BackgroundEmerging SARS-CoV-2 variants have been attributed to the occurrence of secondary, tertiary, quaternary, and quinary COVID-19 epidemic waves threatening vaccine efforts owing to their immune invasiveness. Since the importation of SARS-CoV-2 in South Africa, with the first reported COVID-19 case on March 5, 2020, South Africa has observed 5 consecutive COVID-19 epidemic waves. The evolution of SARS-CoV-2 has played a major role in the resurgence of COVID-19 epidemic waves in South Africa and across the globe.ObjectiveWe aimed to conduct descriptive and inferential statistical analysis on South African COVID-19 epidemiological data to investigate the impact of SARS-CoV-2 lineages and COVID-19 vaccinations in South African COVID-19 epidemiology.MethodsThe general methodology involved the collation and stratification, covariance, regression analysis, normalization, and comparative inferential statistical analysis through null hypothesis testing (paired 2-tailedttests) of South African COVID-19 epidemiological data.ResultsThe mean daily positive COVID-19 tests in South Africa’s first, second, third, fourth, and fifth COVID-19 epidemic wave periods were 11.5% (SD 8.58%), 11.5% (SD 8.45%), 13.3% (SD 9.72%), 13.1% (SD 9.91%), and 14.3% (SD 8.49%), respectively. The COVID-19 transmission rate in the first and second COVID-19 epidemic waves in South Africa was similar, while the COVID-19 transmission rate was higher in the third, fourth, and fifth COVID-19 epidemic waves than in the aforementioned waves. Most COVID-19 hospitalized cases in South Africa were in the general ward (60%-79.1%). Patients with COVID-19 on oxygen were the second-largest admission status (11.2%-16.8%), followed by patients with COVID-19 in the intensive care unit (8.07%-16.7%). Most patients hospitalized owing to COVID-19 in South Africa’s first, second, third, and fourth COVID-19 epidemic waves were aged between 40 and 49 years (16.8%-20.4%) and 50 and 59 years (19.8%-25.3%). Patients admitted to the hospital owing to COVID-19 in the age groups of 0 to 19 years were relatively low (1.98%-4.59%). In general, COVID-19 hospital admissions in South Africa for the age groups between 0 and 29 years increased after each consecutive COVID-19 epidemic wave, while for age groups between 30 and 79 years, hospital admissions decreased. Most COVID-19 hospitalization deaths in South Africa in the first, second, third, fourth, and fifth COVID-19 epidemic waves were in the ages of 50 to 59 years (15.8%-24.8%), 60 to 69 years (15.9%-29.5%), and 70 to 79 years (16.6%-20.7%).ConclusionsThe relaxation of COVID-19 nonpharmaceutical intervention health policies in South Africa and the evolution of SARS-CoV-2 were associated with increased COVID-19 transmission and severity in the South African population. COVID-19 vaccination in South Africa was strongly associated with a decrease in COVID-19 hospitalization and severity in South Africa.