Analysis By Deep Sequencing of Discontinued Neurotropic Yellow Fever Vaccine Strains.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

High-Throughput Nucleotide Sequencing* ; Polymorphism, Genetic* ; Yellow Fever*/epidemiology ; Yellow Fever*/genetics ; Yellow Fever*/prevention & control; Yellow Fever Vaccine/*genetics ; Yellow fever virus/*genetics; Africa/epidemiology ; Animals ; Child ; Child, Preschool ; Encephalomyelitis, Acute Disseminated/epidemiology ; Encephalomyelitis, Acute Disseminated/genetics ; Humans ; Mice ; Sequence Analysis, DNA ; Viral Tropism/genetics ; Yellow Fever Vaccine/administration & dosage ; Yellow Fever Vaccine/adverse effects ; Yellow fever virus/pathogenicity

Deep sequencing of live-attenuated viral vaccines has focused on vaccines in current use. Here we report characterization of a discontinued live yellow fever (YF) vaccine associated with severe adverse events. The French neurotropic vaccine (FNV) strain of YF virus was derived empirically in 1930 by 260 passages of wild-type French viscerotropic virus (FVV) in mouse brain. The vaccine was administered extensively in French-speaking Africa until discontinuation in 1982, due to high rates of post-vaccination encephalitis in children. Using rare archive strains of FNV, viral RNAs were sequenced and analyzed by massively parallel, in silico methods. Diversity and specific population structures were compared in reference to the wild-type parental strain FVV, and between the vaccine strains themselves. Lower abundance of polymorphism content was observed for FNV strains relative to FVV. Although the vaccines were of lower diversity than FVV, heterogeneity between the vaccines was observed. Reversion to wild-type identity was variably observed in the FNV strains. Specific population structures were recovered from vaccines with neurotropic properties; loss of neurotropism in mice was associated with abundance of wild-type RNA populations. The analysis provides novel sequence evidence that FNV is genetically unstable, and that adaptation of FNV contributed to the neurotropic adverse phenotype.

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R21 AI113407 United States AI NIAID NIH HHS; T32 AI060549 United States AI NIAID NIH HHS

0 (Yellow Fever Vaccine)

Date Created: 20180909 Date Completed: 20191104 Latest Revision: 20240330

20250114

PMC6128858

10.1038/s41598-018-31085-2

30194325