Vaccine Information: YF-VAX

YF-VAX- yellow fever virus strain 17d-204 live antigen injection, powder, lyophilized, for suspension
DILUENT- sodium chloride injection
Sanofi Pasteur Inc.

AHFS Category: 80:12Rx only

Yellow Fever Vaccine

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. Each vial of vaccine is supplied with a separate vial of sterile diluent, which contains Sodium Chloride Injection USP – without a preservative. YF-VAX 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. Before reconstitution, YF-VAX is a pinkish color. After reconstitution, YF-VAX is a slight pink-brown suspension.

The vial stoppers for YF-VAX and diluent are not made with natural rubber latex.

CLINICAL PHARMACOLOGY

Yellow fever is an acute viral illness caused by a mosquito-borne flavivirus. Most yellow fever virus infections are asymptomatic. In those individuals who develop disease, the clinical spectrum ranges from nonspecific flu-like illness with fever, malaise, prostration, headache, photophobia, generalized arthralgia and myalgia, nausea, and/or vomiting to potentially lethal pansystemic disease, most prominently involving the liver, kidneys, GI tract, and brain, with recrudescing fever, jaundice, renal failure, severe hemorrhage due to thrombocytopenia, and shock. (1) The case-fatality rate of yellow fever varies widely in different studies but is typically 20% or higher. Jaundice or other gross evidence of severe liver disease is associated with higher mortality rates.

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. Vaccination with 17D strain vaccines 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. (2) 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. (3)

In 24 uncontrolled studies conducted world-wide between 1962 and 1997 evaluating neutralizing antibody responses to 17D vaccines among 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. The seroconversion rate was 81% in one study involving 32 subjects and 97% to 100% in the other four studies. (1) (4) (5) (6) (7)

In 2001, YF-VAX 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 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 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 associated with differences in 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. (8)

For most healthy individuals, a single dose of yellow fever vaccine provides long-lasting protection. (9) (10) In controlled studies where the immune response to vaccination was evaluated, the small percentage of immunologically normal individuals who failed to develop an immune response to an initial vaccination typically did so upon re-vaccination. (11)

In two separate clinical trials of 17D-204 vaccines, 90% of subjects seroconverted within 10 days after vaccination, (12) and 100% of subjects seroconverted within 14 days. (1) Thus, International Health regulations stipulate that the vaccination certificate for yellow fever is valid 10 days after administration of YF-VAX. (13)

YF-VAX Indications and Usage

YF-VAX is indicated for active immunization for the prevention of yellow fever in 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, behaviors and seasonal incidence of disease make it difficult to predict the actual risk for a given individual living in or traveling to a known endemic or epidemic area. Greater risk is associated with living in or traveling to areas of South America and Africa where yellow fever infection is officially reported at the time of travel and with traveling outside the urban areas of countries that do not officially report the disease but that lie in a yellow fever endemic zone.

Persons Traveling Internationally Through Countries with Yellow Fever

Some countries require an individual to have a valid International Certificate of Vaccination or Prophylaxis (ICVP) 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. (13) (14)

Laboratory Personnel

Laboratory personnel who handle virulent yellow fever virus or concentrated preparations of the yellow fever vaccine virus strains may be at risk of exposure by direct or indirect contact or by aerosols. (14)

CONTRAINDICATIONS

Hypersensitivity

YF-VAX is contraindicated in anyone with a history of acute hypersensitivity reaction to any component of the vaccine. (See DESCRIPTION section.) Because the yellow fever virus used in the production of this vaccine is propagated in chicken embryos, do not administer YF-VAX to anyone with a history of acute hypersensitivity to eggs or egg products due to a risk of anaphylaxis. 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, Testing for Hypersensitivity Reactions subsection.) Generally, persons who are able to eat eggs or egg products may receive the vaccine. (14) (15)

Individuals Less Than 9 Months of Age

Vaccination with YF-VAX is contraindicated in infants less than 9 months of age due to an increased risk of encephalitis.

Vaccination with YF-VAX is also contraindicated in lactating women who are providing breastmilk to infants less than 9 months of age due to the potential for transmission of vaccine virus in breastmilk. (See PRECAUTIONS section, Nursing Mothers subsection.)

Immunosuppressed Individuals

Vaccination with YF-VAX, a live virus vaccine, is contraindicated in individuals with severe immunosuppression, including for example, those with acquired immunodeficiency syndrome, leukemia, lymphoma, thymic disease, generalized malignancy, and patients who are undergoing drug therapy (e.g., systemic corticosteroids, alkylating drugs, antimetabolites or other immunomodulatory drugs) or radiation therapy. Thymic disorders associated with abnormal immune cell function (e.g., myasthenia gravis, thymoma) may be an independent risk factor for the development of yellow fever vaccine-associated viscerotropic disease. (See WARNINGS section.) (16)

Do not administer YF-VAX to individuals with severe immunosuppression.

Family members of immunosuppressed persons, who themselves have no contraindications, may receive YF-VAX. (14) (17)

WARNINGS

Severe Allergic Reactions

Severe allergic reactions (e.g., anaphylaxis) may occur following the use of YF-VAX, even in individuals with no prior history of hypersensitivity to the vaccine components. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

Yellow fever vaccine-associated viscerotropic disease

Age greater than 60 years is a risk factor for yellow fever vaccine-associated viscerotropic disease (YEL-AVD) (14) which may present as non-specific multi-organ system failure or can be similar to fulminant yellow fever caused by wild-type yellow fever virus, with liver failure and internal bleeding, leading to death. (See ADVERSE REACTIONS section.) Available evidence suggests that the occurrence of this syndrome may depend upon undefined host factors, rather than intrinsic virulence of the yellow fever strain 17D vaccine, based on characterization of vaccine viruses isolated from individuals with YEL-AVD. YEL-AVD has been reported to occur only after the first dose of yellow fever vaccine; there have been no reports of YEL-AVD following booster dose. (17) The decision to vaccinate individuals 60 years of age and older needs to weigh the risks and benefits of vaccination and the risk for exposure to yellow fever virus. (18) (19) (20) (21)

Yellow fever vaccine-associated neurotropic disease

Age greater than 60 years and immunosuppression are risk factors for post-vaccinal encephalitis, also known as yellow fever vaccine-associated neurotropic disease (YEL-AND). (See ADVERSE REACTIONS section.) Almost all cases of YEL-AND have been in first-time vaccine recipients. (17) The decision to vaccinate individuals 60 years of age and older and immunosuppressed individuals needs to weigh the risks and benefits of vaccination and the risk for exposure to yellow fever virus.

PRECAUTIONS

General

Vaccination with YF-VAX may not protect 100% of individuals.

Do not administer YF-VAX by intravascular, intramuscular, or intradermal routes.

Use a separate, sterile syringe and needle for each patient to prevent transmission of blood borne infectious agents. Do not recap needles. Dispose of needles and syringes according to biohazard waste guidelines.

Testing for Hypersensitivity Reactions

Do not administer YF-VAX to an individual with a history of hypersensitivity to egg or chicken protein. (See CONTRAINDICATIONS section.) However, if an individual is suspected of being an egg-sensitive individual, the following test can be performed before the vaccine is administered:

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