Yellow Fever

Infectious Agent

Yellow fever virus (YFV) is a single-stranded RNA virus that belongs to the genus Flavivirus .

Transmission

Vectorborne transmission occurs via the bite of an infected mosquito, primarily Aedes or Haemagogus spp. Nonhuman and human primates are the main reservoirs of the virus, with anthroponotic (human-to-vector-to-human) transmission occurring. There are 3 transmission cycles for yellow fever: sylvatic (jungle), intermediate (savannah), and urban.

  • The sylvatic (jungle) cycle involves transmission of the virus between nonhuman primates and mosquito species found in the forest canopy. The virus is transmitted via mosquitoes from monkeys to humans when the humans encroach into the jungle during occupational or recreational activities.
  • In Africa, an intermediate (savannah) cycle involves transmission of YFV from tree hole-breeding Aedes spp. to humans living or working in jungle border areas. In this cycle, the virus may be transmitted from monkeys to humans or from human to human via these mosquitoes.
  • The urban cycle involves transmission of the virus between humans and peridomestic mosquitoes, primarily Ae. aegypti .

Humans infected with YFV experience the highest levels of viremia and can transmit the virus to mosquitoes shortly before onset of fever and for the first 3–5 days of illness. Given the high level of viremia, bloodborne transmission theoretically can occur via transfusion or needlesticks. One case of perinatal transmission of wild-type YFV has been documented from a woman who developed symptoms of yellow fever 3 days before giving birth. The infant tested positive for YFV RNA and died of fulminant yellow fever on the 12th day of life.

Epidemiology

Yellow fever occurs in sub-Saharan Africa and tropical South America, where it is endemic and intermittently epidemic (see Tables 3-22 and 3-23 for a list of countries with risk of YFV transmission). Most yellow fever disease in humans is due to sylvatic or intermediate transmission cycles. However, urban yellow fever occurs periodically in Africa and sporadically in the Americas. In areas of Africa with persistent circulation of YFV, natural immunity accumulates with age, and thus, infants and children are at highest risk for disease. In South America, yellow fever occurs most frequently in unimmunized young men who are exposed to mosquito vectors through their work in forested areas.

Table 3-22. Countries with risk of yellow fever virus (YFV) transmission 1
AfricaCentral and South America
  • Angola
  • Benin
  • Burkina Faso
  • Burundi
  • Cameroon
  • Central African Republic
  • Chad 2
  • Congo, Republic of the
  • Côte d’Ivoire
  • Democratic Republic of the Congo 2
  • Equatorial Guinea
  • Ethiopia 2
  • Gabon
  • The Gambia
  • Ghana
  • Guinea
  • Guinea-Bissau
  • Kenya 2
  • Liberia
  • Mali 2
  • Mauritania 2
  • Niger 2
  • Nigeria
  • Senegal
  • Sierra Leone
  • South Sudan
  • Sudan 2
  • Togo
  • Uganda
  • Argentina 2
  • Bolivia 2
  • Brazil 2
  • Colombia 2
  • Ecuador 2
  • French Guiana
  • Guyana
  • Panama 2
  • Paraguay
  • Peru 2
  • Suriname
  • Trinidad and Tobago 2
  • Venezuela 2
1 Countries or areas where “a risk of YFV transmission is present,” as defined by the World Health Organization, are countries or areas where “yellow fever has been reported currently or in the past, plus vectors and animal reservoirs currently exist” (see the current country list within the International Travel and Health publication (Annex 1) at www.who.int/ith/en/index.html).
2 These countries are not holoendemic (only a portion of the country has risk of yellow fever transmission). See Maps 3-14 and 3-15 and yellow fever vaccine recommendations (Yellow Fever & Malaria Information, by Country) for details.
Table 3-23. Countries with low potential for exposure to yellow fever virus (YFV) 1
Africa
  • Eritrea 2
  • Rwanda 3
  • São Tomé and Príncipe 3
  • Somalia 2
  • Tanzania 3
  • Zambia 2
1 Countries listed in this table are not contained on the official World Health Organization list of countries with risk of YFV transmission (Table 3-22). Therefore, proof of yellow fever vaccination should not be required if traveling from any of these countries to another country with a vaccination entry requirement (unless that country requires proof of yellow fever vaccination from all arriving travelers; see Table 3-26). An exception is Bolivia, which requires yellow fever vaccination for people traveling from or transiting through any of the 6 countries with low potential for exposure, in addition to those with risk of YFV transmission.
2 These countries are classified as “low potential for exposure to YFV” in only some areas; the remaining areas of these countries are classified as having no risk of exposure to YFV.
3 The entire area of these countries is classified as “low potential for exposure to YFV.”
Map 3-14. Yellow fever vaccine recommendations in Africa 1

1 Current as of January 2017. This map is an updated version of the 2010 map created by the Informal WHO Working Group on the Geographic Risk of Yellow Fever.

2 Yellow fever (YF) vaccination is generally not recommended in areas where there is low potential for YF virus exposure. However, vaccination might be considered for a small subset of travelers to these areas who are at increased risk for exposure to YF virus because of prolonged travel, heavy exposure to mosquitoes, or inability to avoid mosquito bites. Consideration for vaccination of any traveler must take into account the traveler’s risk of being infected with YF virus, country entry requirements, and individual risk factors for serious vaccine-associated adverse events (such as age or immune status).

Risk for Travelers

A traveler’s risk for 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 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 low level of transmission, a high level of immunity in the population (because of vaccination, for example), or failure of local surveillance systems to detect cases. This “epidemiologic silence” does not equate to absence of risk and should not lead to travel without taking protective measures.

YFV transmission in rural West Africa is seasonal, with an elevated risk during the end of the rainy season and the beginning of the dry season (usually July–October). However, YFV may be episodically transmitted by Ae. aegypti even during the dry season in both rural and densely settled urban areas.

The risk for infection in South America is highest during the rainy season (January–May, with a peak incidence in February and March). Given the high level of viremia that may occur in infected humans and the widespread distribution of Ae. aegypti in many towns and cities, South America is at risk for a large-scale urban epidemic.

From 1970 through 2015, a total of 10 cases of yellow fever were reported in unvaccinated travelers from the United States and Europe who traveled to West Africa (5 cases) or South America (5 cases). Eight (80%) of these 10 travelers died. There has been only 1 documented case of yellow fever in a vaccinated traveler. This nonfatal case occurred in a traveler from Spain who visited several West African countries in 1988. In early 2016, >15 long-term travelers from Africa and Asia developed yellow fever disease after visiting Angola, where one of the largest urban outbreaks was occurring. Reportedly, none of the ill travelers was vaccinated.

The risk of acquiring yellow fever is difficult to predict because of variations in ecologic determinants of virus transmission. For a 2-week stay, the estimated risks for illness and death due to yellow fever for an unvaccinated traveler visiting an endemic area in:

  • West Africa are 50 per 100,000 and 10 per 100,000, respectively
  • South America are 5 per 100,000 and 1 per 100,000, respectively

The risk of illness during outbreaks of the disease is likely higher. These estimates are a rough guideline based on the risk to indigenous populations, often during peak transmission season. Thus, these risk estimates may not accurately reflect the risk to travelers, who may have a different immunity profile, take precautions against getting bitten by mosquitoes, and have less outdoor exposure.

The risk of acquiring yellow fever in South America is lower than that in Africa, because the mosquitoes that transmit the virus between monkeys in the forest canopy in South America do not often come in contact with humans. Additionally, there is a relatively high level of immunity in local residents because of vaccine use, which might reduce the risk of transmission.

Clinical Presentation

Asymptomatic or clinically inapparent infection is believed to occur in most people infected with YFV. For people who develop symptomatic illness, the incubation period is typically 3–6 days. The initial illness presents as a nonspecific influenzalike syndrome with sudden onset of fever, chills, headache, backache, myalgia, prostration, nausea, and vomiting. Most patients improve after the initial presentation. After a brief remission of hours to a day, approximately 15% of patients progress to a more serious or toxic form of the disease, characterized by jaundice, hemorrhagic symptoms, and eventually shock and multisystem organ failure. The case-fatality ratio for severe cases with hepatorenal dysfunction is 20%–50%.

Diagnosis

The preliminary diagnosis is based on the patient’s clinical features, places and dates of travel, and activities. Laboratory diagnosis is best performed by:

  • Virus isolation or nucleic acid amplification tests performed early in the illness for YFV or yellow fever viral RNA. However, by the time more overt symptoms are recognized, the virus or viral RNA might be undetectable. Therefore, virus isolation and nucleic acid amplification should not be used to rule out a diagnosis of yellow fever.
  • Serologic assays to detect virus-specific IgM and IgG antibodies. Because of cross-reactivity between antibodies raised against other flaviviruses, more specific antibody testing, such as a plaque reduction neutralization test, should be done to confirm the infection.

Clinicians should contact their state or local health department or call the CDC Arboviral Diseases Branch at 970-221-6400 for assistance with diagnostic testing for yellow fever infections and for questions about antibody response to vaccination. Yellow fever is a nationally notifiable disease.

Treatment

There are no specific medications to treat YFV infections; treatment is directed at symptomatic relief or life-saving interventions. Rest, fluids, and use of analgesics and antipyretics may relieve symptoms of fever and aching. Care should be taken to avoid medications, such as aspirin or nonsteroidal anti-inflammatory drugs, which may increase the risk for bleeding. Infected people should be protected from further mosquito exposure (staying indoors or under a mosquito net) during the first few days of illness, so they do not contribute to the transmission cycle.

Prevention

Personal Protection Measures

The best way to prevent mosquitoborne diseases, including yellow fever, is to avoid mosquito bites (see Chapter 2, Protection against Mosquitoes, Ticks, & Other Arthropods).

Vaccine

Yellow fever is preventable by a relatively safe, effective vaccine. All yellow fever vaccines currently manufactured are live-attenuated viral vaccines. Only one yellow fever vaccine is licensed for use in the United States (Table 3-24). Studies comparing the reactogenicity and immunogenicity of various yellow fever vaccines, including those manufactured outside the United States, suggest that there is no substantial difference in the reactogenicity or immune response generated by the various vaccines. Thus, people who receive yellow fever vaccines in other countries should be considered protected against yellow fever.

Table 3-24. Vaccine to prevent yellow fever
VaccineTrade Name (Manufacturer)AgeDoseRouteScheduleBooster
17D yellow fever vaccineYF-Vax (Sanofi Pasteur)≥9 months 10.5 mL 2SC1 doseNot recommended for most 3
Abbreviation: SC, subcutaneous.
1 Ages 6–8 months and ≥60 years are precautions and age <6 months is a contraindication to the use of yellow fever vaccine.
2 YF-Vax is available in single-dose and multiple-dose (5-dose) vials.
3 For further details regarding revaccination, see “Vaccine Administration” in this section.

Indications for Use

Yellow fever vaccine is recommended for people aged ≥9 months who are traveling to or living in areas with risk for YFV transmission in South America and Africa. In addition, some countries require proof of yellow fever vaccination for entry. See the Yellow Fever & Malaria Information, by Country section at the end of this chapter for more detailed information on the requirements and recommendations for yellow fever vaccination for specific countries.

Because of the risk of serious adverse events after yellow fever vaccination, clinicians should only vaccinate people who (1) are at risk of exposure to YFV or (2) require proof of vaccination to enter a country. To further minimize the risk of serious adverse events, clinicians should carefully observe the contraindications and consider the precautions to vaccination before administering yellow fever vaccine (Table 3-25). For additional information, refer to the yellow fever vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP) at www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/yf.html.

Table 3-25. Contraindications and precautions to yellow fever vaccine administration
ContraindicationsPrecautions
  • Allergy to vaccine component 1
  • Age <6 months
  • Symptomatic HIV infection or CD4 T lymphocytes <200/mm3 (or <15% of total lymphocytes in children aged <6 years) 2
  • Thymus disorder associated with abnormal immune-cell function
  • Primary immunodeficiencies
  • Malignant neoplasms
  • Transplantation
  • Immunosuppressive and immunomodulatory therapies
  • Age 6–8 months
  • Age ≥60 years
  • Asymptomatic HIV infection and CD4 T lymphocytes 200–499/mm3 (or 15%–24% of total lymphocytes in children aged <6 years) 2
  • Pregnancy
  • Breastfeeding
1 If vaccination is considered essential because of a high risk for acquiring yellow fever, desensitization can be performed under direct supervision of a physician experienced in the management of anaphylaxis.
2 Symptoms of HIV are classified in 1) Adults and Adolescents, Table 1. CDC. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992;41(RR-17). Available from: www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm and 2) Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 2010. Available from http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf. pp. 20–2.

Vaccine Administration

For all eligible people, a single injection of reconstituted vaccine should be administered subcutaneously. Until recently, revaccination has been required by certain countries at 10-year intervals to comply with International Health Regulations (IHR) of the World Health Organization (WHO). However, in 2014, the WHO Strategic Advisory Group of Experts on Immunization concluded that a single primary dose of yellow fever vaccine provides sustained immunity and lifelong protection against yellow fever disease and that a booster dose is not needed. That year the World Health Organization adopted the recommendation to remove the 10-year booster dose requirement from the IHR after a 2-year transition period. As of July 11, 2016, a completed International Certificate of Vaccination or Prophylaxis is valid for the lifetime of the vaccinee and countries cannot require proof of revaccination (booster) against yellow fever as a condition of entry, even if the last vaccination was more than 10 years prior.

The Advisory Committee on Immunization Practices (ACIP) also stated that a single dose of yellow fever vaccine provides long-lasting protection and is adequate for most travelers. However, these guidelines specify that additional doses of yellow fever vaccine are recommended for the following groups of travelers:

  • Women who were pregnant when they received their initial dose of vaccine: they should receive 1 additional dose of yellow fever vaccine before their next travel that puts them at risk for yellow fever.
  • People who received a hematopoietic stem cell transplant after receiving a dose of yellow fever vaccine: they should be revaccinated before their next travel that puts them at risk for yellow fever as long as they are sufficiently immunocompetent to be safely vaccinated.
  • People who were infected with HIV when they received their last dose of yellow fever vaccine: they should receive a dose every 10 years if they continue to be at risk for yellow fever virus infection.

The updated recommendations also note that a booster dose may be considered for travelers who received their last dose of yellow fever vaccine ≥10 years previously and who will be in a higher-risk setting based on season, location, activities, and duration of their travel. This would include travelers who plan to spend a prolonged period in endemic areas, or those traveling to highly endemic areas such as rural West Africa during peak transmission season or an area with an ongoing outbreak. All current ACIP yellow fever vaccine recommendations can be found on the ACIP website at www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/yf.html.

Although booster doses of yellow fever vaccine are not recommended for most travelers, and despite the recent changes to the IHR, clinicians and travelers should review the entry requirements for destination countries. At the time this edition goes to press it is uncertain when and if all countries with yellow fever vaccination requirements will adopt and fully implement this change that is stipulated by the IHR. See the yellow fever vaccination requirements on the CDC Travelers’ Health website (wwwnc.cdc.gov/travel/destinations/list) for more information on country-specific recommendations and requirements.

Vaccine Safety and Adverse Reactions

Common Adverse Reactions

Reactions to yellow fever vaccine are generally mild; 10%–30% of vaccinees report mild systemic adverse events. Reported events typically include low-grade fever, headache, and myalgia that begin within days after vaccination and last 5–10 days. Approximately 1% of vaccinees temporarily curtail their regular activities because of these reactions.

Severe Adverse Reactions

Hypersensitivity

Immediate hypersensitivity reactions, characterized by rash, urticaria, or bronchospasm are uncommon. Anaphylaxis after yellow fever vaccine is reported to occur at a rate of 1.3 cases per 100,000 doses administered.

Yellow Fever Vaccine–Associated Neurologic Disease (YEL-AND)—

YEL-AND represents a conglomerate of clinical syndromes, including meningoencephalitis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, and rarely, cranial nerve palsies. Historically, YEL-AND was seen primarily among infants as encephalitis, but more recent reports have been among people of all ages. YEL-AND is rarely fatal.

Among all cases of YEL-AND reported globally, almost all occurred in first-time vaccine recipients. The onset of illness for documented cases in the United States is 2–56 days after vaccination. The incidence of YEL-AND in the United States is 0.8 per 100,000 doses administered. The rate is higher in people aged ≥60 years, with a rate of 2.2 per 100,000 doses.

Yellow Fever Vaccine–Associated Viscerotropic Disease (YEL-AVD)—

YEL-AVD is a severe illness similar to wild-type disease, with vaccine virus proliferating in multiple organs and often leading to multiple organ dysfunction syndrome or multiorgan failure and death. Since the initial cases of YEL-AVD were published in 2001, >100 confirmed and suspected cases have been reported throughout the world.

YEL-AVD has been reported to occur only after the first dose of yellow fever vaccine; worldwide, there have been no laboratory-confirmed reports of YEL-AVD following booster doses. For YEL-AVD cases reported in the United States, the median time from yellow fever vaccination until symptom onset is 4 days (range, 1–18 days). The case-fatality ratio for all reported YEL-AVD cases in the United States is approximately 46%. The incidence of YEL-AVD in the United States is 0.3 cases per 100,000 doses of vaccine administered. The rate is higher for people aged ≥60 years, with a rate of 1.2 per 100,000 doses. The rate is even higher for people aged ≥70 years.

Contraindications

Infants Younger than 6 Months

Yellow fever vaccine is contraindicated for infants aged <6 months. This contraindication was instituted in the late 1960s in response to a high rate of YEL-AND documented in vaccinated young infants (50–400 per 100,000). The mechanism of increased neurovirulence in infants is unknown but may be due to the immaturity of the blood-brain barrier, higher or more prolonged viremia, or immune system immaturity.

Hypersensitivity

Yellow fever vaccine is contraindicated for people with a history of acute hypersensitivity reaction to a previous dose of the vaccine, as well as those who have a history of an allergic reaction to any of the vaccine components, including eggs, egg products, chicken proteins, or gelatin. The stopper used in vials of vaccine also contains dry natural latex rubber, which may cause an allergic reaction.

If vaccination of a person with a questionable history of hypersensitivity to any of the vaccine components is considered essential because of a high risk for acquiring yellow fever, skin testing, as described in the vaccine package insert, should be performed under close medical supervision. If a person has a positive skin test to the vaccine or has severe egg sensitivity and the vaccination is recommended, desensitization, as described in the package insert, can be performed under direct supervision of a physician experienced in the management of anaphylaxis.

Altered Immune Status

Thymus Disorder—

Yellow fever vaccine is contraindicated for people with a thymus disorder that is associated with abnormal immune cell function, such as thymoma or myasthenia gravis. If travel to a yellow fever–endemic area cannot be avoided in a person with such a thymus disorder, a medical waiver should be provided and counseling on protective measures against mosquito bites should be emphasized. Because there is no evidence of immune dysfunction or increased risk of yellow fever vaccine–associated serious adverse events in people who have undergone incidental surgical removal of their thymus or have had indirect radiation therapy in the distant past, these people can be given yellow fever vaccine if recommended or required.

HIV Infection—

Yellow fever vaccine is contraindicated for people with AIDS or other clinical manifestations of HIV, including people with CD4 T lymphocyte values <200/mm3 or <15% of total lymphocytes for children aged <6 years. This recommendation is based on a potential increased risk of encephalitis in this population.

If travel to a yellow fever–endemic area cannot be avoided by a person with severe immune suppression based on CD4 counts (<200/mm3 or <15% total lymphocytes for children aged <6 years) or symptomatic HIV, a medical waiver should be provided, and counseling on protective measures against mosquito bites should be emphasized. See the following section, Precautions, for other HIV-infected people not meeting the above criteria.

Immunodeficiencies (other than thymus disorder or HIV infection)—

Yellow fever vaccine is contraindicated for people with primary immunodeficiencies, as well as those with malignant neoplasms or transplantation that might be associated with immunosuppression caused either by treatment or the underlying condition. While there are no data on the use of yellow fever vaccine in these people, they presumably are at increased risk for yellow fever vaccine–associated serious adverse events (see Chapter 8, Immunocompromised Travelers). If someone with an immunodeficiency cannot avoid travel to a yellow fever–endemic area, a medical waiver should be provided, and counseling on protective measures against mosquito bites should be emphasized.

Immunosuppressive and Immunomodulatory Therapies—

Yellow fever vaccine is contraindicated for people whose immunologic response is either suppressed or modulated by current or recent radiation therapies or drugs. Drugs with known immunosuppressive or immunomodulatory properties include, but are not limited to, high-dose systemic corticosteroids, alkylating drugs, antimetabolites, tumor necrosis factor-α inhibitors (such as etanercept), interleukin-1 and interleukin-6 blocking agents (such as anakinra and tocilizumab), or other monoclonal antibodies targeting immune cells (such as rituximab or alemtuzumab). There are no specific data on the use of yellow fever vaccine in people receiving these therapies. However, these people are presumed to be at increased risk for yellow fever vaccine–associated serious adverse events, and the use of live attenuated vaccines is contraindicated in the package insert for most of these therapies (see Chapter 8, Immunocompromised Travelers).

Live viral vaccines should be deferred in people who have discontinued these therapies until immune function has improved. If travel to a yellow fever–endemic area cannot be avoided for someone receiving immunosuppressive or immunomodulatory therapies, a medical waiver should be provided and counseling on protective measures against mosquito bites should be emphasized.

Family members of people with altered immune status, who themselves have no contraindications, can receive yellow fever vaccine.

Precautions

Infants Aged 6–8 Months

Age 6–8 months is a precaution for yellow fever vaccination. Two cases of YEL-AND have been reported among infants aged 6–8 months. In infants <6 months of age, the rates of YEL-AND are elevated (50–400 per 100,000). By 9 months of age, risk for YEL-AND is believed to be substantially lower. ACIP generally recommends that, whenever possible, travel to yellow fever–endemic countries should be postponed or avoided for children aged 6–8 months. If travel is unavoidable, the decision of whether to vaccinate these infants needs to balance the risks of YFV exposure with the risk for adverse events after vaccination.

Adults 60 Years of Age or Older

Age ≥60 years is a precaution for yellow fever vaccination, particularly if this is the first dose of the yellow fever vaccine given. From adverse events passively reported to the Vaccine Adverse Events Reporting System (VAERS), the rate of serious adverse events in people aged ≥60 years was 7.7 per 100,000 doses distributed, compared with 3.8 per 100,000 for all vaccine recipients. The risk of YEL-AND and YEL-AVD is also increased in this age group, at 2.2 and 1.2 per 100,000 doses, respectively, compared with 0.8 and 0.3 per 100,000 for all vaccine recipients. Given that YEL-AVD has been reported exclusively, and YEL-AND almost exclusively, in primary vaccine recipients, caution should be exercised with older travelers who may be receiving yellow fever vaccine for the first time. If travel is unavoidable, the decision to vaccinate travelers aged ≥60 years needs to weigh the risks and benefits of the vaccination in the context of their destination-specific risk for exposure to YFV.

HIV Infection

Asymptomatic HIV infection with CD4 T lymphocyte values 200–499/mm3 or 15%–24% of total lymphocytes for children aged <6 years is a precaution for yellow fever vaccination (see also the discussion of HIV infection in the Contraindications section above). Large prospective, randomized trials have not been performed to adequately address the safety and efficacy of yellow fever vaccine among this group. Retrospective and prospective studies that combined included >500 HIV-infected people reported no serious adverse events among patients considered moderately immunosuppressed based on their CD4 counts. However, HIV infection has been associated with a reduced immunologic response to a number of inactivated and live attenuated vaccines, including yellow fever vaccine. The mechanisms for the diminished immune response in HIV-infected people are uncertain but appear to be correlated with HIV RNA levels and CD4 T cell counts.

If an asymptomatic HIV-infected person with moderate immune suppression (CD4 T lymphocyte values 200–499/mm3 or 15%–24% of total lymphocytes for children aged <6 years) is traveling to a yellow fever–endemic area, vaccination may be considered. Vaccinated people should be monitored closely after vaccination; if an adverse event occurs, the state health department or CDC should be notified and a report made to VAERS. However, if international travel requirements—not risk of yellow fever—are the only reason to vaccinate an HIV-infected person, the person should be excused from immunization and issued a medical waiver to fulfill health regulations.

If an asymptomatic HIV-infected person has no evidence of immune suppression based on CD4 counts (CD4 T lymphocyte values ≥500/mm3 or ≥25% of total lymphocytes for children aged <6 years), yellow fever vaccine can be administered if recommended.

Because vaccinating asymptomatic HIV-infected people might be less effective than vaccinating people not infected with HIV, measuring their neutralizing antibody response to vaccination should be considered before travel. Contact the state health department or the CDC Arboviral Diseases Branch (970-221-6400) to discuss serologic testing.

Pregnancy

Pregnancy is a precaution for yellow fever vaccine administration. The safety of yellow fever vaccination during pregnancy has not been studied in a large prospective trial. However, a study of women who were vaccinated with yellow fever vaccine early in their pregnancies found no major malformations in their infants. A slight increased risk was noted for minor, mostly skin, malformations in infants. A higher rate of spontaneous abortions in pregnant women receiving the vaccine was reported but not substantiated in a subsequent study. The proportion of women vaccinated during pregnancy who develop YFV-specific IgG antibodies is variable depending on the study (39% or 98%) and may be correlated with the trimester in which they received the vaccine. Because pregnancy may affect immunologic function, serologic testing can be considered to document a protective immune response to the vaccine.

If travel is unavoidable and the vaccination risks are felt to outweigh the risks of YFV exposure, pregnant women should be excused from immunization and issued a medical waiver to fulfill health regulations. Pregnant women who must travel to areas where YFV exposure is likely should be vaccinated. Although there are no specific data, ACIP recommends that a woman wait 4 weeks after receiving the yellow fever vaccine before conceiving.

Breastfeeding

Breastfeeding is a precaution for yellow fever vaccine administration. Three YEL-AND cases have been reported in exclusively breastfed infants whose mothers were vaccinated with yellow fever vaccine. All 3 infants were diagnosed with encephalitis and aged <1 month at the time of exposure. Further research is needed to document the risk of potential vaccine exposure through breastfeeding. Until more information is available, yellow fever vaccine should be avoided in breastfeeding women. However, when travel of nursing mothers to a yellow fever–endemic area cannot be avoided or postponed, these women should be vaccinated.

Other Considerations

There are no data regarding possible increased adverse events or decreased vaccine efficacy after administration of yellow fever vaccine to patients with other chronic medical conditions (such as renal disease, hepatitis C virus infection, other liver disease, or diabetes mellitus). Caution should be used if considering vaccination of such patients. Factors to consider in assessing patients’ general level of immune competence include disease severity, duration, clinical stability, complications, and comorbidities.

Simultaneous Administration of Other Vaccines and Drugs

No evidence exists that inactivated vaccines interfere with the immune response to yellow fever vaccine. Therefore, inactivated vaccines can be administered either simultaneously or at any time before or after yellow fever vaccination. ACIP recommends that yellow fever vaccine be given at the same time as other live viral vaccines. Otherwise, the clinician should wait 30 days between vaccinations, as the immune response to a live viral vaccine might be impaired if administered within 30 days of another live viral vaccine. One study involving the simultaneous administration of yellow fever and measles-mumps-rubella (MMR) vaccines in children found a decrease in the immune response against yellow fever, mumps, and rubella when the vaccines were given on the same day versus 30 days apart. Additional studies are needed to confirm these findings, but they suggest that if possible, yellow fever and MMR should be given 30 days apart. Limited data suggest oral Ty21a typhoid vaccine, a live bacterial vaccine, can be administered simultaneously or at any interval before or after yellow fever vaccine. There are no data on the immune response to live attenuated influenza and yellow fever vaccines administered simultaneously. However, data from live attenuated influenza and MMR found no evidence of interference.

International Certificate of Vaccination or Prophylaxis (ICVP)

The IHR allow countries to require proof of yellow fever vaccination documented on an ICVP as a condition of entry for travelers arriving from certain countries, even if only in transit, to prevent importation and indigenous transmission of YFV. Some countries require evidence of vaccination from all entering travelers, which includes direct travel from the United States (Table 3-26). Some countries do not require an ICVP for infants younger than a certain age (see Yellow Fever & Malaria Information, by Country section at the end of this chapter for specific age requirements). A traveler who has a specific contraindication to yellow fever vaccine and who cannot avoid travel to a country requiring vaccination should request a waiver from a physician before embarking on travel (see the Medical Waivers [Exemptions] section below). Travelers who arrive in a country that has a yellow fever vaccination entry requirement without proof of yellow fever vaccination or a medical waiver may be quarantined for up to 6 days, refused entry, or vaccinated on site.

Table 3-26. Countries that require proof of yellow fever vaccination from all arriving travelers 1
AngolaGhana
BurundiGuinea-Bissau
CameroonLiberia
Central African RepublicMali
Congo, Republic of theNiger
Côte d’IvoireSierra Leone
Democratic Republic of the CongoTogo
French GuianaUganda
Gabon
1 Country requirements for yellow fever vaccination are subject to change at any time; therefore, CDC encourages travelers to check with the destination country’s embassy or consulate before departure.

Authorization to Provide Vaccinations and to Validate the ICVP

People who received a yellow fever vaccination after December 15, 2007, must provide proof of vaccination on the new ICVP. If the person received the vaccine before December 15, 2007, their original International Certificate of Vaccination against Yellow Fever (ICV) card is still valid as proof of vaccination. Vaccinees should receive a completed ICVP (Figure 3-2), validated (stamped and signed) with the stamp of the center where the vaccine was given (see below). An incomplete or inaccurate ICVP is not valid. Failure to secure validations can cause a traveler to be quarantined, denied entry, or possibly revaccinated at the point of entry to a country. Revaccination at the point of entry is not a recommended option for the traveler.

Figure 3-2. Example International Certificate of Vaccination or Prophylaxis (ICVP)

(1) Name should appear exactly as on the patient’s passport.(2, 5, 7) All dates should be entered with the day in numerals, followed by the month in letters, then the year. For example: in the above example, the patient’s date of birth is 22 March 1960.(3) This space is for the patient’s signature.(4) For a yellow fever vaccination, “Yellow Fever” should be written in both spaces. Should the ICVP be used for a required vaccination or prophylaxis against another disease or condition (following an amendment to the International Health Regulations or by recommendation of the World Health Organization), that disease or condition should be written in this space. Other vaccinations may be listed on the other side.(5) The date on which the vaccination is given should be entered as shown above.(6) A handwritten signature of the clinician—either the stamp holder or another health care provider authorized by the stamp holder—administering or supervising the administration of the vaccine (or prophylaxis) should appear in this box. A signature stamp is not acceptable.(7) The certificate of yellow fever vaccination (ICVP) is valid beginning 10 days after the date of primary vaccination, which should be noted in the box for “certificate valid from.” As of July 2016, the yellow fever vaccine booster requirement was eliminated in the IHR, and a completed ICVP is considered valid for the lifetime of the vaccinee. Suggested wording to write in the ICVP box for “certificate valid until” is “life of person vaccinated.” However, it is uncertain when and if all countries with yellow fever vaccination entry requirements will adopt this change. For the most recent information on yellow fever vaccination entry requirements by country, consult the destination pages of the CDC Travelers’ Health website.(8) The Uniform Stamp of the vaccinating center should appear in this box.

Clinics may purchase ICVPs, CDC 731 (formerly PHS 731), from the US Government Printing Office (http://bookstore.gpo.gov, 866-512-1800). This certificate of vaccination (ICVP) is valid beginning 10 days after the date of primary vaccination. As of July 2016, the yellow fever vaccine booster requirement was eliminated in the IHR and a completed ICVP is considered valid for the lifetime of the vaccinee.

People Authorized to Sign the ICVP and Designated Yellow Fever Vaccination Centers

The ICVP must be signed by a medical provider, who may be a licensed physician or a health care worker designated by the physician, supervising the administration of the vaccine (Figure 3-2). A signature stamp is not acceptable. 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 clinicians. Information about the location and hours of yellow fever vaccination centers may be obtained by visiting CDC’s website at wwwnc.cdc.gov/travel/yellow-fever-vaccination-clinics-search.aspx.

Medical Waivers (Exemptions)

For medical contraindications, a clinician who has decided to issue a waiver should fill out and sign the Medical Contraindications to Vaccination section of the ICVP (Figure 3-3). The clinician should also do the following:

  • Give the traveler a signed and dated exemption letter on letterhead stationery, clearly stating the contraindications to vaccination and bearing the stamp used by the yellow fever vaccination center to validate the ICVP.
  • Inform the traveler of any increased risk for yellow fever infection associated with lack of vaccination and how to minimize this risk by avoiding mosquito bites.

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 its acceptance by the destination country. To improve the likelihood that the waiver will be accepted at the destination country, clinicians can suggest that the traveler take the following additional measures before beginning travel:

  • Obtain specific and authoritative advice from the embassy or consulate of the destination country or countries.
  • Request documentation of requirements for waivers from embassies or consulates and retain these, along with the completed Medical Contraindication to Vaccination section of the ICVP.
Figure 3-3. Medical Contraindication to Vaccination section of the International Certificate of Vaccination or Prophylaxis (ICVP)

Requirements Versus Recommendations

Country entry requirements for proof of yellow fever vaccination under the IHR differ from CDC’s recommendations . Yellow fever vaccine entry requirements are established by countries to prevent the importation and transmission of YFV and are allowed under the IHR. Travelers must comply with these to enter the country, unless they have been issued a medical waiver. Certain countries require vaccination from travelers arriving from all countries (Table 3-26), while some countries require vaccination only for travelers coming from a country with risk of YFV transmission (see Yellow Fever & Malaria Information, by Country at the end of this chapter). WHO defines those areas with risk of YFV transmission as countries or areas where yellow fever has been reported currently or in the past, plus where vectors and animal reservoirs exist. Country requirements are subject to change at any time; therefore, CDC encourages travelers to check with the relevant embassy or consulate before departure.

The information in the section on yellow fever vaccine recommendations is advice given by CDC to prevent YFV infections among travelers. Recommendations are subject to change at any time because of changes in YFV circulation; therefore, CDC encourages travelers to check the destination pages for up-to-date vaccine information and to check for relevant travel notices on the CDC website before departure (www.cdc.gov/travel).

Yellow fever vaccine recommendations for travelers going to specific destinations are based on the risk classification for YFV transmission: endemic, transitional, low potential for exposure, and no risk. Yellow fever vaccination is recommended for travel to endemic and transitional areas (Maps 3-14 and 3-15). Although vaccination is generally not recommended for travel to areas with low potential for exposure, it might be considered for a small subset of travelers whose itinerary could place them at increased risk for exposure to YFV (such as prolonged travel, heavy exposure to mosquitoes, or inability to avoid mosquito bites). Yellow fever vaccination is not recommended in areas with no risk.

Countries that only contain areas with low potential for exposure to YFV (Table 3-23) are not included on the official WHO list of countries with risk of YFV transmission (Table 3-22). Therefore, proof of yellow fever vaccination should not be required if traveling from a country with low potential for exposure to YFV to a country with a vaccination entry requirement (unless that country requires proof of yellow fever vaccination from all arriving travelers; see Table 3-26). An exception is Bolivia, which requires yellow fever vaccination for people traveling from or transiting through any of the 6 countries with low potential for exposure, in addition to those with risk of YFV transmission.

Map 3-15. Yellow fever vaccine recommendations in the Americas 1

1 Current as of January 2017. This map is an updated version of the 2010 map created by the Informal WHO Working Group on the Geographic Risk of Yellow Fever.

2 Yellow fever (YF) vaccination is generally not recommended in areas where there is low potential for YF virus exposure. However, vaccination might be considered for a small subset of travelers to these areas who are at increased risk for exposure to YF virus because of prolonged travel, heavy exposure to mosquitoes, or inability to avoid mosquito bites. Consideration for vaccination of any traveler must take into account the traveler’s risk of being infected with YF virus, country entry requirements, and individual risk factors for serious vaccine-associated adverse events (such as age or immune status).

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 contact the nearest military medical facility to determine the requirements for his or her trip (see also Chapter 8, Special Considerations for US Military Deployments).

CDC website: www.cdc.gov/yellowfever

Bibliography

  1. Gershman MD, Staples JE, Bentsi-Enchill AD, Breugelmans JG, Brito GS, Camacho LA, et al. Viscerotropic disease: case definition and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine. 2012 Jul 13;30(33):5038–58.  [PMID:22561144]
  2. Jentes ES, Poumerol G, Gershman MD, Hill DR, Lemarchand J, Lewis RF, 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 Aug;11(8):622–32.  [PMID:21798462]
  3. Lindsey NP, Rabe IB, Miller ER, Fischer M, Staples JE. Adverse event reports following yellow fever vaccination, 2007-13. J Travel Med. 2016 May;23(5).
  4. Monath TP, Cetron MS. Prevention of yellow fever in persons traveling to the tropics. Clin Infect Dis. 2002 May 15;34(10):1369–78.  [PMID:11981733]
  5. Staples JE, Bocchini JA, Jr., Rubin L, Fischer M. Yellow fever vaccine booster doses: recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep. 2015 Jun 19;64(23):647–50.  [PMID:26086636]
  6. Staples JE, Gershman M, Fischer M. Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010 Jul 30;59(RR-7):1–27.
  7. Staples JE, Monath TP, Gershman MD, Barrett ADT. Yellow fever vaccine. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 7th ed. Philadelphia: Elsevier; In press.
  8. World Health Organization. International Health Regulations, 2005. Geneva: World Health Organization; 2008 [cited 2016 Sep. 27]. Available from: http://whqlibdoc.who.int/publications/2008/9789241580410_eng.pdf.
  9. World Health Organization. Vaccines and vaccination against yellow fever. WHO position paper—June 2013. Wkly Epidemiol Rec. 2013 Jul 5;88(27):269–83.  [PMID:23909008]

Authors

Mark D. Gershman, J. Erin Staples

Citation

* When formatting your citation, note that all book, journal, and database titles should be italicized* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Yellow Fever ID - 204175 Y1 - 2018 PB - CDC Yellow Book UR - https://relief.unboundmedicine.com/relief/view/cdc-yellow-book/204175/all/Yellow_Fever ER -