Florian Bakoa1,2,3,4, Christophe Préhaud1, Guillaume Beauclair4,5, Maxime Chazal4, Nathalie Mantel2, Monique Lafon6, Nolwenn Jouvenet7. 1. Unité de Neuroimmunologie Virale, Institut Pasteur, Paris, France. 2. Research and External Innovation Department, Sanofi Pasteur, Marcy L'Etoile, France. 3. Sorbonne Université, Collège doctoral, Paris, France. 4. Unité de Signalisation Antivirale, CNRS UMR 3569, Institut Pasteur, Paris, France. 5. Institut de Biologie Intégrative de la Cellule, UMR9198, Équipe Autophagie et Immunité Antivirale, Faculté de Pharmacie, Châtenay-Malabry, France. 6. Unité de Neuroimmunologie Virale, Institut Pasteur, Paris, France. monique.lafon@pasteur.fr. 7. Unité de Signalisation Antivirale, CNRS UMR 3569, Institut Pasteur, Paris, France. nolwenn.jouvenet@pasteur.fr.
Abstract
Mass vaccination with the live attenuated vaccine YF-17D is the current way to prevent infection with Yellow fever virus (YFV). However, 0.000012-0.00002% of vaccinated patients develop post-vaccination neurological syndrome (YEL-AND). Understanding the factors responsible for neuroinvasion, neurotropism, and neurovirulence of the vaccine is critical for improving its biosafety. The YF-FNV vaccine strain, known to be associated with a higher frequency of YEL-AND (0.3-0.4%) than YF-17D, is an excellent model to study vaccine neuroinvasiveness. We determined that neuroinvasiveness of YF-FNV occured both via infection and passage through human brain endothelial cells. Plaque purification and next generation sequencing (NGS) identified several neuroinvasive variants. Their neuroinvasiveness was not higher than that of YF-FNV. However, rebuilding the YF-FNV population diversity from a set of isolated YF-FNV-N variants restored the original neuroinvasive phenotype of YF-FNV. Therefore, we conclude that viral population diversity is a critical factor for YFV vaccine neuroinvasiveness.
Mass vaccinationpan> with the live attenuated vaccinpan>e n class="Chemical">YF-17D is the current way to prevent infection with Yellow fever virus (YFV). However, 0.000012-0.00002% of vaccinated patients develop post-vaccination neurological syndrome (YEL-AND). Understanding the factors responsible for neuroinvasion, neurotropism, and neurovirulence of the vaccine is critical for improving its biosafety. The YF-FNV vaccine strain, known to be associated with a higher frequency of YEL-AND (0.3-0.4%) than YF-17D, is an excellent model to study vaccine neuroinvasiveness. We determined that neuroinvasiveness of YF-FNV occured both via infection and passage through human brain endothelial cells. Plaque purification and next generation sequencing (NGS) identified several neuroinvasive variants. Their neuroinvasiveness was not higher than that of YF-FNV. However, rebuilding the YF-FNV population diversity from a set of isolated YF-FNV-N variants restored the original neuroinvasive phenotype of YF-FNV. Therefore, we conclude that viral population diversity is a critical factor for YFV vaccine neuroinvasiveness.
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