Proactive vaccination using multiviral Quartet Nanocages to elicit broad anti-coronavirus responses
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Abstract
Defending against future pandemics requires vaccine platforms that protect across a range of related pathogens. Nanoscale patterning and efficient molecular self-assembly are key to the success of new vaccine approaches. Here we produce quartets of concatenated receptor-binding domains (RBDs) from a panel of SARS-like betacoronaviruses, precisely coupled to the computationally-designed mi3 nanocage through SpyTag/SpyCatcher spontaneous reaction. These Quartet Nanocages, possessing a branched morphology, induce a high level of neutralizing antibodies against several different coronaviruses, including against viruses not represented on the vaccine. Equivalent antibody responses are raised to RBDs close to the nanocage or at the tips of the nanoparticle’s branches. In animals primed with SARS-CoV-2 Spike, boost immunizations with Quartet Nanocages increase the strength and breadth of an otherwise narrow immune response. A Quartet Nanocage including the Omicron XBB.1.5 “Kraken” RBD induced antibodies with binding to a broad range of sarbecoviruses, as well as neutralizing activity against this Variant of Concern. Quartet Nanocages are a nanomedicine approach with potential to confer heterotypic protection against emergent zoonotic pathogens and facilitate proactive pandemic protection.
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Acknowledgements: We thank D. Staunton from the University of Oxford Department of Biochemistry Biophysical Suite for help with biophysical analysis. We thank the Centre for the AIDS Programme of Research in South Africa (CAPRISA) and G. Screaton (University of Oxford) for supplying SARS-CoV-2 variant isolates. The BtKY72 K493Y/T498W Spike plasmid for generating pseudovirus was a kind gift to the Bjorkman lab from D. Veesler (University of Washington). We thank the Cambridge Advanced Imaging Centre for TEM training and access to the microscopy facility. A.H.K. and M.R.H. disclose support for the research of this work from the Biotechnology and Biological Sciences Research Council (BBSRC grant no. BB/S007369/1). M.R.H. discloses support for the research of this work from the University of Oxford COVID-19 Research Response Fund and its donors (reference no. 0009517). R.A.H. discloses support for the research of this work from the Rhodes Trust. T.K.T. discloses support for the research of this work from the EPA Cephalosporin Early Career Teaching and Research Fellowship. R.A.H. and T.K.T. disclose support for the research of this work from the Townsend-Jeantet Prize Charitable Trust (Charity Number 1011770). G.A. discloses support for the research of this work from the University of Cambridge start-up funds. A.R.T. discloses support for the research of this work from the Chinese Academy of Medical Sciences (CAMS) Chinese Innovation Fund for Medical Science (CIFMS), China (grant no. 2018-I2M-2-002). P.J.B. discloses support for the research of this work from the National Institutes of Health (NIH grant no. AI165075), Caltech Merkin Institute and George Mason University Fast Grant.
Funder: Rhodes Trust
Funder: EPA Cephalosporin Early Career Teaching and Research Fellowship, Townsend-Jeantet Prize Charitable Trust
Funder: University of Cambridge
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1748-3395
