학술논문
Stabilized recombinant SARS-CoV-2 spike antigen enhances vaccine immunogenicity and protective capacity
Document Type
article
Author
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; Federico Armando; 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
Source
The Journal of Clinical Investigation, Vol 132, Iss 24 (2022)
Subject
Language
English
ISSN
1558-8238
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.