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Limited evolution of the yellow fever virus 17d in a mouse infection model

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journal contribution
posted on 2019-12-04, 11:17 authored by Dieudonné Buh Kum, Niraj Mishra, Bram Vrancken, Hendrik Jan Thibaut, Annelies Wilder-Smith, Philippe Lemey, Johan Neyts, Kai Dallmeier

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.

Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 733176 (RABYD-VAX consortium), No 734584 (ZikaPLAN) and No 734548 (ZIKAlliance). B.V. was supported by a postdoctoral grant of the FWO (Fonds Wetenschappelijk Onderzoek Vlaanderen).

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