17D Yellow Fever Virus Vaccine

Dear Sir: In a recent article, Edupuganti and others reported a clinical study of co-administration of subcutaneous yellow fever (YF) 17D vaccine (YF-VAX Ò ; Sanofi Pasteur, Lyon, France) and intramuscular immune serum globulin (ISG) (amaSTAN S/D Ò ; Talecris Biotherapeutics, Research Triangle Park, NC) or saline placebo. 1 The study was designed to test whether co-administration of vaccine and ISG containing YF anti-bodies would reduce replication (viremia) of the live 17D vaccine. The rationale for the study was the hypothesis that administration of ISG containing YF-neutralizing antibodies to travelers for hepatitis A prophylaxis might have attenuated YF vaccine–associated viscerotropic adverse events; these events emerged as ISG was replaced by hepatitis A vaccine in 1996. In a previous study published in 1984, lots of ISG contained high titers of YF neutralizing antibodies, and co-administration with vaccine had no effect on immunoge-nicity; however viremia measurements were not evaluated. 2 The current study was statistically powered and many parameters were investigated, including viremia, antibody response, T cell activation, and cytokine responses to YF vaccine. No differences were observed between groups receiving ISG or placebo in the incidence, time-course, or magnitude of viremia measured by quantitative polymerase chain reaction. More importantly, viremia was also assessed by infectivity (plaque) assay; no differences were reported across groups, although only the proportions positive (and not titers of virus or area under the curve) were reported. The authors concluded that cessation of globulin prophylaxis was not responsible for increased reporting of YF vaccine– associated viscerotropic adverse events. This conclusion is complicated by several problems with the design and conduct of the study, none of which, unfortunately, are discussed by the authors. The ISG was administered at the recommended dose for hepatitis A prophylaxis (0.06 mL/kg). However, the lot used had a low titer (1:20–1:40) of YF-neutralizing antibody determined by a 90% plaque-reduction neutralization assay. The passive titers of neutralizing anti-body after administration to the volunteers were not determined , but even assuming 100% distribution to a 5-liter blood volume, would be undetectable (< 1:1). As the authors note, passive titers ³ 1:20 are required for protection against wild-type YF virus infection, 3 although the level of antibody needed to abrogate infection with attenuated 17D virus is unknown. In the previous study published in 1984, 2 we found that contemporary lots of ISG contained much higher titers of YF antibody (1:320–³ 1:640) by the same 90% plaque-reduction neutralization …