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

Feb 26, 2024

Experts: 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, Simon Rothenfusser

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.
© 2024. The Author(s).

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ABOUT THE EXPERTS

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, Simon Rothenfusser

Antonio Santos-Peral

Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany.

Fabian Luppa

Division of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich, Munich, Germany.

Sebastian Goresch

Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany.

Elena Nikolova

Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany.

Magdalena Zaucha

Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany.

Lisa Lehmann

Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany.

Frank Dahlstroem

Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany.

Hadi Karimzadeh

Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany.

Department of Veterinary Sciences, LMU Munich, Munich, Germany.

Julia Thorn-Seshold

Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany.

Faculty of Chemistry and Pharmacy, LMU Munich, Munich, Germany.

Elena Winheim

Institute for Immunology, Biomedical Center (BMC), Medical Faculty, LMU Munich, Munich, Germany.

Ev-Marie Schuster

Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.

Gerhard Dobler

Bundeswehr Institute of Microbiology, Neuherbergstrasse 11, 80937, Munich, Germany.

Michael Hoelscher

Division of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich, Munich, Germany.

German Centre for Infection Research, Partner Site Munich, 80799, Munich, Germany.

Fraunhofer Institute for Translational Medicine and Pharmacology, Immunology, Infection and Pandemic Research, 80799, Munich, Germany.

Beate M Kümmerer

Institute of Virology, Medical Faculty, University of Bonn, 53127, Bonn, Germany.

German Centre for Infection Research, Partner Site Bonn-Cologne, 53127, Bonn, Germany.

Stefan Endres

Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany.

Einheit für Klinische Pharmakologie (EKLiP) Helmholtz Zentrum München German Research Center for Environmental Health (HMGU), Neuherberg, Germany.

Kilian Schober

Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.

FAU Profile Center Immunomedicine, FAU Erlangen-Nürnberg, Erlangen, Germany.

Anne B Krug

Institute for Immunology, Biomedical Center (BMC), Medical Faculty, LMU Munich, Munich, Germany.

Michael Pritsch

Division of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich, Munich, Germany.

Giovanna Barba-Spaeth

Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Unité de Virologie Structurale, Paris, France. giovanna.barba-spaeth@pasteur.fr.

Simon Rothenfusser

Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany. simon.rothenfusser@med.uni-muenchen.de.

Einheit für Klinische Pharmakologie (EKLiP) Helmholtz Zentrum München German Research Center for Environmental Health (HMGU), Neuherberg, Germany. simon.rothenfusser@med.uni-muenchen.de.