IN boosting affords superior protection following SARS-CoV-2 omicron BA.1 challenge in a hamster model. (A) Vaccination and infectious challenge schedule examining the protective efficacy of Ad-WT^IM versus Ad-ο^IM versus Ad-ο^IN boost against a SARS-CoV-2 omicron BA.1 challenge in Syrian golden hamsters. Hamsters were followed for 5 days following challenge, with subgroups killed on day 2 and 5 after challenge to assess tissue responses. (B) Weight change kinetics following BA.1 challenge. Each line represents an individual animal, and the red line is group median. (C) Viral load assessed by PCR of nasal swabs. (D) Viral load assessed by PCR of lung homogenates or nasal washes. (E) Lung weight. (F) Omicron-specific IgG antibody responses in serum and ACE-2–competing omicron S1–specific antibodies (o-ACE2^comp-Abs). For all data, *P < 0.05, **P < 0.01, ***P < 0.001, ****P ≤ 0.0001. Parametric one-way ANOVA tests with multiple comparison testing were performed. On violin plots, the dashed black line represents the group median response and dots represent individual mice. Data shown are from one experiment (n = 14).