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.

Stabilized recombinant SARS-CoV-2 spike antigen enhances vaccine immunogenicity and protective capacity / Christian Meyer Zu, Natrup; Alina, Tscherne; Christine, Dahlke; Malgorzata, Ciurkiewicz; Dai-Lun, Shin; Anahita, Fathi; Cornelius, Rohde; Georgia, Kalodimou; Sandro, Halwe; Leonard, Limpinsel; Jan, H Schwarz; Martha, Klug; Meral, Esen; Nicole, Schneiderhan-Marra; Alex, Dulovic; Alexandra, Kupke; Katrin, Brosinski; Sabrina, Clever; Lisa-Marie, Schünemann; Georg, Beythien; Armando, F; Leonie, Mayer; Marie, L Weskamm; Sylvia, Jany; Astrid, Freudenstein; Tamara, Tuchel; Wolfgang, Baumgärtner; Peter, Kremsner; Rolf, Fendel; Marylyn, M Addo; Stephan, Becker; Gerd, Sutter; Asisa, Volz. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - (2022). [doi: 10.1172/JCI159895.]

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

ARMANDO F;
2022-01-01

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.
2022
Stabilized recombinant SARS-CoV-2 spike antigen enhances vaccine immunogenicity and protective capacity / Christian Meyer Zu, Natrup; Alina, Tscherne; Christine, Dahlke; Malgorzata, Ciurkiewicz; Dai-Lun, Shin; Anahita, Fathi; Cornelius, Rohde; Georgia, Kalodimou; Sandro, Halwe; Leonard, Limpinsel; Jan, H Schwarz; Martha, Klug; Meral, Esen; Nicole, Schneiderhan-Marra; Alex, Dulovic; Alexandra, Kupke; Katrin, Brosinski; Sabrina, Clever; Lisa-Marie, Schünemann; Georg, Beythien; Armando, F; Leonie, Mayer; Marie, L Weskamm; Sylvia, Jany; Astrid, Freudenstein; Tamara, Tuchel; Wolfgang, Baumgärtner; Peter, Kremsner; Rolf, Fendel; Marylyn, M Addo; Stephan, Becker; Gerd, Sutter; Asisa, Volz. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - (2022). [doi: 10.1172/JCI159895.]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2966352
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