Watterson, DanielWijesundara, Danushka KModhiran, NaphakMordant, FLi, JerryAvumegah, Michael SMcMillan, Christopher L DLackenby, Julia AGuilfoyle, Katevan Amerongen, GeertStittelaar, KoertRanasinghe, Charani2023-08-162023-08-162050-0068http://hdl.handle.net/1885/295622Objectives: Efforts to develop and deploy effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue at pace. Here, we describe rational antigen design through to manufacturability and vaccine efficacy of a prefusion-stabilised spike (S) protein, Sclamp, in combination with the licensed adjuvant MF59 ‘MF59C.1’ (Seqirus, Parkville, Australia). Methods: A panel recombinant Sclamp proteins were produced in Chinese hamster ovary and screened in vitro to select a lead vaccine candidate. The structure of this antigen was determined by cryo-electron microscopy and assessed in mouse immunogenicity studies, hamster challenge studies and safety and toxicology studies in rat. Results: In mice, the Sclamp vaccine elicits high levels of neutralising antibodies, as well as broadly reactive and polyfunctional S-specific CD4 and cytotoxic CD8 T cells in vivo. In the Syrian hamster challenge model (n = 70), vaccination results in reduced viral load within the lung, protection from pulmonary disease and decreased viral shedding in daily throat swabs which correlated strongly with the neutralising antibody level. Conclusion: The SARS-CoV-2 Sclamp vaccine candidate is compatible with large-scale commercial manufacture, stable at 2–8°C. When formulated with MF59 adjuvant, it elicits neutralising antibodies and T-cell responses and provides protection in animal challenge models.This work was funded by CEPIapplication/pdfen-AU© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.https://creativecommons.org/licenses/by-nc-nd/4.0/Molecular Clampneutralising antibodiespolyfunctional T cellsrapid responseSARS-CoV-2subunit vaccine202110.1002/cti2.12692022-07-24Creative Commons Attribution-NonCommercial-NoDerivs License