a Schematic description of the prophylactic experimental setting. Transgenic K18-hACE2 mice were administered intraperitoneally with 10 mg/kg of 17T2 (17T2 mAb, n = 10) or an isotype control (IgGb12, n = 10). After 24 h, treated animals were intranasally challenged with an Omicron BA.1.1 SARS-CoV-2 isolate (n = 20), or PBS (Uninfected Control Group) (n = 4). Mice were monitored for 7 days. Euthanasia was performed 3- and 7-days post-infection (dpi) (n = 5 for each treated group per timepoint, n = 2 uninfected per timepoint) for sample and tissue collection. Created with Biorender.com. b Relative K18-hACE2 transgenic mice weight-loss follow-up. Groups include uninfected (gray, n = 4), 17T2 mAb-treated and infected (blue, n = 10), and isotype control-treated and infected (black, n = 10) animals. Solid lines represent mean ± SD. c SARS-CoV-2 viral RNA load quantification (copies/mL) on oropharyngeal swab and lung at 3 and 7 dpi in 17T2 mAb-treated (blue dots, n = 5 per timepoint) or isotype control-treated (black squares, n = 5 per timepoint) infected animals. The limit of detection is represented by a dashed line. Statistical differences were determined using a two-sided Peto-Prentice generalized Wilcoxon test. d Histopathological and immunohistochemical scores of lungs from infected and prophylactically treated K18-hACE2 mice. Lesion (broncho-interstitial pneumonia) scoring: 0 = no lesion, 1 = mild lesion, 2 = moderate lesion, 3 = severe lesion. IHC scoring: 0 = no antigen, 1 = low and multifocal antigen, 2 = moderate and multifocal antigen, 3 = high and diffuse antigen. # indicates an animal which presented focal expression only visible on 1 out of 5 lung sections: it was scored as 1 but with minimal detection of virus replication. All other positive scores showed multifocal distribution on multiple lung sections. Comparisons were performed using a two-sided Asymptotic Generalized Pearson Chi-Squared Test for ordinal data with pairwise comparisons. e Representative histopathological and immunohistochemical findings, at 3 and 7 dpi, in K18-hACE2 transgenic infected mice treated with either 17T2 mAb or an isotype control. Histological slides were stained with hematoxylin and eosin, and immunohistochemistry ones were counterstained with Hematoxylin. Scale Bar = 80 μM. Source data are provided as a Source Data file.