YFV strains are variably neurotropic when directly introduced to central nervous tissues of mice, a property that is exploited in lethality and serological protection assays 10, 11, 12, 13. Reference material for FNV is of very limited availability, and passage histories are not generally accessible. Mechanisms of neutrotropism for YFV vaccines are poorly understood, and information on the FNV is particularly obscure. However, FNV was noted for unacceptable rates of post-vaccinal encephalitis in children, constituting a rationale for restricting administration of the vaccine to those above 10 years of age in 1960, and later discontinuance of the vaccine in 1982 due to the availability of the safer 17D strain (which is routinely given to those aged 9 months and older 9. Deployment of the FNV is credited as a key intervention in the suppression of YF disease in French West Africa between 19, with over 84 million doses distributed during that time 6, 8. Commercial lots were administered between passages 250 through 260, relative to the parental strain 6. FNV was administered by scarification from a reconstitution of infected and desiccated mouse brain, and possessed desirable properties of thermostability and high immunogenicity 6, 7. FVV was serially passaged 128 times in mouse brain the resultant strain was attenuated with respect to both viscerotropism and vector competence however, neurotropic properties were enhanced 4, 5, 6. The vaccine was produced from a wild-type parental strain known as the French viscerotropic virus (FVV), isolated in 1927 from the Lebanese patient Françoise Mayali. Concurrent efforts by the Institut Pasteur (Dakar, Senegal) produced the French neurotropic vaccine (FNV), which was administered extensively in French-speaking Africa starting in 1940. The vaccine strain 17D was developed by passage of wild-type strain Asibi in mouse and chicken tissue in 1936 by the Rockefeller Foundation (New York, USA) derivatives of this strain remain in production today and are administered by the subcutaneous route 3. The vaccines arose from separately isolated parental strains, and distinct attenuating subculture methods. YFV was a considerable obstruction to economic development until the empiric derivation of two live-attenuated vaccine strains in the early twentieth century. Wild-type disease manifestations of YFV infection are viscerotropic, referring to tropism of the virus to the liver and resultant hepatocyte injury, associated with characteristic jaundice and hemorrhage in advanced cases 2. YFV is the prototype member of the family Flaviviridae with a positive-sense RNA genome of 10.8 kb, which is translated as a single open reading frame upon host infection 1. Of particular significance to the study of live-attenuated vaccines are those administered to prevent infection by yellow fever virus (YFV), which are among the oldest live attenuated vaccines. Phenotypic adaptation of viruses arising from serial culture in cell culture or animals is ubiquitous, and constitutes the fundamental property of empirical derivation for live- attenuated vaccines. The analysis provides novel sequence evidence that FNV is genetically unstable, and that adaptation of FNV contributed to the neurotropic adverse phenotype. Specific population structures were recovered from vaccines with neurotropic properties loss of neurotropism in mice was associated with abundance of wild-type RNA populations. Reversion to wild-type identity was variably observed in the FNV strains. Although the vaccines were of lower diversity than FVV, heterogeneity between the vaccines was observed. Lower abundance of polymorphism content was observed for FNV strains relative to FVV. Diversity and specific population structures were compared in reference to the wild-type parental strain FVV, and between the vaccine strains themselves. Using rare archive strains of FNV, viral RNAs were sequenced and analyzed by massively parallel, in silico methods. The vaccine was administered extensively in French-speaking Africa until discontinuation in 1982, due to high rates of post-vaccination encephalitis in children. 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. Here we report characterization of a discontinued live yellow fever (YF) vaccine associated with severe adverse events. Deep sequencing of live-attenuated viral vaccines has focused on vaccines in current use.
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