Official reprint from UpToDate®

www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice,
diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care
professional regarding any medical questions or conditions. The use of UpToDate content is governed by
the UpToDate Terms of Use. ©2018 UpToDate, Inc. All rights reserved.

Yellow fever

Author: Thomas P Monath, MD, FACP, FASTMH

Section Editor: Martin S Hirsch, MD
Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2018. | This topic last updated: Mar 30, 2018.

INTRODUCTION — 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.

VIROLOGY, PATHOGENESIS, AND HISTOPATHOLOGY — 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, lymph nodes, and spleen and are 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].

Injury to hepatocytes is characterized by eosinophilic degeneration with condensed nuclear chromatin

(Councilman bodies) rather than by the ballooning and rarefaction necrosis seen in viral hepatitis. Liver cell
death is due to apoptosis. Hepatocytes in the midzone of the liver lobule express Fas ligand, and
lymphocytes infiltrating the liver mediate apoptosis. Inflammatory cells, mainly CD4+ cells, are present in low
numbers; smaller numbers of NK and CD8+ cells are present [9,10]. There is no disruption of the reticular
architecture of the liver. In nonfatal cases, healing is complete without postnecrotic fibrosis. In fatal cases,
approximately 80 percent of hepatocytes undergo coagulative necrosis.

Renal damage is characterized by eosinophilic degeneration and fatty change of renal tubular epithelium
without inflammation. These findings are believed to be a result of both direct viral injury and nonspecific
changes due to hypotension and the hepatorenal syndrome [5].

Focal injury to the myocardium, characterized by cell degeneration and fatty change, is the result of viral
replication.

The hemorrhagic diathesis in yellow fever is due to decreased synthesis of vitamin K-dependent coagulation
factors by the liver, disseminated intravascular coagulation, and platelet dysfunction.

The late phase of the disease is characterized by circulatory shock. The underlying mechanism may be
cytokine dysregulation, as in the sepsis syndrome. In a series of patients with fatal yellow fever, levels of
proinflammatory cytokines (interleukin [IL]-6, IL-1 receptor antagonist, tumor necrosis factor [TNF]-alpha, and
interferon-inducible protein-10) were elevated compared with patients with nonfatal yellow fever [11]. Patients
dying of yellow fever have cerebral edema at autopsy, probably the result of microvascular dysfunction. Large
amounts of complement-fixing antigen (presumably NS1) have been found in blood of severely ill yellow fever
patients [12].

Some nonhuman primate species develop fatal infection with features similar to the disease in humans [5]. A
model of yellow fever infection in hamsters has been described [13,14]. Clinical, immunologic, and pathologic
features resemble human infection, suggesting that this model might serve to increase the understanding of
the pathogenesis of infection and to explore possible treatments. Interferon-alpha/beta receptor-deficient
mice are also susceptible to viscerotropic infection [15].

EPIDEMIOLOGY

Geographic distribution — Yellow fever occurs in tropical regions of sub-Saharan Africa and South
America; it is an epidemic disease problem of considerable magnitude [16,17]. The incidence of endemic
disease is not well established, but approximately 1 percent of individuals with severe hepatitis in endemic
areas of Africa may be caused by yellow fever [18]. An estimate from serologic and epidemiologic data
concluded that there were 130,000 cases with viscerotropic disease and 78,000 deaths in Africa in 2013 [19].

The incidence of yellow fever in Africa varies widely, and the disease occurs in epidemics [16]. A large Aedes
aegypti–borne epidemic occurred in Angola and neighboring Democratic Republic of the Congo in
south/central Africa between December 2015 and July 2016 with over 2930 confirmed or suspected cases
and 253 deaths and resulting in the emergency distribution of 30 million doses of vaccine [20-22]. Mosquito-
borne epidemics in Africa occur where large human populations reside in high density and immunization
coverage is low. The highest number of outbreaks has occurred in West Africa, but this situation is changing
due to a concerted effort to undertake mass immunization campaigns in that region. Human-to-human
transmission in the absence of the mosquito has not been reported.

Fewer cases occur in South America than in Africa because transmission occurs from enzootic sources
(principally from monkey to human via mosquito vectors), the vector density is relatively low, and vaccination
coverage is relatively high (80 to 90 percent in endemic areas of South America). In typical years, there are
several hundred cases officially notified, but in epidemic years up to 5000 cases are reported.
In Africa and South America, only a small proportion of cases is officially recorded because the disease often
occurs in remote areas, recognition of outbreaks is delayed, and diagnostic facilities are limited. In Africa,
reports of outbreaks in the 1980s noted the incidence of yellow fever infection to be 20 to 40 percent, the
incidence of severe disease to be 3 to 5 percent, and the case-fatality rate to be 20 to 30 percent. In contrast,
case-fatality rates in South America are consistently 50 to 60 percent. It is uncertain whether these disparities
reflect reporting artifact, a real difference in virus strain virulence, and/or differing genetic susceptibility of the
human populations. A racial difference in susceptibility is likely, supported by an analysis of epidemiologic
data from an 1878 epidemic in Tennessee, in which yellow fever attack rates were similar in the Caucasian
and non-Caucasian populations of the city, but the case-fatality rate was 6.8-fold higher in Caucasians [23].

Yellow fever epidemics have never been reported in Asia, and introduction to that region could have
devastating effects since there is no background of specific immunity, and the urban vector (Aedes aegypti) is
prevalent. In the context of the 2016 yellow fever outbreak in Angola, at least 11 Chinese workers developed
yellow fever upon travel home to China, illustrating the danger of introduction and potential secondary spread
[24].

Prior to the reports among travelers from Angola, yellow fever in expatriates and travelers to and from Africa
and South America has been rare since the introduction of vaccination after World War II. Since that time, 10
cases had been recorded up to the time of the 2016 Angolan outbreak [8,25-29]. The situation in Angola
appears to be linked to a large number of Chinese construction workers and other expatriates who entered
the country without vaccination. Changes in human demography, particularly expansion of urban populations
throughout the tropics, expansion of air travel, and rapid spread of other viruses (dengue, Zika, chikungunya)
transmitted between humans by urban Ae. aegypti throughout the southern hemisphere illustrate the global
dangers associated with exportation and spread of yellow fever.

Outbreak in Brazil — An ongoing yellow fever outbreak in Brazil began in December 2016 [30-32].
Between July 1, 2017, and February 16, 2018, 464 confirmed human cases of yellow fever were reported in
Brazil, including 154 deaths [33]. In March 2018, the Brazilian health ministry issued a recommendation for
universal yellow fever vaccination in Brazil [34].

Since January 2018, 10 travel-related cases have been reported in international travelers returning from
Brazil, including four deaths; none of the 10 travelers had received yellow fever vaccination [32]. In March
2018, the United States Centers for Disease Control issued an advisory, which expanded the regions within
Brazil for which travelers should receive yellow fever vaccine [35-37].

Transmission cycles — The primary transmission cycle involves monkeys and daytime biting mosquitoes
(Aedes species in Africa, Haemagogus species in South America).

In Africa, a wide array of Aedes vectors is responsible for transmission. During the rainy season, the virus
circulates via mosquitoes in the savanna vegetational zone in proximity to human settlements. Both humans
and nonhuman primates can be hosts in the transmission cycle, and the rate of virus transmission may
accelerate to reach epidemic levels. Aedes aegypti, a common domestic mosquito that can breed in
containers used to store potable water in heavily settled areas, is capable of serving as an epidemic vector
with humans as the intermediate viremic hosts (so-called "urban yellow fever").

In South America, the larval development of mosquitoes occurs in areas such as tree holes containing
rainwater. Persons entering forested areas are at risk of infection (so-called "jungle yellow fever"); this
accounts for the predominance of cases among young males engaged in forest clearing and agriculture. In
the 1970s, the Aedes aegypti mosquito reinvaded areas of South America where it previously had been
eradicated, increasing the risk that urban yellow fever may reemerge. The first well-documented instance of
an urban-cycle epidemic since 1942 occurred in Paraguay in 2008 [38].
CLINICAL MANIFESTATIONS — The clinical spectrum of yellow fever includes [39]:

● Subclinical infection

● Abortive, nonspecific febrile illness without jaundice

● Life-threatening disease with fever, jaundice, renal failure, and hemorrhage

Yellow fever affects all ages, but disease severity and lethality is highest in older adults. The onset of illness
appears abruptly three to six days (median 4.3 days) after the bite of an infected mosquito [40]. The classical
illness is characterized by three stages:

● Period of infection

● Period of remission

● Period of intoxication

Period of infection — The period of infection consists of viremia, which lasts for three to four days. The
patient is febrile and complains of generalized malaise, headache, photophobia, lumbosacral pain, pain in the
lower extremities, myalgia, anorexia, nausea, vomiting, restlessness, irritability, and dizziness [41]. Symptoms
and signs are relatively nonspecific; at this phase, it is virtually impossible to distinguish yellow fever from
other acute infections.

On physical examination, the patient appears acutely ill with flushed skin, reddening of the conjunctivae and
gums, and epigastric tenderness. Enlargement of the liver with tenderness may be present. The tongue is
characteristically red at the tip and sides with a white coating in the center. The pulse rate is slow relative to
the height of the fever (Faget's sign). The temperature is typically 39ºC but may rise as high as 41ºC.

Laboratory abnormalities include leukopenia (1500 to 2500 per microL) with relative neutropenia; leukopenia
occurs rapidly after the onset of illness. Serum transaminase levels start to rise 48 and 72 hours after onset of
illness, prior to the appearance of jaundice. The degree of liver enzyme abnormalities at this stage may
predict the severity of hepatic dysfunction later in the illness [42].

Period of remission — A period of remission lasting up to 48 hours may follow the period of infection,
characterized by the abatement of fever and symptoms. Patients with abortive infections recover at this
stage. Approximately 15 percent of individuals infected with yellow fever virus enter the third stage of the
disease.

Period of intoxication — The period of intoxication begins on the third to sixth day after the onset of
infection with return of fever, prostration, nausea, vomiting, epigastric pain, jaundice, oliguria, and
hemorrhagic diathesis. The viremia terminates at this stage and antibodies appear in the blood. This phase is
characterized by variable dysfunction of multiple organs including the liver, kidneys, and cardiovascular
system. Multiorgan failure in yellow fever is associated with high levels of proinflammatory cytokines similar to
that seen in bacterial sepsis and systemic immune response syndrome (SIRS) [27].

Hepatic dysfunction — Hepatic dysfunction due to yellow fever differs from other viral hepatitides in that
serum aspartate aminotransferase (AST) levels exceed those of alanine aminotransferase (ALT). This may
be due to concomitant viral injury to the myocardium and skeletal muscle. The levels are proportional to
disease severity. In one study, the mean AST and ALT levels in fatal cases were 2766 and 660 U,
respectively, while in surviving patients with jaundice, the mean levels were 929 and 351 U [43]. Alkaline
phosphatase levels are normal or only slightly elevated. Direct bilirubin levels are typically between 5 and 10
mg/dL, with higher levels in fatal than in nonfatal cases [44].
 Renal dysfunction — Renal damage is characterized by oliguria, azotemia, and very high levels of
protein in the urine. Serum creatinine levels are three to eight times normal. In some patients who survive the
hepatitic phase, renal failure predominates. Death is preceded by virtually complete anuria.

Hemorrhage — Hemorrhage is a prominent component of the third phase of illness, including coffee-
grounds hematemesis, melena, hematuria, metrorrhagia, petechiae, ecchymoses, epistaxis, oozing of blood
from the gums, and bleeding from needle puncture sites. Gastrointestinal hemorrhage may contribute to
circulatory collapse. Laboratory abnormalities include thrombocytopenia, prolonged prothrombin time, and
global reductions in clotting factors synthesized by the liver (factors II, V, VII, IX, and X). Some patients have
findings suggesting disseminated intravascular coagulation, including diminished fibrinogen and factor VIII
and the presence of fibrin split products.

Myocardial injury — The clinical significance of myocardial injury is poorly understood and probably has
been underestimated in clinical studies. In some cases, acute cardiac enlargement has been documented
during the course of infection [45]. The electrocardiogram may show sinus bradycardia without conduction
defects, ST-T abnormalities, particularly elevated T waves, and extrasystoles. Bradycardia and myocarditis
may contribute to hypotension, reduced perfusion, and metabolic acidosis in severe cases. Arrhythmia has
been suggested to explain the rare reports of late death during convalescence.

Central nervous system dysfunction — Patients exhibit variable signs of central nervous system (CNS)
dysfunction including delirium, agitation, convulsions, stupor, and coma. In severe cases, the cerebrospinal
fluid is under increased pressure and may contain elevated protein but no cells. Pathologic changes include
microscopic perivascular hemorrhages and edema. Given the absence of inflammatory changes suggesting
viral neuroinvasion and encephalitis, CNS alterations are probably due to metabolic encephalopathy. True
yellow fever viral encephalitis is exceedingly rare.

Outcome — The outcome is determined during the second week after onset, at which point the patient either
dies or rapidly recovers. Approximately 20 to 50 percent of patients who enter the period of intoxication
succumb to the disease. Poor prognostic signs include anuria, shock, hypothermia, agitation, delirium,
intractable hiccups, seizures, hypoglycemia, hyperkalemia, metabolic acidosis, Cheyne-Stokes respirations,
stupor, and coma.

Convalescence may be associated with fatigue lasting for several weeks. In some cases, jaundice and serum
transaminase elevations may persist for months, although such patients may have yellow fever superimposed
on other hematologic or hepatic diseases. The outcome of yellow fever appears to be comparable in patients
with or without hepatitis B surface antigenemia.

Complications of yellow fever include bacterial superinfections, such as pneumonia, parotitis, and sepsis.
Late deaths during convalescence occur rarely and have been attributed to myocarditis, arrhythmia, or heart
failure.

DIAGNOSIS — Diagnosis is made by serology, detection of viral genome by polymerase chain reaction
(PCR), by viral isolation or histopathology, and immunohistochemistry on postmortem tissues.

Serology — Serologic diagnosis is best accomplished using an enzyme-linked immunosorbent assay

(ELISA) for IgM. The presence of IgM antibodies in a single sample provides a presumptive diagnosis;
confirmation is made by a rise in titer between paired acute and convalescent samples or a fall between early
and late convalescent samples.

Persistence of antibodies from earlier receipt of the live-attenuated vaccine can complicate interpretation of
IgM results [46]. In addition, cross-reactions with other flaviviruses complicate the diagnosis of yellow fever by
serologic methods, particularly in Africa where multiple flaviviruses circulate. The neutralization test is more
specific but requires a specialized laboratory.

Rapid diagnostic tests — Rapid diagnostic tests include PCR to detect viral genome in the blood or tissue
and ELISA for determination of IgM antibody [8]. Next-generation sequencing of RNA directly amplified from
blood has been used to confirm the diagnosis and compare the patient’s strain to known geographic clades of
the virus. These tools are increasingly available in national and regional laboratories in the endemic areas. A
reverse-transcription loop-mediated isothermal amplification (RT-LAMP) yellow fever diagnostic test, which
does not require thermocycling equipment and can be read visually, has shown promise as a sensitive and
rapid test for use in field conditions [47].

Virus isolation — Virus isolation is accomplished by inoculation of mosquito or mammalian cell cultures,
intracerebral inoculation of suckling mice, or intrathoracic inoculation of mosquitoes. The virus may also be
recovered from postmortem liver tissue. During a yellow fever outbreak in Ivory Coast in 1982 including 90
confirmed cases, 30 percent were diagnosed by virus isolation from the blood; the majority of patients had
detectable virus prior to onset of jaundice [48].

Pathology — Liver biopsy during illness due to yellow fever should never be performed, since fatal
hemorrhage may ensue. Postmortem histopathologic examination of the liver often demonstrates the typical
features of yellow fever including midzonal necrosis. A definitive postmortem diagnosis may be made by
immunocytochemical staining for yellow fever antigen in the liver, heart, spleen, or kidney [49-51]. (See
'Virology, pathogenesis, and histopathology' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of yellow fever includes:

● Viral hepatitis (hepatitis A, B, C, D, and E) – These entities are characterized by elevated transaminases;
hepatitis A and E are acute infections transmitted most frequently by the fecal-oral route, whereas
hepatitis B, C, and D can present acutely or chronically and are transmitted by body fluids. In Africa,
severe and fatal hepatitis E in pregnancy has frequently been misdiagnosed as yellow fever. (See related
topics.)

● Influenza – Influenza is associated with fever, headache, malaise, and myalgias. It is not generally
associated with severe hepatic involvement or jaundice. The diagnosis is established by viral detection.
(See "Clinical manifestations of seasonal influenza in adults".)

● Dengue – Dengue and yellow fever are similar in that both are associated with fever, headache and body
aches, and hemorrhagic manifestations. Hepatic involvement can occur in the setting of severe dengue
infection. The diagnosis of dengue is established by serology. (See "Dengue virus infection: Clinical
manifestations and diagnosis".)

● Malaria – Malaria is characterized by fever and anemia; clinical manifestations include jaundice due to
hemolysis. The diagnosis of malaria is established by visualization of parasites on peripheral smear.
(See "Clinical manifestations of malaria in nonpregnant adults and children".)

● Typhoid – Manifestations of typhoid fever include fever and gastrointestinal symptoms. Abnormal liver
function tests are observed but jaundice is not a typical clinical feature. The diagnosis is established by
culture. (See "Epidemiology, microbiology, clinical manifestations, and diagnosis of enteric (typhoid and
paratyphoid) fever".)

● Leptospirosis – Leptospirosis is a bacterial infection characterized by fever, myalgia, headache, and

conjunctival suffusion. Modest elevation of hepatic transaminases may be observed. The diagnosis is
established by serology. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and
diagnosis".)
 ● Q fever – Q fever occurs as a result of infection with Coxiella burnetii; hepatic involvement includes
elevated transaminases, hepatomegaly without jaundice, and granulomas on liver biopsy. The diagnosis
is established by serology. (See "Clinical manifestations and diagnosis of Q fever".)

● Hemorrhagic fever – Yellow fever may be distinguished from other viral hemorrhagic fevers (Lassa fever,
Marburg virus, Ebola virus, Bolivian and Argentine hemorrhagic fevers) in that these other viral
hemorrhagic fevers are not usually associated with jaundice. However, Congo-Crimean hemorrhagic
fever may be associated with severe liver damage; Rift Valley fever and dengue hemorrhagic fever may
present with this complication as well. (See related topics.)

TREATMENT — The treatment of yellow fever consists of supportive care; there is no specific antiviral
therapy available [52]. Management of patients may be improved by modern intensive care, but this is
generally not available in remote areas where yellow fever often occurs. Travelers hospitalized after return to
the United States or Europe have had fatal outcomes in spite of intensive care, demonstrating the inexorable
course of severe yellow fever [53].

Supportive care should include maintenance of nutrition, prevention of hypoglycemia, nasogastric suction to
prevent gastric distention and aspiration, treatment of hypotension by fluid replacement and vasoactive drugs
if necessary, administration of oxygen, management of metabolic acidosis, treatment of bleeding with fresh-
frozen plasma, dialysis if indicated by renal failure, and treatment of secondary infections [39].

All antiviral therapies are at a very early stage of development for use in yellow fever [39,52,54]. Ribavirin is
active against yellow fever virus but only at very high concentrations that may not be achievable clinically
[55].

The benefit of hyperimmune globulin or monoclonal antibody after the onset of clinical illness is uncertain;
further study is required [52,56,57].

PREVENTION — Vaccination is the primary tool for prevention of yellow fever.

Vaccination

Available vaccines — A live-attenuated vaccine against yellow fever was developed in 1936 (yellow fever
17D vaccine). In the United States, the vaccine (YF-VAX) is manufactured by Sanofi-Pasteur (Swiftwater, PA).
Another vaccine formulation derived from a different passage series of the same vaccine virus strain, 17DD,
is manufactured in Brazil [58]. There are six manufacturers of yellow fever vaccine worldwide, which produce
about 70 to 90 million doses annually; four are approved by the World Health Organization (WHO) and supply
the vast majority of doses. In general supply does not meet demand; expansion of vaccine production is
expected.

YF-VAX is unavailable in the United States until mid-2018, when a new production facility is expected to open
[59]. An alternative but similar formulation, Stamaril (produced in France and used in Europe, Australia, and
endemic areas), is available under the US Food and Drug Administration's (FDA's) Expanded Access
Investigational New Drug Program at high-volume yellow fever vaccination centers [60].

The WHO maintains an emergency stockpile of six million doses; this was depleted and replenished three
times in the 2016 Angolan outbreak. Because vaccine was in short supply in the 2016 outbreaks, and there
was apprehension about spread of yellow fever to other countries, especially Asia, WHO considered and
approved the use of fractional (one-fifth) doses (0.1 mL given by subcutaneous route) in emergency
conditions. (See 'Fractional vaccine dosing in outbreaks' below.)

Clinical approach — The estimated risks of illness and death due to yellow fever in an unvaccinated
traveler to an endemic area are relatively high (1 in 1000 and 1 in 5000 per month, respectively) [61]. In the
United States, the risks of YEL-AND and YEL-AVD in travelers are estimated at 0.8 and 0.4 per 100,000
respectively, although the risk is higher in older adults. (See 'Adverse effects' below.)

Whom to vaccinate — In accordance with the United States Centers for Disease Control and
Prevention (CDC), the United States Advisory Committee on Immunization Practices (ACIP), and the World
Health Organization, we recommend vaccination for travelers to yellow fever-endemic areas of Africa and
South America and for residents of those areas (figure 1 and figure 2) [61-64].

In June 2015, the ACIP issued recommendations stating that a single primary dose of yellow fever vaccine is
adequate for most travelers [65]. In July 2016, the World Health Assembly removed the 10-year booster dose
requirement from the International Health Regulations.

Nevertheless, the ACIP does recommend additional doses of yellow fever vaccine for the following patients
[65]:

● Women who were pregnant at the time of initial yellow fever vaccination should receive one additional
dose of yellow fever vaccine prior to subsequent travel to an area with risk for yellow fever virus infection.

● Individuals who received a hematopoietic stem cell transplant after receiving yellow fever vaccination
and who are sufficiently immunocompetent to be safely vaccinated should receive an additional dose of
yellow fever vaccine prior to subsequent travel to an area with risk for yellow fever virus infection. A study
in 21 allogeneic stem cell transplant recipients supported safety and immunogenicity of vaccination at a
median of 33 months after withdrawal of immunosuppression [66].

● Individuals who were infected with HIV at the time of prior yellow fever vaccination, with continued risk
for yellow fever virus infection, should receive a booster dose of yellow fever vaccine every 10 years.

● Individuals whose last dose of yellow fever vaccine was at least 10 years previously and plan to spend a
prolonged period in endemic areas, plan to travel to highly endemic areas (such as rural West Africa)
during peak transmission season, or plan to travel to an area with an ongoing outbreak should receive an
additional dose of yellow fever vaccine.

● Laboratory workers who routinely handle yellow fever virus should have antibody titers measured at least
every 10 years to determine if additional vaccination is warranted.

A biweekly "Blue Sheet" Summary of Health Information for International Travel published by the CDC
provides updated information on countries officially reporting yellow fever [67]. In addition, there is a free
course available online that provides information and training about yellow fever to healthcare professionals
who advise travelers [68]. The WHO is revising the geographic risk areas to create an evidence-based
analysis of the probability of exposure to yellow fever [63].

Due to the risk of serious adverse events (particularly in persons >60 years of age), the benefit of
immunization should be established based on careful review of the traveler's itinerary with respect to potential
for exposure to yellow fever virus [18]. Individuals traveling in rural areas of countries within yellow fever-
endemic zones should be immunized even in the absence of official yellow fever reports, since active
transmission may be underrecognized.

For individuals with allergy to egg proteins who clearly require immunization due to possible exposure to
yellow fever virus, epidermal scratch and intradermal skin testing may be performed to help ascertain whether
the vaccine can be given safely. Otherwise, desensitization may be used [69]. Skin testing and
desensitization are best performed by an experienced allergist. (See "Allergic reactions to vaccines".)
Vaccination against yellow fever in endemic areas is performed as part of the Expanded Program of
Immunization at nine months of age. In some African countries, catch-up mass vaccination campaigns are
undertaken based on assessments of geographic risk, as part of a highly successful initiative spearheaded by
the WHO to increase vaccine coverage [70,71]. Mass campaigns are also conducted in response to
outbreaks in Africa and South America.

Immunization certificates — In the United States, yellow fever vaccine is distributed only through
approved vaccinating centers, including travel clinics and some health departments. These designated
centers are listed in a registry at the CDC travel website [67].

Some countries in yellow fever-endemic zones require a World Health Organization international certificate of
vaccination as evidence of yellow fever immunization prior to entry; these are listed in the publications and
websites of the CDC and WHO [64,67,72]. In addition, some countries outside of yellow fever zones also
require evidence of immunizations prior to entry for individuals with recent travel in endemic countries [73].

The WHO international certificate of immunization for international travel is valid for life.

Individuals with contraindications or precautions deemed to place the traveler at high risk of adverse events
may receive a waiver letter from a physician for travel to areas where vaccination is an international travel
requirement.

The 2016 Angola outbreak revealed that multiple expatriates working in the country had entered the country
without vaccinations; as a result, there have been reports of yellow fever cases in persons travelling from
Angola to the Democratic Republic of the Congo, Kenya, and China. This situation illustrates the potential for
global spread of the virus.

Fractional vaccine dosing in outbreaks — Fractional dosing is a strategy for extending yellow fever
vaccine supply in outbreak situations [74-78]. In June 2016, the WHO Strategic Advisory Group of Experts on
Immunization stated that vaccination with one-fifth the standard dose is sufficient to provide protection against
yellow fever for at least 12 months, and they advocated short-term use of this approach among individuals ≥2
years of age in emergency conditions when vaccine supplies are limited [79,80]. The durability of fractional
dose vaccination beyond 12 months is unknown.

This approach is supported by an observational study including more than 490 seronegative nonpregnant
adults and children ≥2 years in the Democratic Republic of Congo who underwent vaccination with a
fractional dose (one-fifth of standard dose) of the 17DD yellow fever vaccine in the context of an outbreak; the
fractional dose was effective at inducing seroconversion in 98 percent of individuals [78]. Similar findings
have been observed among individuals vaccinated with 1/10th the standard dose of yellow fever 17DD
vaccine [76,77]. Fractional dosing has been used in millions of individuals during outbreaks in Brazil and the
Democratic Republic of Congo due to vaccine shortages.

The titer of vaccine should be reviewed to ensure that the delivered dose exceeds the minimum international
standard (1000 infectious units). Fractional dosing of yellow fever vaccination may not qualify for international
certificate of vaccination. (See 'Immunization certificates' above.)

Full-dose vaccine should be given to children <2 years of age since there are some concerns about lower
efficacy of the vaccine in this group [81]. Fractional vaccine dosing has not been studied in children, HIV-
infected individuals, or pregnant women.

Pregnancy and breastfeeding — Pregnancy is a precaution for yellow fever vaccine administration; in
contrast, most other live vaccines are contraindicated in pregnancy. If travel is unavoidable and the risks for
yellow fever virus exposure are felt to outweigh the vaccination risks, a pregnant woman should be
vaccinated. If the risks for vaccination are felt to outweigh the risks for yellow fever virus exposure, pregnant
women should be issued a medical waiver to fulfill health regulations [82].

The safety of yellow fever vaccination during pregnancy has not been clearly established. Congenital
infection appears to occur at a low rate (probably 1 to 2 percent) and has never been associated with fetal
abnormalities [83,84]. Pregnant woman who inadvertently receive vaccination should be reassured; there is
no rationale to interrupt the pregnancy.

Administration of yellow fever vaccine to breastfeeding women should be avoided except in situations where
exposure to yellow fever viruses cannot be avoided or postponed. Yellow fever vaccine virus can be
transmitted via breastfeeding; in one report, two infants acquired yellow fever vaccine virus via breast milk
from mothers who had undergone yellow fever vaccination; the infant developed YEL-AND requiring
hospitalization [85,86].

Immunocompromised individuals — Yellow fever 17D vaccine should not be administered to

immunocompromised individuals because of theoretical concerns about live-attenuated virus vaccines [82].

Contraindications include inherited immune deficiency, lymphoma, leukemia, HIV/AIDS with low CD4 counts,
immunosuppressive chemotherapy or radiotherapy, thymus disorders, DiGeorge's syndrome, and a history of
thymectomy. Autoimmune disease may be a risk factor for YEL-AVD but is not a listed precaution in the
vaccine label. Immunogenicity seems satisfactory among patients receiving systemic corticosteroid therapy
(median prednisone 7 mg/day for 10 months), although local reactions may occur more frequently in these
patients; further study is needed [87].

Travelers with asymptomatic HIV infection may be immunized if potential exposure warrants; such patients
should be advised of the possible risks of vaccination [82]. In studies of HIV-infected patients with CD4+
counts above 200/microL, all responded serologically and none had adverse events [88,89]. Nevertheless, it
is prudent to confirm development of neutralizing antibodies, since such individuals may have an impaired
ability to respond to yellow fever vaccine. Antibody testing can be arranged through state health department
laboratories or a commercial laboratory. Waiver letters can also be obtained for these patients [82].

Vaccine efficacy — The 17D vaccine produces high levels of protection [90]. Protective immunity occurs
in 90 percent of individuals within 10 days after receiving the 0.5 mL subcutaneous dose and in nearly 100
percent of individuals within three to four weeks after vaccination. A meta-analysis of studies of vaccine
efficacy showed that 97.5 percent of vaccinated individuals mounted a protective serologic response (95% CI
82.9 to 99.7 percent) [91]. The 17DD vaccine produces similar levels of protection [58].

Infants, toddlers, pregnant women, and persons with HIV or other causes of immune suppression may not
respond as vigorously to the 17D vaccine [92]. In one large study, the primary vaccine failure rate in young
children was approximately 9 percent [81].

Immunity after a single dose is long lasting and may provide lifetime protection [92]. The WHO Strategic
Advisory Group of Experts in Immunization concluded in 2013 that a single primary dose of yellow fever
vaccine is sufficient to confer sustained immunity and lifelong protection against yellow fever disease, and a
booster dose of the vaccine is not needed [93,94]. In May 2014, the World Health Assembly adopted the
recommendation to remove the 10-year booster dose requirement from the International Health Regulations
by June 2016. In 2015, the United States Advisory Committee on Immunization Practices issued
recommendations stating that a single primary dose of yellow fever vaccine is adequate for most travelers
[95]. (See 'Whom to vaccinate' above.)

The WHO international certificate of immunization for international travel is valid for 10 years; a booster 0.5
mL dose is required every 10 years for the certificate to be reissued. In May 2014, the World Health Assembly
adopted the recommendation to remove the 10-year booster dose requirement from the International Health
Regulations and this was formally implemented in July 2016. Revaccination is no longer required and a
certificate of vaccination is now valid for life.

The live-attenuated vaccine virus activates myeloid and plasmacytoid dendritic cells to produce a variety of
proinflammatory cytokines and turn on genes that activate signaling pathways [96-102]. Overall, a marked
upregulation of the innate immune system persists for about two weeks after vaccination and drives the
adaptive immune response.

Adverse effects — More than 600 million doses of vaccines have been administered since the 17D
vaccine strain was developed. Serious adverse reactions to the 17D vaccine are very rare events; they
include two syndromes, known as yellow fever vaccine-associated neurotropic disease (YEL-AND) and
yellow fever vaccine-associated viscerotropic disease (YEL-AVD). In the United States, the risks of YEL-AND
and YEL-AVD in civilian travelers are estimated at 0.8 and 0.4 per 100,000 respectively, although the risk is
higher in older individuals.

Mild fever, headache, myalgia and malaise, and soreness at the site of inoculation can occur in the absence
of liver function abnormalities [81,103].

The vaccine is contraindicated for persons with known egg allergy; allergic reactions to residual egg proteins
or gelatin stabilizer in yellow fever 17D vaccine occur, albeit at very low rates.

The yellow fever vaccine virus may be transmitted by transfusion of blood products. Vaccine recipients should
defer blood product donation for at least two weeks [104]. In addition, the vaccine virus may be transmitted
from lactating mothers to breast-fed infants [86].

Neurotropic disease — YEL-AND refers to an encephalitis usually caused by infection of the central
nervous system with 17D virus [105]. Onset occurs two to eight days after vaccination; the event is nearly
always self-limited but rarely is associated with neurological sequelae. Definitive diagnosis is based on virus
isolation, detection of viral genome by polymerase chain reaction (PCR), or detection of IgM antibody in
cerebrospinal fluid. Cases of neuromyelitis optica, Guillain-Barré, and acute disseminated encephalomyelitis
(ADEM) have also been described and presumably have an autoimmune etiology.

YEL-AND has been observed in infants and adults [73,106,107]. Between 2000 and 2006, the rate of YEL-
AND in the United States was 0.8 per 100,000 [108]. The incidence of YEL-AND is higher in older adults;
persons ≥70 years have a rate of 2.3 per 100,000 [109,110]. Among four cases described in adults in 2001 to
2002, all had fever and two had aphasia; cerebrospinal fluid was all positive for yellow fever-specific IgM in all
patients; cultures and PCR were negative [73]. Cases in infants have diminished since restriction of vaccine
administration to children more than nine months of age [73].

Viscerotropic disease — YEL-AVD refers to a syndrome resembling wild-type yellow fever infection
that occurs in the setting of yellow fever 17D vaccination [105,111-113]. Case definitions have been published
[114]. Onset of illness generally occurs three to five days after vaccination with fever, malaise, jaundice,
oliguria, cardiovascular instability, and hemorrhage. The case-fatality rate of YEL-AVD is 63 percent, and
there is no specific treatment [105,115,116].

The estimated incidence of YEL-AVD in the United States is 0.4 per 100,000 but may be sixfold higher among
individuals ≥60 years of age [109]. Based on the relatively small series of cases, there appears to be a higher
incidence in young adult females. In Peru, an unexplained, high incidence of YEL-AVD was reported during a
mass immunization campaign (7.9 per 100,000) [117]. In a large experience of 38 million vaccinations given
in West Africa between 2007 and 2010, during which pharmacovigilance was undertaken, few serious
adverse events and only five suspected YEL-AVD cases were found [71], emphasizing the high safety record
of the vaccine.

Nevertheless, there have been more reports of deaths due to YEL-AVD than due to wild-type disease in
unvaccinated travelers. This emphasizes the importance of careful assessment for vaccination need based
on full understanding of disease epidemiology and travel itinerary, to avoid unnecessary risk of vaccine
adverse effects but to ensure that patients with risk for exposure are protected [18].

Identifying risk factors for YEL-AVD is difficult because of the relatively low incidence. YEL-AVD does not
appear to be caused by mutational changes in the virus [90,105,117]. Rather, YEL-AVD is probably related to
defects in host innate immunity; in affected individuals, the early antiviral response appears to be impaired,
allowing unchecked viral replication before activation of the adaptive immune response [118].

Acquired host factors appear to increase the risk of developing YEL-AVD after vaccination: advanced age
and thymus disease and possibly female gender in younger persons [105,109,110,115,119,120]. A study in
older adults showed that viremia caused by yellow fever 17D vaccine was prolonged and the antibody
response delayed, foreshadowing the role of immune senescence in cases with YEL-AVD [121]. Thymus
disease (eg, thymoma, myasthenia gravis) was present in 4 of the 23 reported cases; all underwent
thymectomy 2 to 20 years before vaccination [122]. In addition, thymic involution increases with age and the
associated immune suppression might contribute to the increase in risk of YEL-AVD in older adults. A fatal
case in a patient with a thymoma detected only at autopsy illustrates the difficulty in assessing underlying
acquired risk factors [120]. There is some evidence that immune dysregulation associated with autoimmune
diseases, such as systemic lupus erythematosus and Addison's disease, may also be a risk factor for YEL-
AVD [18,117].

Development of safer vaccines — Serious adverse events (except acute hypersensitivity reactions) are
caused by replicating virus. Therefore, efforts are underway to develop safer, inactivated vaccines. A whole-
virion inactivated vaccine adsorbed to aluminum hydroxide adjuvant was protective in animal models and was
shown to be well tolerated and immunogenic in a phase I clinical trial [123].

Immune globulin — There is no specific yellow fever immune globulin product available. Immune globulin
produced in the United States (where many military personnel have been vaccinated) may contain yellow
fever-neutralizing antibodies. Passive immunization has been used off label to protect persons traveling to
high-risk areas who have contraindications to vaccination [105]. If exposure to yellow fever virus occurred at a
defined time (eg, in the case of accidental exposure in the laboratory or to blood from an acutely ill patient),
postexposure treatment with immune globulin (from United States donors) or interferon-alfa (preferably not
longer-acting pegylated interferon) would be warranted. Treatment would be expected to be effective only
within the first 24 hours after exposure [52].

SUMMARY AND RECOMMENDATIONS

● Yellow fever is a mosquito-borne viral hemorrhagic fever with a high case-fatality rate. Travelers to
tropical regions of South America and sub-Saharan Africa are at risk for acquisition of infection and
require immunization. (See 'Introduction' above.)

● Mosquito-borne epidemics in Africa occur where human populations reside in high density and
immunization coverage is low (so-called "urban yellow fever"). Fewer cases occur in South America than
in Africa because transmission occurs principally from monkey to human via mosquito vectors, the vector
density is relatively low, and vaccination coverage is relatively high (so-called "jungle yellow fever"). (See
'Epidemiology' above.)

● Yellow fever is characterized by three stages: periods of infection, remission, and intoxication. The period
of infection consists of viremia with nonspecific symptoms and signs including fever, malaise, headache,
 joint pain, nausea, and vomiting. This is followed by a period of remission with abatement of fever and
symptoms lasting up to 48 hours. The subsequent period of intoxication is characterized by hepatic
dysfunction, renal failure, coagulopathy, and shock. (See 'Clinical manifestations' above.)

● Diagnosis may be made by serology, by detection of viral genome by polymerase chain reaction (PCR)
in serum, by virus isolation, or by histopathology and immunocytochemistry (postmortem samples only).
Serologic diagnosis is best accomplished using an enzyme-linked immunosorbent assay (ELISA) for
IgM. The presence of IgM antibodies in a single sample provides a presumptive diagnosis; confirmation
is made by a rise in titer between paired acute and convalescent samples or a fall between early and late
convalescent samples. More specific neutralization tests may be performed but require a specialized
laboratory. (See 'Diagnosis' above.)

● The treatment of yellow fever consists of supportive care; there is no specific antiviral therapy available.
(See 'Treatment' above.)

● In accordance with the United States Centers for Disease Control and Prevention (CDC), the United
States Advisory Committee on Immunization Practices (ACIP), and the World Health Organization
(WHO), we recommend yellow fever vaccine for travelers to yellow fever-endemic areas of Africa and
South America and for residents of those areas (Grade 1A). The vaccine may be administered to
individuals over the age of nine months. (See 'Prevention' above and 'Whom to vaccinate' above.)

● Serious adverse reactions to the 17D vaccine are very rare; they include two syndromes, yellow fever
vaccine-associated neurotropic disease (YEL-AND) and yellow fever vaccine-associated viscerotropic
disease (YEL-AVD). In the United States, the risks of YEL-AND and YEL-AVD in civilian travelers are
estimated at 0.8 and 0.4 per 100,000, respectively, although the risk is higher in older adults, persons
with immune dysregulation, and possibly young females. Serious adverse events have been significantly
less frequently observed during immunization campaigns in endemic countries. In an ongoing epidemic
in Angola, multiple cases of yellow fever have been exported to various countries, including China. This
illustrates the danger of travel to endemic regions without vaccination and the risk of global spread of the
virus. (See 'Adverse effects' above.)

● Some countries in yellow fever-endemic zones require an international certificate of vaccination as

evidence of yellow fever immunization prior to entry. In addition, some countries outside of yellow fever
zones also require evidence of immunizations prior to entry for individuals with recent travel in endemic
countries. The international certificate of immunization is valid for 10 years; a booster 0.5 mL dose is
required every 10 years for the certificate to be reissued. (See 'Immunization certificates' above.)

● Immunity after a single dose is long lasting. In May 2014, the World Health Assembly adopted the
recommendation to remove the 10-year booster dose requirement from the International Health
Regulations by June 2016. Until this time, travelers to countries with a yellow fever vaccination entry
requirement must have received a dose of yellow fever vaccine within the past 10 years. In June 2015,
the United States Advisory Committee on Immunization Practices (ACIP) issued recommendations
stating that a single primary dose of yellow fever vaccine is adequate for most travelers; the ACIP does
recommend additional doses of yellow fever vaccine at-risk laboratory personnel and certain travelers.
(See 'Whom to vaccinate' above.)

● Fractional dosing is a strategy for extending yellow fever vaccine supply in outbreak situations. In 2016,
the World Health Organization Strategic Advisory Group of Experts on Immunization stated that
vaccination with one-fifth the standard dose is sufficient to provide protection against yellow fever for at
least 12 months, and they advocated short-term use of this approach among individuals ≥2 years in
emergency conditions when vaccine supplies are limited. (See 'Fractional vaccine dosing in outbreaks'
 above.)

REFERENCES

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. Hughes TP. Precipiten reaction in yellow fever. J Immunol 1933; 25:275.
13. 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.
14. 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.
15. 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.
16. 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.
17. Robertson SE, Hull BP, Tomori O, et al. Yellow fever: a decade of reemergence. JAMA 1996; 276:1157.
18. Monath TP. Review of the risks and benefits of yellow fever vaccination including some new analyses.
Expert Rev Vaccines 2012; 11:427.
19. 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.
20. World Health Organization. Yellow Fever – Angola. http://www.who.int/csr/don/22-march-2016-yellow-fe
ver-angola/en/ (Accessed on April 05, 2016).
21. ProMED mail. Yellow fever - Countries with dengue: Alert. http://promedmail.org/post/20160328.412398
3 (Accessed on April 05, 2016).
22. Otshudiema JO, Ndakala NG, Mawanda EK, et al. Yellow Fever Outbreak - Kongo Central Province,
Democratic Republic of the Congo, August 2016. MMWR Morb Mortal Wkly Rep 2017; 66:335.
23. Blake LE, Garcia-Blanco MA. Human genetic variation and yellow fever mortality during 19th century
U.S. epidemics. MBio 2014; 5:e01253.
24. World Health Organization. Yellow Fever - China. http://www.who.int/csr/don/6-april-2016-yellow-fever-c
hina/en/ (Accessed on April 13, 2016).
25. McFarland JM, Baddour LM, Nelson JE, et al. Imported yellow fever in a United States citizen. Clin
Infect Dis 1997; 25:1143.
26. Barros ML, Boecken G. Jungle yellow fever in the central Amazon. Lancet 1996; 348:969.
27. 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.
28. Colebunders R, Mariage JL, Coche JC, et al. A Belgian traveler who acquired yellow fever in the
Gambia. Clin Infect Dis 2002; 35:e113.
29. 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.
30. World Health Organization. Yellow fever - Brazil. http://www.who.int/csr/don/13-january-2017-yellow-fev
er-brazil/en/ (Accessed on January 23, 2017).
31. http://www.paho.org/hq/index.php?option=com_docman&task=doc_view&Itemid=270&gid=44111&lang=
en (Accessed on March 22, 2018).
32. Hamer DH, Angelo K, Caumes E, et al. Fatal Yellow Fever in Travelers to Brazil, 2018. MMWR Morb
Mortal Wkly Rep 2018; 67:340.
33. http://www.who.int/csr/don/27-february-2018-yellow-fever-brazil/en/ (Accessed on March 22, 2018).
34. http://portalms.saude.gov.br/noticias/agencia-saude/42849-vacina-de-febre-amarela-sera-ampliada-par
a-todo-o-brasil (Accessed on March 22, 2018).
35. https://wwwnc.cdc.gov/travel/page/yellow-fever-information (Accessed on March 22, 2018).
36. https://wwwnc.cdc.gov/travel/notices/alert/yellow-fever-brazil (Accessed on March 22, 2018).
37. https://www.cdc.gov/media/releases/2018/s0316-yellow-fever-brazil.html (Accessed on March 22, 2018)
.
38. Outbreak news. Yellow fever, Paraguay. Wkly Epidemiol Rec 2008; 83:105.
39. Monath TP. Yellow fever: a medically neglected disease. Report on a seminar. Rev Infect Dis 1987;
9:165.
40. Johansson MA, Arana-Vizcarrondo N, Biggerstaff BJ, Staples JE. Incubation periods of Yellow fever
virus. Am J Trop Med Hyg 2010; 83:183.
41. Barnett ED. Yellow fever: epidemiology and prevention. Clin Infect Dis 2007; 44:850.
42. Tuboi SH, Costa ZG, da Costa Vasconcelos PF, Hatch D. Clinical and epidemiological characteristics of
yellow fever in Brazil: analysis of reported cases 1998-2002. Trans R Soc Trop Med Hyg 2007; 101:169.
43. Oudart JL, Rey M. [Proteinuria, proteinaemia, and serum transaminase activity in 23 confirmed cases of
yellow fever]. Bull World Health Organ 1970; 42:95.
44. ELTON NW, ROMERO A, TREJOS A. Clinical pathology of yellow fever. Am J Clin Pathol 1955; 25:135.
45. Berry GP, Kitchen SF. Yellow fever accidentally contracted in the laboratory: A study of seven cases. Am
J Trop Med Hyg 1931; 11:365.
46. 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.
47. Nunes MR, Vianez JL Jr, Nunes KN, et al. Analysis of a Reverse Transcription Loop-mediated
Isothermal Amplification (RT-LAMP) for yellow fever diagnostic. J Virol Methods 2015; 226:40.
48. 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.
49. 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.
50. 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.
51. 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.
52. Monath TP. Treatment of yellow fever. Antiviral Res 2008; 78:116.
53. Newman AP, Becraft R, Dean AB, et al. Notes from the Field: Fatal Yellow Fever in a Traveler Returning
From Peru - New York, 2016. MMWR Morb Mortal Wkly Rep 2017; 66:914.
54. 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.
55. 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.
56. 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.
57. 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.
58. 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.
59. Gershman MD, Sotir MJ. Update: Temporary Total Depletion of U.S. Licensed Yellow Fever Vaccine for
Civilian Travelers Addressed by Investigational New Drug Use of Imported Stamaril Vaccine. MMWR
Morb Mortal Wkly Rep 2017; 66:780.
60. Centers for Disease Control and Prevention. Search for Yellow Fever Vaccination Clinics. https://wwwnc
.cdc.gov/travel/yellow-fever-vaccination-clinics/search (Accessed on May 19, 2017).
61. Monath TP, Cetron MS. Prevention of yellow fever in persons traveling to the tropics. Clin Infect Dis
2002; 34:1369.
62. 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.
63. 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.
64. Centers for Disease Control and Prevention. Health Information for International Travel 2018: The Yello
w Book. https://wwwnc.cdc.gov/travel/page/yellowbook-home (Accessed on June 20, 2017).
65. 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.
66. Sicre de Fontbrune F, Arnaud C, Cheminant M, et al. Immunogenicity and Safety of Yellow Fever
Vaccine in Allogeneic Hematopoietic Stem Cell Transplant Recipients After Withdrawal of
Immunosuppressive Therapy. J Infect Dis 2018; 217:494.
67. Centers for Disease Control and Prevention. Travelers' Health. www.cdc.gov/travel (Accessed on July 1
8, 2012).
68. Centers for Disease Control and Prevention. Yellow fever vaccine course. http://www.cdc.gov/travel-trai
ning/ (Accessed on October 03, 2011).
69. Mosimann B, Stoll B, Francillon C, Pécoud A. Yellow fever vaccine and egg allergy. J Allergy Clin
Immunol 1995; 95:1064.
70. 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).
71. 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.
72. World Health Organization. International travel and health. www.who.int/ith/ (Accessed on February 08,
2002).
73. 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.
74. 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 (Acce
ssed on April 13, 2016).
75. Wu JT, Peak CM, Leung GM, Lipsitch M. Fractional dosing of yellow fever vaccine to extend supply: a
modelling study. Lancet 2016; 388:2904.
76. 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.
77. 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.
78. Ahuka-Mundeke S, Casey RM, Harris JB, et al. Immunogenicity of Fractional-Dose Vaccine during a
Yellow Fever Outbreak - Preliminary Report. N Engl J Med 2018.
79. 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).
80. http://www.who.int/mediacentre/news/statements/2016/yellow-fever-vaccine/en/ (Accessed on June 27,
2016).
81. 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.
82. 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.
83. 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.
84. Tsai TF, Paul R, Lynberg MC, Letson GW. Congenital yellow fever virus infection after immunization in
pregnancy. J Infect Dis 1993; 168:1520.
85. 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.
86. 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.
 87. 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.
88. 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.
89. Tattevin P, Depatureaux AG, Chapplain JM, et al. Yellow fever vaccine is safe and effective in HIV-
infected patients. AIDS 2004; 18:825.
90. 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.
91. Jean K, Donnelly CA, Ferguson NM, Garske T. A Meta-Analysis of Serological Response Associated
with Yellow Fever Vaccination. Am J Trop Med Hyg 2016; 95:1435.
92. 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.
93. Meeting of the Strategic Advisory Group of Experts on immunization, April 2013 – conclusions and
recommendations. Wkly Epidemiol Rec 2013; 88:201.
94. World Health Organization. Yellow fever vaccination booster not needed. http://www.who.int/mediacentr
e/news/releases/2013/yellow_fever_20130517/en/ (Accessed on June 18, 2015).
95. 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.
96. Pulendran B. Learning immunology from the yellow fever vaccine: innate immunity to systems
vaccinology. Nat Rev Immunol 2009; 9:741.
97. 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.
98. Gaucher D, Therrien R, Kettaf N, et al. Yellow fever vaccine induces integrated multilineage and
polyfunctional immune responses. J Exp Med 2008; 205:3119.
99. 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.
100. 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.
101. 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.
102. 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.
103. 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.
104. 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.
105. Monath TP, Gershman M, Staples JE, Barrett ADT. Yellow fever vaccine. In: Vaccines, 6th ed, Plotkin S
A, Orenstein WA, Offit PA (Eds), Elsevier Saunders, 2012. p.870.
106. Kitchener S. Viscerotropic and neurotropic disease following vaccination with the 17D yellow fever
vaccine, ARILVAX. Vaccine 2004; 22:2103.
107. 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.
108. 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.
109. Lindsey NP, Schroeder BA, Miller ER, et al. Adverse event reports following yellow fever vaccination.
Vaccine 2008; 26:6077.
110. 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.
111. 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.
112. 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.
113. Chan RC, Penney DJ, Little D, et al. Hepatitis and death following vaccination with 17D-204 yellow
fever vaccine. Lancet 2001; 358:121.
114. 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.
115. Hayes EB. Acute viscerotropic disease following vaccination against yellow fever. Trans R Soc Trop
Med Hyg 2007; 101:967.
116. Monath TP. Suspected yellow fever vaccine-associated viscerotropic adverse events (1973 and 1978),
United States. Am J Trop Med Hyg 2010; 82:919.
117. Whittembury A, Ramirez G, Hernández H, et al. Viscerotropic disease following yellow fever vaccination
in Peru. Vaccine 2009; 27:5974.
118. 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.
119. 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.
120. 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.
121. 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.
122. Barwick Eidex R, Yellow Fever Vaccine Safety Working Group. History of thymoma and yellow fever
vaccination. Lancet 2004; 364:936.
123. Monath TP, Fowler E, Johnson CT, et al. An inactivated cell-culture vaccine against yellow fever. N Engl
J Med 2011; 364:1326.

Topic 3032 Version 44.0

Contributor Disclosures
Thomas P Monath, MD, FACP, FASTMH Consultant/Advisory Boards: Inventprise LLC [Cell culture-based
vaccine research (Yellow fever vaccine)]; Sabin Vaccine Institute Inc [Cell culture-based vaccine research and
development (Yellow fever vaccine)]. Martin S Hirsch, MD Nothing to disclose Elinor L Baron, MD,
DTMH Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy