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Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice

Cohen, Alexander A. and Gnanapragasam, Priyanthi N. P. and Lee, Yu E. and Hoffman, Pauline R. and Ou, Susan and Kakutani, Leesa M. and Keeffe, Jennifer R. and Wu, Hung-Jen and Howarth, Mark and West, Anthony P. and Barnes, Christopher O. and Nussenzweig, Michel C. and Bjorkman, Pamela J. (2021) Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice. Science . ISSN 0036-8075. (In Press)

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Protection against SARS-CoV-2 and SARS-related emergent zoonotic coronaviruses is urgently needed. We made homotypic nanoparticles displaying the receptor-binding domain (RBD) of SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans (mosaic nanoparticles; 4-8 distinct RBDs). Mice immunized with RBD-nanoparticles, but not soluble antigen, elicited cross-reactive binding and neutralization responses. Mosaic-RBD-nanoparticles elicited antibodies with superior cross-reactive recognition of heterologous RBDs compared to sera from immunizations with homotypic SARS-CoV-2–RBD-nanoparticles or COVID-19 convalescent human plasmas. Moreover, sera from mosaic-RBD–immunized mice neutralized heterologous pseudotyped coronaviruses equivalently or better after priming than sera from homotypic SARS-CoV-2–RBD-nanoparticle immunizations, demonstrating no immunogenicity loss against particular RBDs resulting from co-display. A single immunization with mosaic-RBD-nanoparticles provides a potential strategy to simultaneously protect against SARS-CoV-2 and emerging zoonotic coronaviruses.

Item Type:Article
Related URLs:
URLURL TypeDescription Materials Paper
Cohen, Alexander A.0000-0002-2818-656X
Keeffe, Jennifer R.0000-0002-5317-6398
Howarth, Mark0000-0001-8870-7147
Barnes, Christopher O.0000-0003-2754-5951
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Alternate Title:Mosaic RBD nanoparticles elicit neutralizing antibodies against SARS-CoV-2 and zoonotic coronaviruses, Neutralization of SARS-CoV-2 and zoonotic coronavirus threats by mosaic nanoparticle vaccination
Additional Information:© 2021 American Association for the Advancement of Science. 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 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. We thank Karl Brune (Genie Biotech) for advice about mi3 production, Jesse Bloom (Fred Hutchinson) and Paul Bieniasz (Rockefeller University) for neutralization assay reagents, Jost Vielmetter and Caltech’s Beckman Institute Protein Expression Center for protein production, Andrew Flyak for help with flow cytometry, Marta Murphy for figures, COVID-19 plasma donors and Drs. Barry Coller and Sarah Schlesinger and the Rockefeller University Hospital Clinical Research Support Office and nursing staff, and Andrew Flyak and Andrew DeLaitsch for critical reading of the manuscript. This work was supported by NIH grant P01-AI138938-S1 (P.J.B. and M.C.N.), the Caltech Merkin Institute for Translational Research (P.J.B.), a George Mason University Fast Grant (P.J.B.), and the Medical Research Council (MR/P001351/1) (M.H.) (this UK-funded award is part of the EDCTP2 program supported by the European Union). M.C.N. is a Howard Hughes Medical Institute Investigator. Author contributions: A.A.C., C.O.B., and P.J.B. conceived and designed experiments. A.A.C., P.N.P.G., Y.E.L., P.R.H., S.O., and L.M.K. performed experiments, H-J.W. generated and validated SpyCatcher003-mi3, M.H. supervised the generation and validation of SpyCatcher003-mi3, A.A.C., J.R.K., A.P.W., C.O.B., M.C.N., and P.J.B. analyzed data and wrote the paper with contributions from other authors. Competing interests: M.H. is an inventor on a patent on SpyTag/SpyCatcher (EP2534484) and a patent application on SpyTag003:SpyCatcher003 (UK Intellectual Property Office 1706430.4), as well as a SpyBiotech cofounder, shareholder and consultant. P.J.B. and A.A.C. are inventors on a provisional application from the California Institute of Technology that covers the mosaic nanoparticles described in this work. Data and materials availability: All data are available in the main text of the supplementary materials. Materials are available upon request to with a signed Material Transfer Agreement.
Group:Richard N. Merkin Institute for Translational Research
Funding AgencyGrant Number
Caltech Merkin Institute for Translational ResearchUNSPECIFIED
George Mason UniversityUNSPECIFIED
Medical Research Council (UK)MR/P001351/1
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:neutralizing antibodies, receptor-binding domain, sarbecoviruses, vaccine, zoonotic coronaviruses
Record Number:CaltechAUTHORS:20201118-120755714
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Official Citation:Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice. Alexander A. Cohen, Priyanthi N. P. Gnanapragasam, Yu E. Lee, Pauline R. Hoffman, Susan Ou, Leesa M. Kakutani, Jennifer R. Keeffe, Hung-Jen Wu, Mark Howarth, Anthony P. West, Christopher O. Barnes, Michel C. Nussenzweig and Pamela J. Bjorkman. Science; Published online 12 Jan. 2021; DOI: 10.1126/science.abf6840
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:106725
Deposited By: Tony Diaz
Deposited On:18 Nov 2020 20:31
Last Modified:13 Jan 2021 22:59

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