Yellow Fever

Infectious agent

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

Transmission

Vector-borne transmission of YF virus occurs via the bite of an infected mosquito, primarily Aedes or Haemagogus spp. Non-human primates and humans are the main reservoirs of the virus, and anthroponotic (human-to-vector-to-human) transmission can occur. YF virus has 3 transmission cycles: sylvatic (jungle), intermediate (savanna), and urban.

The sylvatic (jungle) cycle involves transmission of virus between non-human primates and mosquito species found in forest canopies, namely Ae. africanus, Haemagogus spp., and Sabethes spp. Virus is transmitted from monkeys to humans via mosquitoes when occupational, recreational, or domestic activities encroach into the jungle. In Africa, an intermediate (savanna) cycle involves transmission of YF virus from tree hole–breeding Aedes spp. to humans in jungle border areas. YF virus can be transmitted from monkeys to humans or from human to human via these mosquitoes. The urban cycle involves transmission of virus between humans and peridomestic mosquitoes, Ae. aegypti.

Humans infected with YF virus experience the highest levels of viremia shortly before onset of fever and for the first 3–5 days of illness, during which time they can transmit the virus to mosquitoes. Because of the high level of viremia, solid organ transmission and bloodborne transmission via transfusion or needlesticks theoretically can occur and have occurred with the vaccine virus. Two cases have been recorded of perinatal transmission of wild-type YF virus from women who developed symptoms of YF around the time of delivery. Both infants were infected and died of fulminant YF on the 12th and 19th day of life.

Epidemiology

YF occurs in Sub-Saharan Africa and tropical South America, where it is endemic and intermittently epidemic (see Table 4.21.1 and Table 4.21.2 for lists of countries with risk of YF virus transmission). Most YF disease in humans is due to sylvatic or intermediate transmission cycles. Urban YF occurs periodically in Africa and sporadically in the Americas. In areas of Africa with persistent circulation of YF virus, natural immunity accumulates with age; consequently, infants and children are at greatest risk for disease. In South America, YF occurs most frequently in unimmunized young adults exposed to mosquito vectors through their work in forested areas.

Risk for travelers

A traveler’s risk for acquiring YF is determined by their immunization status as well as destination-specific (e.g., local rate of virus transmission) and travel-associated (e.g., exposure duration, occupational and recreational activities, season) factors. Reported cases of human disease are the principal but crude indicator of disease risk. Case reports from a destination might be absent because of a low level of transmission, a high level of immunity in the population (e.g., due to vaccination), or failure of local surveillance systems to detect cases. Because “epidemiologic silence” does not mean absence of risk, travelers should not visit endemic areas without taking protective measures.

YF virus transmission in Africa is seasonal. In West Africa, YF virus transmission increases during the middle of the rainy season (around August) and peaks during the early dry season (October). In East Africa, YF virus transmission is generally less predictable because long periods (years) often pass between virus activity in this region; when YF virus transmission occurs in East Africa, seasonality is similar to that in West Africa.

The risk of infection by sylvatic vectors in South America is greatest during the rainy season (January–May, with a peak incidence during February and March). Ae. aegypti can transmit YF virus episodically in both rural and densely settled urban areas, even during the dry season.

During 1970–2015, 11 cases of YF were reported in people from the United States and Europe who traveled to West Africa (6 cases) or South America (5 cases); 8 (73%) died. Only 1 traveler had a documented history of YF vaccination; that traveler survived. Starting in 2016, the number of travel-associated YF cases increased substantially, primarily because of outbreaks in Angola and Brazil. During 2016–2018, >37 travel-associated cases were reported in unvaccinated travelers who were residents of non-endemic areas or countries, including ≥15 European travelers and 1 American traveler to Peru. Since 2019, travel-associated cases of YF have again become uncommon likely because of decreases in occurrence of large YF outbreaks and decreases in travel observed during the COVID-19 pandemic.

The risk of acquiring YF during travel is difficult to predict because of variations in ecologic determinants of virus transmission. For a 2-week stay, the estimated risks for illness and for death due to YF for an unvaccinated traveler visiting an endemic area are as follows: for West Africa, risk for illness is 50 per 100,000 and risk for death is 10 per 100,000; for South America, risk for illness is 5 per 100,000 and risk for death is 1 per 100,000. These estimates are based on the risk to resident populations, often during peak transmission season, and might not accurately reflect the risk to travelers who have a different immunity profile, who follow mosquito bite precautions, who have less outdoor exposure, or who travel during off-peak periods. A traveler’s risk for becoming infected is likely greater when outbreaks are occurring at their destination.

Table 4.21.1: Countries with risk for yellow fever (YF) virus transmission¹

Table 4.21.2: Countries with low potential for exposure to yellow fever (YF) virus¹

Clinical presentation

Most people infected with YF virus have minimal or no symptoms and are unlikely to seek medical attention. For those who develop symptomatic illness, the incubation period is typically 3–6 days. The initial illness is non-specific: backache, chills, fever, headache, myalgia, nausea and vomiting, and prostration. Most people improve after the initial presentation. After a brief remission of ≤48 hours, approximately 12% of infected patients progress to a more serious form of the disease, characterized by hemorrhagic symptoms, jaundice, and eventually shock and multisystem organ failure. The case-fatality rate for severe cases is 30%–60%.

Diagnosis

YF is a nationally notifiable disease. A preliminary diagnosis is based on clinical presentation and exposure details. Laboratory diagnosis is best performed by virus isolation or nucleic acid amplification tests (e.g., reverse transcription PCR [RT-PCR]) or by serologic assays. Perform virus isolation or nucleic acid amplification tests for YF virus or YF viral RNA early in the course of the illness. By the time more overt symptoms (e.g., jaundice) are recognized, the virus or viral RNA often is no longer detectable; thus, virus isolation and nucleic acid amplification testing should not be used to rule out a diagnosis of YF.

Serologic assays can be used to detect virus-specific IgM and IgG antibodies. Because of the possibility of cross-reactivity between antibodies against other flaviviruses, more specific antibody testing (e.g., a plaque reduction neutralization test) should be performed to confirm the infection. Contact your state or local health department or call the CDC Arboviral Diseases Branch at 970-221-6400 for assistance with diagnostic testing for YF virus infections.

Treatment

No specific medications are available to treat YF virus infections. Following the recent large outbreaks in Brazil, a systematic review was conducted on specific treatments for YF, including antiviral agents and other drugs (e.g., ribavirin, sofosbuvir, interferon alpha), plasma exchange/apheresis, and liver transplantation. None of these treatments were found to improve the outcome of YF cases. Therefore, treatment is supportive. Fluids, rest, and use of analgesics and antipyretics might relieve symptoms of aching and fever. Avoid prescribing medications that can increase the risk for bleeding (e.g., aspirin or other nonsteroidal anti-inflammatory drugs). During the first few days of illness, protect infected people from further mosquito exposure by keeping them indoors or under a mosquito net, so they do not contribute to the transmission cycle.

Prevention

Personal protective measures

The best way to prevent mosquito-borne diseases, including YF, is to avoid mosquito bites (see Mosquitoes, Ticks, and Other Arthropods chapter).

Vaccine

YF is preventable by a safe, effective vaccine. All YF vaccines currently manufactured are live-attenuated viral vaccines. Only 1 YF vaccine (YF-VAX, Sanofi Pasteur) is licensed for use in the United States (Table 4.21.3). Shortages of YF-VAX have occurred in the United States. From 2015–2021, Stamaril (a YF vaccine comparable to YF-VAX, manufactured by Sanofi Pasteur in France) was imported and used under an expanded-access investigational new drug protocol during a U.S. shortage.

The different YF vaccine products, including those manufactured outside the United States, have no substantial differences in reactogenicity or immunogenicity. Consider people who receive YF vaccines licensed in other countries but not approved by the FDA to be protected against YF.

Table 4.21.3: Vaccine to prevent yellow fever (YF)

Indications for use

YF vaccine is recommended for people aged ≥9 months who are living in or traveling to areas with risk for YF virus transmission in Africa or South America. In addition, some countries require proof of YF vaccination for entry. For country-specific YF vaccination recommendations and country entry requirements, see Yellow Fever Vaccine and Malaria Prevention Information, by Country chapter.

Because of the risk for serious adverse events after YF vaccination, healthcare professionals should only vaccinate people at risk for YF virus exposure. To further minimize the risk for serious adverse events, carefully observe the contraindications and consider vaccination precautions before administering YF vaccine (Box 4.21.1). For additional information, refer to the YF vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP).

Box 4.21.1

Notes

¹If considering vaccination, desensitization can be performed under direct supervision of a physician experienced in the management of anaphylaxis.

²Symptoms of HIV are classified in: CDC (1992). 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults (see Table 1 Adults and Adolescents); and Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection 2010, pp. 20–22.

³In 2010, the Advisory Committee on Immunization Practices (ACIP) used this clinical classification of levels of immunosuppression among HIV-infected people to inform yellow fever vaccine recommendations; see Staples, J. E., Gershman, M., Fischer, M., & Centers for Disease Control and Prevention (CDC). (2010). Yellow fever vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR: Morbidity and Mortality Weekly Report, 59(RR-7), 1–27. A revised surveillance case definition for HIV infection was published in 2014. To date, ACIP has not updated YF vaccine recommendations for people infected with HIV.

Administration

For all eligible people, subcutaneously administer a single 0.5 mL injection of reconstituted vaccine, which is the standard dose. Every vaccine vial is supplied with a separate vial of sterile diluent, containing a specific amount of sodium chloride and other excipients; do not use any other product as a substitute diluent. YF-VAX is a pinkish color before reconstitution and a slight pink-brown suspension after reconstitution. If the wrong diluent is used, the healthcare professional should contact the manufacturer to determine if revaccination is needed and when it should be administered.

Coadministration with other vaccines

Inactivated vaccines

No evidence exists that inactivated vaccines interfere with the immune response to YF vaccine. Therefore, inactivated vaccines can be administered either simultaneously or at any time before or after YF vaccination.

Live attenuated viral vaccines

ACIP recommends that YF vaccine be given at the same time as other live viral vaccines. If simultaneous administration is not possible, wait 1 month between vaccinations because the immune response to a live viral vaccine could be impaired if it is administered within 1 month of another live viral vaccine. One study demonstrated that co-administration of YF vaccine and measles-mumps-rubella (MMR) vaccine decreased the seroconversion rates to all antigens, except measles. Two more recent studies also showed a less robust antibody concentration for YF and rubella in people who seroconverted after vaccine coadministration. These studies suggest that whenever possible, it is best to give YF and MMR vaccines 1 month apart. However, coadministration of YF and MMR vaccines is acceptable if necessary to ensure that travelers are vaccinated appropriately before travel.

No data are available on the immune response to nasally administered live attenuated influenza vaccine given simultaneously with YF vaccine.

Live bacterial vaccines

Data suggest that oral Ty21a typhoid vaccine (Vivotif), a live bacterial vaccine, can be administered simultaneously or at any interval before or after YF vaccine. No data are available on the immune response to live attenuated oral cholera vaccine (Vaxchora) administered simultaneously with YF vaccine.

Fractional dosing

In recent years, several countries have extended vaccine supplies during large YF outbreaks by administering partial vaccine doses, usually 0.1 mL, a practice known as fractional dosing. Limited data have demonstrated that the immune response to a fractional dose is comparable to a full dose of YF vaccine at 1 month and 1 year after administration for healthy persons ≥2 years; however, knowledge gaps regarding fractional dosing remain.

In the United States, FDA has not approved fractional dosing of YF vaccine. Furthermore, the World Health Organization (WHO) notes that fractional dosing does not meet YF vaccination requirements under the International Health Regulations (IHR). Proof of vaccination for international travel cannot be issued to a person who has received only a fractional dose; therefore, revaccination would be recommended for those at risk of acquiring YF virus infection or if required for entry under the IHR and a waiver is not being issued.

Booster doses

In 2014, the WHO Strategic Advisory Group of Experts on Immunization concluded that a single primary dose of YF vaccine provides sustained immunity and lifelong protection against YF disease and that revaccination (i.e., booster dose) is not needed. In 2016, the IHR were officially amended to specify that a completed International Certificate of Vaccination or Prophylaxis (ICVP or “Yellow Card”) is valid for the lifetime of the vaccinee. Further, countries cannot require proof of revaccination against YF as a condition of entry if the last vaccination was >10 years prior.

ACIP also stated that a single dose of YF vaccine provides long-lasting protection and is adequate for most travelers. ACIP guidelines differ slightly from WHO guidelines by specifying that additional doses of YF vaccine are recommended for the following groups of travelers: women who were pregnant when they received their initial dose of vaccine (administer 1 additional dose before they are next at risk for YF); people who received a hematopoietic stem cell transplant after receiving a dose of YF vaccine (revaccinate before they are next at risk for YF if sufficiently immunocompetent); and persons living with HIV (PLWH) when they received their last dose of YF vaccine (administer a dose every 10 years if they continue to be at risk for YF).

ACIP stated that a booster dose can be considered for travelers who received their last dose of YF vaccine ≥10 years previously if they will be going to higher-risk settings based on activities, duration of travel, location, and season. This consideration applies to travelers planning prolonged stays in endemic areas, those traveling to endemic areas (e.g., rural West Africa) during peak transmission season, and travelers visiting areas with ongoing outbreaks.

Healthcare professionals and travelers should nonetheless review the entry requirements for destination countries before traveling. For more information on country-specific recommendations and country entry requirements, see Yellow Fever Vaccine and Malaria Prevention Information, by Country chapter.

Adverse events

Common adverse reactions

Reactions to YF vaccine are generally mild; 10%–30% of vaccinees report mild systemic symptoms, including headache, low-grade fever, and myalgia, that begin within days after vaccination and last 5–10 days.

Serious adverse reactions

Hypersensitivity reactions

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

Yellow fever vaccine-associated neurologic disease

Yellow fever vaccine-associated neurologic disease (YEL-AND) represents a collection of clinical syndromes, including acute disseminated encephalomyelitis, Guillain-Barré syndrome, meningoencephalitis, and, rarely, cranial nerve palsies. Historically, YEL-AND was diagnosed primarily among infants as encephalitis, although more recent case reports have described various neurological syndromes among people of most age groups. YEL-AND is rarely fatal.

Almost all cases of YEL-AND reported globally occur in first-time vaccine recipients. The range of onset of illness for documented cases in the United States is 2–56 days after vaccination. The incidence of YEL-AND following the administration of YF-VAX in the United States is 0.8 per 100,000 doses administered but is greater (2.2 per 100,000 doses) in people aged ≥60 years. When enhanced safety monitoring was implemented for Stamaril, YF vaccine imported from France during a stockout of YF-VAX in the United States, the incidence was found to be 1.0 per 100,000 doses administered for all people and 6.2 per 100,000 doses in people aged ≥60 years.

Yellow fever vaccine-associated viscerotropic disease

Yellow fever vaccine-associated viscerotropic disease (YEL-AVD) is a severe illness similar to wild-type YF disease, in which vaccine virus proliferates in multiple organs, often leading to multiorgan dysfunction or failure and occasionally death. Since 2001, >100 confirmed and suspected cases of YEL-AVD have been reported throughout the world.

YEL-AVD has been reported to occur only after the first dose of YF vaccine; no laboratory-confirmed YEL-AVD has been reported after booster doses. For YEL-AVD cases associated with YF-VAX administration in the United States, the median time from YF vaccination until symptom onset is 4 days (range 1–18 days). The case-fatality ratio is approximately 43% and the incidence is 0.3 cases per 100,000 doses of vaccine administered. The incidence of YEL-AVD is greater for people aged ≥60 years (1.2 per 100,000 doses) and greater still for people aged ≥70 years. The incidence of YEL-AVD was slightly higher when enhanced safety monitoring was performed for Stamaril in the United States, with 0.5 YEL-AVD cases per 100,000 doses among all recipients and 2.1 per 100,000 doses in people aged ≥60 years.

Contraindications

Contraindications to receiving YF vaccine include age <6 months; various forms of altered immunity, including symptomatic HIV infection or HIV infection with severe immunosuppression; and hypersensitivity to vaccine components. People without a known contraindication to vaccination can receive YF vaccine even if they have a family member with an altered immune status.

A person who has an absolute YF vaccine contraindication should not be vaccinated because their condition can increase the risk for having a serious adverse event following vaccination. Encourage those with contraindications to consider alternative travel plans, including postponing travel. If travel to a YF-endemic area cannot be avoided, provide the traveler with a medical waiver (see below for details), emphasize the importance of strict adherence to protective measures against mosquito bites, and discuss risks associated with being unvaccinated.

Age younger than 6 months

YF vaccine is contraindicated in infants aged <6 months because the rate of YEL-AND is high, 50–400 cases per 100,000 infants vaccinated. The mechanism of increased neurovirulence in infants is unknown but could be due to the immaturity of the blood-brain barrier, an increased or more prolonged viremia, or immune system immaturity.

Altered immune status

HIV infection

YF vaccine is contraindicated in people with AIDS or other clinical manifestations of HIV infection, including those with CD4 T lymphocyte counts <200/mL or <15% of total lymphocytes for children aged <6 years. This contraindication is based on the potential increased risk for encephalitis in this population (see the section on Precautions later in this chapter for guidance regarding PLWH who do not meet the above criteria).

Thymus disorder

YF vaccine is contraindicated in people with a thymus disorder associated with abnormal immune cell function (e.g., myasthenia gravis, thymoma). There is no evidence of immune dysfunction or increased risk for YF vaccine-associated serious adverse events in people who have undergone incidental thymectomy or have had indirect radiation therapy in the distant past; these people can be vaccinated.

Other immunodeficiencies

YF vaccine is contraindicated in people who are immunodeficient or immunosuppressed, whether due to an underlying genetic disorder or medical treatment. Organ transplant recipients and patients with malignant neoplasms who are on immunosuppressive therapies are among those for whom YF vaccine is contraindicated (see Immunocompromised Travelers chapter).

Immunosuppressive and immunomodulatory therapies

YF vaccine is contraindicated in people whose immunologic response is either suppressed or modulated by current or recent radiation therapy or drugs. Drugs with known immunosuppressive or immunomodulatory properties include, but are not limited to, alkylating agents, antimetabolites, high-dose systemic corticosteroids, interleukin blocking agents (e.g., anakinra, tocilizumab), monoclonal antibodies targeting immune cells (e.g., alemtuzumab, rituximab), and tumor necrosis THF-alpha inhibitors (e.g., etanercept).

People receiving therapies such as those listed above are presumed to be at increased risk for YF vaccine-associated serious adverse events; administration of live attenuated vaccines is contraindicated in the package insert for most of these drugs (see Immunocompromised Travelers chapter). Even among people who have discontinued immunosuppressive or immunomodulatory therapies, defer administration of live viral vaccines until their immune function has improved.

Hypersensitivity

YF vaccine is contraindicated in people with a history of acute hypersensitivity reaction to a previous dose of the vaccine or to any of the vaccine components, including chicken proteins, eggs, egg products, or gelatin. If vaccination of a person with a questionable history of hypersensitivity to a vaccine component is considered essential, skin testing and, if indicated, desensitization should be performed by an experienced healthcare professional according to instructions provided in the manufacturer’s vaccine prescribing information.

Precautions

A person with a precaution (relative contraindication) to YF vaccine has a condition that might increase their risk for having a serious adverse event following vaccination or that could interfere with the ability of the vaccine to produce immunity. YF vaccination precautions include age 6–8 months, age ≥60 years, asymptomatic HIV infection with moderate immunosuppression, pregnancy, and breastfeeding.

Discussing the benefits and risks of YF vaccination with all patients—but particularly those with underlying precautions—is an essential part of the pre-travel consultation. If travel to a YF risk area is unavoidable for a person with a vaccine precaution, the discussion about vaccination should balance the risk for YF virus exposure against the risk of vaccination (i.e., adverse event or inability to elicit an immune response).

Solicit information from the traveler about their risk tolerance level and include this in the shared decision-making about whether to administer YF vaccine. If the decision is made to not vaccinate the traveler, provide a medical waiver, emphasize the critical importance of adhering to insect bite precautions, and discuss risks associated with being unvaccinated. When no risk of YF exists in the itinerary but country entry requirements are in effect in the traveler’s destination(s), the vaccine risk outweighs the disease; avoiding vaccination and issuing a medical waiver to fulfill health regulations is reasonable, but this decision should be made in deliberation with the patient.

Precautions based on increased risk of serious adverse event

Age 6–8 months

Two cases of YEL-AND have been reported in infants aged 6–8 months. By 9 months of age, risk for YEL-AND is believed to be substantially lower. ACIP recommends that, whenever possible, travel to YF-endemic countries for children aged 6–8 months should be postponed or avoided.

Age ≥60 years

The rate of reported serious adverse events after YF vaccination in people aged ≥60 years is 7.7 per 100,000 doses distributed, compared with 3.8 per 100,000 for all YF vaccine recipients. The risks for YEL-AND and YEL-AVD are increased in this age group. Because YEL-AVD has been reported exclusively, and YEL-AND almost exclusively, in primary vaccine recipients, carefully consider the risks and benefits of vaccinating older travelers against YF vaccine for the first time.

Breastfeeding

At least 3 YEL-AND cases have been reported in exclusively breastfed infants whose mothers were vaccinated with YF vaccine. All 3 infants were aged <1 month at the time of exposure, and encephalitis was diagnosed in all 3 infants. Until specific research data are available, avoid vaccinating breastfeeding women against YF. Vaccination is recommended when a woman who is nursing cannot avoid or postpone travel to YF-endemic areas. Although limited data are available to support the practice, some experts recommend that breastfeeding women should pump and discard their breast milk for at least 2 weeks after YF vaccination before resuming breastfeeding.

Precaution based on increased risk of serious adverse event and inability to produce immunity

Pregnancy

Safety of YF vaccination during pregnancy has not been studied in any large prospective trials (see Pregnant Travelers chapter). In 2 observational studies of women vaccinated against YF during pregnancy, a slightly increased risk for minor congenital abnormalities (mainly pigmented nevi) was detected in 1 study, and a higher rate of spontaneous abortions was reported in the other. Neither finding was substantiated by subsequent studies.

If possible, pregnant women should avoid travel to YF risk areas. If travel is unavoidable and the risk for YF virus exposure is felt to outweigh the vaccination risk, recommending vaccination is appropriate. By contrast, if the vaccine risk is believed to outweigh the risk for YF virus exposure, offer a medical waiver to the traveler to fulfill health regulations.

The proportion of women vaccinated during pregnancy who develop a YF virus-specific IgG antibody response is variable depending on the study (39% or 98%) and might be correlated with the trimester when the vaccine was administered. Because pregnancy can reduce immunologic responsiveness, consider serologic testing to document a protective immune response to the vaccine. In addition, women who received their vaccine during pregnancy are recommended to receive an additional dose before they are at risk and no longer pregnant. Although no specific data are available, ACIP recommends that a woman wait 4 weeks after receiving the YF vaccine before conceiving.

Precautions based on concern for inability to produce immunity

HIV infection

Combined studies of >500 asymptomatic PLWH classified as having moderate immune suppression, defined as CD4 T lymphocyte counts of 200–499/mL for people aged ≥6 years (or 15%–24% of total lymphocytes for children aged <6 years) identified no serious adverse events after receipt of YF vaccine (see Travelers with HIV chapter). HIV infection has, however, been associated with a reduced immunologic response to YF vaccine, and this diminished immune response has been correlated with HIV RNA levels and CD4 T cell counts.

If an asymptomatic PLWH has no evidence of immune suppression based on CD4 counts (CD4 T lymphocyte counts ≥500/mL for people aged ≥6 years or ≥25% of total lymphocytes for children aged <6 years), YF vaccine can be administered. Because YF vaccination might be less effective in eliciting an immune response in asymptomatic PLWH, consider serologic testing to document a protective immune response to the vaccine. In addition, ACIP currently recommends that PLWH receive booster doses of YF vaccine every 10 years if they continue to be at risk of YF.

Other considerations

No data are available regarding possible increased occurrence of adverse events or decreased vaccine efficacy after YF vaccine administration in people with other chronic medical conditions that can affect immune response (e.g., diabetes mellitus, liver disease [including hepatitis C virus infection], and renal disease). Limited data suggest that autoimmune disease, either by itself or in conjunction with other risk factors, including immunosuppressive medication, could increase the risk for YEL-AVD and result in lower rates of seroconversion after vaccination. Use caution if considering vaccination of such patients and provide guidance on mosquito bite avoidance. Factors to consider when assessing a patient’s general level of immune competence include clinical stability, comorbidities, complications, disease severity and duration, and current medications.

International Certificate of Vaccination or Prophylaxis

The IHR permit countries to require proof of YF vaccination documented on an ICVP as a condition of entry for travelers arriving from certain countries, even if only in transit, to prevent YF virus importation and transmission in the destination country (Figure 4.21.1). Some countries require evidence of vaccination from all entering travelers, including those arriving directly from the United States (Table 4.21.4).

People with YF vaccine contraindications, including those with a precaution to vaccination and determined to be at greater risk for a vaccine adverse event than for YF virus infection, who must travel to destinations that require proof of vaccination should receive a medical waiver from a YF vaccine provider before their departure (see Medical Waivers [Exemptions] below). Travelers without proof of vaccination or a medical waiver arriving to destinations that require this documentation for entry could be denied entry, face mandatory quarantine (up to 6 days), or be required to receive a vaccine dose on site.

Table 4.21.4: Countries that require proof of yellow fever (YF) vaccination from all arriving travelers¹

ICVP validation

Vaccinees should receive a completed ICVP, signed by the vaccine provider and validated with the stamp of the center where the vaccine was given. A properly completed ICVP is valid beginning 10 days after the date of primary vaccination. As of July 2016, the YF vaccine booster requirement was eliminated in the IHR, and a completed ICVP is considered valid for the lifetime of the vaccinee regardless of whether the traveler was vaccinated before or after 2016.

Designated yellow fever vaccination centers and healthcare professionals

The ICVP must bear the original signature of a YF vaccine provider, who can be a physician or other authorized licensed healthcare professional who supervises the administration of the vaccine. A signature stamp is not acceptable. YF vaccination must be given at a designated center that possesses an official “uniform stamp,” which must be used to validate the ICVP. In the United States, state and territorial health departments are responsible for designating nonfederal YF vaccination centers and issuing uniform stamps to YF vaccine providers. Information about the location and hours of YF vaccination centers is available from the CDC Travelers’ Health website. Federal facilities do not fall under the jurisdiction of the state and territorial health departments, but they do need an official “uniform stamp”; the facilities should contact their agency leadership for stamp access.

Reissuing an ICVP

Healthcare professionals are encouraged to reissue a replacement ICVP to the traveler if full details of the previous vaccination are confirmed. If the original stamp owner is no longer available to replace the card, it is acceptable for a new healthcare professional to do so as long as proof of initial vaccination exists. If the traveler does not have any information on the previous vaccination, revaccination is required. Reissuing guidance can be found on CDC’s Travelers’ Health website. Note the reissued ICVP should include the original date of vaccination and is valid for “life of the person vaccinated.”

Medical waivers (exemptions)

Reasons other than medical contraindications or precautions are not acceptable for exemption from vaccination. A YF vaccine provider issuing a medical waiver for YF vaccine should complete and sign the Medical Contraindications to Vaccination section of the ICVP (Figure 4.21.2). The YF vaccine provider should also provide the traveler with a signed and dated waiver letter on letterhead stationery, clearly stating that there is a contraindication(s) to vaccination and bearing the imprint of the uniform stamp used by the YF vaccination center to validate the ICVP (see Template Letter 2: Yellow Fever Vaccine Waiver). Risks associated with not being vaccinated should be discussed and the importance of strict adherence to mosquito bite prevention measures emphasized.

Medical waivers might not be accepted by the destination country. To improve the likelihood that a border official will grant a waiver holder entry to their intended destination, recommend that travelers contact the local embassy or consulate of the country or countries well in advance of travel to obtain specific and authoritative advice regarding waiver documentation requirements. The specific U.S. embassy for the country may also be able to provide important information. All information provided should be kept with the completed Medical Contraindications to Vaccination and waiver letter.

Figure 4.21.1

This is an example International Certificate of Vaccination or Prophylaxis (ICVP) card with the various sections (name, date of birth, sex, nationality, national identification document, signature, name of disease, vaccine, date, signature and professional status of supervising clinician, vaccine manufacturer and batch number, certificate valid from date, official stamp of administering center) filled in with Jane Doe information.

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Notes

Clinics offering yellow fever vaccine can purchase ICVP (Form CDC 731; formerly PHS 731), from the U.S. Government Publishing Office (https://bookstore.gpo.gov/) website or by phone (866-512-1800).

Instructions for ICVP completion:

(1) Print the traveler’s name exactly as it appears in their passport.

(2, 5, 7) Enter all dates in the format shown: day (in numerals), month (spelled in letters), year. In the example above, the patient’s date of birth is correctly entered as 22 March 1960.

(3) Space reserved for the patient’s signature.

(4) For yellow fever (YF) vaccination, print “Yellow Fever” in both spaces. If the ICVP is used to document proof of another required vaccination or prophylaxis ( following an amendment to the International Health Regulations or by recommendation of the World Health Organization), write the disease or condition name in this space. Other vaccinations may be listed on the other side of the ICVP booklet.

(5) Enter the date of vaccine administration, as shown.

(6) The healthcare professional should enter their handwritten signature, as shown. A signature stamp is not acceptable. For YF vaccine, the healthcare professional signing the ICVP may be the stamp owner or another healthcare professional authorized by the stamp holder to administer or supervise the administration of the vaccine.

(7) The ICVP is valid beginning 10 days after the date of primary YF vaccination. Add that date to this box along with the suggested wording “life of person vaccinated,” as shown.

(8) Imprint the Uniform Stamp of the vaccinating center in this box.

Figure 4.21.2

This is the medical contraindications to vaccination section of an example ICVP card which certifies a traveler has contraindications that restrict them from receiving a vaccine. Text on the image the physician needs to fill out is Name of disease, Name of traveler, contraindicated because of the following conditions, and Signature and address of physician.

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