In vitro generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2

Dora Buzas; Adrian H Bunzel; Oskar Staufer; Emily J Milodowski; Grace L Edmunds; Joshua C Bufton; Beatriz V Vidana Mateo; Sathish K N Yadav; Kapil Gupta; Charlotte Fletcher; Maia K Williamson; Alexandra Harrison; Ufuk Borucu; Julien Capin; Ore Francis; Georgia Balchin; Sophie Hall; Mirella V Vega; Fabien Durbesson; Srikanth Lingappa; Renaud Vincentelli; Joe Roe; Linda Wooldridge; Rachel Burt; Ross J L Anderson; Adrian J Mulholland; Bristol Uncover Group; Jonathan Hare; Mick Bailey; Andrew D Davidson; Adam Finn; David Morgan; Jamie Mann; Joachim Spatz; Frederic Garzoni; Christiane Schaffitzel; Imre Berger

doi:10.1093/abt/tbad024

In vitro generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2

Antib Ther. 2023 Oct 17;6(4):277-297. doi: 10.1093/abt/tbad024. eCollection 2023 Oct.

Authors

Dora Buzas^{1

2}, Adrian H Bunzel², Oskar Staufer^{1

3}, Emily J Milodowski⁴, Grace L Edmunds⁵, Joshua C Bufton², Beatriz V Vidana Mateo⁵, Sathish K N Yadav², Kapil Gupta^{2

6}, Charlotte Fletcher², Maia K Williamson⁷, Alexandra Harrison², Ufuk Borucu², Julien Capin², Ore Francis⁵, Georgia Balchin², Sophie Hall², Mirella V Vega², Fabien Durbesson⁸, Srikanth Lingappa², Renaud Vincentelli⁸, Joe Roe⁵, Linda Wooldridge⁵, Rachel Burt⁵, Ross J L Anderson², Adrian J Mulholland⁹, Bristol Uncover Group¹⁰, Jonathan Hare⁷, Mick Bailey⁵, Andrew D Davidson⁶, Adam Finn^{10

11}, David Morgan⁶, Jamie Mann⁵, Joachim Spatz^{1

12}, Frederic Garzoni⁷, Christiane Schaffitzel^{2

10}, Imre Berger^{1

2

9

10}

Affiliations

¹ Max Planck Bristol Centre for Minimal Biology, University of Bristol, Bristol BS8 1TS, UK.
² School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK.
³ Leibniz Institute for New Materials, Helmholtz Institute for Pharmaceutical Research and Center for Biophysics, Saarland University, Saarbrücken 66123, Germany.
⁴ Bristol Veterinary School, University of Bristol, Bristol BS40 5DU UK.
⁵ Bristol Veterinary School, University of Bristol, Bristol BS40 5DUUK.
⁶ Imophoron Ltd, Science Creates Old Market, Midland Rd, Bristol BS2 0JZUK.
⁷ School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK.
⁸ Architecture et Fonction des Macromolécules Biologiques, UMR 7257, CNRS, Aix-Marseille Université, Marseille, France.
⁹ School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
¹⁰ Bristol University COVID-19 Emergency Research Group, Bristol BS8 1TH, UK.
¹¹ Children's Vaccine Centre, Bristol Medical School, Bristol BS2 8EFUK.
¹² Max Planck Institute for Medical Research, Heidelberg 69120, Germany.

Abstract

Background: Due to COVID-19, pandemic preparedness emerges as a key imperative, necessitating new approaches to accelerate development of reagents against infectious pathogens.

Methods: Here, we developed an integrated approach combining synthetic, computational and structural methods with in vitro antibody selection and in vivo immunization to design, produce and validate nature-inspired nanoparticle-based reagents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Results: Our approach resulted in two innovations: (i) a thermostable nasal vaccine called ADDoCoV, displaying multiple copies of a SARS-CoV-2 receptor binding motif derived epitope and (ii) a multivalent nanoparticle superbinder, called Gigabody, against SARS-CoV-2 including immune-evasive variants of concern (VOCs). In vitro generated neutralizing nanobodies and electron cryo-microscopy established authenticity and accessibility of epitopes displayed by ADDoCoV. Gigabody comprising multimerized nanobodies prevented SARS-CoV-2 virion attachment with picomolar EC₅₀. Vaccinating mice resulted in antibodies cross-reacting with VOCs including Delta and Omicron.

Conclusion: Our study elucidates Adenovirus-derived dodecamer (ADDomer)-based nanoparticles for use in active and passive immunization and provides a blueprint for crafting reagents to combat respiratory viral infections.

Keywords: ADDomer; Gigabody superbinder; electron cryo-microscopy (cryo-EM); in vitro selection (Ribosome Display); pandemic preparedness; protein nanoparticle design; respiratory viral diseases; synthetic vaccine.

Abstract

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