May 30, 2017
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Yellow Fever Vaccine

"Last February, the World Health Organization declared a public health emergency over concerns about very serious birth defects in Brazil and their possible link to Zika virus. But even before then, concerns about the unprecedented spread of Zika "...




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 promintently 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)


1 Monath TP et al. Yellow fever vaccine. In: Plotkin SA, Orenstein WA and Offit PA, eds. Vaccines. 6th Ed. Elsevier Saunders Inc. 2013:870-968.

2 Mason RA, et al. Yellow fever vaccine: Direct challenge of monkeys given graded doses of 17D vaccine. Appl Microbiol 1973;25(4):539-44.

3 Recommendations to assure the quality, safety and efficacy of live attenuated yellow fever vaccines. WHO Technical Report Series. 2013;978:264.

4 Wisseman CL, et al. Immunological studies with Group B arthropod-borne viruses. Am J Trop Med Hyg 1962;11:550-61.

5 Dukes C, et al. Safety and Immunogenicity of Simultaneous Administration of Typhim Vi (TV), YF-VAX (YV), and Menomune (MV). [abstract]. American Society for Microbiology. The 36th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): 1996; September 15-18:159.

6 Meyer HM, et al. Response of Volta children to jet inoculation of combined live measles, smallpox, and yellow fever vaccines. Bull World Health Org 1964;30:783-94.

7 Jackson J, et al. Comparison of Antibody Response and Patient Tolerance of Yellow Fever Vaccine Administered by the Bioject Needle-Free Injection System versus Conventional Needle/Syringe Injection. Third International Conference on Travel Medicine; Paris 1993;April:25-29;264:209.

8 Monath TP, et al. Comparative safety and immunogenicity of two yellow fever 17D vaccines (ARILVAX and YF-VAX) in a Phase III multicenter, double-blind clinical trial. Am J Trop Med Hyg 66(5)2002;533-41.

9 World Health Organization (WHO). Yellow fever vaccine - position paper. Wkly Epid Rec 2003;40(78):349-60.

10 Staples JE et al. Yellow Fever Vaccine Booster Doses: Recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR 2015;64(23):647-50.

11 Bonnevie-Nielson V, et al. Lymphocytic 2',5' - Oligoadenylate synthetase activity increases prior to the appearance of neutralizing antibodies and Immunoglobulin M and Immunoglobulin G antibodies after primary and secondary immunization with yellow fever vaccine. Clin Diag Lab Immunol 1995;2:302-6.

12 Smithburn KC, et al. Immunization against yellow fever: Studies on the time of development and the duration of induced immunity. Am J Trop Med Page 7 of 8 Hyg 1945;45:217-23.

13 World Health Organization (WHO). International Health Regulations (2005) (2nd edition). Geneva 2008:54-5.

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