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Published October 6, 2023 | Submitted
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Mosaic RBD nanoparticles protect against multiple sarbecovirus challenges in animal models


To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. We thank Jost Vielmetter and the Caltech Protein Expression Center for assistance with protein production, Mark Howarth (Oxford) and Sumi Biswas (SpyBiotech) for helpful discussions about SpyCatcher-SpyTag methodology, Francis Laurent and Ruben Caputo (SPI Pharma) and Harshet Jain (Panacea Biotec) for VAC20 and MF59 adjuvants, respectively, Alexandra Walls and David Veesler (University of Washington) for a modified BtKY72 S gene for pseudovirus neutralization assays, Myndi Holbrook, Emmie de Wit, Brandi Williamson, Andrew Pekosz, Craig Martens, Kent Barbian, Stacey Ricklefs, Sarah Anzick, Ricki Feldmann, and the Public Health Agency of Canada for viruses used at RML, Kestrel Almquist, Allison Darrow, Kaitlyn Bauer, Amanda Weidow, Richard Cole, Lisa Heaney, Maarit Culbert, Brandon Bailes, Corey Henderson, Shane Gallogly, Lydia Crawford, and Taylor Lippincott for animal care at RML, and Claude Kwe Yinda (RML) for technical support. The following reagents were obtained through BEI Resources, NIAID, NIH: Cercopithecus aethiops Kidney Epithelial Cells Expressing Transmembrane Protease, Serine 2 and Human Angiotensin-Converting Enzyme 2 (Vero E6-TMPRSS2-T2AACE2), NR-54970. We thank Labcorp Drug Development–Antibody Reagents and Vaccines (Denver, PA) (formerly Covance, Inc.) for carrying out BALB/c mice immunizations for the RBD epitope mapping study. Funding: Wellcome Leap (PJB); Bill and Melinda Gates Foundation INV-034638 (PJB); INV-004949 and INV-016575 (JDB) Caltech Merkin Institute (PJB) ; George Mason University Fast Grant (PJB); Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) (1ZIAAI001179-01) (VJM); NIAID/NIH contract numbers HHSN272201400006C and 75N93021C00015 (JDB); National Institutes of Health grant R01AI141707 (JDB); ORIP grant S10OD028685 (The Scientific Computing Infrastructure at Fred Hutch); Caribbean Primate Research Center (Grants P40 OD012217 and 2U42OD021458 from ORIP/OD/NIH) (MGL); TNS is a Howard Hughes Medical Institute Fellow of the Damon Runyon Cancer Research Foundation (DRG-2381-19). JDB is an Investigator of the Howard Hughes Medical Institute. TKT is funded by the Townsend-Jeantet Charitable Trust (charity number 1011770) and the EPA Cephalosporin Early Career Researcher Fellowship. Author contributions: Conceptualization: AAC, TKT, ART, PJB Methodology: AAC, NvD, AJG, HA, AS, TNS, JRK, JES, MGL, JDB, VJM, PJB Investigation: AAC, NvD, AJG, HA, AS, JRK, CF, JES, PNPG, LMK, APW, GS, YEL, HG, CAJ Visualization: AAC, CF, AJG, JES, JDB Funding acquisition: PJB, JDB, VJM Project administration: JRK, MGL, JDB, VJM, PJB Supervision: AAC, NvD, HA, AS, JRK, APW, MGL, JDB, VJM, PJB Writing – original draft: AAC, PJB Writing – review & editing: AAC, NvD, AJG, HA, JRK, CF, TKT, ART, TNS, JDB, VJM, PJB Competing interests: P.J.B. and A.A.C. are inventors on a US patent application filed by the California Institute of Technology that covers the mosaic nanoparticles described in this work. J.D.B. consults for Moderna and Flagship Labs 77 on topics related to viral evolution. A.J.G, T.N.S., and J.D.B have the potential to receive a share of IP revenue as inventors on a Fred Hutch optioned technology related to deep mutational scanning of viral proteins and RBD-based vaccine formulations. Data and materials availability: All data are available in the main text or the supplementary materials. Raw Illumina sequencing data for the antibody-escape mapping experiments are available on the NCBI Short Read Archive (SRA) at BioProject PRJNA770094, BioSample SAMN26315988. Antibody-escape scores are available at https://github.com/jbloomlab/SARS-CoV-2-RBD_Beta_mosaic_np_vaccine/blob/main/results/supp_data/all_raw_data.csv. Materials are available upon request to the corresponding author with a signed material transfer agreement. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.

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October 9, 2023
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