Updated project metadata. We sought to compare differences in the human cellular response to distinct SARS-CoV-2 variants of concern. Here, we infected Calu-3 lung epithelial cells with each of the SARS-CoV-2 variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) compared to two early-lineage controls (VIC and IC19). We performed global abundance proteomics and phosphoproteomics at 10, 24, and, for certain samples, 48 hours post infection to comprehensively characterize the host response to infection.