Yellow fever, live attenuated

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. 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.