(A) Venn diagram of differentially expressed genes (DEGs) expressed 3 days post challenge with SARS-CoV-2. Animals either received a control, intramuscular (IM) or intranasal (IN) vaccination. (B) Bubbleplot representing functional enrichment of DEGs shared by all infected groups at 7 days post challenge. Color intensity of each bubble represents the negative log of p-value and the relative size of each bubble represents the number of DEGs belonging to the specified Gene Ontology (GO) term. Heatmaps representing shared GO terms (C) “regulation of innate immune response”, “antigen processing and presentation of exogenous antigen” for downregulated DEGs; and (D) “regulated exocytosis”, “myeloid leukocyte activation” and “neutrophil degranulation” for upregulated DEGs. Expression is represented as the normalized rpkm, where each column represents the median rpkm of the given group. Range of colors is based on scale and centered rpkm values of the represented DEGs. GO term network depicting functional enrichment of DEGs unique to (E) IN and (G) IM using Mediascape. Color-coded clustered nodes correspond to one GO term or KEGG pathway. Node size represents the number of DEGs associated with the indicated term or pathway. Gray lines represent shared interactions between terms/pathways, with density and number indicating the strength of connections between closely related terms/pathways. Heatmaps representing DEGs unique to (F) IN and (H) IM. Exemplar DEGs are annotated. Red represents upregulation, blue presents downregulation. Each column represents the median rpkm of the given group. For all heatmaps, range of colors is based on scale and centered rpkm values of the represented DEGs.