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Meyer Zu Natrup, Christian; 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; Schünemann, Lisa-Marie; Beythien, Georg; Armando, Federico; Mayer, Leonie; Weskamm, Marie L; Jany, Sylvia; Freudenstein, Astrid; Tuchel, Tamara; Baumgärtner, Wolfgang; Kremsner, Peter; Fendel, Rolf; Addo, Marylyn M; Becker, Stephan; Sutter, Gerd; Volz, Asisa
The Journal of clinical investigation, 12/2022, Volume: 132, Issue: 24Journal Article
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.
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