Abstract. Yellow fever (YF) is a significant health problem in South America and Africa. Travelers to these areas require immunization. The United States, infested with Aedes aegypti mosquitoes, is at risk of introduction of this disease. There is only a single U.S. manufacturer of YF 17D vaccine, and supplies may be insufficient in an emergency. A randomized, double-blind outpatient study was conducted in 1,440 healthy individuals, half of whom received the U.S. vaccine (YF-VAX) and half the vaccine manufactured in the United Kingdom (ARILVAX). A randomly selected subset of approximately 310 individuals in each treatment group was tested for YF neutralizing antibodies 30 days after vaccination. The primary efficacy endpoint was the proportion of individuals who developed a log neutralization index (LNI) of 0.7 or higher. Seroconversion occurred in 98.6% of individuals in the ARILVAX group and 99.3% of those in the YF-VAX group. Statistically, ARILVAX was equivalent to YF-VAX (P ‫ס‬ .001). Both vaccines elicited mean antibody responses well above the minimal level (LNI 0.7) protective against wild-type YF virus. The mean LNI in the YF-VAX group was higher (2.21) than in the ARILVAX group (2.06; P ‫ס‬ .010) possibly because of the higher dose contained in YF-VAX. Male gender, Caucasian race, and smoking were associated with higher antibody responses. Both vaccines were well tolerated. Overall, the treatment groups were comparable with respect to safety except that individuals in the ARILVAX group experienced significantly less edema, inflammation, and pain at the injection site than those in the YF-VAX group. No serious adverse events were attributable to either vaccine. YF-VAX participants (71.9%) experienced one or more nonserious adverse events than ARILVAX individuals (65.3%; P ‫ס‬ .008). The difference was due to a higher rate of injection site reactions in the YF-VAX group. Mild systemic reactions (headache, myalgia, malaise, asthenia) occurred in roughly 10% to 30% of participants during the first few days after vaccination, with no significant difference across treatment groups. Adverse events were less frequent in individuals with preexisting immunity to YF, indicating a relationship to virus replication.

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The incidence of serious and severe multisystem adverse events (AEs) following yellow fever (YF) 17D vaccine is higher in persons of advanced age. One hypothesis for the occurrence of these AEs in the elderly is immunological senescence and a reduced ability to clear the vaccine virus infection. We determined age-specific rates of serious and nonserious AEs in two large clinical trials of two YF 17D vaccines from different manufacturers. In addition, we analyzed AEs reported in a large general practice data base in the United Kingdom. Neutralizing antibody responses were compared in young and elderly subjects. In the clinical trials, involving a total of 4,532 subjects, there were no neurological and viscerotropic AEs; interestingly, the incidence of common injection site and systemic AEs was significantly lower in elderly than in younger subjects. The neutralizing antibody categorical and quantitative responses were equivalent across younger and elderly subjects. In contrast, the larger retrospective analysis of 43,555 persons receiving YF 17D in the UK general practice database revealed a higher incidence of significant neurologic and multisystem AEs with advancing age. The age-specific reporting rate ratio (RRR) was approximately twice that in the 25-44 year-old reference group for subjects in the 45-64 year age group (RRR 1.82; 95% CI 0.88,3.77) and 3-fold higher for the 65-74 year-old age group (RRR 2.82; 95% CI 0.81, 9.81). These results are consistent with previous reports on YF vaccine safety in the US (Martin M, et al. Emerg Infect Dis 2001;6:945-51; Khromova et al., Vaccine 2005;23:3256-63). In elderly persons, YF 17D vaccine is associated with a higher frequency of significant AEs in the elderly but a lower incidence of common nonserious side-effects. The neutralizing antibody response, which is the mediator of protective immunity to YF, is not diminished in healthy, elderly persons.

In A-HeFT, patients with lower SBP had a greater risk but a similar relative benefit from the use of FDC I/H as those with higher SBP. The FDC I/H treatment did not reduce SBP in patients with low SBP. An asymptomatic low SBP should not be considered a contraindication to use of FDC I/H in patients with HF.

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