Yellow Fever Vaccine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution [17D-204 strain] [preservative free]:

Stamaril: ≥1000 units per 0.5 mL dose [produced in chicken embryos; packaged with diluent; contains lactose]

YF-VAX: ≥4.74 log₁₀ plaque-forming units (PFU) per 0.5 mL dose [single-dose or 5-dose vial; produced in chicken embryos; contains gelatin; packaged with diluent]

Pharmacology

Mechanism of Action

Yellow fever vaccine is a live vaccine that offers active immunization against yellow fever infection at an effective immune response rate of nearly 100% of patients.

Pharmacokinetics/Pharmacodynamics

Onset of Action

Seroconversion: 10 to 14 days

Duration of Action

≥30 years (possibly life-long protection)

Use: Labeled Indications

Yellow fever prevention: Active immunization against yellow fever virus, primarily among persons traveling to or living in areas where yellow fever infection exists and laboratory workers who may be exposed to the virus; vaccination may also be required for some international travelers

The Advisory Committee on Immunization Practices (ACIP) (CDC/ACIP [Staples 2010]) recommends vaccination for:

• Persons traveling to or living in areas at risk for yellow fever transmission
• Persons traveling to countries which require vaccination for international travel
• Laboratory personnel who may be exposed to the yellow fever virus or concentrated preparations of the vaccine

Although the vaccine is approved for use in children ≥9 months, the CDC recommends use in children as young as 6 months under unusual circumstances (eg, travel to an area where exposure is unavoidable) (CDC/ACIP [Staples 2010]).

Contraindications

Acute hypersensitivity to egg or chick embryo protein, or any component of the formulation, including gelatin; infants <9 months (per manufacturer); infants <6 months (CDC/ACIP 2010 guidelines); severely immunosuppressed patients (eg HIV infection, leukemia, lymphoma, thymic disease, generalized malignancy, or immunosuppression due to drugs or radiation); lactating women providing breast-milk to infants <9 months

Dosage and Administration

Dosing: Adult

Yellow fever prevention:

Primary immunization: SubQ: One dose (0.5 mL) ≥10 days before travel

Booster: Based on currently available data, the World Health Organization (WHO) and CDC/ACIP have determined that vaccine failure is rare and booster doses are generally not needed. A single dose of the vaccine is adequate for most travelers. The World Health Assembly removed the 10-year booster dose requirement from the International Health Regulations in July 2016 (WHO 2016a). However, booster dose(s) are recommended for certain patient populations with conditions at the time of their initial dose that may limit immune response (eg, pregnant women, hematopoietic stem cell transplant recipients, HIV patients). A booster dose may also be given (≥10 years after last dose) to those who may be at increased risk for yellow fever disease (eg, certain laboratory workers [depending on antibody titers] and travelers to endemic locations for prolonged periods) (CDC/ACIP [Staples 2015]; WHO 2013).

Fractionated doses during community outbreak: Refer to WHO guidelines for information regarding fractional dosing as a vaccine dose-sparing initiative (WHO 2016b).

Dosing: Geriatric

Refer to adult dosing. Monitor closely due to an increased incidence of serious adverse events in patients ≥60 years of age, particularly in patients receiving their first dose. The ACIP guidelines note that if travel is unavoidable, the decision to vaccinate travelers ≥60 years should be made after weighing the risks vs benefits (CDC/ACIP [Staples 2010]).

Dosing: Pediatric

Yellow fever prevention (immunization):

Primary immunization (CDC/ACIP [Staples 2010]):

Infants 6 months to <9 months: Limited data available: SubQ: 0.5 mL as a single dose ≥10 days before travel

Infants ≥9 months, Children, and Adolescents: SubQ: 0.5 mL as a single dose ≥10 days before travel

Booster: Based on currently available data, the World Health Organization (WHO) and CDC/ACIP have determined that vaccine failure is rare and booster doses are generally not needed. A single dose of the vaccine is adequate for most travelers. The World Health Assembly removed the 10-year booster dose requirement from the International Health Regulations in July 2016 (WHO 2016). However, additional dose(s) are recommended for certain patient populations with conditions at the time of their initial dose that may limit immune response (pregnant women, hematopoietic stem cell transplant recipients, HIV patients). A booster dose may also be given (≥10 years after last dose) to those who may be at high risk for yellow fever disease (eg, certain laboratory workers [depending on antibody titers] and travelers to endemic locations for prolonged periods) (CDC/ACIP [Staples 2015]).

Reconstitution

Reconstitute only with diluent provided; for YF-VAX single-dose vial: 0.6 mL of diluent; for 5-dose vial: 3 mL of diluent. Inject diluent slowly into vial and allow to stand for 1 to 2 minutes. Gently swirl until a uniform suspension forms; swirl well before withdrawing dose. Avoid vigorous shaking to prevent foaming of suspension.

Administration

SubQ: For SubQ injection only. Do not administer intradermal, IM, or IV; if inadvertently administered IM, the dose does not need repeated. Use of expired vaccine is not considered a valid dose and should be repeated after 28 days. For booster doses, if the date of previous vaccination cannot be determined and the patient requires vaccination, the booster dose can be given (CDC/ACIP [Staples 2010]). Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (ACIP [Kroger 2017]). To prevent syncope related injuries, patients should be vaccinated while seated or lying down (ACIP [Kroger 2017]). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, and the administering person's name, title, and address be entered into the patient's permanent medical record.

Blood donation following vaccine administration: Transfusion-related transmission of yellow fever vaccine virus has been reported; wait 2 weeks after immunization with yellow fever vaccine to donate blood (CDC 59[2] 2010).

Storage

Store at 2°C to 8°C (35°F to 46°F); do not freeze. Vaccine must be used within 60 minutes of reconstitution. Keep suspension refrigerated until used (CDC/ACIP [Staples 2010]).

Drug Interactions

Axicabtagene Ciloleucel: May enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of infection may be increased. Axicabtagene Ciloleucel may diminish the therapeutic effect of Vaccines (Live). Management: Avoid live virus vaccines for at least 6 weeks prior to initiation of lymphodepleting therapy, during axicabtagene ciloleucel infusion, and after treatment until full immune recovery is achieved. Consider therapy modification

AzaTHIOprine: May enhance the adverse/toxic effect of Vaccines (Live). AzaTHIOprine may diminish the therapeutic effect of Vaccines (Live). Management: Low-dose azathioprine (3 mg/kg/day or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns and is not a contraindication for administration of zoster vaccine. Higher doses of azathioprine should be avoided. Consider therapy modification

Belimumab: May enhance the adverse/toxic effect of Vaccines (Live). Avoid combination

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Vaccines (Live). Corticosteroids (Systemic) may diminish the therapeutic effect of Vaccines (Live). Management: Doses equivalent to less than 2 mg/kg or 20 mg per day of prednisone administered for less than 2 weeks are not considered sufficiently immunosuppressive to create vaccine safety concerns. Higher doses and longer durations should be avoided. Consider therapy modification

Daclizumab: May enhance the adverse/toxic effect of Vaccines (Live). Daclizumab may diminish the therapeutic effect of Vaccines (Live). Avoid combination

Dimethyl Fumarate: May enhance the adverse/toxic effect of Vaccines (Live). Specifically, Dimethyl Fumarate may increase the risk of vaccinal infection. Dimethyl Fumarate may diminish the therapeutic effect of Vaccines (Live). Management: Canadian labeling for dimethyl fumarate states that live attenuated vaccine administration is not recommended during treatment. U.S. labeling does not mention this. Consider therapy modification

Dupilumab: May enhance the adverse/toxic effect of Vaccines (Live). Avoid combination

Fingolimod: May enhance the adverse/toxic effect of Vaccines (Live). Vaccinal infections may develop. Fingolimod may diminish the therapeutic effect of Vaccines (Live). Avoid combination

Fotemustine: May enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk for vaccine-related disease may be increased. Avoid combination

Guselkumab: May enhance the adverse/toxic effect of Vaccines (Live). Avoid combination

Immunosuppressants: May enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: AzaTHIOprine; Beclomethasone (Oral Inhalation); Betamethasone (Systemic); Budesonide (Systemic); Corticotropin; Cortisone; Cytarabine (Liposomal); Deflazacort; DexAMETHasone (Systemic); Fludrocortisone; Fluticasone (Oral Inhalation); Hydrocortisone (Systemic); Leflunomide; Mercaptopurine; Methotrexate; MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE; Triamcinolone (Systemic). Avoid combination

Leflunomide: May enhance the adverse/toxic effect of Vaccines (Live). Leflunomide may diminish the therapeutic effect of Vaccines (Live). Management: The ACIP guidelines state that live-attenuated vaccines should generally be avoided for at least 3 months after cessation of immunosuppressant therapy. However, the ACR does not recommend avoiding live vaccines in patients being treated with leflunomide. Consider therapy modification

Mercaptopurine: May enhance the adverse/toxic effect of Vaccines (Live). Mercaptopurine may diminish the therapeutic effect of Vaccines (Live). Management: Low-dose 6-mercaptopurine (1.5 mg/kg/day or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns and is not a contraindication for administration of zoster vaccine. Higher doses of mercaptopurine should be avoided. Consider therapy modification

Methotrexate: May enhance the adverse/toxic effect of Vaccines (Live). Methotrexate may diminish the therapeutic effect of Vaccines (Live). Management: Low-dose methotrexate (0.4 mg/kg/week or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns. Higher doses of methotrexate should be avoided. Consider therapy modification

Ocrelizumab: May enhance the adverse/toxic effect of Vaccines (Live). Ocrelizumab may diminish the therapeutic effect of Vaccines (Live). Avoid combination

Risankizumab: May enhance the adverse/toxic effect of Vaccines (Live). Avoid combination

Tildrakizumab: May enhance the adverse/toxic effect of Vaccines (Live). The risk for contracting an infection from the vaccine may be increased. Tildrakizumab may diminish the therapeutic effect of Vaccines (Live). Avoid combination

Tisagenlecleucel: May enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of infection may be increased. Tisagenlecleucel may diminish the therapeutic effect of Vaccines (Live). Management: Avoid live virus vaccines for two weeks prior to initiation of lymphodepleting therapy, during tisagenlecleucel infusion, and after treatment until full immune recovery is achieved. Consider therapy modification

Tuberculin Tests: Vaccines (Live) may diminish the diagnostic effect of Tuberculin Tests. Management: If a parenteral live vaccine has been recently administered, a scheduled PPD skin test should not be administered for at least 4-6 weeks following the administration of the vaccine. Consider therapy modification

Vaccines (Live): May diminish the therapeutic effect of other Vaccines (Live). Management: Two or more injectable or nasally administered live vaccines not administered on the same day should be separated by at least 28 days (ie, 4 weeks). If not, the vaccine administered second should be repeated at least 4 week later. Exceptions: Adenovirus (Types 4, 7) Vaccine; Cholera Vaccine; Rotavirus Vaccine. Monitor therapy

Venetoclax: May enhance the adverse/toxic effect of Vaccines (Live). Venetoclax may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live, attenuated vaccines before, during, or after (prior to B-cell recovery) venetoclax treatment. Avoid combination

Adverse Reactions

1% to 10%: Dermatologic: Skin rash (3%)

Frequency not defined:

Central nervous system: Headache, malaise

Local: Erythema at injection site, localized edema (at injection site), pain at injection site

Neuromuscular & skeletal: Myalgia, weakness

Miscellaneous: Fever

<1%, postmarketing, and/or case reports: Acute disseminated encephalomyelitis, anaphylaxis, brain disease, cranial nerve palsy (bulbar), Guillain-Barré syndrome, hypersensitivity at injection site, hypersensitivity reaction (immediate; including asthma, dyspnea, bronchospasm, pharyngeal edema), residual mass at injection site, urticaria, vaccine-associated neurotropic disease (rare), vaccine-associated viscerotropic disease (rare; may be associated with multi-organ failure)

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid/hypersensitivity reactions: Immediate treatment (including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during vaccine use (ACIP [Kroger 2017]). Use is contraindicated in patients with immediate-type hypersensitivity reactions to eggs. Less severe or localized manifestations of allergy are not contraindications; in general, persons who are able to eat eggs or egg products may receive the vaccine. A hypersensitivity screening test and desensitization procedure is available for persons with suspected or known severe egg sensitivity. Consult manufacturer's labeling for details.
• Syncope: Syncope has been reported with use of injectable vaccines and may result in serious secondary injury (eg, skull fracture, cerebral hemorrhage); typically reported in adolescents and young adults and within 15 minutes after vaccination. Procedures should be in place to avoid injuries from falling and to restore cerebral perfusion if syncope occurs (ACIP [Kroger 2017]).
• Vaccine-associated neurotropic disease (YEL-AND): Isolated cases of post-vaccine encephalitis (some fatal) have been reported within 30 days after administration. Risk factors include age <9 months, age >60 years, and immunodeficiency.
• Vaccine-associated viscerotropic disease (YEL-AVD): Has been reported following first dose of vaccine; may present as non-specific multi-organ system failure or symptoms similar to fulminant wild-type yellow fever virus (including potentially fatal hepatic failure and internal bleeding). Age >60 years is a risk factor.

Disease-related concerns:

• Acute illness: The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and the etiology of the disease. Use is contraindicated in patients with severe or febrile illness; vaccination should not be delayed for patients with mild acute illness (with or without fever) (ACIP [Kroger 2017]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Vaccines: In order to maximize vaccination rates, the ACIP recommends simultaneous administration (ie, >1 vaccine on the same day at different anatomic sites) of all age-appropriate vaccines (live or inactivated) for which a person is eligible at a single clinic visit, unless contraindications exist (ACIP [Kroger 2017]).

Special populations:

• Altered immunocompetence: Patients who are immunosuppressed have a theoretical risk of encephalitis with yellow fever vaccine administration; consider delaying travel or obtaining a waiver letter. Patients on low-dose or short-term corticosteroids are not considered immunosuppressed and may be offered the vaccine. If vaccination is only to satisfy an international requirement (as opposed to decreasing risk of infection), efforts should be made to obtain a waiver letter. Per the ACIP guidelines, use is contraindicated in patients with symptomatic HIV infection or patients with CD4+ counts <200/mm³ (or <15% of total lymphocytes in children <6 years); use caution when administering the vaccine to patients with asymptomatic infection with CD4+ counts 200 to 499/mm³ (or 15% to 24% of total lymphocytes in children <6 years) (CDC/ACIP [Staples 2010]). In general, household and close contacts of persons with altered immunocompetence may receive all age appropriate vaccines (ACIP [Kroger 2017]; IDSA [Rubin 2014]). Live vaccines should be administered ≥4 weeks prior to planned immunosuppression and avoided within 2 weeks of immunosuppression when feasible; live vaccines should not be administered for at least 3 months after immunosuppressive therapy. Specific recommendations for use of this vaccine in immunocompromised patients considering international travel as well as contacts of immunocompromised patients are available from the IDSA (ACIP [Kroger 2017; IDSA [Rubin 2014]).
• Elderly: Due to an increased incidence of serious adverse events observed in older adults compared to younger adults, use with caution in the elderly ≥60 years, particularly in patients who have not previously received the vaccine. The risk for vaccine-associated neurologic disease (YEL-AND) and vaccine-associated viscerotropic disease (YEL-AVD) is also increased. The ACIP guidelines note that if travel is unavoidable, the decision to vaccinate travelers ≥60 years should be made after weighing the risks vs benefits (CDC/ACIP [Staples 2010]).
• Pediatric: The manufacturer contraindicates use in infants <9 months of age due to risk of encephalitis. The CDC allows for use in infants 6-8 months of age when possible exposure with the yellow fever virus is unavoidable and the risk of infection exists (CDC/ACIP [Staples 2010]).

Dosage form specific issues:

• Gelatin: Product may contain gelatin

Other warnings/precautions:

• Antipyretics: Antipyretics have not been shown to prevent febrile seizures; antipyretics may be used to treat fever or discomfort following vaccination (ACIP [Kroger 2017]). One study reported that routine prophylactic administration of acetaminophen to prevent fever prior to vaccination decreased the immune response of some vaccines; the clinical significance of this reduction in immune response has not been established (Prymula 2009).
• Blood donation: Transfusion-related transmission of yellow fever vaccine virus has been reported; wait 2 weeks after immunization with yellow fever vaccine to donate blood (CDC/ACIP [Staples 2010]).
• Effective immunity: Vaccination may not result in effective immunity in all patients. Response depends upon multiple factors (eg, type of vaccine, age of patient) and may be improved by administering the vaccine at the recommended dose, route, and interval. Vaccines may not be effective if administered during periods of altered immune competence (ACIP [Kroger 2017]).
• Malnutrition: Malnourished persons may have a decreased response to vaccination (CDC/ACIP [Staples 2010]).

Monitoring Parameters

Monitor for anaphylaxis and syncope for 15 minutes following administration. If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion. Monitor for adverse effects 10 days after vaccination (specifically in the elderly) (ACIP [Kroger 2017]; CDC/ACIP [Staples 2010]).

Pregnancy

Pregnancy Considerations

Avoid use in pregnant women unless travel to high-risk areas is unavoidable. Pregnant women may not produce an adequate immune response to the vaccine, particularly in the third trimester (CDC/ACIP [Staples 2015]). Adverse events were not observed in the mother or fetus following vaccination during the third trimester of pregnancy in Nigerian women (n=101, including 89 in their third trimester); however, maternal seroconversion was reduced (39% seroconversion at 2 to 4 weeks after administration) (Nasidi 1993). Inadvertent exposure early in the first trimester of pregnancy (n=480, mean gestational age 5.7 ± 4.9 weeks) in Brazilian women did not show decreased maternal seroconversion (98.2% seropositive at ≥6 weeks after administration); no increased risk for major congenital abnormalities was observed (Suzano 2006). Cord blood from an infant whose mother was vaccinated during the first trimester tested positive for IgM antibodies (indicating congenital infection); no adverse events were noted in the infant (Tsai 1993). Vaccine should be administered if travel to an endemic area is unavoidable and the infant should be monitored after birth. Tests to verify maternal immune response may be considered (CDC/ACIP [Staples 2010]). If a pregnant woman is to be vaccinated only to satisfy an international requirement (as opposed to decreasing risk of infection), efforts should be made to obtain a waiver letter.

Due to variable seroconversion during pregnancy, women who were initially vaccinated while pregnant may need a booster dose prior to traveling again to an area at risk for yellow fever virus infection (CDC/ACIP [Staples 2015].

Women should wait 4 weeks after receiving vaccine before conceiving (CDC/ACIP [Staples 2010]).

Patient Education

• Discuss specific use of vaccine and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience injection site pain, edema, or irritation. Have patient report immediately to prescriber signs of kidney problems (unable to pass urine, blood in urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), confusion, facial paralysis, burning or numbness feeling, abnormal movements, severe dizziness, passing out, seizures, severe muscle pain, headache, severe loss of strength and energy, difficulty breathing, bruising, or bleeding (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.