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SpyVector; a modular capsid decoration platform to boost adenovirus vaccine-induced humoral immunity

B Charlton(1) R D’Agostino(1) R A Russell(1) L M Rose(1) L AH Bowman(1) C Graham(2) Z Li(3) H Kleanthous(5) C Woods(5) K J Doores(2) M H Malim(2) D H Barouch(3) S Biswas(1,4) M DJ Dicks(1)

1:SpyBiotech; 2:King's College London; 3:BIDMC/Harvard Medical school; 4:The Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK; 5:Bill & Melinda Gates Foundation, Seattle, WA 98109, USA

Adenovirus (Ad) vector vaccines have been widely and successfully deployed in response to COVID-19. However, while Ad vectors are potent inducers of cellular immunity, improvement of vaccine-specific antibody responses upon homologous boosting is modest compared to other technologies. Here we describe a platform, SpyVector, enabling modular decoration of Ad capsid surfaces with vaccine antigens from a range of target pathogens, and demonstrate potent induction of humoral immunity against these displayed antigens.

Ligand attachment via a covalent bond was achieved using a protein superglue, DogTag/DogCatcher in a rapid and spontaneous reaction requiring only co-incubation of ligand and vector components. DogTag (23 amino acids) was genetically inserted into surface-exposed loops in the adenovirus hexon capsid protein to allow attachment of ligands fused to DogCatcher (a 15 kDa protein domain) on virus particles.

Capsid decoration shielded Ad particles from vector neutralizing antibodies and other undesirable capsid interactors. In both mice and NHP, Ad decorated with the receptor binding domain (RBD) of SARS-CoV-2 Spike (S) induced >10-fold higher SARS-CoV-2 neutralization titers compared to an undecorated Ad encoding S. Importantly, decorated Ad achieved equivalent or superior T cell immunogenicity against encoded antigens compared to undecorated Ad. We extend this work to develop pan-coronavirus vaccines by decorating Ad capsid surfaces with multiple RBDs from diverse coronaviruses with pandemic potential.

We propose capsid decoration as an effective strategy to improve safety, efficacy and boostability of Ad vector vaccines and therapeutics, with its customizable nature offering utility in personalized medicine, pandemic preparedness and outbreak settings.

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