1. Prior flavivirus immunity skews the yellow fever vaccine response to expand cross-reactive antibodies with increased risk of antibody dependent enhancement of Zika and dengue virus infection
- Author
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Antonio Santos-Peral, Fabian Luppa, Sebastian Goresch, Elena Nikolova, Magdalena Zaucha, Lisa Lehmann, Frank Dahlstroem, Hadi Karimzadeh, Beate M Kummerer, Julia Thorn-Seshold, Elena Winheim, Gerhard Dobler, Michael Hoelscher, Stefan Endres, Anne B Krug, Michael Pritsch, Giovanna Barba-Spaeth, Simon Rothenfusser, Ludwig-Maximilians-Universität München (LMU), Rheinische Friedrich-Wilhelms-Universität Bonn, German Centre for Infection Research (DZIF), Bundeswehr Institute of Microbiology, Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Helmholtz Zentrum München (HMGU), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was supported by FlavImmunity a combined grant of the German Research foundation (DFG) project number 391217598 to SR and ABK and the French National Research Agency (ANR) project number ANR-17-CE15-0031-01 to GBS, by DFG TRR237 grant project number 369799452 to SR and ABK (TRR237 TPB14) and BMK (TRR237 TPA04), by grants of the iMed consortium of the German Helmholtz Societies to SR, by the Einheit für Klinische Pharmakologie (EKLIP), Helmholtz Zentrum München, Neuherberg, Germany to SR and SE, a Stipend (TI 07.003) by the German Center for Infection Research (DZIF) to FL, grants by the Friedrich Baur Foundation (FBS) to JTS, HK and MP, a Metiphys fellowship of the Medical Faculty of the LMU Munich to MP, by the FöFoLe Program of the Medical Faculty of the LMU Munich to SG, EN, LL, FL, the international doctoral program 'iTarget: Immunotargeting of cancer'funded by the Elite Network of Bavaria to ASP, MZ, SG, LL, EN., and ANR-17-CE15-0031,FLAVIMMUNITY,Comprendre les mécanismes de l'efficacité du vaccin de la fièvre jaune 17D: Une approche immuno-structurelle vers la conception d'un vaccin Pan-flavivirus(2017)
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vaccine immunogenicity ,immunodominance ,cross-reactivity ,[SDV]Life Sciences [q-bio] ,pre-existing flavivirus immunity ,yellow fever virus - Abstract
Human pathogenic flaviviruses pose a significant health concern and vaccination is the most effective instrument to control their circulation. How pre-existing immunity to antigenically related viruses modulates immunization outcome remains poorly understood. In this study, we evaluated the effect of vaccination against tick-borne encephalitis virus (TBEV) on the epitope immunodominance and immunogenicity of the yellow fever 17D vaccine (YF17D) in a cohort of 250 human vaccinees.Following YF17D vaccination, all study participants seroconverted and generated protective neutralizing antibody titers. At day 28, TBEV pre-immunity did not affect the polyclonal neutralizing response which largely depended on the IgM fraction. We found that sera from TBEV-immunized individuals enhanced YF17D vaccine virus infection via antibody-dependent enhancement (ADE). Upon vaccination, individuals with TBEV pre-immunity had higher concentrations of cross-reactive IgG antibodies with limited neutralizing capacity against YF17D whereas vaccinees without prior flavivirus exposure showed a non-cross-reacting response. Using a set of recombinant YF17D envelope protein mutants displaying different epitopes, we identified quaternary epitopes as the primary target of neutralizing antibodies. Sequential immunizations redirected the IgG response towards the pan-flavivirus fusion loop epitope (FLE) with the potential to mediate enhancement of dengue and Zika virus infections whereas TBEV naïve individuals elicited an IgG response directed towards neutralizing epitopes without an enhancing effect.We propose that the YF17D vaccine effectively conceals the FLE and primes a neutralizing IgG response in individuals with no prior flavivirus exposure. In contrast, the response in TBEV-experienced recipients favors weakly-neutralizing, cross-reactive epitopes potentially increasing the risk of severe dengue and Zika disease due to ADE.
- Published
- 2023