TY - JOUR T1 - Modular capsid decoration boosts adenovirus vaccine-induced humoral and cellular immunity against SARS-CoV-2 JF - bioRxiv DO - 10.1101/2022.02.20.480711 SP - 2022.02.20.480711 AU - Matthew D. J. Dicks AU - Louisa M. Rose AU - Lesley A. H. Bowman AU - Carl Graham AU - Katie J. Doores AU - Michael H. Malim AU - Simon J. Draper AU - Mark Howarth AU - Sumi Biswas Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/02/22/2022.02.20.480711.abstract N2 - 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 immunityCompeting Interest StatementMDJD, 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. ER -