Genomic Surveillance Reveals the Rapid Expansion of the XBB Lineage Among Circulating SARS-CoV-2 Omicron Lineages in Southeastern Wisconsin, USA

SARS-CoV-2 caused a life-threatening COVID-19 pandemic outbreak worldwide. The Southeastern Region of Wisconsin, USA (SERW) includes large urban Milwaukee and six suburban counties, namely Kenosha, Ozaukee, Racine, Walworth, Washington and Waukesha. Due to the lack of detailed SARS-CoV-2 genomic surveillance in the suburban populations of the SERW, whole-genome sequencing was employed to investigate circulating SARS-CoV-2 lineages and characterize dominant XBB lineages among this SERW population from November 2021 to April 2023. For an unbiased data analysis, we combined our 6709 SARS-CoV-2 sequences with 1520 sequences from the same geographical region submitted by other laboratories. Our study shows that SARS-CoV-2 genomes were distributed into 357 lineages/sublineages belonging to 13 clades, of which 88.8% were from Omicron. We document dominant sublineages XBB.1.5 and surging XBB.1.16 and XBB.1.9.1 with a few additional functional mutations in Spike, which are known to contribute to higher viral reproduction, enhanced transmission and immune evasion. Mutational profile assessment of XBB.1.5 Spike identifies 38 defining mutations with high prevalence occurring in 49.8-99.6% of the sequences studied, of which 32 mutations were in three functional domains. Phylogenetic and genetic relatedness between XBB.1.5 sequences reveal potential virus transmission occurring within households and within and between Southeastern Wisconsin counties. A comprehensive phylogeny of XBB.1.5 with global sub-dataset sequences confirms the wide spread of genetically similar SARS-CoV-2 strains within the same geographical area. Altogether, this study identified proportions of circulating Omicron variants and genetic characterization of XBB.1.5 in the SERW population, which helped state and national public health agencies to make compelling mitigation efforts to reduce COVID-19 transmission in the communities and monitor emerging lineages for their impact on diagnostics, treatments and vaccines.