Elderly Subjects Have a Delayed Antibody Response and Prolonged Viraemia following Yellow Fever Vaccination: A Prospective Controlled Cohort Study

Abstract

BackgroundYellow fever vaccination (YF-17D) can cause serious adverse events (SAEs). The mechanism of these SAEs is poorly understood. Older age has been identified as a risk factor. We tested the hypothesis that the humoral immune response to yellow fever vaccine develops more slowly in elderly than in younger subjects.MethodWe vaccinated young volunteers (18–28 yrs, N = 30) and elderly travelers (60–81 yrs, N = 28) with YF-17D and measured their neutralizing antibody titers and plasma YF-17D RNA copy numbers before vaccination and 3, 5, 10, 14 and 28 days after vaccination.ResultsTen days after vaccination seroprotection was attained by 77% (23/30) of the young participants and by 50% (14/28) of the elderly participants (p = 0.03). Accordingly, the Geometric Mean Titer of younger participants was higher than the GMT of the elderly participants. At day 10 the difference was +2.9 IU/ml (95% CI 1.8–4.7, p = 0.00004) and at day 14 +1.8 IU/ml (95% CI 1.1–2.9, p = 0.02, using a mixed linear model. Viraemia was more common in the elderly (86%, 24/28) than in the younger participants (60%, 14/30) (p = 0.03) with higher YF-17D RNA copy numbers in the elderly participants.ConclusionsWe found that elderly subjects had a delayed antibody response and higher viraemia levels after yellow fever primovaccination. We postulate that with older age, a weaker immune response to yellow fever vaccine allows the attenuated virus to cause higher viraemia levels which may increase the risk of developing SAEs. This may be one piece in the puzzle of the pathophysiology of YEL-AVD.Trial RegistrationTrialregitser.nl NTR1040

Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans

“…Several of our elderly vaccinees showed late serum viremia at days 7 or 10, confirming similar observations by Roukens et al (47). Late serum viremia has been furthermore reported in a 64-y-old vaccinee who experienced YF-SAE (48) and in aged mice after primary influenza virus infection (49).…”

Current status and future prospects of yellow fever vaccines

“…Similarly, widespread dissemination of genetically tagged 17D strains was observed in a mouse model lacking alpha/beta interferon receptors [66]. In a study comparing naive 17D recipients in young and elderly age groups, viremia in the older subjects was found to be relatively greater [67]. Mutations localized to CCR5/RANTES genes or their regulatory elements are associated with variable response to viral infection, and thus have been hypothesized to influence development of YEL-AVD, however the association of known alleles with the adverse syndrome is inconclusive [68].…”

Serious adverse events associated with yellow fever vaccine

“…[35][36] Moreover, the elderly may also have prolonged viremia after vaccination with YFV 17D virus. 37 So, it would be no surprise if some tissues also have RNA positivity for a long time after vaccination. The Brighton definition correctly requires that besides RNA positivity in tissues, there should be characteristic histopathology (eg, liver midzonal necrosis, Councilman bodies) for confirmation of YEL-AVD.…”