Yellow fever: Treatment and prevention

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 the treatment and prevention of yellow fever will be reviewed here. Issues related to virology, pathogenesis, epidemiology, clinical manifestations, and diagnosis of yellow fever are discussed separately. (See "Yellow fever: Epidemiology, clinical manifestations, and diagnosis".)

TREATMENT

Supportive care — The treatment of yellow fever consists of supportive care; there is no specific antiviral therapy available [1]. 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 [2].

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, prophylactic anticonvulsant therapy, management of metabolic acidosis, treatment of bleeding with fresh-frozen plasma, dialysis if indicated by renal failure, and treatment of secondary infections [3,4].

Investigational agents — Antiviral therapies for yellow fever are under investigation [1,3,5].

Ribavirin is active against yellow fever virus but only at very high concentrations that may not be achievable clinically [6].

Sofosbuvir may be useful for treatment against YFV, based on in vitro data and case reports [7].

The benefit of hyperimmune globulin or monoclonal antibody after the onset of clinical illness is uncertain; further study is required [1,8,9].

TY014 is an engineered anti-yellow fever virus human immunoglobulin (Ig)G monoclonal antibody. In a clinical trial including 27 participants enrolled in phase 1a (to assess the safety, side-effect profile, and pharmacokinetics of TY014), and 10 participants enrolled in phase 1b (to assess the efficacy of TY014 in abrogating viremia following administration of live yellow fever vaccine), all five participants who received TY014 were aviremic throughout the trial; in contrast, among the five participants who received placebo, two had detectable viremia 48 hours later and two others had detectable viremia 72 hours later [10]. During a 12-week follow-up period, at least one mild or moderate adverse event occurred among 22 participants who received TY014 and among 8 participants who received placebo. In addition, asymptomatic premature ventricular contractions (a severe event) occurred in one participant who received TY014. Further study of TY014 is planned.

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). 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 majority of doses. In the United States, the vaccine (YF-VAX) is manufactured by Sanofi-Pasteur. Stamaril is an alternative but similar formulation (produced in France and used in Europe, Australia, and endemic areas) [11]. Another vaccine formulation derived from a different passage series of the same vaccine virus strain, 17DD, is manufactured in Brazil [12].

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, the WHO endorsed the use of fractional (one-fifth) doses (0.1 mL given by subcutaneous route) in emergency conditions [13]. (See 'Fractional vaccine dosing' 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) [14]. 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.)

Yellow fever vaccine may be administered to individuals ≥9 months of age. The vaccine should never be administered to children <6 months of age, due to elevated risk of severe adverse events including vaccine-associated encephalitis [15]. Vaccination of children ≥6 months and <9 months of age should also be avoided, as an elevated risk of neurotropic adverse events has been reported in this age group as well [15].

Whom to vaccinate

Individuals in endemic areas — The global strategy aims at ending yellow fever epidemics by 2026 and consists of three objectives: (1) protect at-risk populations, (2) prevent international spread, and (3) contain outbreaks rapidly [16]. We are in agreement with the WHO which recommends that endemic countries incorporate yellow fever vaccination into routine immunization programs [17]. Vaccination against yellow fever in endemic areas is performed as part of the Expanded Program of Immunization at 9 months of age. In some African countries, catch-up mass vaccination campaigns are undertaken based on assessments of geographic risk, as part of a WHO initiative to increase vaccine coverage [18,19].

Travelers — In accordance with the United States Centers for Disease Control and Prevention (CDC), the United States Advisory Committee on Immunization Practices (ACIP), and the WHO, we recommend vaccination for travelers to yellow fever-endemic areas of Africa and South America (figure 1 and figure 2) [14,20-22].

For all travelers regardless of age, a careful risk-benefit assessment should be undertaken. Due to the risk of serious adverse events (particularly in individuals >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 [23]. 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 under-recognized. For travelers older than 60 years, especially those with comorbidities or on concomitant medication resulting in immunosuppression, a waiver letter prior to travel may be indicated. (See 'Immunocompromised individuals' below.)

It is uncertain whether travelers warrant routine booster vaccination [24-26]. In older travelers, a single vaccination is sufficient to convey long-lasting immunity for at least 10 years. However, in children who received their first dose before age 2, booster vaccination may be warranted; one systematic review on duration of seroprotection following a single dose noted that, in children vaccinated before age 2, the seroprotection rate was 52 percent within five years after primary vaccination [26].

We are in agreement with the approach to yellow fever vaccination outlined by the ACIP in June 2015, which states that a single primary dose of yellow fever vaccine is adequate for most travelers; additional doses of vaccine are warranted for at-risk laboratory personnel and certain travelers (as follows) [27]:

●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 [28].

●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 [29].

●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.

Data regarding the optimal approach to booster vaccination for travelers are limited [30]. In one study including 355 vaccine recipients in nonendemic areas, the rate of seropositivity (90 percent plaque reduction neutralization test [PRNT] ≥1:10) ≥10 years following vaccination was 79 percent [31]. In another study including 66 individuals vaccinated ≥10 years previously, 82 percent had a positive PRNT [30].

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 [32]. Skin testing and desensitization are best performed by an experienced allergist. (See "Allergic reactions to vaccines".)

A biweekly "Blue Sheet" Summary of Health Information for International Travel published by the CDC provides updated information on countries officially reporting yellow fever [33]. In addition, there is a free online course that provides information and training about yellow fever to health care professionals who advise travelers [34].

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 [33].

Some countries in yellow fever-endemic zones require a WHO 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 [22,33,35]. 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 [36].

The WHO international certificate of immunization for international travel is valid for life [37].

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.

Fractional vaccine dosing — Fractional dosing is a strategy for extending yellow fever vaccine supply in situations of vaccine shortage [38-43]. 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 [44,45].

The rationale for this recommendation was that standard doses of WHO-prequalified yellow fever vaccines (Bio-Manguinhos-Fiocruz, Chumakov Institute of Poliomyelitis and Viral Encephalitides, Institut Pasteur Dakar, and Sanofi Pasteur) are highly potent, with average doses between 12,874 and 43,651 international units (IU), far above the WHO’s recommended minimum of 1000 IU. Some countries have considered the use of fractional dose yellow fever vaccination outside an emergency situation due to vaccine shortages [13].

Use of fractional dose yellow fever vaccine is supported by a randomized trial including more than 900 adults age 18 to 59 years in Uganda and Kenya randomly assigned to receive standard dose or one-fifth fractional dose of one of the four WHO-prequalified yellow fever vaccines [46]. At 28 days postvaccination, rates of seroconversion (defined as neutralizing antibody titers at least four times prevaccination levels, measured by 50 percent plaque reduction neutralization test [PRNT₅₀]) in the fractional dose groups were noninferior to standard dose for all vaccines. Neutralizing antibodies remained high up to one year after vaccination for both fractional and standard doses for all vaccines. There were no serious vaccine-related adverse events. Long-term studies are warranted to substantiate the duration of seroprotection; in addition, further data are needed in children and older adults.

Prior to the above study, an observational study including more than 490 seronegative nonpregnant adults and children ≥2 years in the Democratic Republic of Congo who received one-fifth of standard dose vaccine in the context of an outbreak demonstrated that the fractional dose was effective at inducing seroconversion in 98 percent of individuals [43]. Similar findings were observed among individuals vaccinated with 1/10^th the standard dose of yellow fever 17DD vaccine [41,42]. Fractional dosing has been used in millions of individuals during outbreaks in Brazil and the Democratic Republic of Congo due to vaccine shortages.

However, fractional yellow fever vaccination is not yet compliant with the International Health Regulations (IHR). Several knowledge gaps still need to be addressed before such use will be IHR compliant [38,47]. (See 'Immunization certificates' above.)

Fractional dosing of the yellow fever vaccine may induce protective antibodies for at least 10 years. This was illustrated in a randomized trial including 75 adults who received primary vaccination with 17D yellow fever vaccine (40 patients received a 0.1-mL fractional dose and 35 patients received the standard 0.5-mL dose); the number of participants with protective levels of yellow fever-neutralizing antibodies at 10-year follow-up was comparable between the groups (98 versus 97 percent, respectively) [48]. A limitation of these findings is that fewer than half of participants from the original trial participated in the study.

Full-dose vaccine should be given to children <2 years of age since there are some concerns about lower vaccine efficacy in this group [49]. Studies of fractional vaccine dosing is ongoing in children, patients with HIV infection, and pregnant women.

In 2018, Brazil launched a mass immunization campaign to deliver fractional doses of yellow fever vaccine to residents of 69 municipalities in the states of Rio de Janeiro and São Paulo. This represents the world's largest vaccination campaign using fractional doses of yellow fever vaccine. Some 23.8 million people were vaccinated during the campaign, including 10.3 million in the state of São Paulo, 10 million in the state of Rio de Janeiro, and 3.3 million people in Bahia State [50].

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 [51].

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 [52,53]. 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 [54,55].

Immunocompromised individuals — Yellow fever 17D vaccine should not be administered to immunocompromised individuals because of theoretical concerns about live-attenuated virus vaccines [51,56].

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 [57].

Travelers with asymptomatic HIV infection may be immunized if potential exposure warrants; such patients should be advised of the possible risks of vaccination [51]. In studies of HIV-infected patients with CD4+ counts above 200/microL, all responded serologically and none had adverse events [58,59]. 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 [51].

Vaccine efficacy — The 17D vaccine produces high levels of protection [60]. 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 seroprotection showed that 97.5 percent of vaccinated individuals mounted a protective serologic response (95% CI 82.9 to 99.7 percent) [61]. The 17DD vaccine produces similar levels of protection [12].

Infants, toddlers, pregnant women, and persons with HIV or other causes of immune suppression may not respond as vigorously to the 17D vaccine [62]. In one large study, the primary vaccine failure rate in young children was approximately 9 percent [49].

Immunity after a single dose is long lasting and may provide lifetime protection [62]. In a study of United States travelers who received one dose of yellow fever vaccine, among those vaccinated <10 years previously, 94 percent had a positive PRNT; among those vaccinated ≥10 years previously, 82 percent had positive PRNT [30]. Postvaccination PRNT titers demonstrated a time-dependent decline. Individuals with immunocompromising conditions were less likely to have a positive PRNT (77 percent) compared with those who were not immunocompromised.

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 [63,64]. 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 [27]. (See 'Whom to vaccinate' above.)

Before 2014, the WHO international certificate of immunization for international travel was valid for 10 years; a booster 0.5 mL dose was required every 10 years for the certificate to be reissued. Revaccination is no longer required and a certificate of vaccination is now valid for life. Issues related to booster doses are discussed further above [30]. (See 'Whom to vaccinate' above.)

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 [65-71]. 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 700 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.

In the United States between 2007 through 2013, 938 adverse events following yellow fever vaccination were reported to the Vaccine Adverse Event Reporting System (VAERS). Of these, 9 percent were classified as Serious Adverse Events (SAE) for a rate of 3.8 per 100,000 doses distributed. Reporting rates of SAEs increased with increasing age (6.5 per 100,000 for individuals 60 to 69 years and 10.3 per 100,000 for individuals ≥70 years) [72]. The reporting rate for anaphylaxis was 1.3 per 100,000 doses distributed and was highest in persons ≤18 years (2.7 per 100,000). Reporting rates of Yellow Fever Vaccine Associated Neurological Disease and Yellow Fever Vaccine Associated Viscerotropic Disease were 0.8 and 0.3 per 100,000 doses distributed, respectively; both rates increased with increasing age.

Mild fever, headache, myalgia and malaise, and soreness at the site of inoculation can occur in the absence of liver function abnormalities [49,73].

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 [74]. In addition, the vaccine virus may be transmitted from lactating mothers to breast-fed infants [55].

Neurotropic disease — YEL-AND refers to an encephalitis usually caused by infection of the central nervous system with 17D virus [75]. 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 [36,76,77]. Between 2000 and 2006, the rate of YEL-AND in the United States was 0.8 per 100,000 [78]. The incidence of YEL-AND is higher in older adults; persons ≥70 years have a rate of 2.3 per 100,000 [79,80]. 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 [36]. Cases in infants have diminished since restriction of vaccine administration to children more than nine months of age [36].

Viscerotropic disease — YEL-AVD refers to a syndrome resembling wild-type yellow fever infection that occurs in the setting of yellow fever 17D vaccination [75,81-83]. Case definitions have been published [84]. 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 [75,85,86].

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 [79]. 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) [87]. 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 [19], 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 [23].

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 [60,75,87]. 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 [88].

Acquired host factors appear to increase the risk of developing YEL-AVD after vaccination: advanced age and thymus disease and possibly female sex in younger persons [75,79,80,85,89,90]. 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 [91]. Thymus disease (eg, thymoma, myasthenia gravis) was present in 4 of the 23 reported cases; all underwent thymectomy 2 to 20 years before vaccination [92]. 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 [90]. 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 [23,87].

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 [93]. However, inactivated vaccines are unlikely to confer the same extent of clinical protection as live-attenuated vaccines.

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 individuals traveling to high-risk areas who have contraindications to vaccination [75].

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 [1].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Travel medicine".)

SUMMARY AND RECOMMENDATIONS

●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, 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 ≥9 months of age. (See '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. (See 'Immunization certificates' above.)

●It is uncertain whether travelers warrant routine booster vaccination. We are in agreement with the approach to yellow fever vaccination outlined by the ACIP in June 2015, which states that a single primary dose of yellow fever vaccine is adequate for most travelers; additional doses of vaccine are warranted for at-risk laboratory personnel and certain travelers (summarized above). (See 'Travelers' above.)

●Fractional dosing is a strategy for extending yellow fever vaccine supply in outbreak situations. In 2016, the WHO Strategic Advisory Group of Experts on Immunization stated that vaccination with one-fifth the standard dose is sufficient for seroprotection 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' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Thomas Monath, MD, FACP, FASTMH, and Edward T Ryan, MD, DTMH, who contributed to earlier versions of this topic review.