RBD-depleted SARS-CoV-2 spike generates protective immunity in cynomolgus macaques
The SARS-CoV-2 pandemic revealed the rapid evolution of circulating strains. This led to new variants carrying mostly mutations within the receptor binding domain, which is immunodominant upon immunization and infection. In order to steer the immune response away from RBD epitopes to more conserved domains, we generated S glycoprotein trimers without RBD and stabilized them by formaldehyde cross-linking. The cryoEM structure demonstrated that SΔRBD folds into the native prefusion conformation, stabilized by one specific cross-link between S2 protomers. SΔRBD was coated onto lipid vesicles, to produce synthetic virus-like particles, SΔRBD-LV, which were utilized in a heterologous prime-boost strategy. Immunization of cynomolgus macaques either three times with the mRNA Comirnaty vaccine or two times followed by SΔRBD-LV showed that the SΔRBD-LV boost induced similar antibody titers and neutralization of different variants, including omicron. Upon challenge with omicron XBB.3, both the Comirnaty only and Comirnaty/SΔRBD-LV vaccination schemes conferred similar overall protection from infection for both the Comirnaty only and Comirnaty/SΔRBD-LV vaccination schemes. However, the SΔRBD-LV boost indicated better protection against lung infection than the Comirnaty strategy alone. Together our findings indicate that SΔRBD is highly immunogenic and provides improved protection compared to a third mRNA boost indicative of superior antibody-based protection.
Authors
- Sylvie van der Werf (ORCID: https://orcid.org/0000-0002-1148-4456)
- Anne-Sophie Gallouët (ORCID: https://orcid.org/0000-0001-5815-3454)
- Nathalie Dereuddre‐Bosquet (ORCID: https://orcid.org/0000-0001-6682-6313)
- Julie Morin
- Marco Léonec
- Matthieu Van Tilbeurgh (ORCID: https://orcid.org/0000-0002-3790-9467)
- Marit J. van Gils (ORCID: https://orcid.org/0000-0003-3422-8161)
- Francis Relouzat (ORCID: https://orcid.org/0000-0002-6387-8481)
- Pascal Poignard (ORCID: https://orcid.org/0000-0002-0021-7192)
- Winfríed Weissenhorn (ORCID: https://orcid.org/0000-0001-5532-4959)
- Roger Le Grand (ORCID: https://orcid.org/0000-0002-4928-4484)
- Judith A. Burger (ORCID: https://orcid.org/0000-0002-7311-9921)
- Delphine Guilligay
- Hélène Letscher (ORCID: https://orcid.org/0000-0002-9202-6368)
- Axelle Amen (ORCID: https://orcid.org/0000-0002-0449-4445)
- Laëtitia Bossevot (ORCID: https://orcid.org/0000-0002-5752-9277)
- Cécile Hérate (ORCID: https://orcid.org/0000-0002-8261-1328)
- Guidenn Sulbarán
- Mariangela Cavarelli (ORCID: https://orcid.org/0000-0002-8468-0263)
- Laura Junges
- Grégory Effantin (ORCID: https://orcid.org/0000-0002-6957-0875)
- Rogier W. Sanders (ORCID: https://orcid.org/0000-0002-2324-8573)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Paris Cité (FR)
- Cornell University (US)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Centre Hospitalier Universitaire de Grenoble (FR)
- CEA Grenoble (FR)
- Department of Virology (FR)
- CEA Paris-Saclay (FR)
- Infectious Disease Models and Innovative Therapies (FR)
- Amsterdam University Medical Centers (NL)
- Institut de Biologie Structurale (FR)
- University of Amsterdam (NL)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- npj Vaccines
- Published
- 2025-03-30
- DOI
- https://doi.org/10.1038/s41541-025-01113-0
- Citations
- 5
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 6.98
Funders
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Sixth Framework Programme