The Journal of Clinical Investigation (Dec 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,
  • 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

Journal volume & issue
Vol. 132, no. 24

Abstract

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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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