Stabilized recombinant SARS-CoV-2 spike antigen enhances vaccine immunogenicity and protective capacity
Christian Meyer zu Natrup, … , Gerd Sutter, Asisa Volz
Christian Meyer zu Natrup, … , Gerd Sutter, Asisa Volz
Published October 27, 2022
Citation Information: J Clin Invest. 2022;132(24):e159895. https://doi.org/10.1172/JCI159895.
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Research Article Infectious disease

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

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.

Authors

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

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Figure 4

Virus-neutralizing antibody responses to SARS-CoV-2 BavPat1, Alpha, Beta, Zeta, Delta, and Omicron variants in vaccinated BALB/c mice.

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Virus-neutralizing antibody responses to SARS-CoV-2 BavPat1, Alpha, Beta...
SARS-CoV-2 neutralization titers measured by the plaque reduction assay (PRNT50) and virus neutralization test (VNT100) from BALB/c mice vaccinated with PBS, MVA, MVA-S, or MVA-ST. (A) PRNT50 and (B) VNT100 assays using SARS-CoV-2 BavPat1. (C) VNT100 against SARS-CoV-2 BavPat1, Alpha, Beta, and Zeta variants. PRNT50 assay using SARS-CoV-2 (D) Delta and (E) Omicron variants. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Tukey’s multiple comparisons test of log-transformed data (A–C) and Kruskal-Wallis test with Dunn’s multiple comparisons test (D and E). LOD, limit of detection; ULOD and LLOD, upper and lower LOD.