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Yellow fever

Thomas P Monath, MD, FACP, FASTMH
Section Editor
Martin S Hirsch, MD
Deputy Editor
Elinor L Baron, MD, DTMH


Yellow fever is a mosquito-borne viral hemorrhagic fever with a high case fatality rate. Clinical manifestations include hepatic dysfunction, renal failure, coagulopathy, and shock. Travelers to tropical regions of South America and sub-Saharan Africa where the disease is endemic are at risk for acquisition of infection and require immunization.

Issues related to virology, pathogenesis, epidemiology, clinical manifestations, diagnosis, treatment, and prevention of yellow fever will be reviewed here.


Yellow fever is the prototype member of the family Flaviviridae, a group of small (40 to 60 nm), enveloped, positive-sense, single-stranded RNA viruses that replicate in the cytoplasm of infected cells. Yellow fever virus is a single serotype and is antigenically conserved, so the vaccine protects against all strains of the virus. At the nucleotide sequence level, it is possible to distinguish seven major genotypes representing West Africa (two genotypes), Central-East Africa and Angola (three genotypes), and South America (two genotypes) [1,2]. Humans are highly susceptible to infection and disease. Most nonhuman primate species are susceptible to infection, and some species of nonhuman primates develop clinical manifestations.

An infected female mosquito inoculates approximately 1000 to 100,000 virus particles intradermally during blood feeding. Virus replication begins at the site of inoculation, probably in dendritic cells in the epidermis, and spreads through lymphatic channels to regional lymph nodes. Lymphoid cells, particularly monocyte-macrophages and large histiocytes, appear to be the preferred cell types for primary replication. The virus reaches other organs via the lymph and then the bloodstream, seeding other tissues. Large amounts of virus are produced in the liver and spleen and released into the blood. During the viremic phase (days three to six), infection may be transmitted to blood-feeding mosquitoes.

Yellow fever is characterized by hepatic dysfunction, renal failure, coagulopathy, and shock [3-6]. The midzone of the liver lobule is principally affected, with sparing of cells bordering the central vein and portal tracts [7]. Viral antigen localizes to the midzone, indicating that it is the site of direct viral injury. Very high virus loads have been found in the liver and spleen of fatal cases [8].


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Literature review current through: Sep 2016. | This topic last updated: Jun 27, 2016.
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  1. Mutebi JP, Wang H, Li L, et al. Phylogenetic and evolutionary relationships among yellow fever virus isolates in Africa. J Virol 2001; 75:6999.
  2. Vasconcelos PF, Bryant JE, da Rosa TP, et al. Genetic divergence and dispersal of yellow fever virus, Brazil. Emerg Infect Dis 2004; 10:1578.
  3. Dennis LH, Reisberg BE, Crosbie J, et al. The original haemorrhagic fever: yellow fever. Br J Haematol 1969; 17:455.
  4. Tigertt WD, Berge TO, Gochenour WS, et al. Experimental yellow fever. Trans N Y Acad Sci 1960; 22:323.
  5. Monath TP, Brinker KR, Chandler FW, et al. Pathophysiologic correlations in a rhesus monkey model of yellow fever with special observations on the acute necrosis of B cell areas of lymphoid tissues. Am J Trop Med Hyg 1981; 30:431.
  6. Monath TP, Barrett AD. Pathogenesis and pathophysiology of yellow fever. Adv Virus Res 2003; 60:343.
  7. Quaresma JA, Barros VL, Fernandes ER, et al. Reconsideration of histopathology and ultrastructural aspects of the human liver in yellow fever. Acta Trop 2005; 94:116.
  8. Bae HG, Drosten C, Emmerich P, et al. Analysis of two imported cases of yellow fever infection from Ivory Coast and The Gambia to Germany and Belgium. J Clin Virol 2005; 33:274.
  9. Quaresma JA, Barros VL, Pagliari C, et al. Revisiting the liver in human yellow fever: virus-induced apoptosis in hepatocytes associated with TGF-beta, TNF-alpha and NK cells activity. Virology 2006; 345:22.
  10. Quaresma JA, Barros VL, Fernandes ER, et al. Immunohistochemical examination of the role of Fas ligand and lymphocytes in the pathogenesis of human liver yellow fever. Virus Res 2006; 116:91.
  11. ter Meulen J, Sakho M, Koulemou K, et al. Activation of the cytokine network and unfavorable outcome in patients with yellow fever. J Infect Dis 2004; 190:1821.
  12. Tesh RB, Guzman H, da Rosa AP, et al. Experimental yellow fever virus infection in the Golden Hamster (Mesocricetus auratus). I. Virologic, biochemical, and immunologic studies. J Infect Dis 2001; 183:1431.
  13. Xiao SY, Zhang H, Guzman H, Tesh RB. Experimental yellow fever virus infection in the Golden hamster (Mesocricetus auratus). II. Pathology. J Infect Dis 2001; 183:1437.
  14. Meier KC, Gardner CL, Khoretonenko MV, et al. A mouse model for studying viscerotropic disease caused by yellow fever virus infection. PLoS Pathog 2009; 5:e1000614.
  15. Monath TP. Yellow fever: Victor, Victoria? Conqueror, conquest? Epidemics and research in the last forty years and prospects for the future. Am J Trop Med Hyg 1991; 45:1.
  16. Robertson SE, Hull BP, Tomori O, et al. Yellow fever: a decade of reemergence. JAMA 1996; 276:1157.
  17. Monath TP. Review of the risks and benefits of yellow fever vaccination including some new analyses. Expert Rev Vaccines 2012; 11:427.
  18. Garske T, Van Kerkhove MD, Yactayo S, et al. Yellow Fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data. PLoS Med 2014; 11:e1001638.
  19. World Health Organization. Yellow Fever – Angola. http://www.who.int/csr/don/22-march-2016-yellow-fever-angola/en/ (Accessed on April 05, 2016).
  20. ProMED mail. Yellow fever - Countries with dengue: Alert. http://promedmail.org/post/20160328.4123983 (Accessed on April 05, 2016).
  21. World Health Organization. Yellow Fever - China. http://www.who.int/csr/don/6-april-2016-yellow-fever-china/en/ (Accessed on April 13, 2016).
  22. McFarland JM, Baddour LM, Nelson JE, et al. Imported yellow fever in a United States citizen. Clin Infect Dis 1997; 25:1143.
  23. Barros ML, Boecken G. Jungle yellow fever in the central Amazon. Lancet 1996; 348:969.
  24. Centers for Disease Control and Prevention (CDC). Fatal yellow fever in a traveler returning from Venezuela, 1999. MMWR Morb Mortal Wkly Rep 2000; 49:303.
  25. Colebunders R, Mariage JL, Coche JC, et al. A Belgian traveler who acquired yellow fever in the Gambia. Clin Infect Dis 2002; 35:e113.
  26. Centers for Disease Control and Prevention (CDC). Fatal yellow fever in a traveler returning from Amazonas, Brazil, 2002. MMWR Morb Mortal Wkly Rep 2002; 51:324.
  27. Outbreak news. Yellow fever, Paraguay. Wkly Epidemiol Rec 2008; 83:105.
  28. Monath TP. Yellow fever: a medically neglected disease. Report on a seminar. Rev Infect Dis 1987; 9:165.
  29. Johansson MA, Arana-Vizcarrondo N, Biggerstaff BJ, Staples JE. Incubation periods of Yellow fever virus. Am J Trop Med Hyg 2010; 83:183.
  30. Barnett ED. Yellow fever: epidemiology and prevention. Clin Infect Dis 2007; 44:850.
  31. Oudart JL, Rey M. [Proteinuria, proteinaemia, and serum transaminase activity in 23 confirmed cases of yellow fever]. Bull World Health Organ 1970; 42:95.
  32. ELTON NW, ROMERO A, TREJOS A. Clinical pathology of yellow fever. Am J Clin Pathol 1955; 25:135.
  33. Berry GP, Kitchen SF. Yellow fever accidentally contracted in the laboratory: A study of seven cases. Am J Trop Med Hyg 1931; 11:365.
  34. Gibney KB, Edupuganti S, Panella AJ, et al. Detection of anti-yellow fever virus immunoglobulin m antibodies at 3-4 years following yellow fever vaccination. Am J Trop Med Hyg 2012; 87:1112.
  35. Lhuillier M, Sarthou JL, Cordellier R, et al. [Rural epidemic of yellow fever with interhuman transmission in the Ivory Coast in 1982]. Bull World Health Organ 1985; 63:527.
  36. Monath TP, Ballinger ME, Miller BR, Salaun JJ. Detection of yellow fever viral RNA by nucleic acid hybridization and viral antigen by immunocytochemistry in fixed human liver. Am J Trop Med Hyg 1989; 40:663.
  37. Vieira WT, Gayotto LC, de Lima CP, de Brito T. Histopathology of the human liver in yellow fever with special emphasis on the diagnostic role of the Councilman body. Histopathology 1983; 7:195.
  38. De Brito T, Siqueira SA, Santos RT, et al. Human fatal yellow fever. Immunohistochemical detection of viral antigens in the liver, kidney and heart. Pathol Res Pract 1992; 188:177.
  39. Monath TP. Treatment of yellow fever. Antiviral Res 2008; 78:116.
  40. Gabrielsen B, Monath TP, Huggins JW, et al. Antiviral (RNA) activity of selected Amaryllidaceae isoquinoline constituents and synthesis of related substances. J Nat Prod 1992; 55:1569.
  41. Sbrana E, Xiao SY, Guzman H, et al. Efficacy of post-exposure treatment of yellow fever with ribavirin in a hamster model of the disease. Am J Trop Med Hyg 2004; 71:306.
  42. Stephen EL, Sammons ML, Pannier WL, et al. Effect of a nuclease-resistant derivative of polyriboinosinic-polyribocytidylic acid complex on yellow fever in rhesus monkeys (Macaca mulatta). J Infect Dis 1977; 136:122.
  43. Arroyo JI, Apperson SA, Cropp CB, et al. Effect of human gamma interferon on yellow fever virus infection. Am J Trop Med Hyg 1988; 38:647.
  44. de Melo AB, da Silva Mda P, Magalhães MC, et al. Description of a prospective 17DD yellow fever vaccine cohort in Recife, Brazil. Am J Trop Med Hyg 2011; 85:739.
  45. Galler R, Pugachev KV, Santos CL, et al. Phenotypic and molecular analyses of yellow fever 17DD vaccine viruses associated with serious adverse events in Brazil. Virology 2001; 290:309.
  46. Vratskikh O, Stiasny K, Zlatkovic J, et al. Dissection of antibody specificities induced by yellow fever vaccination. PLoS Pathog 2013; 9:e1003458.
  47. Gotuzzo E, Yactayo S, Córdova E. Efficacy and duration of immunity after yellow fever vaccination: systematic review on the need for a booster every 10 years. Am J Trop Med Hyg 2013; 89:434.
  48. Belmusto-Worn VE, Sanchez JL, McCarthy K, et al. Randomized, double-blind, phase III, pivotal field trial of the comparative immunogenicity, safety, and tolerability of two yellow fever 17D vaccines (Arilvax and YF-VAX) in healthy infants and children in Peru. Am J Trop Med Hyg 2005; 72:189.
  49. Meeting of the Strategic Advisory Group of Experts on immunization, April 2013 – conclusions and recommendations. Wkly Epidemiol Rec 2013; 88:201.
  50. World Health Organization. Yellow fever vaccination booster not needed. http://www.who.int/mediacentre/news/releases/2013/yellow_fever_20130517/en/ (Accessed on June 18, 2015).
  51. Staples JE, Bocchini JA Jr, Rubin L, et al. Yellow Fever Vaccine Booster Doses: Recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep 2015; 64:647.
  52. Pulendran B. Learning immunology from the yellow fever vaccine: innate immunity to systems vaccinology. Nat Rev Immunol 2009; 9:741.
  53. Querec TD, Akondy RS, Lee EK, et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol 2009; 10:116.
  54. Gaucher D, Therrien R, Kettaf N, et al. Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. J Exp Med 2008; 205:3119.
  55. Scherer CA, Magness CL, Steiger KV, et al. Distinct gene expression profiles in peripheral blood mononuclear cells from patients infected with vaccinia virus, yellow fever 17D virus, or upper respiratory infections. Vaccine 2007; 25:6458.
  56. Querec T, Bennouna S, Alkan S, et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med 2006; 203:413.
  57. Miller JD, van der Most RG, Akondy RS, et al. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity 2008; 28:710.
  58. Cao W, Manicassamy S, Tang H, et al. Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol 2008; 9:1157.
  59. Monath TP, Nichols R, Archambault WT, et al. Comparative safety and immunogenicity of two yellow fever 17D vaccines (ARILVAX and YF-VAX) in a phase III multicenter, double-blind clinical trial. Am J Trop Med Hyg 2002; 66:533.
  60. Centers for Disease Control and Prevention (CDC). Transfusion-related transmission of yellow fever vaccine virus--California, 2009. MMWR Morb Mortal Wkly Rep 2010; 59:34.
  61. Kuhn S, Twele-Montecinos L, MacDonald J, et al. Case report: probable transmission of vaccine strain of yellow fever virus to an infant via breast milk. CMAJ 2011; 183:E243.
  62. Monath TP, Gershman M, Staples JE, Barrett ADT. Yellow fever vaccine. In: Vaccines, 6th ed, Plotkin SA, Orenstein WA, Offit PA. (Eds), Elsevier Saunders, 2012. p.870.
  63. Centers for Disease Control and Prevention (CDC). Adverse events associated with 17D-derived yellow fever vaccination--United States, 2001-2002. MMWR Morb Mortal Wkly Rep 2002; 51:989.
  64. Kitchener S. Viscerotropic and neurotropic disease following vaccination with the 17D yellow fever vaccine, ARILVAX. Vaccine 2004; 22:2103.
  65. Kengsakul K, Sathirapongsasuti K, Punyagupta S. Fatal myeloencephalitis following yellow fever vaccination in a case with HIV infection. J Med Assoc Thai 2002; 85:131.
  66. McMahon AW, Eidex RB, Marfin AA, et al. Neurologic disease associated with 17D-204 yellow fever vaccination: a report of 15 cases. Vaccine 2007; 25:1727.
  67. Lindsey NP, Schroeder BA, Miller ER, et al. Adverse event reports following yellow fever vaccination. Vaccine 2008; 26:6077.
  68. Khromava AY, Eidex RB, Weld LH, et al. Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. Vaccine 2005; 23:3256.
  69. Martin M, Tsai TF, Cropp B, et al. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases. Lancet 2001; 358:98.
  70. Vasconcelos PF, Luna EJ, Galler R, et al. Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. Lancet 2001; 358:91.
  71. Chan RC, Penney DJ, Little D, et al. Hepatitis and death following vaccination with 17D-204 yellow fever vaccine. Lancet 2001; 358:121.
  72. Gershman MD, Staples JE, Bentsi-Enchill AD, et al. Viscerotropic disease: case definition and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 2012; 30:5038.
  73. Hayes EB. Acute viscerotropic disease following vaccination against yellow fever. Trans R Soc Trop Med Hyg 2007; 101:967.
  74. Monath TP. Suspected yellow fever vaccine-associated viscerotropic adverse events (1973 and 1978), United States. Am J Trop Med Hyg 2010; 82:919.
  75. Whittembury A, Ramirez G, Hernández H, et al. Viscerotropic disease following yellow fever vaccination in Peru. Vaccine 2009; 27:5974.
  76. Breugelmans JG, Lewis RF, Agbenu E, et al. Adverse events following yellow fever preventive vaccination campaigns in eight African countries from 2007 to 2010. Vaccine 2013; 31:1819.
  77. Pulendran B, Miller J, Querec TD, et al. Case of yellow fever vaccine--associated viscerotropic disease with prolonged viremia, robust adaptive immune responses, and polymorphisms in CCR5 and RANTES genes. J Infect Dis 2008; 198:500.
  78. Martin M, Weld LH, Tsai TF, et al. Advanced age a risk factor for illness temporally associated with yellow fever vaccination. Emerg Infect Dis 2001; 7:945.
  79. DeSilva M, Sharma A, Staples E, et al. Notes from the field: fatal yellow fever vaccine-associated viscerotropic disease--Oregon, September 2014. MMWR Morb Mortal Wkly Rep 2015; 64:279.
  80. Roukens AH, Soonawala D, Joosten SA, et al. Elderly subjects have a delayed antibody response and prolonged viraemia following yellow fever vaccination: a prospective controlled cohort study. PLoS One 2011; 6:e27753.
  81. Barwick Eidex R, Yellow Fever Vaccine Safety Working Group. History of thymoma and yellow fever vaccination. Lancet 2004; 364:936.
  82. Monath TP, Cetron MS. Prevention of yellow fever in persons traveling to the tropics. Clin Infect Dis 2002; 34:1369.
  83. Centers for Disease Control and Prevention. Health Information for International Travel 2016: The Yellow Book. http://wwwnc.cdc.gov/travel/page/yellowbook-home (Accessed on August 19, 2015).
  84. Cetron MS, Marfin AA, Julian KG, et al. Yellow fever vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2002. MMWR Recomm Rep 2002; 51:1.
  85. Jentes ES, Poumerol G, Gershman MD, et al. The revised global yellow fever risk map and recommendations for vaccination, 2010: consensus of the Informal WHO Working Group on Geographic Risk for Yellow Fever. Lancet Infect Dis 2011; 11:622.
  86. Glidewell J, Olney RS, Hinton C, et al. State Legislation, Regulations, and Hospital Guidelines for Newborn Screening for Critical Congenital Heart Defects - United States, 2011-2014. MMWR Morb Mortal Wkly Rep 2015; 64:625.
  87. Centers for Disease Control and Prevention. Travelers' Health. www.cdc.gov/travel (Accessed on July 18, 2012).
  88. Centers for Disease Control and Prevention. Yellow fever vaccine course. http://www.cdc.gov/travel-training/ (Accessed on October 03, 2011).
  89. Mosimann B, Stoll B, Francillon C, Pécoud A. Yellow fever vaccine and egg allergy. J Allergy Clin Immunol 1995; 95:1064.
  90. World Health Organization. The Yellow Fever Initiative: providing an opportunity of a lifetime. http://www.who.int/csr/disease/yellowfev/brochure/en/index.html (Accessed on August 09, 2002).
  91. World Health Organization. International travel and health. www.who.int/ith/ (Accessed on February 08, 2002).
  92. Hickling J, Jones R. Yellow fever vaccination: The potential of dose-sparing to increase vaccine supply and availability. PATH, Seattle, WA 2013. http://www.path.org/publications/files/TS_vtg_yf_rpt.pdf (Accessed on April 13, 2016).
  93. Martins RM, Maia Mde L, Farias RH, et al. 17DD yellow fever vaccine: a double blind, randomized clinical trial of immunogenicity and safety on a dose-response study. Hum Vaccin Immunother 2013; 9:879.
  94. Campi-Azevedo AC, de Almeida Estevam P, Coelho-Dos-Reis JG, et al. Subdoses of 17DD yellow fever vaccine elicit equivalent virological/immunological kinetics timeline. BMC Infect Dis 2014; 14:391.
  95. World Health Organization. Yellow Fever: Strategic Response Plan - June-August 2016. WHO, Geneva 2016. http://apps.who.int/iris/bitstream/10665/246103/1/WHO-YF-ENB-16.2-eng.pdf (Accessed on June 27, 2016).
  96. http://www.who.int/mediacentre/news/statements/2016/yellow-fever-vaccine/en/ (Accessed on June 27, 2016).
  97. Staples JE, Gershman M, Fischer M, Centers for Disease Control and Prevention (CDC). Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010; 59:1.
  98. Nasidi A, Monath TP, Vandenberg J, et al. Yellow fever vaccination and pregnancy: a four-year prospective study. Trans R Soc Trop Med Hyg 1993; 87:337.
  99. Tsai TF, Paul R, Lynberg MC, Letson GW. Congenital yellow fever virus infection after immunization in pregnancy. J Infect Dis 1993; 168:1520.
  100. Centers for Disease Control and Prevention (CDC). Transmission of yellow fever vaccine virus through breast-feeding - Brazil, 2009. MMWR Morb Mortal Wkly Rep 2010; 59:130.
  101. Kernéis S, Launay O, Ancelle T, et al. Safety and immunogenicity of yellow fever 17D vaccine in adults receiving systemic corticosteroid therapy: an observational cohort study. Arthritis Care Res (Hoboken) 2013; 65:1522.
  102. Veit O, Niedrig M, Chapuis-Taillard C, et al. Immunogenicity and safety of yellow fever vaccination for 102 HIV-infected patients. Clin Infect Dis 2009; 48:659.
  103. Tattevin P, Depatureaux AG, Chapplain JM, et al. Yellow fever vaccine is safe and effective in HIV-infected patients. AIDS 2004; 18:825.
  104. Monath TP, Fowler E, Johnson CT, et al. An inactivated cell-culture vaccine against yellow fever. N Engl J Med 2011; 364:1326.