Prior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection

Antonio Santos-Peral, Fabian Luppa, Sebastian Goresch, Elena Nikolova, Magdalena Zaucha, Lisa Lehmann, Frank Dahlstroem, Hadi Karimzadeh, Julia Thorn-Seshold, Elena Winheim, Ev-Marie Schuster, Gerhard Dobler, Michael Hoelscher, Beate M. Kümmerer, Stefan Endres, Kilian Schober, Anne B. Krug, Michael Pritsch, Giovanna Barba-Spaeth () and Simon Rothenfusser ()
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Antonio Santos-Peral: LMU University Hospital, LMU Munich
Fabian Luppa: LMU University Hospital, LMU Munich
Sebastian Goresch: LMU University Hospital, LMU Munich
Elena Nikolova: LMU University Hospital, LMU Munich
Magdalena Zaucha: LMU University Hospital, LMU Munich
Lisa Lehmann: LMU University Hospital, LMU Munich
Frank Dahlstroem: LMU University Hospital, LMU Munich
Hadi Karimzadeh: LMU University Hospital, LMU Munich
Julia Thorn-Seshold: LMU University Hospital, LMU Munich
Elena Winheim: Medical Faculty, LMU Munich
Ev-Marie Schuster: Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg
Gerhard Dobler: Bundeswehr Institute of Microbiology
Michael Hoelscher: LMU University Hospital, LMU Munich
Beate M. Kümmerer: University of Bonn
Stefan Endres: LMU University Hospital, LMU Munich
Kilian Schober: Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg
Anne B. Krug: Medical Faculty, LMU Munich
Michael Pritsch: LMU University Hospital, LMU Munich
Giovanna Barba-Spaeth: Université Paris Cité, CNRS UMR 3569, Unité de Virologie Structurale
Simon Rothenfusser: LMU University Hospital, LMU Munich

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The yellow fever 17D vaccine (YF17D) is highly effective but is frequently administered to individuals with pre-existing cross-reactive immunity, potentially impacting their immune responses. Here, we investigate the impact of pre-existing flavivirus immunity induced by the tick-borne encephalitis virus (TBEV) vaccine on the response to YF17D vaccination in 250 individuals up to 28 days post-vaccination (pv) and 22 individuals sampled one-year pv. Our findings indicate that previous TBEV vaccination does not affect the early IgM-driven neutralizing response to YF17D. However, pre-vaccination sera enhance YF17D virus infection in vitro via antibody-dependent enhancement (ADE). Following YF17D vaccination, TBEV-pre-vaccinated individuals develop high amounts of cross-reactive IgG antibodies with poor neutralizing capacity. In contrast, TBEV-unvaccinated individuals elicit a non-cross-reacting neutralizing response. Using YF17D envelope protein mutants displaying different epitopes, we identify quaternary dimeric epitopes as the primary target of neutralizing antibodies. Additionally, TBEV-pre-vaccination skews the IgG response towards the pan-flavivirus fusion loop epitope (FLE), capable of mediating ADE of dengue and Zika virus infections in vitro. Together, we propose that YF17D vaccination conceals the FLE in individuals without prior flavivirus exposure but favors a cross-reactive IgG response in TBEV-pre-vaccinated recipients directed to the FLE with potential to enhance dengue virus infection.

Date: 2024
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DOI: 10.1038/s41467-024-45806-x

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