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Adverse reactions to 17D yellow fever vaccine include mild headaches, myalgia, low-grade fevers, or other minor symptoms for 5 to 10 days. Local reactions including edema, hypersensitivity, pain or mass at the injection site have also been reported following yellow fever vaccine administration. Immediate hypersensitivity reactions, characterized by rash, urticaria, and/or asthma, are uncommon and occur principally among persons with histories of egg allergy.1,2,24

No placebo-controlled trials to assess the safety of yellow fever 17D vaccines have been performed. However, between 1953 and 1994, reactogenicity of 17D-204 vaccine was monitored in 10 uncontrolled clinical trials. The trials included a total of 3,933 adults and 264 infants greater than 4 months old residing in Europe or in yellow fever endemic areas. Self-limited and mild local reactions consisting of erythema and pain at the injection site and systemic reactions consisting of headache and/or fever occurred in a minority of subjects (typically less than 5%) 5 to 7 days after immunization. In one study involving 115 infants age 4 to 24 months the incidence of fever was as high as 21%. Also in this study, reactogenicity of the vaccine was markedly reduced among a subset of subjects who had serological evidence of previous exposure to yellow fever virus. Only two of the ten studies provided diary cards for daily reporting; this method resulted in a slightly higher incidence of local and systemic complaints.1

In 2001, YF-VAX vaccine was used as a control in a double-blind, randomized comparative 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. Safety data were collected by diary card for days 1 through 10 after vaccination and by interview on days 5, 11, and 31. Among subjects who received YF-VAX vaccine, there were no serious adverse events, and 71.9% experienced non-serious adverse events judged to have been related to vaccination. Most of these were injection site reactions of mild to moderate severity. Four such local reactions were considered severe. Rash occurred in 3.2% and urticaria in two subjects. Systemic reactions (headache, myalgia, malaise, and asthenia) were usually mild and occurred in 10% to 30% of subjects during the first few days after vaccination. The incidence of non-serious adverse reactions, including headache, malaise, injection site edema, and pain, was significantly lower in subjects > 60 years compared to younger subjects. Adverse events were less frequent in the 1.7% of vaccinated subjects who had pre-existing immunity to yellow fever virus, compared to those who had not been previously exposed.16

A CDC analysis of data submitted to the Vaccine Adverse Events Reporting System (VAERS) between 1990 and 1998 suggests that patients aged 65 or older are at increased risk for systemic adverse events temporally associated with vaccination, compared to the 25- to 44-year-old age group (see PRECAUTIONS section, Geriatric Use subsection). The rate of systemic adverse events occurring post-vaccination in patients age 65 to 74 was 2.5 times higher than the rate occurring in patients age 25 to 44, based on incidence rates of 6.21 and 2.49 per 100,000 doses of vaccine in the two groups, respectively.38

Neurotropic Disease

Vaccine-associated neurotropic disease2, previously described as post-vaccinal encephalitis1, is a known rare serious adverse event associated with 17D vaccination. Age less than 9 months and immunosuppression are known risk factors. Twenty-one cases of vaccine-associated neurotropic disease associated with all licensed 17D vaccines have been reported between 1952 and 2004, 18 in children or adolescents. Fifteen of these cases occurred prior to 1960, thirteen of which occurred in infants 4 months of age or younger, and two of which occurred in infants six and seven months old. Six cases were reported between 1960 and 1996, world-wide. Three occurred in children, including a one-month-old infant, a three-year-old, and a thirteen-year-old. The three-year-old died of encephalitis, and a genetic variant of the vaccine virus was isolated from the brain in this case.39 This is the only verified fatality due to yellow fever vaccineassociated neurotropic disease. The three remaining cases of vaccine-associated neurotropic disease since 1960 occurred in adults.1

The incidence of vaccine-associated neurotropic disease in infants less than 4 months old is estimated to be between 0.5 and 4 per 1,000, based on two historical reports where denominators are available.40,41 No data are available for calculation of an age-specific incidence rate in the 4- to 9-month-age group. A study in Senegal42 described two fatal cases of encephalitis possibly associated with 17D-204 vaccination among 67,325 children between the ages of 6 months and 2 years, for an incidence rate of 3 per 100,000. One study conducted in Kenya in 1993 detected four cases of encephalitis temporally associated with vaccination, one in a 2-year-old child and three in adults, for an incidence of 5.3 cases per million vaccinees of all ages.1

Other very rare neurological signs and symptoms have been reported and include Guillain-Barre syndrome, seizures and focal neurological deficits.43

Viscerotropic Disease

Vaccine-associated viscerotropic disease, previously described as multiple organ system failure26, is a known rare serious adverse event associated with 17D vaccination. No cause and effect relationship has been established between vaccination and these subsequent illnesses. Physicians should therefore be cautious to administer yellow fever vaccine only to those persons truly at risk of exposure to wild-type yellow fever virus infection.2

Between 1996 and 1998, four patients, ages 63, 67, 76, and 79, became severely ill 2 to 5 days after vaccination with YF-VAX vaccine. Three of these 4 subjects died. The clinical presentations were characterized by a non-specific febrile syndrome with fatigue, myalgia, and headache, rapidly progressing to a severe illness including respiratory failure, elevated hepatocellular enzymes, lymphocytopenia and thrombocytopenia, hyperbilirubinemia, and renal failure requiring hemodialysis.26 None of these subjects had vaccine-associated neurotropic disease. In two cases where vaccine virus was recovered from serum, limited nucleotide sequence analysis of the viral genome suggested that the isolates had not undergone a mutation associated with an increase in virulence. The incidence rate for these serious adverse events was estimated at 1 per 400,000 doses of YF-VAX vaccine, based on the total number of doses administered in the US civilian population during the surveillance period.

Vaccine-associated viscerotropic disease temporally associated with yellow fever vaccination has also been reported in Australia and Brazil. One Australian citizen became ill after receiving an immunization with the 17D-204 strain of yellow fever vaccine in his home country,28 and two Brazilian citizens (age 5 and 22 years) became ill three to four days after receiving 17DD vaccine in Brazil.29 In the Brazilian and Australian cases, histopathologic changes in the liver included midzonal necrosis, microvesicular fatty change, and Councilman bodies, which are characteristic of wild-type yellow fever. Vaccine-type yellow fever virus was isolated from blood and autopsy material (ie, brain, liver, kidney, spleen, lung, skeletal muscle, or skin) of each of these three persons, all of whom died 8 to 11 days after vaccination. In Brazil, an estimated 23 million vaccine doses were administered during the 15-month period during which the two cases of multiple organ system failure were reported.29

In view of the data cited above, both the 17D-204 and 17DD yellow fever vaccines may be considered as a possible, but rare, cause of vaccine-associated viscerotropic disease2 that is similar to fulminant yellow fever caused by wild-type yellow fever virus. All available evidence from complete nucleotide sequence analysis and testing in experimental animals of vaccine-type yellow fever viruses isolated from the Brazilian subjects suggests that the occurrences are due to undefined host factors, rather than to intrinsic virulence of the 17DD vaccine viruses.27

Because of a lack of tissue specimens from most of the US cases of vaccine-associated viscerotropic disease and the qualitative differences between the US cases and those identified in Brazil and Australia, no definitive support for a causal relationship exists between receipt of YFVAX vaccine and vaccine-associated viscerotropic disease. However, the temporal association with recent receipt of yellow fever vaccine and the similarity of the clinical presentations among all four US cases suggest that the vaccine may play a role in pathogenesis of the cases.

Pregnancy

Safety of YF-VAX vaccine was evaluated in a study involving 101 Nigerian women, the majority of whom (88%) were in the third trimester of pregnancy. In this study, it appeared that vaccinating pregnant women with the 17D-204 strain of yellow fever vaccine was not associated with adverse events affecting the mother or fetus. There were no adverse events among 40 infants who were carefully followed up for one year after birth, and none of these infants tested positive for IgM antibodies as a criterion for transplacental infection. However, the percentage of pregnant women who seroconverted was significantly reduced compared to a non-pregnant control group (38.6% vs. 81.5%).18

Following a mass immunization campaign in Trinidad, during which 100 to 200 pregnant females were immunized, no adverse events related to pregnancy were reported. In addition, 41 cord blood samples were obtained from infants born to mothers immunized during the first trimester. One of these infants tested positive for IgM antibodies in cord blood. The infant appeared normal at delivery and no subsequent adverse sequelae of infection were reported. However, this result suggests that transplacental infection with 17D vaccine viruses can occur.44

A recent case-control study of spontaneous abortion following vaccination of Brazilian women found no significant difference in the odds ratio among vaccinated women compared to a similar unvaccinated group.45

Reporting Of Adverse Events

The US Department of Health and Human Services has established the Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine. Reporting of all adverse events occurring after vaccine administration is encouraged from vaccine recipients, parents/guardians and the health care provider. Adverse events following immunization should be reported to VAERS. Reporting forms and information about reporting requirements or completion of the form can be obtained from VAERS through a toll-free number 1-800-822-7967.30 Reporting forms may also be obtained at the FDA web site at http://vaers.hhs.gov.

Health-care providers also should report these events to Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 or call 1-800-822-2463.