Journal Article

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

Weskamm, Marie L., Shin, Dai-Lun, Dahlke, Christine, Beythien, Georg, Mayer, Leonie, Tuchel, Tamara, Fendel, Rolf, Tscherne, Alina, Clever, Sabrina, Becker, Stephan, Armando, Federico, Kremsner, Peter, Meyer zu Natrup, Christian, Schwarz, Jan H., Schneiderhan-Marra, Nicole, Fathi, Anahita, Rohde, Cornelius, Brosinski, Katrin, Jany, Sylvia, Freudenstein, Astrid, Kalodimou, Georgia, Halwe, Sandro, Esen, Meral, Schünemann, Lisa-Marie, Addo, Marylyn M., Sutter, Gerd, Baumgärtner, Wolfgang, Kupke, Alexandra, Dulovic, Alex, Ciurkiewicz, Malgorzata, Limpinsel, Leonard, Klug, Martha, Volz, Asisa

2022

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antibodies / Antibodies, Neutralizing / Antibodies, Viral / Antigens / Biomedical research / Cell surface / Coronaviruses / COVID-19 - prevention & control / COVID-19 vaccines / Disease transmission / Genetic aspects / Health aspects / Humans / Immune response / Immune system / Immunization / Immunogenicity / Immunogenicity, Vaccine / Infections / Infectious disease / Investigations / Lung diseases / Mice / Mutation / Polypeptides / Proteins / Proteolysis / Recombinant molecules / SARS-CoV-2 - genetics / Severe acute respiratory syndrome coronavirus 2 / Vaccines / Vaccinia virus - genetics / Viral antigens / Viral Vaccines - genetics