background: Breakthrough infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) has occurred in populations with high vaccination rates. methods: In a longitudinal cohort study, pre-breakthrough infection sera for Omicron breakthroughs (n?=?12) were analyzed. Assays utilized include a laboratory-developed solid phase binding assay to recombinant spike protein, a commercial assay to the S1 domain of the spike protein calibrated to the World Health Organization (WHO) standard, and a commercial solid-phase surrogate neutralizing activity (SNA) assay. All assays employed spike protein preparations based on sequences from the Wuhan-Hu-1 strain. results: Pre-breakthrough binding antibody titers ranged from 1:800 to 1:51,200 for the laboratory-developed binding assay, which correlated well and agreed quantitatively with the commercial spike S1 domain WHO calibrated assay. SNA was detected in 10/12 (83%) samples. conclusions: Neither high binding titers nor SNA were markers of protection from Omicron infection/re-infection.