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 (yellow fever vaccine) 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 (yellow fever vaccine) 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 (yellow fever vaccine) 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)
Vaccine-associated neurotropic disease (2), previously described as post-vaccinal encephalitis (1), 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 vaccine-associated 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 1000, 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 Senegal (42) 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)
Vaccine-associated viscerotropic disease, previously described as multiple organ system failure (26), 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 (yellow fever vaccine) 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 (yellow fever vaccine) 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 disease (2) 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 YF-VAX (yellow fever vaccine) 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.
Safety of YF-VAX (yellow fever vaccine) 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.
Read the Yf-Vax (yellow fever vaccine) Side Effects Center for a complete guide to possible side effects »
Data are limited in regard to the interaction of YF-VAX (yellow fever vaccine) 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)
Patients on Corticosteroid Therapy
Oral Prednisone or other systemic corticosteroid therapy may have an immunosuppressive effect on recipients of yellow fever vaccine that potentially decreases immunogenicity and increases the risk of adverse events (see CONTRAINDICATIONS section). Intra-articular, bursal, or tendon injections with Prednisone or other corticosteroids should not constitute an increased hazard to recipients of yellow fever vaccine.
Patients with Asymptomatic HIV Infection
Subjects with asymptomatic HIV infection who have had recent laboratory verification of adequate immune system function and who cannot avoid potential exposure to yellow fever virus should be offered the choice of vaccination. Vaccinees should be monitored for possible adverse effects. The seroconversion rate to 17D vaccines is likely to be reduced in these patients. (17) Therefore, documentation of a protective antibody response is recommended before travel. (See CLINICAL PHARMACOLOGY section.) For discussion of this subject and for documentation of the immune response to vaccine where it is deemed essential, the CDC may be contacted 1-970-221-6400.
1. Monath TP. Yellow Fever. Plotkin SA, Orenstein WA (eds.). Vaccines. 3rd Edition, WB Saunders Company. 1999;815-879.
2. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Yellow Fever Vaccine. 2002. MMWR 2002;51(RR17):1-10.
12. Dukes C, et al. Safety and Immunogenicity of Simultaneous Administration of Typhim Vi (TV), YF-VAX (yellow fever vaccine) (YV), and Menomune (MV). [abstract]. American Society for Microbiology. The 36th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): 1996; September 15-18:159.
17. Goujon C, et al. Good Tolerance and Efficacy of Yellow Fever Vaccine Among Subjects Carriers of Human Immunodeficiency Virus. Fourth International Conference on Travel Medicine; Acapulco, Mexico 1995; April:23-27;32:63.
18. Nasidi A, et al. Yellow fever vaccination and pregnancy: a four-year prospective study. Transactions of the Royal Society of Tropical Medicine and Hygiene 1993;87:337-339.
24. Sanofi Pasteur Inc. Data on File œ 080601;120104.
33. Ruben FL, et al. Simultaneous administration of smallpox, measles, yellow fever, and diphtheria-pertussistetanus antigens to Nigerian children. Bull WHO 1973;48:175-181.
34 Dumas R, et al. Safety and immunogenicity of a new inactivated hepatitis A vaccine and concurrent administration with a typhoid fever vaccine or a typhoid fever + yellow fever vaccine. Adv Therapy 1997;14:160-167.
35. Coursaget P, et al. Simultaneous injection of plasma-derived or recombinant hepatitis B vaccines with yellow fever and killed polio vaccines. Vaccine 1995;13:109-111.
36. Kaplan JE, et al. The effect of immune globulin on the response to trivalent oral poliovirus and yellow fever vaccinations. Bull WHO 1984;62(4):585-590.
37. Tsai TF, et al. Chloroquine does not adversely affect the antibody response to yellow fever vaccine. J Infect Dis 1986;154(4):726-727.
16. Monath TP, et al. Comparative safety and immunogenicity of two yellow fever 17D vaccines (ARILVAX and YF-VAX (yellow fever vaccine) ) in a Phase III multicenter, double-blind clinical trial. Am J Trop Med Hyg 66(5)2002;533-541.
18. Nasidi A, et al. Yellow fever vaccination and pregnancy: a four-year prospective study. Transactions of the Royal Society of Tropical Medicine and Hygiene 1993;87:337-339.
26. Martin M, et al. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases. Lancet 2001;358:98-104.
27. Galler R, et al. Phenotypic and molecular analyses of yellow fever 17DD vaccine viruses associated with serious adverse events in Brazil. Virology 2001;290:309-319.
28. Chan RC, et al.Hepatitis and death following vaccination with yellow fever 17D-204 vaccine. Lancet 2001;358:121-122.
29. Vasconcelos PFC, et al. Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. Lancet 2001;358:91-97.
30. CDC. Vaccine Adverse Event Reporting System - United States. MMWR 1990;39:730-733.
38. Martin M, et al. Advanced age a risk factor for illness temporally associated with yellow fever vaccination. Emerg Infect Dis 2001;7:945-951.
39. Jennings AD, et al. Analysis of a yellow fever virus isolated from a fatal case of vaccine-associated human encephalitis. J Infect Dis 1994;169:512-518.
40. Stuart G. Reactions following vaccination against yellow fever. In Smithburn KC, Durieux C, Koerber R, et al (eds.). Yellow Fever Vaccination. Geneva, WHO 1956;143-189.
41. Louis JJ, et al. A case of encephalitis after 17D strain yellow fever vaccination. Pediatr 1981;36(7):547-550.
42. Rey M, et al. Epidemiological and clinical aspects of encephalitis following yellow fever vaccination. Bull Soc Méd Afr Noire Lgue fr 1966;v XI,(3),560-574.
43. Sanofi Pasteur Inc. Data on File - 080207.
44. Tsai TF, et al. Congenital yellow fever virus infection after immunization in pregnancy. J Infect Dis 1993;168:1520-1523.
45. Nishioka SA, et al. Yellow fever vaccination during pregnancy and spontaneous abortion: a case-control study. Trop Med Int Health 1998;3(1):29-33.
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