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 Africa2 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.3-8
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®. The seroconversion rate was 81% in one study involving 32 subjects and 97% to 100% in the other four studies. 11-15
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 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®. 21
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