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Yellow Book

CDC Health Information for International Travel 2008

Chapter 4
Prevention of Specific Infectious Diseases

Yellow Fever


Yellow fever is a viral disease that is transmitted to humans through the bite of infected mosquitoes. Illness ranges in severity from an influenza-like syndrome to severe hepatitis and hemorrhagic fever. Yellow fever virus (YFV) is maintained in nature by mosquito-borne transmission between nonhuman primates. Transmission by mosquitoes from one human to another occurs during epidemics of “urban yellow fever.”


The disease occurs only in sub-Saharan Africa and tropical South America (see Maps 4-15 and 4-16), where it is endemic and intermittently epidemic (see Table 4-23 for a list of countries in the endemic zone). Areas considered endemic for yellow fever have evidence of yellow fever transmission to humans and/or its potential, due to the presence of both a competent vector and YFV in nonhuman primates. In Africa, where most cases are reported, a variety of mosquitoes transmit the virus. The case-fatality rate of yellow fever in Africa is highly variable but approximates 20%. Infants and children are at greatest risk of severe disease. In South America, yellow fever occurs most frequently in young men who are exposed through their work to mosquito vectors in forested or transitional areas of Bolivia, Brazil, Colombia, Ecuador, Venezuela, Guyana, French Guiana, and Peru (1).

Risk for Travelers

A traveler’s risk of acquiring yellow fever is determined by various factors, including immunization status, location of travel, season, duration of exposure, occupational and recreational activities while traveling, and the local rate of virus transmission at the time of travel. Although reported cases of human disease are the principal indicator of disease risk, case reports may be absent because of a high level of immunity in the population (e.g., due to vaccination campaigns), or because cases are not detected by local surveillance systems (1). Only a small proportion of yellow fever cases is recognized and officially reported because the involved areas are often remote and lack specific diagnostic capabilities.

During interepidemic periods, low-level transmission may not be detected by public health surveillance. Such interepidemic conditions may last years or even decades in certain countries or regions. This “epidemiologic silence” does not equate to absence of risk and should not lead to travel without the protection provided by vaccination. Surveys in rural West Africa during “silent” periods have estimated an annual incidence of yellow fever of 1.1-2.4 cases per 1,000 persons and 0.2-0.5 deaths per 1,000 persons. YFV transmission in rural West Africa is seasonal, with elevated risk during the 2-4 months that the rainy season ends and the dry season begins (usually July-October); therefore, the annual incidence reflects incidence during a transmission season of 2-4 months.

The incidence of yellow fever in South America is lower than that in Africa because the mosquitoes that transmit the virus between monkeys in the forest canopy do not often come in contact with humans and because immunity in the indigenous human population is high. Urban epidemic transmission has not occurred in South America for many years, although the risk of introduction of the virus into towns and cities is ever present. For travelers, the risks of illness and death due to yellow fever are probably 10 times greater in rural West Africa than in South America; the risk varies greatly according to specific location and season. In West Africa, virus transmission is highest during the late rainy and early dry seasons (July-October). In Brazil, the risk of infection is highest during the rainy season (January-March) (2).

The low incidence of yellow fever in South America, generally a few hundred reported cases per year, could lead to complacency among travelers. However, it is important to note that four of the six cases of yellow fever reported among travelers from the United States and Europe in 1996-2002 acquired yellow fever in South America (3-8). All six cases were fatal and occurred among unvaccinated travelers. An increase in enzootic and epizootic yellow fever transmission in South America during the 1990s and the potential for epidemiologic change in the Americas remains a concern (see Chapter 5).

The risk of acquiring yellow fever is difficult to predict because of variations in ecologic determinants of virus transmission. As a rough guideline, the risks of illness and death due to yellow fever in an unvaccinated traveler in endemic areas in West Africa during the highest risk season from July to October have been estimated at 100 per 100,000 and 20 per 100,000 per month, respectively; for a 2-week stay, the estimated risks of illness and death were 50 per 100,000 and 10 per 100,000, respectively (2). The risks of illness and death in South America are probably 10 times lower (5 per 100,000 and 1 per 100,000, respectively for a 2-week trip) (2). These estimates are based on risk to indigenous populations and may not accurately reflect the true risk to travelers, who may have a different immunity profile, take precautions against getting bitten by mosquitoes, and have less outdoor exposure. Based on data for U.S. travelers during 1996-2004, the overall risk for serious illness and death due to yellow fever in travelers has been roughly estimated to be 0.05 -0.5 per 100,000 travelers to yellow fever-endemic areas. This range reflects an unvaccinated population of 10-90% and assumes that all travelers visiting holo-endemic countries are at risk and 10% of travelers to non holo-endemic countries are visiting risk areas.



Travelers to areas with yellow fever transmission should take precautions against exposure to mosquitoes. Staying in air-conditioned or well-screened quarters and wearing long-sleeved shirts and long pants will help prevent mosquito bites. Insect repellents containing DEET or picaridin should be used on exposed skin and reapplied as directed on the label. Permethrin-containing repellents should be applied to clothing (see Chapter 2).


Yellow fever is preventable by a relatively safe, effective vaccine. For all eligible persons, a single injection of 0.5 mL of reconstituted vaccine should be administered subcutaneously.

Adverse Reactions
General Events

Reactions to yellow fever vaccine are generally mild. Vaccine recipients have reported mild headaches, myalgia, low-grade fevers, or other minor symptoms that may begin within days after vaccination and last 5-10 days. In clinical trials, the incidence of mild adverse events has been ~25%, but many events may have been unrelated, as the trials were not placebo-controlled. Approximately 1% of vaccinees find it necessary to curtail regular activities. Immediate hypersensitivity reactions, characterized by rash, urticaria, or asthma or a combination of these, are uncommon (incidence <0.8 per 100,000 vaccinees) (9).

Yellow Fever Vaccine-Associated Neurologic Disease

Historically, yellow fever vaccine-associated adverse events were seen primarily among infants and presented as encepha-litis. Since 1992, six cases of encephalitis among adult recipients of yellow fever vaccine have been reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) (10,11; unpublished data, CDC). In addition, 10 cases of autoimmune neurologic disease have been reported to VAERS, including patients with Guillian-Barré syndrome and acute disseminated encephalomyelitis. All patients with yellow fever vaccine-associated neurologic disease (YEL-AND) had onset of illness 4-27 days after vaccination. All cases were in first-time vaccine recipients. The risk for YEL-AND does not appear to be limited to infants, and the overall reported rate in the United States is estimated to be approximately 0.5 per 100,000 doses distributed.

Yellow Fever Vaccine-Associated Viscerotropic Disease

A serious adverse reaction syndrome has been described within the last 10 years among recipients of yellow fever vaccines produced by several different manufacturers. This syndrome was previously reported as febrile multiple organ system failure and is now called yellow fever vaccine-associated viscerotropic disease (YEL-AVD). Since 1996, 12 cases of YEL-AVD, a disease that is clinically and pathologically similar to naturally acquired yellow fever, have been reported in the United States (10,11; unpublished data, CDC); an additional 24 suspected cases have been identified worldwide as of August 2006 (12)-22; unpublished data, CDC). All U.S. cases required intensive care after experiencing severe illness variably characterized by fever, hypotension, respiratory failure, elevated hepatocellular enzymes, lymphocytopenia, and thrombocytopenia. Seven (58%) of the U.S. cases have been fatal. In several cases for which tissue samples were available, immunohistochemical staining demonstrated viral antigen in liver, and sometimes other tissues including lung, kidney, spleen, lymph node, brain, and smooth muscle. In many cases, tissue samples were not available for histopathologic review or detection of virus. All cases reported thus far have occurred in primary vaccinees. Yellow fever vaccines must be considered as a possible, but rare, cause of YEL-AND that is similar to fulminant yellow fever caused by wild-type YFV. Crude estimates of the reported incidence of YEL-AND in the United States indicate an overall reporting rate of 0.3 – 0.5 cases per 100,000 doses of vaccine distributed. This frequency appears to be higher for persons older than 60 years of age; the estimated reporting rate in this group is approximately 1.8 cases per 100,000 doses distributed.

Because of recent reports of deaths due to yellow fever among unvaccinated travelers to yellow fever-endemic areas, yellow fever vaccination of travelers to high-risk areas should be encouraged as a key prevention strategy; however, because severe adverse events can follow yellow fever vaccination, physicians should be careful to administer the vaccine only to persons truly at risk for exposure to yellow fever. Studies are being conducted to clarify the cause and risk factors for these rare serious adverse events associated with yellow fever vaccine.

Precautions and Contraindications

The risk for adverse reactions appears to be age related. Infants younger than 6 months of age should not be vaccinated because they are more susceptible to the serious adverse reaction of YEL-AND (also known as postvaccinal encephalitis) than are older children (23). Immunization should be delayed until an infant is at least 9 months of age. (See Chapter 8 for a discussion of yellow fever immunization for infants and children.) In unusual circumstances, physicians considering vaccinating infants aged younger than 9 months should contact the Division of Vector-Borne Infectious Diseases (970-221-6400) or the Division of Global Migration and Quarantine (404-498-1600) at CDC for advice.

Analysis of adverse events passively reported to VAERS indicate that persons older than 60 years of age may be at increased risk for systemic adverse events following vaccination compared with younger persons. The risk of any serious adverse event following vaccination has been estimated at about 4 per 100,000 doses for people aged 60-69 years old and 7.5 per 100,000 doses for people 70 years and older (24). Travelers older than 60 years should discuss with their physicians the risks and benefits of vaccination in the context of their destination- specific risk for exposure to YFV.

History of Thymus Disease

A history of thymus disease has recently been identified as a contraindication to yellow fever vaccine (13). Four (11%) of the 36 vaccine recipients with YEL-AVD reported worldwide have had a history of diseases involving the thymus, all of which are extremely rare, suggesting that compromised thymic function is an independent risk factor for YEL-AVD. One fatal case in the United States occurred in a 67-year-old woman who had a history of thymectomy for a malignant thymoma approximately 2 years before vaccination. A second case in the United States occurred in a 70-year-old man who had a history of hyperthyroidism, myasthenia gravis, and thymectomy for thymoma 20 years before vaccination. This patient survived. A third case was reported from Switzerland and occurred in a 50-year-old man who had a history of thymectomy due to thymoma 8 years prior to vaccination. This patient also survived. Most recently, a fatal case (male, age 44 years) of viscerotropic disease with fulminant hepatic failure temporally associated with yellow fever vaccine was reported from Colombia. This patient had a thymectomy due to benign thymoma 2 years before vaccination.

In addition to concerns about vaccinating elderly travelers, health-care providers should be careful to ask about a history of thymus disorder, including myasthenia gravis, thymoma, or prior thymectomy, when screening a patient before administering yellow fever vaccine. For persons with such a history, alternative means of prevention should be recommended, if travel plans cannot be altered to avoid yellow fever-endemic areas.


The safety of yellow fever vaccination during pregnancy has not been well established, and the vaccine should be administered to pregnant women only if travel to an area with risk of yellow fever is unavoidable. If international travel requirements, rather than an increased risk of acquiring yellow fever, are the only reason to vaccinate a pregnant woman, efforts should be made to obtain a waiver letter from the traveler’s physician. Pregnant women who must travel to areas where the risk for yellow fever infection is high should be vaccinated. Despite the apparent safety of this vaccine, infants born to these women should be monitored closely for evidence of congenital infection and other possible adverse effects resulting from yellow fever vaccination. Since pregnancy may affect immunologic function, if vaccination of a pregnant woman is deemed necessary, serologic testing to document a protective immune response to the vaccine can be considered (25;26). To discuss the need for serologic testing, the appropriate state health department or CDC’s Division of Vector-Borne Infectious Diseases at 970-221-6400 or Division of Global Migration and Quarantine at 404-498-1600 should be contacted for more information.


Whether this vaccine is excreted in breast milk is not known. There have been no reports of adverse events or transmission of the vaccine virus from nursing mother to infant. As a precautionary measure, vaccination of nursing mothers should be avoided, because of the theoretical risk of vaccine virus transmission to the breastfed infant. When travel of nursing mothers to high-risk yellow fever endemic areas cannot be avoided or postponed, these women should be vaccinated.


Infection with yellow fever vaccine virus poses a theoretical risk for travelers with immunosuppression in association with HIV infection; leukemia, lymphoma, or generalized malignancy; with a history of thymus disease or thymectomy; or who are receiving corticosteroids, alkylating drugs, antimetabolites, or radiation. There is a single report of a 53-year-old patient with undiagnosed HIV infection who had a low CD4 count (108 cells/mm3) and who developed YEL-AND and died of meningoencephalitis (27). Other HIV-infected people with CD4 counts above 200 cells/mm3 have been successfully vaccinated without serious adverse effects from the vaccine. Immunosuppressed patients who are unable to effectively resist viral infections should not be vaccinated. If travel to a yellow fever-endemic zone is necessary for such individuals, patients should be advised of the risks posed by such travel, instructed in methods for avoiding vector mosquitoes, and supplied with vaccination waiver letters by their physicians. Low-dose (i.e., 20 mg prednisone or equivalent/day); short-term (i.e., less than 2 weeks) systemic corticosteroid therapy or intra-articular, bursal, or tendon injections with corticosteroids; and intranasal corticosteroids are not thought to be sufficiently immunosuppressive to constitute an increased hazard to recipients of yellow fever vaccine (see Chapter 9).

Persons who are HIV-infected but do not have AIDS or other symptomatic manifestations of HIV infection, who have established laboratory verification of adequate immune system function (e.g., CD4 T lymphocyte cell counts >200/mm3), and who cannot avoid potential exposure to YFV should be offered the vaccination and monitored closely for possible adverse effects (23). If international travel requirements are the only reason to vaccinate an asymptomatic HIV-infected person, rather than an increased risk for acquiring yellow fever, efforts should be made to obtain a waiver letter from the traveler’s physician. Family members of immunosuppressed or HIV-infected persons who themselves have no contraindications can receive yellow fever vaccine.

Data regarding seroconversion rates after yellow fever vaccination among asymptomatic HIV-infected persons are limited, but indicate that the seroconversion rate among such persons may be reduced (23). Because vaccination of asymptomatic HIV-infected persons might be less effective than that of persons not infected with HIV, measurement of the neutralizing antibody response to vaccination should be considered before travel. Physicians should consult the applicable state health department or CDC’s Division of Vector-Borne Infectious Diseases at 970-221-6400 or Division of Global Migration and Quarantine at 404-498-1600, for more information.


Live yellow fever vaccine is produced in chick embryos and should not be given to persons hypersensitive to eggs. Generally, persons who are able to eat eggs or egg products may receive the vaccine. However, some egg-sensitive persons are not allergic to cooked eggs and may not know they are susceptible to allergic reactions following raw eggs or egg-containing vaccines. If vaccination of a person with a questionable history of egg or chicken hypersensitivity is considered essential because of high risk for acquiring yellow fever, an intradermal test dose of vaccine may be administered under close medical supervision. Specific directions for vaccine skin testing are found in the vaccine package insert. In some instances, small test doses of vaccine administered intradermally have led to an antibody response. Gelatin is used as a stabilizer in several vaccines, including yellow fever vaccine, and might be the stimulus for some allergic reactions to yellow fever vaccine. If international travel regulations are the only reason to vaccinate a traveler hypersensitive to eggs or gelatin, efforts should be made to obtain a waiver.

Simultaneous Administration of Other Vaccines and Drugs

Studies have shown that the immune response to yellow fever vaccine is not inhibited by administration of certain other live, attenuated vaccines concurrently or at various intervals of a few days to 1 month (1) (see Chapter 1).

A prospective study of persons given yellow fever vaccine along with 5 mL of commercially available immune globulin showed no alteration of the immunologic response to yellow fever vaccine when compared with controls (28). Although chloroquine inhibits replication of YFV in vitro, it does not adversely affect antibody responses to yellow fever vaccine in persons receiving the drug as antimalarial prophylaxis (29).


Patients with yellow fever should receive supportive care. In general, no specific treatments have proven benefit for patients with yellow fever or yellow fever vaccine-associated viscerotropic disease.

International Certificate of Vaccination or Prophylaxis (ICVP) for Yellow Fever

The International Health Regulations allow countries to require proof of vaccination for entry and/or from travelers arriving from certain countries (30). Travelers arriving without a completed ICVP may be quarantined or refused entry unless submitting to onsite vaccination. For purposes of international travel, yellow fever vaccine produced by different manufacturers worldwide must be approved by WHO and administered at an approved yellow fever vaccination center. Vaccinees should receive a completed ICVP, signed and validated with the center’s stamp where the vaccine was given (see below). This certificate is valid 10 days after vaccination and for a subsequent period of 10 years.

To prevent importation and indigenous transmission of YFV, a number of countries require a certificate of vaccination from travelers arriving from endemic areas, even if only in transit. Such requirements may be strictly enforced, particularly for persons traveling from Africa or South America to Asia. Some countries in Africa require evidence of vaccination from all entering travelers; others may waive the requirements for travelers coming from non-endemic areas and staying in the country less than 2 weeks (see Chapter 5). Travelers with a specific contraindication to yellow fever vaccine should be advised to obtain a waiver letter before traveling to countries requiring vaccination.

An ICVP must be complete in every detail; if incomplete or inaccurate, it is not valid. Only the most recent ICVP (Form CDC 731) complies with the 2005 International Health Regulations and should be used for any vaccine administered on or after December 15, 2007. Previously issued certificates remain acceptable proof of vaccination against yellow fever as long as the certificate is valid. ICVPs may be ordered in packages of 25 or 100 from the U.S. Government Printing Office in Washington, D.C.. See or call (866) 512-1800.


Yellow fever vaccination must be given at a certified center in possession of an official “Uniform Stamp” which can be used to validate the ICVP. State health departments are responsible for designating nonfederal yellow fever vaccination centers and issuing Uniform Stamps to health-care providers. The ICVP must be validated by the center that administers the vaccine. Most city, county, and state health department's immunization or travel clinics, as well as private travel clinics or individual health-care providers are designated sites. Information about the location and hours of yellow fever vaccination centers may be obtained by contacting local or state health departments or visiting CDC’s Travelers’ Health website at Health-care providers should emphasize to travelers that an ICVP must be validated to be acceptable to quarantine authorities. Failure to secure validations can cause a traveler to be revaccinated, quarantined, or denied entry.

The following section of the ICVP should be completed at the time of vaccination:

ICVP page 1

Persons Authorized To Sign the Certificate

The International Certificate of Vaccination or Prophylaxis must be signed by a licensed health-care provider or by a person designated by the health-care provider. A signature stamp is not acceptable.


For direct travel from the United States, only the following countries require an International Certificate of Vaccination or Prophylaxis against yellow fever.


Some countries do not require an International Certificate of Vaccination or Prophylaxis for infants younger than 6 months of age, younger than 9 months of age, or younger than 1 year of age. Travelers should be advised to check the individual country requirements in Chapter 5.

If a physician concludes that a yellow fever vaccine should not be administered for medical reasons only, the traveler should be given a signed and dated exemption letter on the physician’s letterhead stationery. Reasons other than medical contraindications are not acceptable for exemption from vaccination. The traveler should be advised that issuance of a waiver does not guarantee that the destination country will accept it; on arrival at the destination the traveler may be faced with quarantine, refusal of entry or vaccination on site.

Waiver Letters from Physicians

A physician’s letter clearly stating the contraindications to vaccination is acceptable to some governments. Ideally, it should be written on letterhead stationery and bear the stamp used by health department and official immunization centers to validate the ICVP. Under these conditions, it is also useful for the traveler to obtain specific and authoritative advice from the embassy or consulate of the country or countries he or she plans to visit. Waivers of requirements obtained from embassies or consulates should be documented by appropriate letters and retained for presentation with the completed Medical Contraindication to Vaccination section of the ICVP.

ICVP page 2

Vaccination for Travel on Military Orders

Because military requirements may exceed those indicated in this publication, any person who plans to travel on military orders (civilians and military personnel) should be advised to contact the nearest military medical facility to determine the requirements for the trip.



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TABLE 4-23. Countries within the Yellow Fever-Endemic Zone†

Burkina Faso
Central African Republic
Côte d’Ivoire
Democratic Republic of Congo
Equatorial Guinea
The Gambia
Sierra Leone
São Tomé and Principe
French Guiana
Trinidad and Tobago

†As of November 2006. For current information travelers should consult official resources such as or the WHO web site prior to travel.
1These countries are not holo-endemic. Please see Map 4-16 and yellow fever vaccine recommendations for details.
(Updated July 9, 2007)

MAP 4-15 Yellow fever-endemic zones in Africa, 2007.

Map 4-15

(Updated July 18, 2007)

MAP 4-16 Yellow fever-endemic zones in the Americas, 2007.

Note: For the most current country-specific yellow fever risk areas for Argentina, Brazil and Ecuador, see Updated CDC Yellow Fever Risk Map for Argentinaupdated Yellow Fever vaccination recommendations map for Brazil PDF (Updated January 6, 2009) , and Updated CDC Yellow Fever Risk Map for Ecuador (Updated May 5, 2008).

Map 4-16

TABLE 4-24. Countries that require proof of vaccination against yellow fever for all arriving travelers


Bolivia (or signed affidavit at point of entry)
Burkina Faso
Central African Republic
Côte d’Ivoire
Democratic Republic of the Congo

French Guiana
Mauritania (for a stay >2 weeks)
São Tomé and Principe
Sierra Leone

No vaccinations are currently required for return to the United States. (Updated July 29, 2008)

  • Page last updated: January 07, 2009
  • Content source:
    Division of Global Migration and Quarantine
    National Center for Preparedness, Detection, and Control of Infectious Diseases
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