Vaccine-associated enhanced respiratory pathology in COVID-19 hamsters after TH2-biased immunization

Aileen Ebenig; Samada Muraleedharan; Julia Kazmierski; Daniel Todt; Arne Auste; Martina Anzaghe; André Gömer; Dylan Postmus; Patricia Gogesch; Marc Niles; Roland Plesker; Csaba Miskey; Michelle Gellhorn Serra; Angele Breithaupt; Cindy Hörner; Carina Kruip; Rosina Ehmann; Zoltan Ivics; Zoe Waibler; Stephanie Pfaender; Emanuel Wyler; Markus Landthaler; Alexandra Kupke; Geraldine Nouailles; Christine Goffinet; Richard J P Brown; Michael D Mühlebach

doi:10.1016/j.celrep.2022.111214

Vaccine-associated enhanced respiratory pathology in COVID-19 hamsters after T_H2-biased immunization

Cell Rep. 2022 Aug 16;40(7):111214. doi: 10.1016/j.celrep.2022.111214. Epub 2022 Aug 3.

Authors

Aileen Ebenig¹, Samada Muraleedharan¹, Julia Kazmierski², Daniel Todt³, Arne Auste⁴, Martina Anzaghe⁵, André Gömer⁶, Dylan Postmus², Patricia Gogesch⁵, Marc Niles⁵, Roland Plesker⁷, Csaba Miskey⁸, Michelle Gellhorn Serra⁹, Angele Breithaupt¹⁰, Cindy Hörner⁴, Carina Kruip¹, Rosina Ehmann¹¹, Zoltan Ivics⁸, Zoe Waibler⁵, Stephanie Pfaender¹², Emanuel Wyler¹³, Markus Landthaler¹⁴, Alexandra Kupke¹⁵, Geraldine Nouailles¹⁶, Christine Goffinet², Richard J P Brown¹⁷, Michael D Mühlebach¹⁸

Affiliations

¹ Product Testing of IVMPs, Div. of Veterinary Medicines, Paul-Ehrlich-Institut, 63225 Langen, Germany.
² Institute of Virology, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany.
³ Department for Molecular and Medical Virology, Ruhr-University, 44801 Bochum, Germany; European Virus Bioinformatics Center (EVBC), 07743 Jena, Germany.
⁴ Product Testing of IVMPs, Div. of Veterinary Medicines, Paul-Ehrlich-Institut, 63225 Langen, Germany; German Center for Infection Research, Gießen-Marburg-Langen, Germany.
⁵ Div. of Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany.
⁶ Department for Molecular and Medical Virology, Ruhr-University, 44801 Bochum, Germany; Institute of Virology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
⁷ Animal Facilities, Div. Veterinary Medicines, Paul-Ehrlich-Institut, 63225 Langen, Germany.
⁸ Div. of Medical Biotechnology, Paul-Ehrlich-Institut, 63225 Langen, Germany.
⁹ Institute for Virology, Phillipps-University, 35043 Marburg, Germany.
¹⁰ Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 17493 Greifswald-Insel Riems, Germany.
¹¹ Institute for Microbiology, Bundeswehr, 80937 München, Germany.
¹² Department for Molecular and Medical Virology, Ruhr-University, 44801 Bochum, Germany.
¹³ Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany.
¹⁴ Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany; IRI Life Sciences, Institute for Biology, Humboldt-Universität zu Berlin, 10115 Berlin, Germany.
¹⁵ German Center for Infection Research, Gießen-Marburg-Langen, Germany; Institute for Virology, Phillipps-University, 35043 Marburg, Germany.
¹⁶ Division of Pulmonary Inflammation, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany.
¹⁷ Virus Tropism and Immunogenicity, Div. of Veterinary Medicine, Paul-Ehrlich-Institut, 63225 Langen, Germany.
¹⁸ Product Testing of IVMPs, Div. of Veterinary Medicines, Paul-Ehrlich-Institut, 63225 Langen, Germany; German Center for Infection Research, Gießen-Marburg-Langen, Germany. Electronic address: michael.muehlebach@pei.de.

Abstract

Vaccine-associated enhanced respiratory disease (VAERD) is a severe complication for some respiratory infections. To investigate the potential for VAERD induction in coronavirus disease 2019 (COVID-19), we evaluate two vaccine leads utilizing a severe hamster infection model: a T helper type 1 (T_H1)-biased measles vaccine-derived candidate and a T_H2-biased alum-adjuvanted, non-stabilized spike protein. The measles virus (MeV)-derived vaccine protects the animals, but the protein lead induces VAERD, which can be alleviated by dexamethasone treatment. Bulk transcriptomic analysis reveals that our protein vaccine prepares enhanced host gene dysregulation in the lung, exclusively up-regulating mRNAs encoding the eosinophil attractant CCL-11, T_H2-driving interleukin (IL)-19, or T_H2 cytokines IL-4, IL-5, and IL-13. Single-cell RNA sequencing (scRNA-seq) identifies lung macrophages or lymphoid cells as sources, respectively. Our findings imply that VAERD is caused by the concerted action of hyperstimulated macrophages and T_H2 cytokine-secreting lymphoid cells and potentially links VAERD to antibody-dependent enhancement (ADE). In summary, we identify the cytokine drivers and cellular contributors that mediate VAERD after T_H2-biased vaccination.

Keywords: ADE; COVID-19 vaccines; CP: Immunology; CP: Microbiology; TH2 immune responses; VAERD; antibody-dependent enhancement; dexamethasone treatment; mechanism of immunopathogenesis; protein vaccines; vaccine safety; vaccine-associated enhanced respiratory disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Viral
COVID-19*
Cricetinae
Cytokines / metabolism
Immunization
Lung / pathology
Mice
Mice, Inbred BALB C
Th1 Cells
Th2 Cells
Vaccination
Vaccines*

Substances

Antibodies, Viral
Cytokines
Vaccines