Yellow Fever Vaccine (Systemic)

VA CLASSIFICATION
Primary: IM100


Note: In the U.S. and Canada, yellow fever vaccine is supplied only to designated Yellow Fever Vaccination Centers approved by the World Health Organization (WHO) and authorized to issue valid International Certificates of Vaccination against yellow fever. In the U.S., state or local health departments, or the Division of Vector-borne Infectious Diseases, Centers for Disease Control, Fort Collins, Colorado (telephone no.: 303-221-6400) can provide information concerning the location of these centers and specific international requirements for vaccination ^{{11} {12} {17} {23}}. In Canada, this information is provided by the provincial health departments or the Laboratory Center for Disease Control, Ottawa (telephone no.: 613-957-8739) ^{24}.

Commonly used brand name(s): YF-Vax.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Immunizing agent (active)—

Indications

Accepted

Yellow fever (prophylaxis)—Yellow fever vaccine is indicated for active immunization against yellow fever (urban and sylvatic or jungle forms), which is caused by a flavivirus, an arthropod-borne virus of yellow fever. Urban yellow fever is transmitted to humans by the bites of infective Aedes aegypti mosquitoes, while the sylvatic form is transmitted by the bites of several species of forest mosquitoes of the genus Haemagogus ^{{14} {15}}.
—Active immunization against yellow fever is indicated for all persons 9 months of age or older who are:
—Traveling to or living in areas of Africa or South America where yellow fever infection is endemic and officially reported ^{{02} {05} {11} {12} {13} {15} {17} {23}}; or
—Traveling to countries that require yellow fever immunization (certificate of vaccination) as a condition for entry ^{{02} {05} {11} {17} {23}}; or
—Traveling outside the urban areas of countries that do not report the disease officially but lie in the yellow fever endemic zone ^{{11} {12} {15} {23}}.
—Yellow fever immunization is recommended for infants 6 to 9 months of age and pregnant women only if they are traveling to areas experiencing ongoing epidemic yellow fever, when travel cannot be postponed and a high level of protection against exposure to mosquitoes is not possible ^{{05} {11} {12} {13}}.
—Yellow fever immunization should be considered for infants 4 to 6 months of age only under unusual circumstances. Infants younger than 4 months of age should never be vaccinated because of the risk of encephalitis ^{{11} {12} {15} {23}}.
—Yellow fever immunization is also recommended for laboratory personnel who might be exposed to the virulent yellow fever virus by direct or indirect contact, or by aerosols ^{{11} {12} {23}}.

Note: Under the International Health Regulations, the certificate of vaccination for yellow fever is valid for 10 years, beginning 10 days after the primary vaccination ^{{02} {05} {11} {23}}, or on the date of revaccination if within 10 years of the first injection ^{{11} {23}}.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Yellow fever vaccine is a live attenuated virus preparation made from the 17-D yellow fever virus strain cultured in chicken embryo ^{{02} {05} {12} {13} {17} {23}}.

Mechanism of action/Effect:

Following subcutaneous injection, yellow fever vaccine induces the formation of protective antibodies in susceptible individuals ^{{05} {08} {23}}. This provides active immunity against yellow fever infection that probably lasts for more than 10 years ^{{04} {05} {13} {23}}.


Protective effect

Yellow fever vaccine induces protective antibodies in more than 90% of recipients ^{{13} {14} {15}}.


Time to protective effect

Effective immunity occurs within 7 to 10 days after primary vaccination ^{{02} {15}}. Some studies reported that major antibody response to yellow fever vaccine almost always occurred within 28 days of vaccination ^{10}.


Duration of protective effect

Immunity against yellow fever lasts more than 10 years ^{{04} {13}}. It may persist for at least 30 to 35 years and probably lasts for life ^{{04} {09} {10} {12} {23}}. Revaccination at intervals of 10 years is still required by the International Health Regulations ^{{11} {12} {13} {15} {17}} to boost antibody titer ^{12} for repeated exposure ^{13}.


Precautions to Consider

Cross-sensitivity and/or related problems

Persons allergic to eggs or chicken protein may be allergic to the live yellow fever vaccine available in the U.S. and Canada, since it is produced in chick embryo cell cultures. A history of hypersensitivity reactions other than anaphylaxis generally does not preclude immunization ^{{02} {05} {11} {12} {13} {23}}.

Intradermal skin testing under close medical supervision must be performed on individuals with a history of possible egg hypersensitivity if vaccination is being considered because of high risk of exposure ^{{11} {12} {23}}. Yellow fever vaccine is not recommended for persons with a positive intradermal skin test reaction. An intradermal skin test consists of an intradermal injection of 0.02–0.03 mL of yellow fever vaccine, and a 0.9% sodium chloride injection at a separate site to serve as a control. A positive intradermal skin test result consists of an urticarial wheal, with or without pseudopods, surrounded by an erythematous zone. Epinephrine injection (1:1000) and a tourniquet should be at hand to combat any unexpected anaphylactic or other allergic reactions.

Small test doses administered intracutaneously may be sufficient to induce antibody response ^{{02} {05} {11} {23}}. The presence of antibodies in the serum must be confirmed through evaluation performed approximately 4 weeks after skin testing ^{{02} {05} {23}}.

If compliance with international travel requirements, rather than a high risk of infection, is the only reason for vaccination, a person with hypersensitivity ^{24} to eggs or chicken protein may obtain from a physician a waiver letter stating why vaccination is contraindicated. Ideally, the waiver letter should be written on letterhead stationery and bear the stamp used by health departments and official immunization centers to validate the International Certificate of Vaccination. The traveler should also contact the embassies of the countries he/she intends to visit for advice ^{{12} {13} {23}}.

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans ^{{02} {06} {07}}. It is not known whether yellow fever vaccine can affect reproductive capacity or can cause adverse effects on the fetus. Pregnant women theoretically should not be vaccinated unless high risk exposure is unavoidable ^{{02} {05} {06} {07} {11} {12} {13} {17} {19} {23}}, especially in the first trimester of pregnancy ^{{02} {15}}. Susceptible or non-immunized pregnant women should postpone travel to epidemic areas ^{{07} {23}} and postpone vaccination ^{{12} {13}}, until after delivery ^{11}. However, pregnant women who must travel to high-risk areas should be vaccinated. In this case, the risk to both the mother and the fetus of complications due to yellow fever exceeds the risk of vaccination ^{{11} {12} {23}}. If the vaccine is necessary, yellow fever vaccine should be given to pregnant women during the second or third trimester to minimize concern over teratogenic effects on the fetus. If travel does not pose any risk of infection and the only reason for vaccination is compliance with the international travel requirements, a waiver letter stating the contraindication should be obtained from the traveler's physician. Ideally, the waiver letter should be written on letterhead stationery and bear the stamp used by health departments and official immunization centers to validate the International Certificate of Vaccination. The traveler should also contact the embassies of the countries she intends to visit for advice ^{{11} {12} {13} {23}}.

Studies have not been done in animals ^{{02} {23}}.

FDA Pregnancy Category C ^{02}.

Breast-feeding

Yellow fever vaccine is not distributed into breast milk following vaccination and therefore, may be given to nursing women ^{{11} {23}}.

Pediatrics


The Immunization Practices Advisory Committee (ACIP) and World Health Organization (WHO) recommend the following:

Yellow fever vaccine should be given to children 9 months of age or older if they are traveling to or living in areas of South America or Africa where yellow fever is officially reported, or traveling to countries that require yellow fever immunization (certificate of vaccination), or traveling outside urban areas of countries that do not report the disease officially but lie in the yellow fever endemic zone ^{{02} {05} {11} {12} {13} {15} {23}}.

Children 6 to 9 months of age should be vaccinated only if they are traveling to areas of ongoing yellow fever epidemic, or when travel cannot be postponed and a high level of protection against mosquito bites is not feasible ^{{05} {11} {12} {13} {23}}.

Children 4 to 6 months of age should be considered for immunization only under unusual circumstances (high-risk exposure) ^{{02} {05} {11} {12} {15} {23}}, and infants under 4 months of age should never be vaccinated because they are particularly susceptible to encephalitis, which appears to be the major complication in this age group ^{{04} {11} {12} {15} {23}}.



Geriatrics


Appropriate studies on the relationship of age to the effects of yellow fever vaccine have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Immunosuppressive agents or
» Radiation therapy    (because normal defense mechanisms are suppressed, concurrent use with yellow fever vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to yellow fever vaccine. Vaccination should be deferred until use of immunosuppressive agents has been discontinued. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to yellow fever vaccine or to other live virus vaccines is estimated to vary from 3 months to 1 year, depending on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors. Patients with leukemia in remission should not receive yellow fever vaccine until at least 3 months after their last chemotherapy. The precaution does not apply to corticosteroids used as replacement therapy, for short-term [less than 2 weeks] systemic therapy, or by other routes of administration that do not cause immunosuppression ^{{02} {05} {11} {12} {13} {16} {19} {23}})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Febrile illness, severe    (to avoid confusing manifestations of illness with possible side/adverse effects of vaccine. Minor illnesses, such as upper respiratory infection [with or without low grade fever] or mild diarrhea, do not preclude administration of vaccine ^{23})


» Immune deficiency conditions, congenital or hereditary, family history of or
» Immune deficiency conditions, primary or acquired    (because of reduced or suppressed defense mechanisms, the use of live virus vaccines, including yellow fever vaccine, may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to yellow fever; if travel to a yellow fever endemic zone is necessary, patients should be advised of the risks, given instructions to protect themselves against mosquito bites, and provided with a vaccination waiver letter by their physician)

    (persons with leukemia may receive live virus vaccines if at least 3 months have passed since their last chemotherapy treatment)

    (persons infected with human immunodeficiency virus [HIV] who cannot avoid potential exposure to yellow fever virus may receive this vaccine if they are asymptomatic; however, they should be monitored for possible adverse effects; it is also possible that the immune response may be less pronounced than in non-HIV infected individuals ^{{02} {05} {11} {12} {13} {17} {19} {23}})


Risk-benefit should be considered when the following medical problems exist
Hypersensitivity to eggs or chicken protein    (patients allergic to eggs or chicken protein may be allergic to the yellow fever vaccine since it is produced in chicken embryo culture ^{{02} {05} {11} {12} {13} {15}})


Sensitivity to yellow fever vaccine


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Anaphylaxis or anaphylactoid reaction (convulsions; coughing; difficulty in breathing or swallowing; fast heartbeat; generalized rash and itching; reddening of skin; sense of agitation or uneasiness; sensation of burning, crawling, or tingling of skin; sneezing; throbbing in the ears; sudden and severe unusual tiredness or weakness)
    
encephalitis^{{02}{05}{11}{12}{13}{20} {02}{04}{05}{11}{12}{13}}(confusion; convulsions; irritability; severe headache; stiff neck; vomiting)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Low grade fever
    
mild headache
    
myalgia ^{{02}{05}{11}{12}{13}}(muscle pain)
    
pain at inoculation site^{04}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Yellow Fever Vaccine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to chicken protein, eggs, or yellow fever vaccine

Pregnancy—Not recommended for pregnant women unless high-risk exposure is unavoidable, especially for those in first trimester of pregnancy, because of theoretical risk of birth defects; non-immunized pregnant women should postpone travel to epidemic areas and postpone vaccination until after delivery, but if travel to high-risk areas is necessary, they should be vaccinated because the risk to both the mother and the fetus of complications due to yellow fever exceeds the risk of vaccination; however, if the only reason for vaccination is compliance with the international travel requirements, a waiver letter (official-looking on letterhead stationery) stating the contraindication should be obtained from the physician





Use in children—Recommended for children 9 months of age or older if they are traveling to or living in areas of South America or Africa where yellow fever is officially reported, or traveling to countries that require yellow fever immunization (certificate of vaccination), or traveling outside urban areas of countries that do not report the disease officially but lie in the yellow fever endemic zone; children 6 to 9 months of age should be vaccinated only if they travel to areas of ongoing yellow fever epidemic, or when travel cannot be postponed and a high level of protection against mosquito bites is not feasible; children 4 to 6 months of age should be considered for immunization only under unusual circumstances (high-risk exposure), and infants under 4 months of age should never be vaccinated, because of the risk of encephalitis

Other medications, especially immunosuppressive agents or radiation therapy
Other medical problems, especially severe febrile illness and immune deficiency conditions


Side/adverse effects
Signs of potential side effects, especially allergic reaction and encephalitis


General Dosing Information
Anaphylaxis may occur following yellow fever vaccination, even in individuals with no prior history of hypersensitivity to the vaccine components. Intradermal skin tests with the vaccine and sterile normal saline (0.9% sodium chloride injection) to serve as a control must be performed on individuals with a history of hypersensitivity to eggs or chicken protein. A tourniquet and epinephrine injection (1:1000) should be at hand to combat any unexpected anaphylactic or other allergic reactions ^{{02} {05}}. An intracutaneous dose of 0.02 mL administered for hypersensitivity testing may be sufficient to induce immunity. However, in such cases, the presence of specific protective antibodies must be confirmed through evaluation of serum obtained approximately 4 weeks after skin testing. It is recommended that the state, provincial, or public health laboratory be contacted for assistance in this matter ^{{02} {24}}.

A separate sterile syringe and needle should be used for each vaccination to prevent transmission of hepatitis or other infectious agents from one person to another ^{{02} {05}}.

The vaccine should be used within 60 minutes following reconstitution. The contents of the vial should be swirled well, but not shaken vigorously, before each dose is withdrawn. All reconstituted vaccine and containers that remain unused after 1 hour must be sterilized and discarded ^{{02} {05}}. The reconstituted vaccine is not to be diluted ^{02}.

Immunity develops by the tenth day after primary vaccination. WHO requires revaccination every 10 years to maintain traveler's vaccination certificates ^{02}.

Yellow fever vaccine may be given concomitantly with, or at any time before or after, the commercially available immune globulin ^{{11} {12} {13} {23}}.

For treatment of adverse effects


Recommended treatment consists of the following:


For anaphylaxis—
For adults: If anaphylaxis occurs, 0.2 to 0.5 mg of epinephrine (base) (1:1000 solution) may be administered subcutaneously in the arm that was not injected with the yellow fever vaccine, the dose being repeated every 20 to 30 minutes for three doses as needed. The dosage may be increased up to a maximum of 1 mg per dose, if necessary ^{{21} {22}}. A tourniquet should be applied at once above the site of injection of the antigen ^{{02} {05} {20}}, and an additional injection of epinephrine may be given subcutaneously at the site of injection to help retard systemic absorption. The tourniquet should be released in 15 minutes. For more severe reactions, antihistamines, aminophylline, and/or glucocorticoids also may be given ^{20}.

For children: If anaphylaxis occurs, 10 mcg (0.01 mg) of epinephrine (base) per kg of body weight or 300 mcg (0.3 mg) per square meter of body surface up to a maximum of 500 mcg (0.5 mg) per dose may be administered subcutaneously in the arm that was not injected with the yellow fever vaccine, or in the thigh in children younger than 3 years of age, the dose being repeated every 15 minutes for two doses, then administered every 4 hours as needed ^{{01} {18} {22}}. A tourniquet should be applied at once above the site of injection of the antigen ^{{02} {05} {18}}, and an additional injection of epinephrine may be given subcutaneously at the site of injection to help retard systemic absorption. The tourniquet should be released in 15 minutes ^{18}. For more severe reactions, antihistamines, aminophylline, and/or glucocorticoids also may be given ^{20}.

Supportive measures include intravenous (IV) fluids and oxygen.




Parenteral Dosage Form

YELLOW FEVER VACCINE (FOR INJECTION) USP

Usual adult and adolescent dose
Subcutaneous, 0.5 mL as a single dose ^{{02} {04} {11} {12} {13} {19}}.

Primary dose–At initial visit.

Booster dose–After 10 years.

Usual pediatric dose
See Usual adult and adolescent dose ^{{02} {04} {11} {12} {13}}.

Strength(s) usually available
U.S.—


Yellow fever vaccine contains not less than 5.04 log10 Plaque Forming Units (PFU) per 0.5 mL (Rx) [YF-Vax]

Canada—


Yellow fever vaccine contains not less than 5.04 log10 Plaque Forming Units (PFU) per 0.5 mL (Rx)[Generic]

Packaging and storage:
Yellow fever vaccine is preferably stored at a temperature between 0 and 5 °C (32 and 41 °F) ^{{02} {03} {05}} until reconstituted for use ^{05}. The vial of diluent should not be frozen. Reconstituted vaccine must be kept cool or refrigerated and should be used within 60 minutes following reconstitution ^{05}.

Yellow fever vaccine should be preserved during shipment in a suitable container packed with solid carbon dioxide (dry ice) or with other means of refrigeration, to ensure a constant temperature of 0 °C (32 °F). When solid carbon dioxide is used for packing, the shipping container must contain some solid carbon dioxide upon arrival to ensure that the vaccine has been maintained at a temperature of 0 °C (32 °F) throughout shipping ^{{02} {03} {05} {23}}.

Preparation of dosage form:
To reconstitute, only the diluent (sodium chloride injection) provided by the manufacturer should be used. The volume of specified diluent shown on the diluent label should be withdrawn into the syringe and all the diluent in the syringe slowly injected into the vial containing the vaccine. The vial should remain undisturbed for 1 to 2 minutes, then the mixture should be swirled carefully to achieve a uniform suspension. The mixture should not be shaken vigorously, because this causes foaming of the suspension ^{{02} {05}}.

The reconstituted vaccine should not be diluted ^{02}.

Stability:
Yellow fever vaccine contains sorbitol and gelatin as stabilizers, but no preservative. The reconstituted vaccine should be refrigerated and used within 60 minutes. All vaccines and containers that are not used within an hour after reconstitution should be sterilized and discarded.

The reconstituted vaccine is slightly opalescent and light orange in color. It should not be used if it is discolored ^{{02} {05}}.

Incompatibilities:
Preservatives may inactivate the vaccine; only the diluent supplied by the manufacturer should be used for reconstitution ^{{02} {05} {23}}.

Auxiliary labeling:
   • Refrigerate.
   • Sterilize and discard reconstituted vaccine and container if not used within one hour ^{{02} {05} {23}}.

Developed: 11/22/1993

References

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2. YF-Vax package insert (Connaught Lab, Inc.—US), Rev 10/86, Rec 3/15/93.
   

3. The United States pharmacopeia. The national formulary. USP 22nd revision (January 1, 1990). NF 17th ed (January 1, 1990). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1990: 1461.
   

4. Osinusi K, Akinkugbe FM, Akinwolere OA, Fabiyi A. Safety and efficacy of yellow fever vaccine in children less than one-year-old. West Afr J of Med 1990; 9(3): 200-3.
   

5. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 27th ed. Ottawa: Canadian Pharmaceutical Association, 1992: 1388.
   

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9. Poland JD, Calisher CH, Monath TP, Downs WG, Murphy K. Persistence of neutralizing antibody 30-35 years after immunization with 17-D yellow fever vaccine. Bull WHO 1981; 59(6): 895-900.
   

10. Kaplan JE, Nelson DB, Schonberger LB, et al. The effect of immuneglobulin on the response to trivalent oral poliovirus and yellow fever vaccinations. Bull WHO 1984; 62(4): 585-90.
    

11. Health information for international travel. U.S. Dept. of Health and Human Services. Public Health Service June 1991: 76-7, 122-5.
    

12. Yellow Fever Vaccine. Recommendations of the Immunization Practice Advisory Committee (ACIP). Morb Mortal wkly Rep 1990 May 4; 39 RR 6: 1-6.
    

13. Yellow fever vaccine. Handbook of differential diagnosis. Roche Lab 1988; 6(15): 14.
    

14. Wilson JD, Braunwald E, Isselbacher KJ, et al. editors. Harrison's principles of internal medicine. 12th ed. New York: McGraw-Hill, Inc., 1991: 676, 725-39.
    

15. Benenson AS, editor. Control of communicable diseases in man. 15th ed. Washington: American Public Health Association, 1990: 486-90.
    

16. Scott, White. Immunologic interactions. Pharmacy and Therapeutics Newsletter 1990; 9(2): 4-5.
    

17. Abramowicz M, editor. Advice for travelers. Med Lett Drugs Ther May 1992; 34(869): 41-3.
    

18. Behrman RE, Vaughan VC III, editors. Nelson textbook of pediatrics. 13th ed. Philadelphia: W.B. Saunders Company, 1987: 505-6.
    

19. Gardner P, Schaffner W. Immunization of adults. New Engl J Med 1993; 328(17): 1252-8.
    

20. Berkow R, editor. The Merck manual of diagnosis and therapy. 16th ed. Rahway, NJ: Merck Research Laboratories, 1992: 304, 306-8.
    

21. Lichtenstein LM. Anaphylaxis. In: Wyngaarden JB, Smith, Jr LH, editors. Cecil's textbook of medicine. Philadelphia: WB Saunders Co, 1988: 1957.
    

22. Taketomo CK, Hodding JH, Kraus DM. Pediatric dosage handbook. Hudson: Lexi-Comp Inc., 1992: 179.
    

23. McEvoy GK, editor. AHFS Drug information 93. Bethesda, MD: American Society of Hospital Pharmacists, 1993: 2147-9.
    

24. Panel comment, 10/93.