With the availability of widespread SARS-CoV-2 vaccination, high-throughput quantitative antispike serological testing will likely become increasingly important. Here, we investigated the performance characteristics of the recently FDA-authorized semiquantitative antispike AdviseDx SARS-CoV-2 IgG II assay compared to the FDA-authorized antinucleocapsid Abbott Architect SARS-CoV-2 IgG, Roche Elecsys anti-SARS-CoV-2-S, EuroImmun anti-SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA), and GenScript surrogate virus neutralization assays and examined the humoral response associated with vaccination, natural protection, and breakthrough infection.