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Modular capsid decoration boosts adenovirus vaccine-induced humoral and cellular immunity against SARS-CoV-2

View ORCID ProfileMatthew D. J. Dicks, Louisa M. Rose, View ORCID ProfileLesley A. H. Bowman, Carl Graham, View ORCID ProfileKatie J. Doores, View ORCID ProfileMichael H. Malim, View ORCID ProfileSimon J. Draper, View ORCID ProfileMark Howarth, View ORCID ProfileSumi Biswas
doi: https://doi.org/10.1101/2022.02.20.480711
Matthew D. J. Dicks
1SpyBiotech Ltd, 7600 The Quorum, Oxford Business Park North, Oxford, OX4 2JZ, UK
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  • For correspondence: matthew.dicks@spybiotech.com
Louisa M. Rose
1SpyBiotech Ltd, 7600 The Quorum, Oxford Business Park North, Oxford, OX4 2JZ, UK
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Lesley A. H. Bowman
1SpyBiotech Ltd, 7600 The Quorum, Oxford Business Park North, Oxford, OX4 2JZ, UK
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Carl Graham
2Department of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, SE1 9RT, UK
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Katie J. Doores
2Department of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, SE1 9RT, UK
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Michael H. Malim
2Department of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, SE1 9RT, UK
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Simon J. Draper
1SpyBiotech Ltd, 7600 The Quorum, Oxford Business Park North, Oxford, OX4 2JZ, UK
3Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK
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Mark Howarth
1SpyBiotech Ltd, 7600 The Quorum, Oxford Business Park North, Oxford, OX4 2JZ, UK
3Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK
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Sumi Biswas
1SpyBiotech Ltd, 7600 The Quorum, Oxford Business Park North, Oxford, OX4 2JZ, UK
4The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
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Abstract

Adenovirus vector vaccines have been widely and successfully deployed in response to COVID-19. However, despite inducing potent T cell immunity, improvement of vaccine-specific antibody responses upon homologous boosting is modest compared to other technologies. Here, we describe a system to enable modular decoration of adenovirus capsid surfaces with protein antigens and demonstrate induction of potent humoral immunity against these displayed antigens. Ligand attachment via a covalent isopeptide bond was achieved in a rapid and spontaneous reaction, requiring simple co-incubation of ligand and vector components. We used a recently described protein superglue, DogTag/DogCatcher, which is similar to the widely used SpyTag/SpyCatcher ligation system but performs better in loop structures. DogTag was inserted into surface-exposed loops in the adenovirus hexon protein to allow attachment of DogCatcher-fused ligands on virus particles. Efficient coverage of the capsid surface was achieved using a variety of ligands and vector infectivity was retained in each case. Capsid decoration shielded particles from anti-adenovirus neutralizing antibodies. In prime-boost regimens, proof-of-concept COVID-19 adenovirus vaccines decorated with the receptor-binding domain (RBD) of SARS-CoV-2 spike induced >10-fold higher SARS-CoV-2 neutralization titers compared to an undecorated adenovirus vector encoding spike. Importantly, decorated vectors retained robust T cell immunogenicity to encoded antigens, a key hallmark of adenovirus vector vaccines. We propose capsid decoration via protein superglue-mediated covalent ligation as a novel strategy to improve the efficacy and boostability of adenovirus-based vaccines and therapeutics.

One Sentence Summary Decorating the capsid surface of adenovirus vaccine vectors using a spontaneous protein superglue induces potent pathogen-specific immunity

Competing Interest Statement

MDJD, LMR, and LAHB are employees of SpyBiotech Ltd. SB is CEO and co-founder of SpyBiotech Ltd. SJD and MH are co-founders of SpyBiotech Ltd, and MH is also an author on a number of patents relating to protein superglues, including the DogTag/DogCatcher technology. CG, KJD, MHM have no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted February 22, 2022.
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Modular capsid decoration boosts adenovirus vaccine-induced humoral and cellular immunity against SARS-CoV-2
Matthew D. J. Dicks, Louisa M. Rose, Lesley A. H. Bowman, Carl Graham, Katie J. Doores, Michael H. Malim, Simon J. Draper, Mark Howarth, Sumi Biswas
bioRxiv 2022.02.20.480711; doi: https://doi.org/10.1101/2022.02.20.480711
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Modular capsid decoration boosts adenovirus vaccine-induced humoral and cellular immunity against SARS-CoV-2
Matthew D. J. Dicks, Louisa M. Rose, Lesley A. H. Bowman, Carl Graham, Katie J. Doores, Michael H. Malim, Simon J. Draper, Mark Howarth, Sumi Biswas
bioRxiv 2022.02.20.480711; doi: https://doi.org/10.1101/2022.02.20.480711

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