Stabilized recombinant SARS-CoV-2 spike antigen enhances vaccine immunogenicity and protective capacity

zu Natrup, Christian Meyer; Tscherne, Alina; Dahlke, Christine; Ciurkiewicz, Malgorzata; Shin, Dai-Lun; Fathi, Anahita; Rohde, Cornelius; Kalodimou, Georgia; Halwe, Sandro; Limpinsel, Leonard; Schwarz, Jan H.; Klug, Martha; Esen, Meral; Schneiderhan-Marra, Nicole; Dulovic, Alex; Kupke, Alexandra; Brosinski, Katrin; Clever, Sabrina; Schuenemann, Lisa-Marie; Beythien, Georg; Armando, Federico; Mayer, Leonie; Weskamm, Marie L.; Jany, Sylvia; Freudenstein, Astrid; Tuchel, Tamara; Baumgaertner, Wolfgang; Kremsner, Peter; Fendel, Rolf; Addo, Marylyn M.; Becker, Stephan; Sutter, Gerd und Volz, Asisa (2022): Stabilized recombinant SARS-CoV-2 spike antigen enhances vaccine immunogenicity and protective capacity. In: Journal of Clinical Investigation, Bd. 132, Nr. 24, e159895

Abstract

The SARS-CoV-2 spike (S) glycoprotein is synthesized as a large precursor protein and must be activated by proteolytic cleavage into S1 and S2. A recombinant modified vaccinia virus Ankara (MVA) expressing native, full-length S protein (MVA-SARS-2-S) is currently under investigation as a candidate vaccine in phase I clinical studies. Initial results from immunogenicity monitoring revealed induction of S-specific antibodies binding to S2, but low-level antibody responses to the S1 domain. Follow-up investigations of native S antigen synthesis in MVA-SARS-2-S-infected cells revealed limited levels of S1 protein on the cell surface. In contrast, we found superior S1 cell surface presentation upon infection with a recombinant MVA expressing a stabilized version of SARS-CoV-2 S protein with an inactivated S1/S2 cleavage site and K986P and V987P mutations (MVA-SARS-2-ST). When comparing immunogenicity of MVA vector vaccines, mice vaccinated with MVA-SARS-2-ST mounted substantial levels of broadly reactive anti-S antibodies that effectively neutralized different SARS-CoV-2 variants. Importantly, intramuscular MVA-SARS-2-ST immunization of hamsters and mice resulted in potent immune responses upon challenge infection and protected from disease and severe lung pathology. Our results suggest that MVA-SARS-2-ST represents an improved clinical candidate vaccine and that the presence of plasma membrane-bound S1 is highly beneficial to induce protective antibody levels.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Tiermedizin > Veterinärwissenschaftliches Department
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0021-9738
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 398066876