Repertoire characterization and validation of gB-specific human IgGs directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV

Sebastian J. Theobald (1, 2) , Christoph Kreer (3, 4) , Sahamoddin Khailaie (5) , Agnes Bonifacius (1) , Britta Eiz-Vesper (1) , Constanca Figueiredo (1) , Michael Mach (6) , Marija Backovic (7) , Matthias Ballmaier (1) , Johannes Koenig (1, 2) , Henning Olbrich (1, 2) , Andreas Schneider (1, 2) , Valery Volk (1, 2) , Simon Danisch (1, 2) , Lutz Gieselmann (3, 4, 8) , Meryem Seda Ercanoglu (3, 4) , Martin Messerle (2, 1) , Constantin Von Kaisenberg (1) , Torsten Witte (1) , Frank Klawonn (5, 9) , Michael Meyer-Hermann (5, 10, 1) , Florian Klein (3, 4, 8) , Renata Stripecke (1, 2)

1 MHH - Medizinische Hochschule Hannover = Hannover Medical School
2 DZIF - German Center for Infection Research - partner site Hannover-Braunschweig
3 University of Cologne
4 University Hospital of Cologne [Cologne]
5 HZI - Helmholtz Centre for Infection Research
6 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
7 Virologie Structurale - Structural Virology
8 DZIF - German Center for Infection Research - Partner Site Bonn-Cologne
9 Ostfalia University of Applied Sciences
10 Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig]

Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8+ and CD4+ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4+, liver B/IgA+ and spleen B/IgG+ cells as predictive biomarkers of immunization (≈87% accuracy). CD8+ and CD4+ T cell responses against gB were validated. Splenic gB-binding IgM-/IgG+ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation.

Domaines: Sciences du Vivant [q-bio]

Sebastian J. Theobald, Christoph Kreer, Sahamoddin Khailaie, Agnes Bonifacius, Britta Eiz-Vesper, et al.. Repertoire characterization and validation of gB-specific human IgGs directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV. PLoS Pathogens, 2020, 16 (7), pp.e1008560. ⟨10.1371/journal.ppat.1008560⟩. ⟨pasteur-03259757⟩