Yellow Fever Vaccine (Monograph)

Brand name: YF-VAX
Drug class: Vaccines
ATC class: J07B101
VA class: IM100

Medically reviewed by Drugs.com on Jul 1, 2024. Written by ASHP.

Introduction

Live, attenuated virus vaccine.^{100 106 115 106} Available in US as vaccine prepared using the 17D-204 strain of yellow fever virus;^{100 106} available in other countries as vaccines prepared using either the 17D-204 or 17DD strain.^{100 106 115}

Uses for Yellow Fever Vaccine

Prevention of Disease Caused by Yellow Fever Virus

Prevention of disease caused by yellow fever virus in adults, adolescents, and children ≥9 months of age residing or traveling in areas of Africa or South America where yellow fever is endemic or officially reported or where an International Certificate of Vaccination or Prophylaxis (ICVP) against yellow fever is required as a condition for entry.^{106 115}

Prevention of disease caused by yellow fever virus in laboratory personnel who might be exposed by direct or indirect contact or by aerosols to virulent yellow fever virus or to concentrated preparations of the yellow fever vaccine strain.^{100 106}

Yellow fever virus, a Flavivirus^{100 105 106 115} closely related to Dengue, Japanese encephalitis virus, St. Louis encephalitis viruses, and West Nile virus (WNV),^{100 105} is transmitted to humans through the bite of infected mosquitoes that acquired the virus by biting infected humans or nonhuman primates (monkeys).^{100 101 106 115}

Disease caused by yellow fever virus ranges from mild, nonspecific febrile illness to severe disease with jaundice, hemorrhagic symptoms, and eventually shock and multisystem organ failure;^{100 104 115} case fatality rate for severe disease is 20–50%.^{100 104} WHO estimates that about 200,000 cases of yellow fever and 30,000 fatalities related to the disease occur annually worldwide.^{100 101}

Travelers to areas of sub-Saharan Africa and tropical South America where yellow fever virus is endemic and intermittently epidemic are at high risk of disease caused by yellow fever virus.^{100 101 104 115} Risk depends on several factors, including vaccination status, use of personal protective measures against mosquito bites, travel locations, season, duration of exposure, occupational and recreational activities while traveling, and local rate of yellow fever virus transmission at the time of travel.^{100 101 104 115}

For US travelers, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) and CDC recommend primary immunization with yellow fever vaccine in adults, adolescents, and children ≥9 months of age who will be traveling to or living in yellow fever endemic or epidemic areas of Africa and South America.^{100 115} However, because serious adverse effects have been reported with yellow fever vaccine (see Cautions), base vaccination decisions on careful consideration of the individual's overall risk for travel-associated yellow fever, the high mortality rate reported for yellow fever, international regulations regarding yellow fever vaccination for countries on the travel itinerary, and all known precautions and contraindications for the vaccine.^{100 115}

ACIP states that primary immunization with a single dose of yellow fever vaccine provides long-lasting protection and is adequate for most travelers, but revaccination is recommended for certain travelers who will be visiting countries with a risk of yellow fever virus transmission (e.g., women who received primary immunization during pregnancy, individuals who received a hematopoietic stem cell transplant after receiving primary immunization, individuals who had HIV infection when they received their last dose of yellow fever vaccine).¹⁰⁴ ACIP also states revaccination (booster dose) may be given to travelers who received their last dose of yellow fever vaccine at least 10 years previously and who will be in higher-risk settings based on location, season, activities, and duration of travel.¹⁰⁴ This includes travelers who plan to spend prolonged periods in endemic areas or those traveling to highly endemic areas (e.g., rural West Africa during peak transmission season) or to areas with an ongoing outbreak of yellow fever.¹⁰⁴

International health regulations (IHR) of the World Health Organization (WHO) allow countries to require proof of yellow fever vaccination documented on a validated ICVP as a condition of entry for travelers arriving from infected areas or from countries with infected areas, even if only in transit.^{100 115} Some countries require evidence of yellow fever vaccination from all entering travelers, including those traveling directly from the US.^{100 115} Travelers who have a specific contraindication to yellow fever vaccine and who cannot avoid travel to a country requiring vaccination should obtain a medical waiver before embarking on travel (see Medical Waivers under Cautions).^{100 115} Requirements regarding ICVPs may be strictly enforced and travelers arriving without a valid ICVP or medical waiver may be quarantined for up to 6 days, denied entry, or possibly vaccinated or revaccinated at the point of entry.^{100 115}

Vaccinees should receive a completed yellow fever vaccine ICVP that is signed and validated with the official uniform stamp of the yellow fever vaccination center where the vaccine was given.^{100 106 115} These certificates are valid for 10 years beginning 10 days after vaccination with yellow fever vaccine.^{100 106 115} As of July 2016, WHO no longer requires revaccination (booster dose) of yellow fever vaccine every 10 years and states that a completed ICVP is considered valid for the lifetime of the vaccinee.¹¹⁵ However, it is uncertain when or if all countries with entry requirements for yellow fever vaccination will adopt this change.¹¹⁵

In addition to vaccination, individuals traveling to areas with yellow fever should take precautions to avoid exposure to mosquitoes (e.g., stay in air-conditioned or well-screened quarters, wear long-sleeved shirts and long pants to cover the body, use appropriate insect repellents, use mosquito nets between dusk and dawn).¹¹⁵ Although yellow fever transmission is unusual in urban areas and only occurs during an epidemic, travelers to rural areas of South America and Africa may be exposed to mosquitoes transmitting the disease and other mosquito-borne diseases.¹¹⁵

The most recent information regarding geographic areas associated with risk of yellow fever, information on country-specific requirements for yellow fever vaccination for travelers, and information on regulations regarding ICVPs and medical waivers is available from CDC at [Web] and [Web].¹¹⁵

Laboratory personnel with potential exposure to virulent yellow fever virus or to concentrated preparations of yellow fever vaccine virus by direct or indirect aerosol contact should receive primary immunization with yellow fever vaccine.¹⁰⁶ ACIP states that laboratory workers who routinely handle wild-type yellow fever virus and are at continued high risk of exposure to the virus should be tested for yellow fever virus-specific neutralizing antibody titers at least every 10 years after primary immunization to determine whether revaccination (booster dose) of the vaccine is indicated.¹⁰⁴ (See Duration of Immunity under Cautions.)

Yellow Fever Vaccine Dosage and Administration

General

• Because of risk of serious adverse effects in vaccine recipients (see Cautions), administer yellow fever vaccine only when clearly indicated for individuals truly at risk for exposure to yellow fever virus.^{100 106 115} (See Uses.)

• Prior to administration, evaluate patient for history of sensitivity to egg or chicken protein.¹⁰⁶ (See Allergy to Egg-related Antigens under Cautions.) If the vaccine is considered essential in an individual with history of hypersensitivity to eggs or egg products, perform sensitivity test.^{100 106 115} (See Sensitivity Testing and Desensitization under Cautions.)

• In the US, yellow fever vaccine can only be administered at certain sites authorized to issue valid ICVPs.^{100 106 115} Vaccinees should receive a completed ICVP that is signed and validated with the official uniform stamp of the yellow fever vaccination center.^{100 106 115} Consult CDC or local or state public health departments for information regarding locations of these vaccination centers.¹¹⁵ (See Restricted Distribution under Preparations.)

Administration

Administer by sub-Q injection.¹⁰⁶

Do not administer IM.¹⁰⁰ However, if inadvertently given IM, ACIP states that a repeat dose given sub-Q is unnecessary since immunologic response probably not affected.¹⁰⁰

After vaccination, observe vaccinee for at least 15 minutes for signs and symptoms of allergic reaction.¹⁰⁰ (See Sensitivity Reactions under Cautions.)

Syncope (vasovagal or vasodepressor reaction; fainting) may occur following vaccination;¹³⁴ such reactions occur most frequently in adolescents and young adults.¹³⁴ Syncope and secondary injuries may be averted if vaccinees sit or lie down during and for 15 minutes after vaccination.¹³⁴ If syncope occurs, observe patient until symptoms resolve.¹³⁴

If multiple parenteral vaccines are administered during a single health-care visit, give each vaccine using different syringe and at a different injection site.¹³⁴ Separate injection sites by at least 1 inch (if anatomically feasible) to allow appropriate attribution of any local adverse effects that may occur.¹³⁴

Sub-Q Injection

In infants <12 months of age, administer sub-Q preferably into anterolateral thigh.¹³⁴

In adults, adolescents, and children ≥12 months of age, administer sub-Q into upper-outer triceps area.¹³⁴

To ensure appropriate delivery, make sub-Q injections at a 45° angle using a 5/8-inch, 23- to 25-gauge needle.^{106 134}

Before withdrawing dose, carefully swirl reconstituted vaccine until a uniform suspension is obtained;¹⁰⁶ avoid vigorous shaking to prevent foaming.¹⁰⁶

Reconstituted vaccine should appear as a slightly pink-brown suspension;¹⁰⁶ discard if it appears discolored or contains extraneous particulates.¹⁰⁶

After administering vaccine, carefully dispose of vial and any unused vaccine (e.g., sterilize, discard as medical waste).¹⁰⁶

Reconstitution

To reconstitute, withdraw volume of diluent specified by the manufacturer from the vial containing diluent (0.9% sodium chloride injection) using a syringe and slowly inject into vial of lyophilized vaccine.¹⁰⁶ Use only the diluent supplied by the manufacturer.¹⁰⁶

Allow reconstituted vaccine to stand for 1–2 minutes, then carefully swirl until a uniform suspension is obtained.¹⁰⁶ Avoid vigorous shaking to prevent foaming.¹⁰⁶

Must be administered within 1 hour following reconstitution.¹⁰⁶

Dosage

Pediatric Patients

Prevention of Disease Caused by Yellow Fever Virus

Children and Adolescents 9 Months to 18 Years of Age

Sub-Q

Primary immunization consists of a single dose of 0.5 mL.^{100 106}

Administer at least 10 days prior to potential exposure to yellow fever virus.^{100 106 115}

Manufacturer recommends revaccination with a single 0.5-mL dose every 10 years in individuals at risk of exposure to yellow fever virus.¹⁰⁶ ACIP states revaccination no longer considered necessary for most travelers, but is recommended in certain individuals (see Uses).¹⁰⁴ WHO states revaccination every 10 years no longer considered necessary, but uncertain whether all countries with entry requirements for yellow fever vaccination will adopt this change.¹¹⁵ (See Duration of Immunity under Cautions.)

Adults

Prevention of Disease Caused by Yellow Fever Virus

Adults ≥19 Years of Age

Sub-Q

Primary immunization consists of a single dose of 0.5 mL.¹⁰⁶

Administer at least 10 days prior to potential exposure to yellow fever virus.^{100 106 115}

Manufacturer recommends revaccination with a single 0.5-mL dose every 10 years in individuals at risk of exposure to yellow fever virus.¹⁰⁶ ACIP states revaccination no longer considered necessary for most US travelers, but is recommended in certain individuals (see Uses).¹⁰⁴ WHO states revaccination every 10 years no longer considered necessary, but uncertain whether all countries with entry requirements for yellow fever vaccination will adopt this change.¹¹⁵ (See Duration of Immunity under Cautions.)

Laboratory Personnel

Sub-Q

Primary immunization consists of a single dose of 0.5 mL.¹⁰⁶

To determine need for revaccination (booster dose) in those at continued high risk of exposure, ACIP recommends measuring yellow fever virus-specific neutralizing antibody titers at least every 10 years after primary immunization.¹⁰⁴ If neutralizing antibody titers cannot be measured,¹⁰⁴ ACIP recommends giving a vaccine dose every 10 years as long as laboratory worker remains at risk.¹⁰⁴

Special Populations

Geriatric Patients

No specific dosage recommendations.¹⁰⁶ Use with caution and consider possibility of increased risk for adverse systemic effects in this age group.^{100 106 115} (See Geriatric Use under Cautions.)

Cautions for Yellow Fever Vaccine

Contraindications

• History of acute hypersensitivity to eggs, egg products, or chicken protein.¹⁰⁶ (See Allergy to Egg-related Antigens under Cautions.)

• Hypersensitivity to any ingredient in the formulation, including gelatin.¹⁰⁶ (See Sensitivity Reactions under Cautions.)

• Immunosuppression.¹⁰⁶ (See Individuals with Altered Immunocompetence under Cautions.)

• Immunosuppressive therapy.¹⁰⁶ (See Specific Drugs and Laboratory Tests under Interactions.)

• Children <9 months of age.¹⁰⁶ (See Pediatric Use under Cautions.)

• Nursing mothers, particularly when nursing infants are <9 months of age.¹⁰⁶ (See Lactation under Cautions.)

Warnings/Precautions

Warnings

Vaccine-associated Neurotropic Disease

Yellow fever vaccine-associated neurotropic disease (YEL-AND; formerly known as postvaccinal encephalitis) occurs rarely following administration of yellow fever vaccine.^{100 106 108 115}

Potentially fatal and may include meningoencephalitis (neurotropic disease), Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis, and, rarely, cranial nerve palsies.^{100 115}

Historically, most cases reported in children <9 months of age;^{100 106} has now been reported in vaccinees in all age groups.¹¹⁵ Almost all cases reported worldwide have occurred after primary vaccination;^{104 115} only rarely reported following revaccination (booster dose).¹⁰⁴

CDC estimates that the incidence of YEL-AND in vaccine recipients in the US is 0.8 cases per 100,000 doses administered, but may be 2.2 cases per 100,000 doses in vaccinees ≥60 years of age.¹¹⁵ In documented US cases of YEL-AND, onset of illness was 2–56 days after vaccination.¹¹⁵

Other adverse neurologic effects (e.g., Guillain-Barré syndrome [GBS], seizures, focal neurologic deficits) reported rarely.¹⁰⁶

Because of risk for serious YEL-AND, use the vaccine only in individuals truly at risk for exposure to yellow fever virus.^{100 106 115}

Promptly report any patients with symptoms suggestive of neurotropic illness following a dose of yellow fever vaccine to the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or [Web].¹⁰⁶

Vaccine-associated Viscerotropic Disease

Yellow fever vaccine-associated viscerotropic disease (YEL-AVD; previously known as febrile multiple organ system failure) reported rarely following administration of yellow fever vaccine.^{100 106 108 110 115 120}

Resembles fulminant yellow fever caused by wild-type yellow fever virus.^{100 106} Varies in severity from moderate illness with focal organ dysfunction to fatal disease with overt multiple organ system failure and death.^{115 120}

All cases reported to date worldwide have occurred after primary vaccination;^{100 115} laboratory-confirmed cases not reported to date following revaccination (booster dose).^{100 115}

CDC estimates that the incidence of YEL-AVD in vaccine recipients in the US is 0.3 cases per 100,000 doses;¹¹⁵ incidence is higher (1.2 cases per 100,000 doses) in vaccinees ≥60 years of age and may be even higher in those ≥70 years of age.¹¹⁵ In US cases of YEL-AVD, median time from vaccine administration to onset of symptoms has been 4 days (range: 1–18 days) and case fatality rate has been approximately 46%.¹¹⁵

Risk factors for YEL-AVD include older age and history of thymus disease associated with abnormal immune cell function (e.g., myasthenia gravis, thymoma) or thymectomy.^{100 106} No conclusive evidence to date that this adverse effect is caused by a reversion to increased virulence in the vaccine virus.¹⁰⁰

Because of risk for serious YEL-AVD, use the vaccine only in individuals truly at risk for exposure to yellow fever virus.^{100 106 115}

Promptly report any patients with symptoms suggestive of viscerotropic illness following a dose of yellow fever vaccine to VAERS at 800-822-7967 or [Web].¹⁰⁶

Individuals with Altered Immunocompetence

Because yellow fever vaccine contains live, attenuated virus, viral replication and development of infection with the vaccine virus may be potentiated by altered immune status and risk of encephalitis or other serious adverse effects may be increased in immunocompromised individuals.^{100 106 134 155}

Contraindicated in individuals with severe underlying disease (e.g., leukemia, lymphoma, thymic disease, generalized malignancy), gammaglobulin deficiency (e.g., agammaglobulinemia, hypogammaglobulinemia, dysgammaglobulinemia), or immunosuppression secondary to AIDS or other manifestations of HIV infection.^{100 106 115} Also contraindicated in individuals receiving immunosuppressive agents or immunomodulatory therapy (e.g., alkylating agents, antimetabolites, corticosteroids, interleukin-1 blocking agents, monoclonal antibodies targeting immune cells, tumor necrosis factor alpha [TNF-α] inhibitors, radiation).^{100 106 115} (See Specific Drugs and Laboratory Tests under Interactions.)

Evidence suggests that thymic dysfunction may be an independent risk factor for development of YEL-AVD.¹⁰⁶ (See Vaccine-associated Viscerotropic Disease under Cautions.) Prior to administration of yellow fever vaccine, ask individuals about a history of thymus disorder (e.g., myasthenia gravis, thymoma, prior thymectomy) since the vaccine is contraindicated in such individuals.¹⁰⁶ However, ACIP and CDC state that the vaccine can be used in individuals who have undergone incidental surgical removal of their thymus or have had direct radiation therapy in the distant past since there is no evidence of immune dysfunction or increased risk of yellow fever vaccine-associated serious adverse effects in such individuals.^{100 115}

Advise individuals with altered immunocompetence to postpone or avoid travel to yellow fever endemic areas.¹⁰⁶ If travel to such areas cannot be avoided, advise immunocompromised patients of the risk, give instructions on methods for avoiding bites by vector mosquitoes, and provide a medical waiver letter to use with the required ICVP to fulfill international health regulations.^{100 106 115} (See Medical Waivers under Cautions.)

Individuals with symptomatic HIV infection and severe immunosuppression (i.e., CD4⁺ T-cell count <200/mm³ in adults and children ≥6 years of age or CD4⁺ T-cell percentage <15% in children <6 years of age): Contraindicated.^{100 115}

Individuals with asymptomatic HIV infection and moderate immunosuppression (i.e., CD4⁺ T-cell count of 200–499/mm³ in adults and children ≥6 years of age or CD4⁺ T-cell percentage of 15–24% in children <6 years of age): Use with caution and monitor closely for possible adverse effects.^{100 106 115} Because immune response may be reduced,^{100 103 106 115 116} consider serologic testing to document seroconversion prior to travel (see Pre- and Postvaccination Serologic Testing under Cautions).^{106 115}

Individuals with asymptomatic HIV infection and no evidence of immunosuppression (i.e., CD4⁺ T-cell count ≥500/mm³ in adults and children ≥6 years of age or CD4⁺ T-cell percentage ≥25% in children <6 years of age): May be administered if indicated based on the destination-specific risk for exposure to yellow fever virus.^{100 115 155}

The manufacturer, ACIP, and CDC state that family members of immunosuppressed or HIV-infected individuals may receive yellow fever vaccine, provided they have no contraindications for the vaccine.^{100 106 115}

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis and other immediate hypersensitivity reactions manifested as rash, urticaria, and/or respiratory symptoms (e.g., asthma, dyspnea, bronchospasm, pharyngeal edema) reported rarely following administration of yellow fever vaccine.^{100 106}

Hypersensitivity reactions reported principally in individuals with history of egg allergy,^{100 106} but anaphylaxis also reported in individuals with no history of reactions to the components of yellow fever vaccine.¹⁰⁰

Epinephrine and other appropriate agents should be readily available in case anaphylaxis or other serious allergic reaction occurs.¹⁰⁶

Allergy to Egg-related Antigens

Because yellow fever vaccine is produced in chick embryos, it is contraindicated in individuals with a history of acute hypersensitivity to eggs, egg products, or chicken protein.¹⁰⁶ Less severe or localized manifestations of allergy to eggs or to feathers not considered contraindications.¹⁰⁶

Prior to administration of yellow fever vaccine, obtain a history for evidence of sensitivity to egg or chicken protein.¹⁰⁶ Asking individuals whether they can eat eggs without adverse effects is a reasonable screening method since individuals who are able to eat eggs or egg products generally can receive the vaccine safely.^{100 106 115 134}

If yellow fever vaccine is considered necessary in an individual with a possible history of acute hypersensitivity to eggs or egg products, perform a skin test for hypersensitivity prior to administration of the vaccine.^{100 115} Less severe or localized manifestations of allergy to eggs or to feathers usually do not warrant skin testing with the vaccine.¹⁰⁶ If vaccination is considered essential despite a positive skin test, desensitization can be considered.¹⁰⁶ (See Sensitivity Testing and Desensitization under Cautions.)

If international travel regulations are the only reason to vaccinate an individual hypersensitive to egg or chicken protein, make efforts to obtain a medical waiver.¹¹⁵ (See Medical Waivers under Cautions.)

Sensitivity Testing and Desensitization

In individuals hypersensitive to eggs or chicken protein, perform a scratch and intradermal skin test prior to administration of yellow fever vaccine.¹⁰⁶ Consider desensitization only if the vaccine is considered essential in an individual with history of severe egg sensitivity and positive sensitivity test.^{100 106 115}

Scratch test: Use a 1:10 dilution of yellow fever vaccine in 0.9% sodium chloride.¹⁰⁶ Place a drop of the 1:10 dilution of vaccine on a superficial scratch, prick, or puncture on the volar surface of the forearm;¹⁰⁶ also use positive (histamine) and negative (0.9% sodium chloride) controls.¹⁰⁶ Read scratch test after 15–20 minutes.¹⁰⁶ A positive scratch test consists of a wheal with a diameter that is 3 mm larger than that of the 0.9% sodium chloride negative control, usually with surrounding erythema.¹⁰⁶ The histamine control must be positive for valid interpretation.¹⁰⁶ If scratch test is negative, perform an intradermal test.¹⁰⁶

Intradermal skin test: Use 0.02 mL of a 1:100 dilution of yellow fever vaccine in 0.9% sodium chloride injection.¹⁰⁶ Give intradermally on the volar surface of the forearm.¹⁰⁶ Administer positive and negative controls intradermally concurrently at separate sites.¹⁰⁶ A positive intradermal skin test reaction consists of a wheal that has a diameter that is at least 5 mm larger than that of the negative control and with surrounding erythema.¹⁰⁶

Desensitization: Perform only under direct supervision of a clinician experienced in management of anaphylaxis and with necessary emergency equipment immediately available.¹⁰⁶ Give the following increasing doses of yellow fever vaccine sub-Q at 15- to 20-minute intervals: 0.05 mL of a 1:10 dilution, 0.05 mL of undiluted vaccine, 0.1 mL of undiluted vaccine, 0.15 mL of undiluted vaccine, 0.2 mL of undiluted vaccine.¹⁰⁶

Gelatin Sensitivity

Contains gelatin as a stabilizer.¹⁰⁶ Consider possibility of allergic reactions in individuals sensitive to gelatin.^{106 134}

ACIP states use vaccines containing gelatin as a stabilizer with extreme caution in individuals who have had an anaphylactic reaction to gelatin or gelatin-containing products.¹³⁴

General Precautions

Acute Illness

Decision whether to administer or delay administration of yellow fever vaccine in an individual with a current or recent febrile illness depends largely on the severity and etiology of the illness.¹³⁴

Manufacturer recommends deferring vaccination in individuals with acute or febrile illness, but minor acute illness with low-grade fever generally does not preclude vaccination.¹⁰⁶

ACIP states that minor acute illness, such as mild upper respiratory infection (with or without fever) or mild diarrhea, does not preclude vaccination.¹³⁴ However, vaccination of individuals with moderate or severe acute illness generally should be deferred until they have recovered from the acute phase of the illness.¹³⁴

Chronic Illness

Contraindicated in individuals with chronic illness associated with altered immunocompetence.^{100 105 106 115 134} (See Individuals with Altered Immunocompetence under Cautions.)

Data limited regarding possible increased incidence of adverse effects or decreased vaccine efficacy if administered to patients with other chronic medical conditions (e.g., diabetes mellitus, renal disease, HCV infection or other liver disease).¹¹⁵ Consider use in such patients with caution, taking into account patient's general level of immune competence, disease severity and duration, and comorbidities.¹¹⁵

Pre- and Postvaccination Serologic Testing

Because immunocompromised individuals may have a reduced immune response to yellow fever vaccine, consider postvaccination serologic testing to document seroconversion if the vaccine is used in asymptomatic HIV-infected individuals.^{106 115}

Because there is some evidence that the immune response to yellow fever vaccine may be lower in pregnant women than in other healthy women, consider postvaccination serologic testing to document seroconversion if the vaccine is used in a pregnant woman.^{100 115} (See Pregnancy under Cautions.)

ACIP recommends serologic testing at least every 10 years to determine whether revaccination with yellow fever vaccine is indicated in laboratory workers who routinely handle wild-type yellow fever virus and are at continued high risk of exposure to the virus.¹⁰⁴

Consult appropriate state health departments or CDC (970-221-6400) for information on serologic testing.^{100 115}

Medical Waivers

If international health regulations are the only reason to vaccinate a traveler with a contraindication to yellow fever vaccine (e.g., hypersensitivity to egg or chicken protein, immunosuppression, pregnancy), the medical contraindications to vaccination section of the ICVP should be filled out and signed by a clinician.^{100 115} In addition, provide a letter clearly stating the traveler's contraindication;¹¹⁵ the letter should be written on letterhead stationery and stamped with the uniform stamp of the yellow fever vaccination center.^{100 115}

Issuance of a medical waiver does not guarantee its acceptance by the destination country.^{100 115} It also is helpful for the traveler to obtain specific and authoritative advice from the country or countries to be visited (e.g., by contacting their embassies or consulates).¹¹⁵ Document any waivers of requirements obtained from embassies or consulates with appropriate letters and retain for presentation with the ICVP.¹¹⁵

Information on country-specific requirements for yellow fever vaccination for travelers and information on regulations regarding ICVPs and medical waivers is available from CDC at [Web].^{100 115}

Transmission of Vaccine Virus

Yellow fever vaccine contains live, attenuated yellow fever virus.¹⁰⁶ Low-level viremia caused by the yellow fever vaccine virus (17D-204 strain) may occur 3–7 days after vaccination and persist for 1–3 days.¹⁰⁰ This level of viremia is high enough for the vaccine virus to be transmitted through blood products.¹⁰⁰

Transfusion-related transmission of yellow fever vaccine virus has been documented in a few individuals who received blood products that were collected from individuals who received yellow fever vaccine 4 days before their blood donation.¹⁰⁰ Advise vaccinees to defer blood donation for 2 weeks after receiving yellow fever vaccine.¹⁰⁰

A least 1 case of intrauterine transmission of yellow fever vaccine virus from mother to child during pregnancy has been reported.^{100 115} (See Pregnancy under Cautions.)

There is evidence that yellow fever vaccine virus can be transmitted via milk to nursing infants.^{100 122 123} (See Lactation under Cautions.)

Limitations of Vaccine Effectiveness

May not protect all vaccine recipients against yellow fever virus infection.¹⁰⁶

A single dose of yellow fever vaccine given 10–14 days prior to yellow fever virus exposure probably will protect most individuals.¹⁰⁶

Data suggest the small percentage of immunologically healthy individuals who fail to develop an immune response to initial vaccination with yellow fever vaccine may do so following revaccination.¹⁰⁶

Duration of Immunity

Duration of protection and need for revaccination or additional (booster) doses after primary immunization with yellow fever vaccine not fully determined.^{102 103 104 106}

Following primary immunization with a single vaccine dose in healthy individuals, 80–100% of vaccinees develop protective levels of yellow fever virus neutralizing antibodies within 10 days and there is some evidence that immunity may persist for at least 30–35 years and possibly for life.^{100 101 103 106}

Revaccination boosts levels of yellow fever virus-specific neutralizing antibody;^{100 106} the degree of this increase may be inversely correlated with the preexisting level of antibody.¹⁰⁰

Manufacturer recommends revaccination every 10 years in those at risk of exposure to yellow fever virus.¹⁰⁶

ACIP states that a single primary dose provides long-lasting protection against yellow fever virus and is adequate for most travelers.¹⁰⁴ However, because data not available on vaccine efficacy or protective antibody titers (i.e., seroprotection) related to long-term immunogenicity after administration of yellow fever vaccine, ACIP recommends revaccination in certain individuals who may have had a less robust or less sustained immune response to the vaccine, certain travelers who will be in higher-risk settings, and laboratory personnel at continued high risk of exposure to yellow fever virus.¹⁰⁴ (See Uses.)

WHO states that a single primary dose provides sustained immunity and lifelong protection against yellow fever virus and that revaccination (booster dose) every 10 years is no longer considered necessary.¹¹⁵ Although international health regulations no longer require revaccination and WHO states that an ICVP is considered valid for the lifetime of the vaccinee, it is uncertain when or if all countries with entry requirements for yellow fever vaccination will adopt this change.¹¹⁵ (See Uses.)

Improper Storage and Handling

Improper storage or handling of vaccines may reduce vaccine potency resulting in reduced or inadequate immune response in vaccinees.¹³⁴

Inspect all vaccines upon delivery and monitor during storage to ensure that the appropriate temperature is maintained.¹³⁴ (See Storage under Stability.)

Do not administer yellow fever vaccine that has been mishandled or has not been stored at the recommended temperature.¹³⁴

Yellow fever vaccine is heat sensitive and potency is substantially reduced if stored at room temperature.¹⁰⁶ This information is important for countries or areas where there is an inadequate cold chain and where there is potential for inadvertent exposure to abnormal temperatures during shipping and/or storage of the vaccine.¹⁰⁶

If there are concerns about mishandling, contact the manufacturer or state or local immunization or health departments for guidance on whether the vaccine is usable.¹³⁴

Specific Populations

Pregnancy

Category C.¹⁰⁶

Not known whether yellow fever vaccine can cause fetal harm when administered to pregnant women.¹⁰⁶ Animal reproduction studies not performed.¹⁰⁶

Limited data indicate that if yellow fever vaccine is administered during pregnancy, the vaccine virus can cross the placenta and infect the developing fetus;^{100 106} potential risks of such congenital infection not known.¹¹⁵

Live, attenuated virus vaccines administered during pregnancy pose a theoretical risk to the fetus and such vaccines generally are contraindicated during pregnancy unless the disease to be prevented poses a greater risk to the pregnant woman or fetus than the vaccine.^{105 134}

Postpone travel to areas with a substantial risk of exposure to yellow fever until after delivery.^{105 115}

If travel to high-risk areas is unavoidable during pregnancy and the risks of the vaccine are felt to outweigh the risks of exposure to yellow fever virus, advise pregnant women of the risk, give information on methods for avoiding bites by vector mosquitoes, and provide a medical waiver letter to use with the required ICVP to fulfill international health regulations.^{100 105 115} (See Medical Waivers under Cautions.)

If travel to high-risk areas is unavoidable during pregnancy and the risks of exposure to yellow fever virus are felt to outweigh the risks of the vaccine (e.g., travel to high-risk area unavoidable and high level of protection against mosquito exposure not feasible), ACIP, CDC, and AAP state that yellow fever vaccine can be administered.^{100 105 115}

If a pregnant woman receives yellow fever vaccine, monitor her infant closely for evidence of congenital infection and other possible vaccine adverse effects.¹¹⁵ In addition, because some data indicate lower seroconversion rates in pregnant women, consider performing serologic testing to document seroconversion after vaccination.^{100 115} (See Pre- and Postvaccination Serologic Testing under Cautions.)

Although specific data not available, ACIP and CDC recommend advising women who are planning to become pregnant to wait ≥4 weeks after vaccination before conceiving.^{100 115}

Lactation

Contraindicated in nursing women, especially those with infants <9 months of age.¹⁰⁶

ACIP and CDC state avoid yellow fever vaccine in nursing women whenever possible.^{100 115} However, these experts state that the vaccine can be used with caution in a nursing woman if travel with their infants to areas with substantial risk of exposure to yellow fever cannot be postponed.^{100 115}

There is evidence that yellow fever vaccine virus can be transmitted via milk from nursing mothers to their infants.^{100 122 123}

Pediatric Use

Contraindicated in children <9 months of age because of increased risk of serious adverse reactions in this age group, especially an increased risk of YEL-AND.¹⁰⁶ (See Vaccine-associated Neurotropic Disease under Cautions.)

Individuals planning to travel with infants <9 months of age to areas where yellow fever is endemic or epidemic should postpone or avoid such travel, whenever possible.^{100 106 115}

ACIP, CDC, and AAP state that there might be some situations in which vaccination of a child 6–8 months of age^{† [off-label]} might be considered;^{100 105 115} base such decisions on the relative risk of exposure to yellow fever virus and risk of serious adverse effects associated with yellow fever vaccine.^{100 105 115}

ACIP, CDC, and AAP state that children <6 months of age should not receive yellow fever vaccine under any circumstance.^{100 105 115}

Geriatric Use

Adults ≥60 years of age may be at increased risk for adverse systemic effects after receiving yellow fever vaccine compared with younger adults.^{100 106 115}

Manufacturer states limit use of yellow fever vaccine in adults >65 years of age to those traveling to or residing in known yellow fever endemic or epidemic areas.¹⁰⁶

ACIP and CDC state use yellow fever vaccine with caution in adults ≥60 years of age, especially in those receiving their first dose of the vaccine (i.e., primary immunization).^{100 115}

If travel is unavoidable, base decision regarding whether to vaccinate an adult ≥60 years of age on the risks and benefits of the vaccine in the context of the destination-specific risk for exposure to yellow fever virus.^{100 115}

If use of yellow fever vaccine considered necessary in a geriatric individual, evaluate their health status prior to vaccination and carefully monitor for adverse effects for 10 days after vaccination.¹⁰⁶

Common Adverse Effects

Low-grade fever, mild headache, myalgia, malaise, injection site reactions (edema, hypersensitivity, erythema, pain).^{106 115}

Drug Interactions

Other Vaccines

Only limited data available regarding concurrent administration of yellow fever vaccine with other vaccines.¹⁰⁶ (See Specific Drugs and Laboratory Tests under Interactions)

Make decisions regarding whether to administer yellow fever vaccine concomitantly with other vaccines based on information regarding possible interference with immune responses to the vaccines and take into consideration the convenience to the traveler in completing desired vaccinations before travel.^{100 106} If data not available to support concurrent administration, manufacturer states give yellow fever vaccine and the other vaccine 4 weeks apart.¹⁰⁶

Yellow fever vaccine is a live, attenuated virus vaccine.^{100 106} Because of theoretical concerns that immune responses to a parenteral live virus vaccine might be impaired if given within 28–30 days (i.e., 4 weeks) of another parenteral live virus vaccine, administer either concurrently with (using different syringes and different injection sites) or at least 30 days (4 weeks) apart from other live vaccines.^{100 134}

May be administered concurrently with (using different syringes and different injection sites) or at any interval before or after inactivated vaccines, recombinant vaccines, polysaccharide vaccines, or toxoids.^{100 134}

Specific Drugs and Laboratory Tests

Stability

Storage

Parenteral

For Injection, for Sub-Q Use

Prior to reconstitution, store at 2–8°C.¹⁰⁶ Do not freeze.¹⁰⁶

Discard reconstituted yellow fever vaccine if not used within 1 hour.¹⁰⁶

Yellow fever vaccine does not contain thimerosal or any other preservatives.¹⁰⁶

Actions

• Yellow fever vaccine available in US is a lyophilized preparation of live, attenuated organisms of the 17D-204 strain of yellow fever virus.¹⁰⁶ The vaccine is prepared by culturing the 17D-204 strain of live yellow fever virus in living chick embryos free of avian leukosis virus (ALV).¹⁰⁶

• Each 0.5-mL of the vaccine contains ≥4.74 log₁₀ plaque-forming units (PFU) throughout the life of the product.¹⁰⁶

• Yellow fever is transmitted by mosquito vectors.^{100 106 115} The disease has an abrupt onset after an incubation period of 3–6 days.^{100 106} A subclinical illness and influenza-like syndrome may occur or the disease may progress to an overwhelming pansystemic disease with hepatic and renal failure and hemorrhage caused by platelet and clotting abnormalities.^{106 108 115}

• Yellow fever vaccine stimulates active immunity to yellow fever virus infection by inducing production of yellow fever virus-specific IgM neutralizing antibodies.¹⁰⁶ Immune response to the vaccine is similar to that induced by wild-type infection.¹⁰⁶

• Anti-yellow fever antibodies are detectable in most individuals within 10–14 days after a single dose of yellow fever vaccine.¹⁰⁶

• Yellow fever vaccine is highly immunogenic in most adults, adolescents, and children >9 months of age.¹⁰⁶ In US studies using the currently available vaccine, the seroconversion rate was 80–100% in adults.^{100 106} Although there was no evidence of age-related differences in the immune response to the vaccine in early studies,^{103 106} more recent studies suggest that children have lower immune responses than adults and that the difference in seroconversion rates is most pronounced in children 9–36 months of age.¹⁰³

• Reduced immune responses to yellow fever vaccine and lower antibody titers may occur in immunocompromised individuals (e.g., HIV-infected individuals).^{100 103 106 115 116}

• Seroconversion rate after vaccination in pregnant women may be reduced compared with that in other healthy women, especially when the vaccine is given late in pregnancy.^{100 103 106}

• The minimum titer of anti-yellow fever antibodies conferring protection against yellow fever not definitely established to date.¹⁰⁶ WHO considers a log₁₀ neutralization index of ≥0.7 measured by a plaque reduction assay to be indicative of an adequate response to yellow fever vaccine and this was the level used to define seroconversion in clinical trials of the vaccine.¹⁰⁶

Advice to Patients

• Prior to administration of the vaccine dose, provide a copy of the appropriate CDC Vaccine Information Statement (VIS) to the patient or patient's legal representative (VISs are available at [Web]).¹¹²

• Advise patient and/or patient's parent or guardian of the risks and benefits of vaccination with yellow fever vaccine.¹⁰⁶

• Advise patient and/or patient's parent or guardian that yellow fever vaccine should not be used in individuals with life-threatening allergic reactions to eggs, egg products, or chicken protein, vaccine ingredients or packaging components (e.g., gelatin), or a previous dose of the vaccine.¹⁰⁶ Importance of informing clinician of any history of sensitivity to egg or chicken protein since sensitivity testing may be necessary prior to vaccination.¹⁰⁶ (See Sensitivity Reactions under Cautions.)

• Importance of informing clinicians if the patient has a weakened immune system (e.g., leukemia, lymphoma, HIV/AIDS, thymic disease) or is receiving treatment that may weaken the immune system (e.g., high-dose corticosteroids).

• Advise patient and/or patient's parent or guardian that yellow fever vaccine is given only at certain vaccination centers authorized to issue valid ICVPs and that the completed document will be needed as proof of vaccination before the individual is allowed to enter certain countries.^{100 106 115} Current information regarding which countries are in yellow fever endemic zones and/or have vaccination requirements for entry is available at CDC website ([Web]).¹¹⁵

• Advise patient and/or patient's parent or guardian that yellow fever vaccine may not provide protection in all vaccinees.¹⁰⁶ In addition to being vaccinated, importance of avoiding exposure to mosquitoes while in yellow fever endemic areas (e.g., stay in air-conditioned or well-screened areas, wear long-sleeved shirts and long pants to cover the body, use appropriate insect repellents, use mosquito nets between dusk and dawn).¹¹⁵

• Advise patient and/or patient's guardian of the signs and symptoms of an allergic reaction (e.g., urticaria, angioedema, rash, dyspnea, bronchospasm, pharyngeal edema, wheezing, throat tightness) and importance of immediately contacting a clinician if any symptoms of an allergic reaction develop following vaccination.¹⁰⁰

• Importance of informing clinicians if any adverse reactions (including allergic reactions) occur ≤30 days after vaccination with yellow fever vaccine.¹⁰⁶ Clinicians or individuals can report any adverse reactions that occur following vaccination to VAERS at 800-822-7967 or [Web].¹⁰⁶

• Advise individuals ≥60 years of age that they may be at increased risk for adverse effects after receiving yellow fever vaccine compared with younger adults.^{106 115} (See Geriatric Use under Cautions.)

• Advise patients with young children that yellow fever vaccine should not be used in infants <9 months of age and of the importance of avoiding yellow fever endemic areas if traveling with children in this age group.¹⁰⁶ (See Pediatric Use under Cautions.)

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹⁰⁶

• Importance of women informing clinicians if they are or plan to become pregnant.¹⁰⁶ Advise such women that the vaccine should be used during pregnancy only when clearly needed and that efforts should be made to postpone travel to yellow fever endemic areas until after delivery. ¹⁰⁶ If travel to yellow fever endemic areas cannot be avoided during pregnancy, discuss the risks and benefits of vaccination. (See Pregnancy under Cautions.)

• Importance of women informing clinicians if they plan to breast-feed.¹⁰⁶ Advise such women that the vaccine is not recommended for use in nursing women, particularly when breast-feeding infants are <9 months of age.¹⁰⁶ (See Lactation under Cautions.)

• Importance of informing patients of other important precautionary information.¹⁰⁶ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In the US, yellow fever vaccine is supplied only to designated Yellow Fever Vaccination Centers authorized to issue valid ICVPs for documentation of vaccination against yellow fever.^{100 106 115} Consult CDC yellow fever vaccination clinic search page at [Web] or local or state public health departments for information regarding the location of these vaccination centers.^{100 106 115}

Medical Disclaimer