Background Emerging 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. Objective We 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. Methods The general methodology involved the collation and stratification, covariance, regression analysis, normalization, and comparative inferential statistical analysis through null hypothesis testing (paired 2-tailed t tests) of South African COVID-19 epidemiological data. Results The 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%). Conclusions The 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.

BACKGROUND Emerging 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. OBJECTIVE We 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. METHODS The general methodology involved the collation and stratification, covariance, regression analysis, normalization, and comparative inferential statistical analysis through null hypothesis testing (paired 2-tailed <i>t</i> tests) of South African COVID-19 epidemiological data. RESULTS The 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%). CONCLUSIONS The 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.

The manuscript [2] is well written, and the subject addressed in this manuscript is worth investigating; however, the manuscript partly failed to present a clear picture of its analytical methodology and presentation of results.Response: The authors have revised the methodology and presentation of the results.The following are some minor concerns for consideration. I suggest that the authors (a) extend the study to include the recent Omicron variant.Response: The authors have extended the study to include the Omicron variant.The following are some minor concerns for consideration. I suggest that the authors (b) present results with complete models.Response: The authors have presented results with complete model methodologies.The following are some minor concerns for consideration. I suggest that the authors (c) avoid excessive references (~71).Response: The authors have tried to reduce the references in the manuscript to critical references. Reviewer BQ [3] General CommentsThis manuscript is well written, comprehensive, and filled with detail. This is both a strength and a possible weakness. The strength is that the data included have been analyzed in depth, and one can be fairly certain that the results obtained are likely to be accurate. On the other hand, depending on the audience, some readers may struggle to engage with the data appropriately; the dissemination of data and reporting has not been formatted

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