Abstract
ABSTRACT By infecting mice with the yellow fever virus vaccine strain 17D (YFV-17D; Stamaril®), the dose dependence and evolutionary consequences of neurotropic yellow fever infection was assessed. Highly susceptible AG129 mice were used to allow for a maximal/unlimited expansion of the viral populations. Infected mice uniformly developed neurotropic disease; the virus was isolated from their brains, plaque purified and sequenced. Viral RNA populations were overall rather homogenous [Shannon entropies 0−0.15]. The remaining, yet limited intra-host population diversity (0−11 nucleotide exchanges per genome) appeared to be a consequence of pre-existing clonal heterogeneities (quasispecies) of Stamaril®. In parallel, mice were infected with a molecular clone of YFV-17D which was in vivo launched from a plasmid. Such plasmid-launched YFV-17D had a further reduced and almost clonal evolution. The limited intra-host evolution during unrestricted expansion in a highly susceptible host is relevant for vaccine and drug development against flaviviruses in general. Firstly, a propensity for limited evolution even upon infection with a (very) low inoculum suggests that fractional dosing as implemented in current YF-outbreak control may pose only a limited risk of reversion to pathogenic vaccine-derived virus variants. Secondly, it also largely lowers the chance of antigenic drift and development of resistance to antivirals.
Highlights
Yellow fever (YF) is an acute haemorrhagic disease caused by the yellow fever virus (YFV), an enveloped, positive-sense RNA virus that belongs to the genus Flavivirus
To investigate the evolution of yellow fever virus 17D (YFV-17D) and plasmidlaunched YFV-17D in mice, six to eight weeks old AG129 mice were inoculated intraperitoneally with either 10−2, 10−1 or 104 plaque-forming unit (PFU) (> 105 CCID50) of YFV-17D, or with 20 μg of the Plasmid-Launched Live-Attenuated Virus Vaccine (PLLAV)-YFV-17D plasmid (n = 2, 1, 3, and 7, respectively); infectious titres and viral RNA loads in mouse brains at the time point of euthanasia were determined by plaque assay and qRT-PCR, respectively (Supplementary Figure S1)
73 full virus genomes from the brains of six mice that had been inoculated with YFV-17D were analysed, each comprising in total 10862 nucleotides and collectively resulting in the identification of 46 distinct nucleotide changes as compared to the consensus sequence of Stamaril® that had been used as the virus inoculum (Supplementary Table S4)
Summary
Yellow fever (YF) is an acute haemorrhagic disease caused by the yellow fever virus (YFV), an enveloped, positive-sense RNA virus that belongs to the genus Flavivirus. Other clinically important flaviviruses include the dengue (DENV), Zika (ZIKV), West Nile (WNV), tick-borne encephalitis (TBEV) and Japanese encephalitis (JEV) viruses. Their genome encodes for a single polyprotein that is co- and post-translationally processed into 3 structural proteins and 7 non-structural proteins (NS1-5), the latter responsible for intracellular replication of the viral RNA genome. The live-attenuated YFV-17D is considered as one of the most efficient vaccines ever developed with long immunogenicity [10, 11] It induces a vigorous, multi-specific and possibly lifelong lasting protective immunity in >95% of the vaccinees within 10 days after vaccination [12,13]
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