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YF-VAX — yellow fever virus live antigen, a
Sanofi Pasteur Inc.

AHFS Category 80:12

Rx only

DESCRIPTION

YF-VAX®, Yellow Fever Vaccine, for subcutaneous use, is prepared by culturing the 17D-204 strain of yellow fever virus in living avian leukosis virus-free (ALV-free) chicken embryos. The vaccine contains sorbitol and gelatin as a stabilizer, is lyophilized, and is hermetically sealed under nitrogen. No preservative is added. The vaccine must be reconstituted immediately before use with the sterile diluent provided (Sodium Chloride Injection USP – contains no preservative). YF-VAX vaccine is formulated to contain not less than 4.74 log₁₀ plaque forming units (PFU) per 0.5 mL dose throughout the life of the product. YF-VAX vaccine is a slight pink-brown suspension after reconstitution.

CLINICAL PHARMACOLOGY

Yellow fever is an acute viral illness caused by a mosquito-borne flavivirus. The clinical spectrum of yellow fever is highly variable, from subclinical infection to overwhelming pansystemic disease. Yellow fever has an abrupt onset after an incubation period of 3 to 6 days, and usually includes fever, prostration, headache, photophobia, lumbosacral pain, extremity pain (especially the knee joints), epigastric pain, anorexia, and vomiting. The illness may progress to liver and renal failure, and hemorrhagic symptoms and signs caused by thrombocytopenia and abnormal clotting and coagulation may occur. The case-fatality rate of yellow fever varies widely in different studies and may be different for Africa compared to South America, but is typically 20% or higher. Jaundice or other gross evidence of severe liver disease is associated with higher mortality rates. (1)

Two live, attenuated yellow fever vaccines, strains 17D-204 and 17DD, were derived in parallel in the 1930s. Historical data suggest that these “17D vaccines” have identical safety and immunogenicity profiles. Despite a marked reduction in the world-wide incidence of yellow fever in the last five decades due to the extensive use of 17D vaccines and mosquito eradication programs, at least seven tropical South American countries (Bolivia, Brazil, Colombia, Ecuador, French Guiana, Peru, and Venezuela) and much of sub-Saharan Africa (2) currently experience yellow fever epidemics. However, the actual areas of yellow fever virus activity far exceed the infected zones officially reported for epidemics. Approximately 200,000 yellow fever cases have been reported to occur world-wide each year. Six fatalities from yellow fever were reported between 1996 and July 2002, among unimmunized American and European travelers who visited rural areas within the yellow fever endemic zone. (3) (4) (5) (6) (7) (8)

Vaccination with 17D strain viruses is predicted to elicit an immune response identical in quality to that induced by wild-type infection. This response is presumed to result from initial infection of cells in the dermis or other subcutaneous tissues near the injection site, with subsequent replication and limited spread of virus leading to the processing and presentation of viral antigens to the immune system, as would occur during infection with wild-type yellow fever virus. The humoral immune response to the viral structural proteins, as opposed to a cell-mediated response, is most important in the protective effect induced by 17D vaccines. Yellow fever antibodies with specificities that prevent or abort infection of cells are detected as neutralizing antibodies in assays that measure the ability of serum to reduce plaque formation in tissue culture cells. The titer of virus neutralizing antibodies in sera of vaccinees is a surrogate for efficacy. A log₁₀ neutralization index (LNI, measured by a plaque reduction assay) of 0.7 or greater was shown to protect 90% of monkeys from lethal intracerebral challenge. (9) This is the definition of seroconversion adopted for clinical trials of yellow fever vaccine. The standard has also been adopted by the World Health Organization (WHO) for efficacy of yellow fever vaccines in humans. (10)

The neutralizing antibody response to 17D vaccines has been evaluated in several uncontrolled studies since the late 1930s. In 24 studies conducted world-wide between 1962 and 1997 using 17D vaccines involving a total of 2,529 adults and 991 infants and children, the seroconversion rate was greater than 91% in all but two studies and never lower than 81%. There were no significant age-related differences in immunogenicity. (1)

Five of these 24 studies were conducted in the US between 1962 and 1993 and included 208 adults who received YF-VAX vaccine. The seroconversion rate was 81% in one study involving 32 subjects and 97% to 100% in the other four studies. (11) (12) (13) (14) (15)

In 2001, YF-VAX vaccine was used as a control in a double-blind, randomized comparison trial with another 17D-204 vaccine, conducted at nine centers in the US. YF-VAX vaccine was administered to 725 adults ≥18 years old with a mean age of 38 years. Three hundred twelve of these subjects who received YF-VAX vaccine were evaluated serologically, and 99.3% of them seroconverted with a mean LNI of 2.21. The LNI was slightly higher among males compared to females and slightly lower among Hispanic and African-American subjects compared to others, but these differences were not significant with respect to the protective effect of the vaccine. There was no difference in mean LNI for subjects <40 years old compared to subjects ≥40 years old. Due to the small number of subjects (1.7%) with prior flavivirus immunity, it was not possible to draw conclusions about the role of this factor in the immune response. (16)

Results of one clinical trial involving 33 HIV-positive adults residing in the US indicate that the seroconversion rate to 17D-204 vaccine may be reduced in these patients. (17)

In pregnancy or in immunosuppressed individuals the seroconversion rate after administration of yellow fever vaccine may be significantly reduced. (18)

Existing data suggest that the small percentage of immunologically normal subjects who fail to develop an immune response to an initial vaccination may do so upon re-vaccination. (19)

In two separate clinical trials of 17D-204 vaccines, 90% of subjects seroconverted within 10 days after vaccination, (20) and 100% of subjects seroconverted within 14 days. (11) Thus, International Health regulations stipulate that the vaccination certificate for yellow fever is valid 10 days after administration of YF-VAX vaccine. (21)

YF-VAX Indications and Usage

YF-VAX vaccine is recommended for active immunization of persons 9 months of age and older in the following categories:

Persons Living in or Traveling to Endemic Areas

While the actual risk for contracting yellow fever during travel is probably low, variability of itineraries and behaviors and the seasonal incidence of disease make it difficult to predict the actual risk for a given individual traveling to a known endemic or epidemic area. Persons greater than or equal to 9 months of age traveling to or living in areas of South America and Africa where yellow fever infection is officially reported at the time of travel should be vaccinated. Vaccination is also recommended for travel outside the urban areas of countries that do not officially report the disease but that lie in a yellow fever endemic zone.

International Travel

Yellow fever vaccination may be required for international travel. Some countries in Africa require evidence of vaccination from all entering travelers and some countries may waive the requirements for travelers staying less than 2 weeks that are coming from areas where there is no current evidence of significant risk for contracting yellow fever. Some countries require an individual, even if only in transit, to have a valid International Certificate of Vaccination if the individual has been in countries either known or thought to harbor yellow fever virus. The certificate becomes valid 10 days after vaccination with YF-VAX vaccine. (2) (21)

In no instance should infants less than 9 months of age receive yellow fever vaccine, because of the risk of encephalitis (see CONTRAINDICATIONS and ADVERSE REACTIONS sections).

Laboratory Personnel

Those laboratory personnel who might be exposed to virulent yellow fever virus or to concentrated preparations of the yellow fever vaccine strain by direct or indirect contact or by aerosols should be vaccinated. (2)

As with any vaccine, vaccination with YF-VAX vaccine may not protect 100% of individuals (see CLINICAL PHARMACOLOGY section).

For concomitant administration with other vaccines see PRECAUTIONS section, Drug Interactions subsection.

CONTRAINDICATIONS

Hypersensitivity

YF-VAX vaccine is contraindicated in anyone with a history of acute hypersensitivity reaction to any components (including gelatin). (22) Because the yellow fever virus used in the production of this vaccine is propagated in chicken embryos, YF-VAX vaccine should not be administered to anyone with a history of acute hypersensitivity to eggs or egg products; anaphylaxis may occur. Less severe or localized manifestations of allergy to eggs or to feathers are not contraindications to vaccine administration and do not usually warrant vaccine skin testing (see PRECAUTIONS section, Hypersensitivity Reactions subsection). Generally, persons who are able to eat eggs or egg products may receive the vaccine. (2) (23)

Acute or Febrile Disease

Vaccination should be postponed in case of an acute or febrile disease; a disease with low-grade fever is usually not a reason to postpone vaccination.

Infants

Vaccination of infants less than 9 months of age IS CONTRAINDICATED because of the risk of encephalitis, and travel of such persons to rural areas in yellow fever endemic zones or to countries experiencing an epidemic should be postponed or avoided, whenever possible.

Immunosuppressed Patients

Exposure to yellow fever vaccine, which is a live virus vaccine, poses a risk of encephalitis or other serious adverse events to patients with illnesses that commonly result in immunosuppression (eg, acquired immunodeficiency syndrome or other manifestations of human immunodeficiency virus (HIV) infection, leukemia, lymphoma, thymic disease, generalized malignancy), or patients whose immunologic responses are suppressed by drug therapy (eg, corticosteroids, alkylating drugs, or antimetabolites) or radiation. There is evidence suggesting that thymic dysfunction is an independent risk factor for the development of yellow fever vaccine-associated viscerotropic disease, and health care providers should be careful to ask about a history of thymus disorder, including myasthenia gravis, thymoma or prior thymectomy. (24)

Immunosuppressed subjects should not be immunized, and travel to yellow fever endemic areas should be postponed or avoided. If travel to a yellow fever-infected zone is unavoidable, immunosuppressed patients should be advised of the risk, instructed in methods for avoiding vector mosquitoes, and supplied with vaccination waiver letters by their physicians (see ADVERSE REACTIONS section). Family members of immunosuppressed persons, who themselves have no contraindications, may receive yellow fever vaccine. (2) (25)

Lactation

Lactation: (See PRECAUTIONS section, Nursing Mothers subsection.)

WARNINGS

The stopper of the vial contains dry natural latex rubber that may cause allergic reactions.

Anaphylaxis may occur following the use of YF-VAX vaccine, even in individuals with no prior history of hypersensitivity to the vaccine components.

EPINEPHRINE INJECTION (1:1000) SHOULD ALWAYS BE IMMEDIATELY AVAILABLE IN CASE OF AN UNEXPECTED ANAPHYLACTIC OR OTHER SERIOUS ALLERGIC REACTION.

Yellow fever vaccines must be considered as a possible, but rare, cause of vaccine-associated viscerotropic disease (2) (previously described as multiple organ system failure), (2) (26) that is similar to fulminant yellow fever caused by wild-type yellow fever virus. Available evidence suggests that the occurrence of this syndrome may depend upon the presence of undefined host factors, rather than intrinsic virulence of the yellow fever strain 17D vaccine viruses isolated from subjects with vaccine-associated viscerotropic disease. (26) (27) (28) (29) (See ADVERSE REACTIONS section.)

Vaccine-associated neurotropic disease (2), previously described as post-vaccinal encephalitis (1), is a known rare adverse event associated with yellow fever vaccination. Age less than 9 months and immunosuppression are known risk factors for this adverse event. (See CONTRAINDICATIONS and ADVERSE REACTIONS sections.)

PRECAUTIONS

General

Prior to an injection of any vaccine, all known precautions should be taken to prevent adverse events. The patient’s previous immunization history, current health status, and medical history should be reviewed for previous hypersensitivity reactions and other adverse events related to this vaccine or similar vaccines and for possible sensitivity to dry natural latex rubber. The stopper of the vial contains dry natural latex rubber that may cause allergic reactions. In some instances where symptoms appear soon after a vaccine is administered, differentiation between allergic reaction to the vaccine and reaction to an environmental allergen may not be possible. (23)

EPINEPHRINE INJECTION (1:1000) SHOULD ALWAYS BE IMMEDIATELY AVAILABLE IN CASE OF AN UNEXPECTED ANAPHYLACTIC OR OTHER SERIOUS ALLERGIC REACTION.

A separate, sterile syringe and needle or a sterile disposable unit should be used for each patient to prevent transmission of blood borne infectious agents. Needles should not be recapped and should be disposed of according to biohazard waste guidelines.

Hypersensitivity Reactions

YF-VAX vaccine should not be administered to an individual with a history of hypersensitivity to egg or chicken protein (see CONTRAINDICATIONS section). However, if a subject is suspect as being an egg-sensitive individual, the following test can be performed before the vaccine is administered: (23)

1.

Scratch, prick, or puncture test: Place a drop of a 1:10 dilution of the vaccine in physiologic saline on a superficial scratch, prick, or puncture on the volar surface of the forearm. Positive (histamine) and negative (physiologic saline) controls should also be used. The test is read after 15 to 20 minutes. A positive test is a wheal 3 mm larger than that of the saline control, usually with surrounding erythema. The histamine control must be positive for valid interpretation. If the result of this test is negative, an intradermal (ID) test should be performed.

2.

Intradermal test: Inject a dose of 0.02 mL of a 1:100 dilution of the vaccine in physiologic saline. Positive and negative control skin tests should be performed concurrently. A wheal 5 mm or larger than the negative control with surrounding erythema is considered a positive reaction.

If vaccination is considered essential, despite a positive skin test, then desensitization can be considered (see DOSAGE AND ADMINISTRATION section, Desensitization subsection).

Information for Patients

Prior to administration of YF-VAX vaccine, potential vaccinees or their parents or guardians should be asked about their recent health status. All potential vaccinees or their parents or guardians should be fully informed of the benefits and risks of immunization and potential for adverse events that have been temporally associated with YF-VAX vaccine administration. Vaccinees or their parents or guardians should be instructed to report all serious adverse events that occur up to 30 days post-vaccination to their health-care provider.

All travelers should seek information regarding vaccination requirements by consulting local health departments, the Centers for Disease Control and Prevention (CDC), and WHO. Travel agencies, international airlines, and/or shipping lines may also have up-to-date information. Such requirements may be strictly enforced, particularly for persons traveling from Africa or South America to Asia. Travelers should consult the latest published version of Health Information for International Travel to determine requirements and regulations for vaccination. (25)

An International Certificate of Vaccination should be completed, signed, and validated with the center’s stamp where the vaccine is administered and provided to all vaccinees. The immunization record should contain the date, lot number and manufacturer of the vaccine administered. (30) (31) (32) Subjects should be told that US vaccination certificates are valid for a period of 10 years commencing 10 days after initial vaccination or revaccination.

Drug Interactions

Data are limited in regard to the interaction of YF-VAX vaccine with other vaccines.

• Measles (Schwartz strain) vaccine, diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP), (33) Hepatitis A and Hepatitis B vaccines, (2) (12) (34) (35) meningococcal vaccine, Menomune® – A/C/Y/W-135, and typhoid vaccine, Typhim Vi®, (2) (12) (34) have been administered with yellow fever vaccine at separate injection sites.
• No data exist on possible interference between yellow fever and rabies or Japanese encephalitis vaccines. (2)
• In a prospective study, persons given 5 cc of commercially available immune globulin did not experience alterations in immunologic responses to the yellow fever vaccine. (2) (36)
• The anti-malarial drug chloroquine has been administered with yellow fever vaccine. (2) (37)