PT  - JOURNAL ARTICLE
AU  - Haley E. Mudrick
AU  - Erin B. McGlinch
AU  - Brian J. Parrett
AU  - Jack R. Hemsath
AU  - Mary E. Barry
AU  - Jeffrey D. Rubin
AU  - Chisom Uzendu
AU  - Michael J. Hansen
AU  - Courtney L. Erskine
AU  - Virginia P. VanKeulen
AU  - Aleksandra Drelich
AU  - Chien-Te Kent Tseng
AU  - Shane Massey
AU  - Madiha Fida
AU  - Gina A. Suh
AU  - Tobias Peikert
AU  - Matthew S. Block
AU  - Gloria R. Olivier
AU  - Michael A. Barry
TI  - Comparison of Mucosal and Intramuscular Immunization against SARS-CoV-2 with Replication-Defective and Replicating Single-cycle Adenovirus Vaccines
AID  - 10.1101/2021.04.20.440651
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.20.440651
4099  - http://biorxiv.org/content/early/2021/04/20/2021.04.20.440651.short
4100  - http://biorxiv.org/content/early/2021/04/20/2021.04.20.440651.full
AB  - SARS-CoV-2 enters the body at mucosal surfaces, such as the nose and lungs. These events involve a small number of virions at these mucosal barriers and are therefore a strategic point to stop a COVID-19 infection before it starts. Despite this, most vaccines against COVID-19 are being injected into the muscle where they will not generate the highest levels of mucosal protection. The vaccines that are approved for use in humans are all replication-defective (RD) mRNA, DNA, or adenovirus (Ad) vaccines that do not amplify antigen transgenes. We developed single cycle adenovirus (SC-Ad) vectors that replicate antigen genes up to 10,000-fold in human cells, but that are disabled from producing infectious Ad particles. We show here that SC-Ad expressing the full-length SARS-CoV-2 spike protein produces 100-fold more spike protein than a matched RD-Ad-Spike vector. When Ad-permissive hamsters were immunized with these vaccines by intranasal (IN) or intramuscular (IM) routes, SC-Ad produced significantly stronger antibody responses as compared to RD-Ad against the spike protein that rose over 14 weeks after one immunization. Single IN or IM immunizations generated significant antibody responses in serum and in bronchoalveolar lavages (BALs). IN priming, but not IM priming, generated HLA-restricted CD8 T cell responses in BALs. SC-Ad-Spike generated antibodies that retain binding to spike receptor binding domains (RBDs) with mutations from new viral variants. These data suggest empowering the genomes of gene-based vaccines with the ability to amplify antigen genes can increase potency. This may be particularly advantageous when applying mucosal vaccines to combat mucosal pathogens like SARS-CoV-2.One Sentence Summary Arming adenovirus vaccines with the ability to replicate vaccine antigen genes may increase potency for systemic, or more importantly, mucosal immunization against mucosal pathogens.Competing Interest StatementAll authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: MAB reports grants from Fast grants, grants from Harrington Foundation during the conduct of the study; In addition, Dr. Barry has a patent US10131921B2 licensed to Tetherex, a patent US10465206B2 licensed to Tetherex, and a patent US10640786B2 licensed to Tetherex. MSB reports grants from Bristol-Myers Squibb, grants from Genentech, grants from Immune Design, grants from Marker Therapeutics, grants from Merck, grants from Pharmacyclics, grants from Sorrento Therapeutics, grants from Transgene, other from Sorrento Therapeutics, from TILT Biotherapeutics, from Viewpoint Molecular Targeting, outside the submitted work; TP reports serving on an advisory board from AstraZeneca on areas outside of the submitted work.