In South Africa, there was identification of the SARS-CoV-2 omicron variant of concern in November, 2021, which was linked with a rise in COVID-19 cases. In this study, the clinical severity of infections with the omicron variant was determined using S gene target failure (SGTF) on the Thermo Fisher Scientific TaqPath COVID-19 PCR test as a proxy.

• Data linkages were conducted for national, South African COVID-19 case data, SARS-CoV-2 laboratory test data, SARS-CoV-2 genome data, and COVID-19 hospital admissions data.

• A total of 161,328 cases of COVID-19 were reported from October 1 (week 39) to December 6 (week 49), 2021.

• TaqPath PCR tests were used to diagnose 38,282 people and identification of 29,721 SGTF infections and 1,412 non-SGTF infections was made.

• Individuals with SGTF were noted to be at significantly reduced risks of hospitalization vs those diagnosed non-SGTF infections during the same time period.

• There appeared significantly reduced odds of severe disease among SGTF-infected individuals vs with individuals infected earlier with the delta variant.

• Previous immunity may have resulted in some of this reduced severity.