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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, <jats:italic>in silico<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41598-018-31085-2","type":"journal-article","created":{"date-parts":[[2018,9,3]],"date-time":"2018-09-03T09:48:28Z","timestamp":1535968108000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Analysis By Deep Sequencing of Discontinued Neurotropic Yellow Fever Vaccine Strains"],"prefix":"10.1038","volume":"8","author":[{"given":"Andrew S.","family":"Beck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven G.","family":"Widen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill K","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan D. T.","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,9,7]]},"reference":[{"key":"31085_CR1","doi-asserted-by":"crossref","unstructured":"Monath, T. P., Gershman, M., Staples, J. E. & Barrett, A. D. T. Yellow Fever Vaccine, in Vaccines, Plotkin, S., Orenstein, W., Offit, P., editors, Philadelphia, PA: Elsevier Inc., sixth edition (2013).","DOI":"10.1016\/B978-1-4557-0090-5.00043-4"},{"key":"31085_CR2","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1016\/j.mehy.2006.01.060","volume":"67","author":"JAS Quaresma","year":"2006","unstructured":"Quaresma, J. A. S., Duarte, M. I. S. & Vasconcelos, P. F. C. Midzonal lesions in yellow fever: A specific pattern of liver injury caused by direct virus action and in situ inflammatory response. Medical Hypotheses 67, 618\u2013621 (2006).","journal-title":"Medical Hypotheses"},{"key":"31085_CR3","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1084\/jem.65.6.767","volume":"65","author":"M Theiler","year":"1937","unstructured":"Theiler, M. & Smith, H. H. The Effect of Prolonged Cultivation in Vitro Upon the Pathogenicity of Yellow Fever Virus. The Journal of Experimental Medicine 65, 767\u2013786 (1937).","journal-title":"The Journal of Experimental Medicine"},{"key":"31085_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4269\/ajtmh.1933.s1-13.1","volume":"13","author":"W Lloyd","year":"1933","unstructured":"Lloyd, W. & Penna, H. A. Studies on the pathogenesis of neurotropic yellow fever virus in Macacus rhesus. The American Journal of Tropical Medicine and Hygiene 13, 1\u201345 (1933).","journal-title":"The American Journal of Tropical Medicine and Hygiene"},{"key":"31085_CR5","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1084\/jem.56.6.853","volume":"56","author":"NC Davis","year":"1932","unstructured":"Davis, N. C., Lloyd, W. & Frobisher, M. The Transmission of Neurotropic Yellow Fever Virus by Stegomyia Mosquitoes. The Journal of Experimental Medicine 56, 853\u2013865 (1932).","journal-title":"The Journal of Experimental Medicine"},{"key":"31085_CR6","unstructured":"Durieux, C. Preparation of yellow fever vaccine at the Institut Pasteur, Dakar. World Health Organization, Yellow Fever Vaccination Monograph Series 31\u201332 (1956)."},{"key":"31085_CR7","unstructured":"Stuart, G. The Problem of Mass Vaccination Against Yellow Fever. World Health Organization, Expert Committee on Yellow Fever, Technical Report WHO\/YF\/20 (1953)."},{"key":"31085_CR8","unstructured":"Durieux, C. Mass yellow fever vaccination in French Africa South of the Sahara. World Health Organization, Yellow Fever Vaccination Monograph Series 115\u2013121 (1956)."},{"key":"31085_CR9","unstructured":"Vainio, J. & Cutts, F. Yellow Fever. World Health Organization, Technical Report WHO\/EPI\/GEN\/98.1 (1998)."},{"key":"31085_CR10","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1126\/science.71.1840.367","volume":"71","author":"M Theiler","year":"1930","unstructured":"Theiler, M. Susceptibility of White Mice to the Virus of Yellow Fever. Science (New York, N.Y.) 71, 367 (1930).","journal-title":"Science (New York, N.Y.)"},{"key":"31085_CR11","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1080\/00034983.1931.11684668","volume":"25","author":"M Theiler","year":"1931","unstructured":"Theiler, M. Neutralization tests with immune yellow fever sera and a strain of yellow fever virus adapted to mice. Annals of Tropical Medicine and Parasitology 25, 69\u201377 (1931).","journal-title":"Annals of Tropical Medicine and Parasitology"},{"key":"31085_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1099\/0022-1317-46-1-1","volume":"46","author":"R Fitzgeorge","year":"1980","unstructured":"Fitzgeorge, R. & Bradish, C. J. The in vivo differentiation of strains of yellow fever virus in mice. The Journal of General Virology 46, 1\u201313 (1980).","journal-title":"The Journal of General Virology"},{"key":"31085_CR13","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1099\/0022-1317-67-4-631","volume":"67","author":"ADT Barrett","year":"1986","unstructured":"Barrett, A. D. T. & Gould, E. A. Comparison of Neurovirulence of Different Strains of Yellow Fever Virus in Mice. The Journal of General Virology 67, 631\u2013637 (1986).","journal-title":"The Journal of General Virology"},{"key":"31085_CR14","unstructured":"World Health Organization. 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