Yellow Fever

Section Contents

Key Points
General Concepts
Epidemiology & Transmission
Clinical Presentation & Pathogenesis
Diagnosis & Treatment
General Prevention & Yellow Fever Vaccine
References

Key Points

Yellow Fever (YF) is a mosquito-borne viral disease transmitted and can lead to severe hemorrhagic complications with multiorgan failure.
About 90% of the cases are found in Africa, and less commonly in South America.
Diagnosis can be confirmed by RT-PCR in the first 3-4 days of the disease, but more often may be done by documenting IgM seroconversion of convalescent serum.
Vaccination is highly effective and confers long-lasting immunity, except in a small subset of patients which may require booster doses.
Rarely, YF vaccine can induce neurotropic or viscerotropic disease in susceptible individuals.

General Concepts

Yellow fever (YF) is a mosquito-borne anthropo-zoonosis caused by the Yellow Fever Virus (YFV) - a Flavivirus. The name "yellow fever" alludes to the icteric sclera and mucosa of those who contract the virus, but it is misleading as this is not universally present. Historically, it has also been called the “black vomit” because of the appearance of the hematemesis in reference to the hemorrhagic complications of YF.

NOTE: Medically relevant Flaviviruses:

Dengue virus
Yellow fever virus
Japanese/St Louis encephalitis virus
Powassan virus
West Nile virus
Zika virus

Figure 1. Aedes aegypti

Epidemiology & Transmission

To date, there is only transmission of YFV in certain regions of South America and Sub Saharan Africa. About 90% of cases worldwide occur in Africa. The virus is transmitted between hosts (animal-animal, animal-human, or human-human) via a mosquito and circulates in different transmission cycles:

Sylvatic (jungle) cycle

Here, the YFV replicates in a variety of animals, but primarily among 6 monkey genus (Aotus - nightmonkey; Alouatta - howler monkey; Cebus - capuchin monkeys; Ateles - spider monkey; Callithrix - marmoset monkey; Saimiri - squirrel monkeys). The vector is the mosquito of the genus Aedes (in Africa and South America) or Haemagogus & Sabethes (in South America). Humans play a minor role in the transmission of YFV in the sylvatic cycle, but unimmunized individuals can get incidentally infected when exposed to mosquitos in forested areas or in close contact with monkeys.

Note: Because monkeys can also acquire the disease, wildlife surveillance is used as a surrogate of upcoming outbreaks.

Savannah (intermediate or semi-domestic) cycle

Urban (domestic) cycle

	Sylvatic cycle	Savannah cycle	Urban cycle
Distribution	Africa & South America	Africa	Africa & South America
Pricipal vector	Africa: Aedes	Africa: Aedes	Africa: Aedes
Pricipal vector	South America: Aedes, Haemagogus, & Sabethes	South America: Aedes	South America: Aedes
Hosts involved	Animal-Animal	Animal-Human Human-Human	Human-Human

Note: Arboviruses transmitted by Haemagogus spp. (in South America):

Yellow fever
Mayaro virus

Clinical Presentation & Pathogenesis

Incubation period is 3-6 days. The course of the disease is classically described in two phases:

Mild cases (75-85%)/Acute phase: can range from asymptomatic to mild symptoms - characterized by a nonspecific febrile illness plus headaches, chills, nausea, vomiting, myalgias, weakness, and malaise. Typically lasts 3-4 days.
Severe cases (15-25%)/Toxic phase: after a remission of hours to days, the symptoms relapse with very acute-onset high-grade fever >40C, chills, headaches, myalgias, conjunctival injection, and can progress to multiorgan failure. This phase reflects the viscerotropic nature of the YFV (invasion to multiple tissues, with intense replication in the liver leading to a cytokine storm). Multisystem involvement is as follows:
1. Neurologic: toxic metabolic encephalopathy → agitation, stupor, coma.
2. Cardiac: intrinsic cardiac damage → Faget’s sign (relative bradycardia), shock.
3. Hepatic: acute liver failure → jaundice (“yellow fever”).
4. Renal: acute renal failure → oliguria.
5. Hematologic: coagulopathy & disseminated intravascular coagulation → bleeding tendency (epistaxis, gastrointestinal bleeding (“black vomit”), purpura).
Prognosis: Mortality is about 50% with no medical attention and typically occurs 7-10 days into the illness. Infection confers life-long immunity for those who survive.

Diagnosis & Treatment

Diagnosis is challenging and it is suggested to consult with a specialist. There are two main testing modalities:

RT-PCR: can be detected in serum samples during the first days of symptom onset, but YFV viremia is quite short (about 3-4 days). A positive result confirms the diagnosis. A negative result DOES NOT exclude the diagnosis.
Serology (ELISA, microsphere immunoassay): IgM appears during the first week of illness and can be detected up to 3 months following infection. Laboratory confirmation requires seroconversion of convalescent plasma (at least 1 week apart). Does not differentiate between natural infection and immunization. For full algorithm recommend consulting the PAHO/WHO guidelines (page 4).

There is no specific antiviral treatment for YF. Treatment is supportive (ie, intravenous fluids, transfusion of blood products as needed, reversal of coagulopathy, dialysis).

General Prevention

Vector avoidance: use insect repellents, permethrin-sprayed clothes, protective clothing (long pants & sleeves), and nets.

Figure 2. Yellow fever vaccination card

Vector control: decrease mosquito breeding sites (dump stagnant water), mosquito traps.

Yellow Fever Vaccine

This is arguably, the most important section of the whole module - because depending on where you practice, you will deal with the Yellow Fever vaccine more often than with the virus itself. It's out of our scope to explain all nuances, but we outlined the most high-yield concepts for you! (click here for more information).

The YF vaccine is a live attenuated vaccine made out of the 17D strain. Please click through the options below for more information:

Efficacy

Indications

Contraindications

Severe allergies (anaphylaxis) to eggs or other components of the YF vaccine.
Immunocompromised individuals (ie, PLHIV, malignancy, transplant, those on immunosuppressive medications).
Severe immunodeficiency, notably thymus disorders including: myasthenia gravis, thymoma, thymectomy, DiGeorge syndrome, thymic damage from chemo radiation or GVHD, etc.
Pregnancy or breastfeeding (may induce neurotropic in the infant).
Age ≥60 (although not an absolute contraindication, one should be VERY careful in giving the YF vaccine in elder individuals because of the risk of neurotropic or viscerotropic disease).

Adverse effects

Mild: ~25% report mild side effects (HA, myalgia, low grade fever).
Severe:
- Anaphylaxis (rare) primarily in egg allergy.
- YF vaccine associated neurotropic disease (YF-AND): can produce meningoencephalitis, myelitis, Guillain-Barre syndrome, etc. Risk factors: breastfeeding, extremes of ages.
- YF vaccine associated viscerotropic disease (YF-AVD): similar to naturally acquired YF disease (including multiorgan failure and death). Risk factors: age >60, immunosuppression and thymus disorders. Can be differentiated from infections due to wild-type virus by sequencing the strain 17D (vaccine virus).

Other considerations

Precautions → patients >60 years should be informed of risks of YF vaccine and balanced against the risk of naturally acquiring the virus during travel!

Co-administration with other vaccines: other live vaccines can be given the same day (e.g., MMR, Japanese encephalitis) or at least 4 weeks apart - some institutions may only accept blood donations 4 weeks after a live attenuated vaccine is given.
Pre-travel → some countries will require proof of vaccination before traveling. Check with the embassy/consulate of your destination country before your visit. If unable to get the vaccine due to medical reasons, then an exemption letter and a Medical Contraindications section in your vaccination card may be filled out by a physician.

References

View All References

Beeching, N. and Gill, G. (2014) Lecture notes tropical medicine, 7th edition. John Wiley & Sons.
Blumberg, L. et al. (2021) Oxford Handbook of Tropical Medicine. Oxford: Oxford University Press.
Reyes Romero, H., Navarro Rojas, P. and Reyes Barrios, H. (2013) Medicina tropical y enfermedades del viajero Vol Tomo I. Caracas: Consejo de Desarrollo Científico y Humanístico Universidad Central de Venezuela.
Staples, J. E., Barrett, A. D. T., Wilder-Smith, A., & Hombach, J. (2020). Review of data and knowledge gaps regarding yellow fever vaccine-induced immunity and duration of protection. Npj Vaccines, 5(1).
Oyono, M. G., Kenmoe, S., Abanda, N. N., Takuissu, G. R., Ebogo-Belobo, J. T., Kenfack-Momo, R., Kengne-Nde, C., Mbaga, D. S., Tchatchouang, S., Kenfack-Zanguim, J., Fogang, R. L., Menkem, E. Z., Ondigui, J. L. N., Kame-Ngasse, G. I., Magoudjou-Pekam, J. N., Bowo-Ngandji, A., Esemu, S. N., & Ndip, L. (2022). Epidemiology of yellow fever virus in humans, arthropods, and non-human primates in sub-Saharan Africa: A systematic review and meta-analysis. PLoS Neglected Tropical Diseases, 16(7), e0010610
Reno, E., Quan, N. G., Franco-Paredes, C., Chastain, D. B., Chauhan, L., Rodriguez-Morales, A. J., & Henao-Martínez, A. F. (2020). Prevention of yellow fever in travellers: an update. The Lancet Infectious Diseases, 20(6), e129–e137.
Juan-Giner, A., & Hombach, J. (2024). The life-long protective immunity of yellow fever vaccination: time to review? The Lancet Global Health, 12(3), e352–e353.
Uwishema, O., Eneh, S. C., Chiburoma, A. G., Elhassan, W. a. F., Adekunle, A. A., Rogose, M. S., Zaki, E., Akilimali, A., & Onyeaka, H. (2022). Yellow fever outbreak in Kenya: A review. Annals of Medicine and Surgery, 82.
Yellow fever. (2023, December 14). The Australian Immunisation Handbook. https://immunisationhandbook.health.gov.au/contents/vaccine-preventable-diseases/yellow-fever
Gianchecchi, E., Cianchi, V., Torelli, A., & Montomoli, E. (2022). Yellow Fever: origin, epidemiology, preventive strategies and future prospects. Vaccines, 10(3), 372.
De Azevedo Fernandes, N. C., Guerra, J. M., Díaz-Delgado, J., Cunha, M. S., Saad, L. D., Iglezias, S. D., Ressio, R. A., Cirqueira, C. D. S., Kanamura, C. T., Jesus, I. P., Maeda, A. Y., Vasami, F. G., De Carvalho, J., De Araújo, L. J., De Souza, R. P., Nogueira, J. S., Spinola, R. M., & Catão-Dias, J. L. (2020). Differential Yellow Fever Susceptibility in New World Nonhuman Primates, Comparison with Humans, and Implications for Surveillance. Emerging Infectious Diseases, 27(1), 47–56.
Pan American Health Organization. World Health Organization. (2018). Laboratory diagnosis of yellow fever virus infection. https://cdn.who.int/media/docs/default-source/inaugural-who-partners-forum/laboratory-diagnosis-yellow-fever-infection-sep-2018fa192479-3fff-47a3-9cc7-a39d4da55bba.pdf?sfvrsn=907f5db_1&download=true
Clinical features and diagnosis of yellow fever. (2024, May 15). Yellow Fever Virus. https://www.cdc.gov/yellow-fever/hcp/clinical-diagnosis/?CDC_AAref_Val=https://www.cdc.gov/yellowfever/healthcareproviders/healthcareproviders-diagnostic.html

This lesson was last updated September 4 2025