=978-0-8263-3065-9 }}</ref>

Major outbreaks have also occurred in southern Europe. [[Gibraltar]] lost many lives to outbreaks in 1804, 1814, and 1828.<ref>{{cite journal | vauthors = Sawchuk LA, Burke SD | title = Gibraltar's 1804 yellow fever scourge: the search for scapegoats | journal = Journal of the History of Medicine and Allied Sciences | volume = 53 | issue = 1 | pages = 3–42 | date = January 1998 | pmid = 9510598 | doi = 10.1093/jhmas/53.1.3 }}</ref> [[Barcelona]] suffered the loss of several thousand citizens during an outbreak in 1821. The [[Armand-Emmanuel de Vignerot du Plessis, Duc de Richelieu|Duke de Richelieu]] deployed 30,000 French troops to the border between [[France]] and [[Spain]] in the [[Pyrenees Mountains]], to establish a ''[[Cordon sanitaire (medicine)|cordon sanitaire]]'' to prevent the epidemic from spreading from Spain into France.<ref name = "Taylor">James Taylor, ''The age we live in: a history of the nineteenth century,'' Oxford University, 1882; p. 222.</ref>

===Causes and transmission===
[[Ezekiel Stone Wiggins]], known as the Ottawa Prophet, proposed that the cause of a yellow fever epidemic in [[Jacksonville, Florida]], in 1888, was astrological.<ref>{{Cite web |date=2020-06-30 |title=World Diseases – 'Yellow Fever' |work=West Bend News |url=https://www.westbendnews.net/autonews/2020/06/30/world-diseases-yellow-fever/ |access-date=2022-04-25 |language=en-US}}</ref>

{{blockquote|The planets were in the same line as the sun and earth and this produced, besides Cyclones, Earthquakes, etc., a denser atmosphere holding more carbon and creating microbes. Mars had an uncommonly dense atmosphere, but its inhabitants were probably protected from the fever by their newly discovered [[Mars canals|canals]], which were perhaps made to absorb carbon and prevent the disease.<ref>[http://historicaltextarchive.com/print.php?action=section&artid=781 John W. Cowart, "Yellow Jack in Jacksonville, Yellow Fever visited Duval County, Florida, in 1888"] {{webarchive|url=https://web.archive.org/web/20130105144757/http://historicaltextarchive.com/print.php?action=section&artid=781 |date=2013-01-05 }}, Historical Text Archive</ref>}}

In 1848, [[Josiah C. Nott]] suggested that yellow fever was spread by insects such as moths or mosquitoes, basing his ideas on the pattern of transmission of the disease.<ref>Josiah C. Nott (1848) [https://babel.hathitrust.org/cgi/pt?id=hvd.32044103099172;view=1up;seq=601 "Yellow Fever contrasted with Bilious Fever – Reasons for believing it a disease sui generis – Its mode of Propagation – Remote Cause – Probable insect or animalcular origin"], ''The New Orleans Medical and Surgical Journal,'' "4" : 563–601.</ref> [[Carlos Finlay]], a Cuban-Spanish doctor and scientist, proposed in 1881 that yellow fever might be transmitted by previously infected [[mosquito]]es rather than by direct contact from person to person, as had long been believed.<ref>Carlos Juan Finlay (presented:  August 14, 1881; published:  1882) [https://books.google.com/books?id=cMMYAAAAYAAJ&pg=PA147 "El mosquito hipoteticamente considerado como agente de transmission de la fiebre amarilla"] ({{webarchive|url=https://web.archive.org/web/20170223052838/https://books.google.com/books?id=cMMYAAAAYAAJ&pg=PA147 |date=2017-02-23 }}) (The mosquito hypothetically considered as an agent in the transmission of yellow fever) ''Anales de la Real Academia de Ciencias Médicas, Físicas y Naturales de la Habana'', '''18''' : 147–169.  Available online in English at:
*  Charles Finlay, with Rudolph Matas, translator (1881) [https://books.google.com/books?id=Qd9DAQAAIAAJ&pg=PA601 "The mosquito hypothetically considered as an agent in the transmission of yellow fever poison,"] {{webarchive|url=https://web.archive.org/web/20170223042231/https://books.google.com/books?id=Qd9DAQAAIAAJ&pg=PA601 |date=2017-02-23 }} ''New Orleans Medical and Surgical Journal,'' '''9''' : 601–616.
*  [http://www.deltaomega.org/documents/finlay.pdf Delta Omega.org] {{webarchive|url=https://web.archive.org/web/20120509234452/http://www.deltaomega.org/documents/finlay.pdf |date=2012-05-09 }}</ref><ref name="Chaves-Carballo_2005">{{cite journal | vauthors = Chaves-Carballo E | title = Carlos Finlay and yellow fever: triumph over adversity | journal = Military Medicine | volume = 170 | issue = 10 | pages = 881–885 | date = October 2005 | pmid = 16435764 | doi = 10.7205/milmed.170.10.881 | doi-access = free }}</ref> Since the losses from yellow fever in the [[Spanish–American War]] in the 1890s were extremely high, U.S. Army doctors began research experiments with a team led by [[Walter Reed]], and composed of doctors [[James Carroll (scientist)|James Carroll]], [[Aristides Agramonte]], and [[Jesse William Lazear]]. They successfully proved Finlay's "mosquito hypothesis". Yellow fever was the first virus shown to be transmitted by mosquitoes. The physician [[William Gorgas]] applied these insights and eradicated yellow fever from [[Havana]]. He also campaigned against yellow fever during the construction of the [[Panama Canal]]. A previous effort of canal building by the French had failed in part due to mortality from the high incidence of yellow fever and malaria, which killed many workers.<ref name=Barr2007/>

Although Reed has received much of the credit in United States history books for "beating" yellow fever, he had fully credited Finlay with the discovery of the yellow fever vector, and how it might be controlled. Reed often cited Finlay's papers in his articles and also credited him for the discovery in his correspondence.<ref name="pierce">{{cite book | vauthors = Pierce JR, Writer J |title=Yellow Jack: How Yellow Fever Ravaged America and Walter Reed Discovered Its Deadly Secrets |url=https://archive.org/details/yellowjackhowyel0000pier |url-access=registration |publisher=Wiley |year=2005 |isbn=978-0-471-47261-2 }}</ref> The acceptance of Finlay's work was one of the most important and far-reaching effects of the U.S. Army Yellow Fever Commission of 1900.<ref>{{cite web |url=http://exhibits.hsl.virginia.edu/yellowfever/ |title=U.S. Army Yellow Fever Commission |work=UVA Health Sciences: Historical Collections |archive-url= https://web.archive.org/web/20170426200032/http://exhibits.hsl.virginia.edu/yellowfever/ |archive-date=2017-04-26 |url-status=live |access-date=2017-08-01}}</ref> Applying methods first suggested by Finlay, the United States government and Army eradicated yellow fever in Cuba and later in Panama, allowing completion of the Panama Canal. While Reed built on the research of Finlay, historian François Delaporte notes that yellow fever research was a contentious issue. Scientists, including Finlay and Reed, became successful by building on the work of less prominent scientists, without always giving them the credit they were due.<ref>{{cite book | vauthors = Delaporte F |title=The History of Yellow Fever: An Essay on the Birth of Tropical Medicine |url=https://archive.org/details/historyofyellowf00dela |url-access=registration |year=1991 |publisher=MIT Press |location=Cambridge |pages=[https://archive.org/details/historyofyellowf00dela/page/89 89–90]|isbn=978-0-262-04112-6 }}</ref> Reed's research was essential in the fight against yellow fever. He is also credited for using the first type of [[informed consent|medical consent]] form during his experiments in Cuba, an attempt to ensure that participants knew they were taking a risk by being part of testing.<ref>{{cite book | vauthors = Crosby MC |title=The American Plague |year=2006 |publisher=Berkley Publishing Group |location=New York |page=177}}</ref>

Like Cuba and Panama, Brazil also led a highly successful sanitation campaign against mosquitoes and yellow fever. Beginning in 1903, the campaign led by [[Oswaldo Cruz]], then director general of public health, resulted not only in eradicating the disease but also in reshaping the physical landscape of Brazilian cities such as Rio de Janeiro.<ref>{{cite journal | vauthors = Wilson AL, Courtenay O, Kelly-Hope LA, Scott TW, Takken W, Torr SJ, Lindsay SW | title = The importance of vector control for the control and elimination of vector-borne diseases | journal = PLOS Neglected Tropical Diseases | volume = 14 | issue = 1 | article-number = e0007831 | date = January 2020 | pmid = 31945061 | pmc = 6964823 | doi = 10.1371/journal.pntd.0007831 | doi-access = free }}</ref> During rainy seasons, Rio de Janeiro regularly suffered floods, as water from the bay surrounding the city overflowed into Rio's narrow streets. Coupled with the poor drainage systems found throughout Rio, this created swampy conditions in the city's neighborhoods. Pools of stagnant water stood year-long in city streets and proved to be fertile ground for disease-carrying mosquitoes. Thus, under Cruz's direction, public health units known as "mosquito inspectors" fiercely worked to combat yellow fever throughout Rio by spraying, exterminating rats, improving drainage, and destroying unsanitary housing. Ultimately, the city's sanitation and renovation campaigns reshaped Rio de Janeiro's neighborhoods. Its poor residents were pushed from city centers to Rio's suburbs, or to towns found in the outskirts of the city. In later years, Rio's most impoverished inhabitants would come to reside in ''[[favela]]s''.<ref>{{cite book |doi=10.1002/9781394266500.ch6 |chapter=Immigration, and Urban and Rural Life |title=A History of Modern Latin America |date=2022 |pages=142–162 |isbn=978-1-394-26650-0 }}</ref>

During 1920–1923, the [[Rockefeller Foundation]]'s [[International Health Board]] <!-- (IHB) --> undertook an expensive and successful yellow fever eradication campaign in Mexico.<ref>{{cite book | vauthors = Fosdick RB |title=The Story of the Rockefeller Foundation |date=1952 |publisher=Harper & Brothers |location=New York |pages=58–79}}</ref> The IHB gained the respect of Mexico's federal government because of the success. The eradication of yellow fever strengthened the relationship between the US and Mexico, which had not been very good in the years prior. The eradication of yellow fever was also a major step toward better global health.<ref name="pmid10501641">{{cite journal | vauthors = Birn AE, Solórzano A | title = Public health policy paradoxes: science and politics in the Rockefeller Foundation's hookworm campaign in Mexico in the 1920s | journal = Social Science & Medicine | volume = 49 | issue = 9 | pages = 1197–1213 | date = November 1999 | pmid = 10501641 | doi = 10.1016/s0277-9536(99)00160-4 }}</ref>

In 1927, scientists isolated the Yellow fever virus in West Africa.<ref name=Bigon>{{cite journal | vauthors = Bigon L |year=2014 |title=Transnational Networks of Administrating Disease and Urban Planning in West Africa: The Inter-Colonial Conference on Yellow Fever, Dakar, 1928 |journal=GeoJournal |volume=79 |number=1 |pages=103–111 |doi=10.1007/s10708-013-9476-z |bibcode=2014GeoJo..79..103B |s2cid=153603689 }}</ref> Following this, two [[vaccine]]s were developed in the 1930s. [[Max Theiler]] led the completion of the 17D [[yellow fever vaccine]] in 1937, for which he was subsequently awarded the [[Nobel Prize in Physiology or Medicine]].<ref>{{cite web | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1951/index.html | title = The Nobel Prize in Physiology or Medicine 1951 | access-date = 2017-11-30 | publisher = Nobel Foundation}}</ref> That vaccine, 17D, is still in use, although newer vaccines, based on [[vero cell]]s, are in development (as of 2018).<ref name=Toll2009/><ref name=NIH-2016>{{cite press release |url=https://www.nih.gov/news-events/nih-launches-early-stage-yellow-fever-vaccine-trial |archive-url=https://web.archive.org/web/20160826202158/https://www.nih.gov/news-events/nih-launches-early-stage-yellow-fever-vaccine-trial |url-status=dead |archive-date=26 August 2016 |title=NIH launches early-stage yellow fever vaccine trial |date=July 27, 2016 |author=National Institutes of Health |publisher=[[United States Department of Health and Human Services]] |access-date=July 14, 2019 |author-link=National Institutes of Health }}</ref><ref name=ClinicalTrials-2018>{{citation |url=https://clinicaltrials.gov/ct2/show/NCT02743455 |title=A Phase I Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of MVA-BN Yellow Fever Vaccine With and Without Montanide ISA-720 Adjuvant in 18–45 Year Old Healthy Volunteers (NCT number: NCT02743455) |date=June 1, 2018 |author=[[National Institute of Allergy and Infectious Diseases]] (NIAID) |publisher=[[United States National Library of Medicine]] |access-date=July 14, 2019}}.</ref>

<gallery widths="160" heights="200">
File:Juan Manuel Blanes Episodio de la Fiebre Amarilla.jpg|A painting by [[Juan Manuel Blanes]] depicting [[yellow fever in Buenos Aires]], 1871
File:Finlay Carlos 1833-1915.jpg|[[Carlos Finlay]]
File:WalterReed.jpeg|[[Walter Reed]]
File:Max Theiler nobel.jpg|[[Max Theiler]]
</gallery>

===Current status===
Using vector control and strict vaccination programs, the urban cycle of yellow fever was nearly eradicated from South America.<ref>{{Cite web |title=Yellow fever |url=https://www.who.int/news-room/fact-sheets/detail/yellow-fever |access-date=2022-04-25 |website=World Health Organization |language=en}}</ref> Since 1943, only a single urban outbreak in [[Santa Cruz de la Sierra]], Bolivia, has occurred. Since the 1980s, however, the number of yellow fever cases has been increasing again, and ''A. aegypti'' has returned to the urban centers of South America. This is partly due to limitations on available insecticides, as well as habitat dislocations caused by climate change. It is also because the vector control program was abandoned. Although no new urban cycle has yet been established, scientists believe this could happen again at any point. An outbreak in [[Paraguay]] in 2008 was thought to be urban in nature, but this ultimately proved not to be the case.<ref name=Toll2009/>

In Africa, virus eradication programs have mostly relied upon vaccination.<ref>{{cite journal | vauthors = Deressa W, Kayembe P, Neel AH, Mafuta E, Seme A, Alonge O | title = Lessons learned from the polio eradication initiative in the Democratic Republic of Congo and Ethiopia: analysis of implementation barriers and strategies | journal = BMC Public Health | volume = 20 | issue = Suppl 4 | page = 1807 | date = December 2020 | pmid = 33339529 | pmc = 7747367 | doi = 10.1186/s12889-020-09879-9 | doi-access = free }}</ref> These programs have largely been unsuccessful because they were unable to break the [[sylvatic cycle]] involving wild primates. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the future spread of the virus more likely.<ref name=Toll2009/>

==Research==
In the hamster model of yellow fever, early administration of the antiviral [[ribavirin]] is an effective treatment of many pathological features of the disease.<ref name="Sbrana_2004">{{cite journal | vauthors = Sbrana E, Xiao SY, Guzman H, Ye M, Travassos da Rosa AP, Tesh RB | title = Efficacy of post-exposure treatment of yellow fever with ribavirin in a hamster model of the disease | journal = The American Journal of Tropical Medicine and Hygiene | volume = 71 | issue = 3 | pages = 306–312 | date = September 2004 | pmid = 15381811 | doi = 10.4269/ajtmh.2004.71.306 | doi-access = free }}</ref> Ribavirin treatment during the first five days after virus infection improved survival rates, reduced tissue damage in the liver and [[spleen]], prevented hepatocellular [[steatosis]], and normalised levels of alanine aminotransferase, a liver damage marker. The mechanism of action of ribavirin in reducing liver pathology in Yellow fever virus infection may be similar to its activity in the treatment of [[hepatitis C]], a related virus.<ref name="Sbrana_2004" /> Because ribavirin had failed to improve survival in a virulent rhesus model of yellow fever infection, it had been previously discounted as a possible therapy.<ref name="Huggins_1989">{{cite journal | vauthors = Huggins JW | title = Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad-spectrum antiviral drug | journal = Reviews of Infectious Diseases | volume = 11 | issue = Suppl 4 | pages = S750–S761 | year = 1989 | pmid = 2546248 | doi = 10.1093/clinids/11.Supplement_4.S750 }}</ref> Infection was reduced in mosquitoes with the wMel strain of ''[[Wolbachia]]''.<ref>{{cite journal | vauthors = van den Hurk AF, Hall-Mendelin S, Pyke AT, Frentiu FD, McElroy K, Day A, Higgs S, O'Neill SL | display-authors = 6 | title = Impact of Wolbachia on infection with chikungunya and yellow fever viruses in the mosquito vector Aedes aegypti | journal = PLOS Neglected Tropical Diseases | volume = 6 | issue = 11 | article-number = e1892 | year = 2012 | pmid = 23133693 | pmc = 3486898 | doi = 10.1371/journal.pntd.0001892 | doi-access = free }}</ref>

Yellow fever has been researched by several countries as a potential [[biological weapon]].<ref name=Endicott1998>{{cite book | vauthors = Endicott SL, Hageman E |title=The United States and Biological Warfare: Secrets from the Early Cold War and Korea |publisher=Indiana University Press |year=1998 |isbn=978-0-253-33472-5 |url=https://archive.org/details/unitedstatesbiol00endi }}</ref>

==Notes==
{{reflist|group=note}}

== References ==
{{Reflist}}

== Further reading ==
{{Library resources box}}
{{refbegin}}
* {{Cite book |vauthors=Crosby M |year=2006 |title=The American Plague: The Untold Story of Yellow Fever, the Epidemic that Shaped Our History |url=https://archive.org/details/americanplagueun00cros_0 |location=New York |publisher=The Berkley Publishing Group |isbn=978-0-425-21202-8}}
* {{Cite book |vauthors=Espinosa M |year=2009 |title=Epidemic Invasions: Yellow Fever and the Limits of Cuban Independence, 1878–1930 |url=https://books.google.com/books?id=XWYaZrgf-ZcC |location=Chicago |publisher=University of Chicago Press |isbn=978-0-226-21811-3}}
* {{Cite journal |vauthors=Finlay CJ |date=January 2012 |title=The Mosquito Hypothetically Considered as the Transmitting Agent of Yellow Fever |journal=MEDICC Review |volume=14 |issue=1 |pages=56–59 |doi=10.37757/MR2012V14.N1.10 |doi-access=free |pmid=34503309}}
* {{Cite book |vauthors=Gessner I |year=2016 |title=Yellow Fever Years: An Epidemiology of Nineteenth-Century American Literature and Culture |location=Frankfurt on Main |publisher=Peter Lang |isbn=978-3-631-67412-3 }}
* {{Cite journal |vauthors=Harcourt-Smith S |date=1974 |title='Yellow Jack': Caribbean Fever |journal=History Today |volume=23 |issue=9 |pages=618–624 }}
* {{Cite book |vauthors=Murphy J |year=2003 |title=An American Plague: The True and Terrifying Story of the Yellow Fever Epidemic of 1793 |url=https://archive.org/details/americanplaguetr00murp |location=New York |publisher=Clarion Books |isbn=978-0-395-77608-7}}
* {{Cite book |vauthors=Nuwer DS |year=2009 |title=Plague Among the Magnolias: The 1878 Yellow Fever Epidemic in Mississippi |publisher=University of Alabama Press |isbn=978-0-8173-1653-2 }}
{{refend}}

== External links ==
{{sister project links||d=154874|c=Category:Yellow fever|n=no|q=no|b=no|v=no|voy=Yellow fever|m=no|mw=no|s=no|wikt=Yellow fever|species=no}}
{{offline|med}}
* [http://exhibits.hsl.virginia.edu/yellowfever/ "U.S. Army Yellow Fever Commission."] Claude Moore Health Sciences Library, [[University of Virginia]]
* {{cite web |title=Yellow fever virus |work=NCBI Taxonomy Browser |url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=11089 |id=11089}}
{{Zoonotic viral diseases}}
{{Medical condition classification and resources
| ICD11          = {{ICD11|1D47}}
| ICD10          = {{ICD10|A|95||a|90}}
| ICD9           = {{ICD9|060}}
| ICDO           =
| OMIM           =
| DiseasesDB     = 14203
| MedlinePlus    = 001365
| eMedicineSubj  = med
| eMedicineTopic = 2432
| eMedicine_mult = {{eMedicine2|emerg|645}}
| MeshID = D015004
}}
{{taxonbar|from=Q836749}}
{{Authority control}}
{{Portalbar|Medicine|Viruses}}

{{DEFAULTSORT:Yellow Fever}}
[[Category:Yellow fever| ]]
[[Category:Zoonotic viral diseases]]
[[Category:Biological agents]]
[[Category:Epidemics]]
[[Category:Tropical diseases]]
[[Category:Vaccine-preventable diseases]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Wikipedia infectious disease articles ready to translate]]