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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, 371 (6530). pp. 735-741. ISSN 0036-8075. PMCID PMC7928838 ; PMC7685334.

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Protection against severe acute respiratory syndrome coronavirus 2 (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 with four to eight 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 relative to sera from immunizations with homotypic SARS-CoV-2–RBD nanoparticles or COVID-19 convalescent human plasmas. Moreover, after priming, sera from mosaic RBD–immunized mice neutralized heterologous pseudotyped coronaviruses as well as or better than sera from homotypic SARS-CoV-2–RBD nanoparticle immunizations, demonstrating no loss of immunogenicity 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 CentralDiscussion Paper CentralArticle
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. Received 12 November 2020; accepted 7 January 2021 Published online 12 January 2021. We thank K. Brune (Genie Biotech) for advice about mi3 production; J. Bloom (Fred Hutchinson) and P. Bieniasz (Rockefeller University) for neutralization assay reagents; J. Vielmetter and Caltech’s Beckman Institute Protein Expression Center for protein production; A. Flyak for help with flow cytometry; M. Murphy for figures; COVID-19 plasma donors, B. Coller, S. Schlesinger, and the Rockefeller University Hospital Clinical Research Support Office and nursing staff; and A. Flyak and A. DeLaitsch for critical reading of the manuscript. Funding: 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; and 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 or the supplementary materials. Materials are available upon request to the corresponding author with a signed material transfer agreement.
Group:Richard N. Merkin Institute for Translational Research, COVID-19
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
Issue or Number:6530
PubMed Central ID:PMC7928838 ; PMC7685334
Record Number:CaltechAUTHORS:20201118-120755714
Persistent URL:
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 371 (6530), 735-741; DOI: 10.1126/science.abf6840; originally published online January 12, 2021.
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:26 Aug 2021 19:09

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