Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models

Creators: Cohen, Alexander A.; van Doremalen, Neeltje; Greaney, Allison J.; Andersen, Hanne; Sharma, Ankur; Starr, Tyler N.; Keeffe, Jennifer R.; Fan, Chengcheng; Schulz, Jonathan E.; Gnanapragasam, Priyanthi N. P.; Kakutani, Leesa M.; West, Anthony P., Jr.; Saturday, Greg; Lee, Yu E.; Gao, Han; Jette, Claudia A.; Lewis, Mark G.; Tan, Tiong K.; Townsend, Alain R.; Bloom, Jesse D.; Munster, Vincent J.; Bjorkman, Pamela J.

Abstract

To combat future severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles that present randomly arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against epitopes that are conserved and relatively occluded rather than variable, immunodominant, and exposed. 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 and observed 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 Omicrons, 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 that mosaic-8 RBD nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

Additional Information

© 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. 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. Submitted 17 March 2022; accepted 29 June 2022. We thank J. Vielmetter and the Caltech Protein Expression Center for assistance with protein production; M. Howarth (Oxford) and S. Biswas (SpyBiotech) for helpful discussions about SpyCatcher-SpyTag methodology; F. Laurent and R. Caputo (SPI Pharma) and H. Jain (Panacea Biotec) for VAC20 and EmulsiPan adjuvants, respectively; A. Walls and D. Veesler (University of Washington) for a modified BtKY72 S gene for pseudovirus neutralization assays; M. Holbrook, E. de Wit, B. Williamson, A. Pekosz, C. Martens, K. Barbian, S. Ricklefs, S. Anzick, R. Feldmann, and the Public Health Agency of Canada for viruses used at RML; K. Almquist, A. Darrow, K. Bauer, A. Weidow, R. Cole, L. Heaney, M. Culbert, B. Bailes, C. Henderson, S. Gallogly, L. Crawford, and T. Lippincott for animal care at RML; and C. 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-T2A-ACE2), NR-54970. We thank Labcorp Drug Development–Antibody Reagents and Vaccines (Denver, PA) (formerly Covance) for carrying out BALB/c mice immunizations for the RBD epitope mapping study. This work was supported by Wellcome Leap (P.J.B.); Bill and Melinda Gates Foundation INV-034638 (P.J.B.); INV-004949 and INV-016575 (J.D.B.); Caltech Merkin Institute (P.J.B.); George Mason University Fast Grant (P.J.B.); Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) (1ZIAAI001179-01) (V.J.M.); NIAID/NIH contract numbers HHSN272201400006C and 75N93021C00015 (J.D.B.); NIH grant R01AI141707 (J.D.B.); ORIP grant S10OD028685 (The Scientific Computing Infrastructure at Fred Hutch); Caribbean Primate Research Center (grants P40 OD012217 and 2U42OD021458 from ORIP/OD/NIH) (M.G.L.). T.N.S. is a Howard Hughes Medical Institute fellow of the Damon Runyon Cancer Research Foundation (DRG-2381-19). J.D.B. is an investigator of the Howard Hughes Medical Institute. T.K.T. is funded by the Townsend-Jeantet Charitable Trust (charity number 1011770) and the EPA Cephalosporin Early Career Researcher Fellowship. Author contributions: Conceptualization: A.A.C., T.K.T., A.R.T., and P.J.B. Methodology: A.A.C., N.v.D., A.J.G., H.A., A.S., T.N.S., J.R.K., J.E.S., M.G.L., J.D.B., V.J.M., and P.J.B. Investigation: A.A.C., N.v.D., A.J.G., H.A., A.S., J.R.K., C.F., J.E.S., P.N.P.G., L.M.K., A.P.W., G.S., Y.E.L., H.G., and C.A.J. Visualization: A.A.C., C.F., A.J.G., J.E.S., and J.D.B. Funding acquisition: P.J.B., J.D.B., and V.J.M. Project administration: J.R.K., M.G.L., J.D.B., V.J.M., and P.J.B.; Supervision: A.A.C., N.v.D., H.A., A.S., J.R.K., A.P.W., M.G.L., J.D.B., V.J.M., and P.J.B.; Writing – original draft: A.A.C. and P.J.B. Writing – review and editing: A.A.C., N.v.D., A.J.G., H.A., J.R.K., C.F., T.K.T., A.R.T., T.N.S., J.D.B., V.J.M., P.J.B. Competing interests: P.J.B. and A.A.C. are inventors on a US patent application (17/523,813) filed by the California Institute of Technology that covers the mosaic nanoparticles described in this work, and P.J.B., A.A.C., and C.F. are inventors on provisional US patent applications (63/341,314; 63/285,441) filed by the California Institute of Technology that cover antibodies elicited by the mosaic nanoparticles. 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 intellectual property revenue as inventors on a Fred Hutchinson Cancer Center–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.

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