The COVID-19 pandemic, caused by SARS-CoV-2, resulted in millions of infections and deaths worldwide. Despite vaccine development, the virus continued to mutate, leading to variants with varying transmission rates and clinical severity. Accurate estimation of clinical severity is crucial for effective resource allocation, prioritization of interventions (social distancing, school closures, etc.), and disease modeling. Existing studies showed significant variability in reported clinical severity across different countries and variants. This study aimed to provide pooled estimates of clinical severity for different SARS-CoV-2 variants (Alpha, Beta, Delta, Omicron) during mass vaccination, considering variations across countries and age groups and assessing the impact of vaccination programs on severity.

Several studies have evaluated the clinical severity of COVID-19, but considerable differences exist in reported severity across studies and countries. For instance, the confirmed case-hospitalization risk (cCHR) for the Delta variant varied widely, from 1.34% in Norway to 27.27% in Qatar. This heterogeneity highlights the need for a comprehensive meta-analysis to provide more accurate estimates, considering factors like healthcare systems, public health policies, and vaccination strategies.

A systematic review and meta-analysis were conducted following PRISMA guidelines. PubMed was searched on 1 February 2022 for studies published between 1 January 2020 and 1 February 2022. Studies were included if they reported laboratory-confirmed COVID-19 cases during mass vaccination, had over 100 confirmed cases across multiple age groups, and focused on Alpha, Beta, Delta, or Omicron variants. Four clinical severity metrics (cCHR, cCFR, HFR, HIR) were calculated for each study. Heterogeneity was assessed using the I² index. Random-effects or fixed-effects models were used for meta-analysis, with meta-regression analysis applied to examine the association between severity and vaccination rates. Data analysis was performed using R version 4.1.2. The search process initially yielded 3536 studies, which were screened based on title and abstract (3194 excluded), and then full text (342 excluded), leaving 13 studies for meta-analysis. The data extraction included confirmed cases, hospitalizations, ICU admissions, and deaths, along with vaccine coverage data from the studies and Our World in Data.

The meta-analysis included data from 13 studies across nine countries (US, UK, France, Norway, Israel, Qatar, Canada, India, Denmark). Twenty-one sets of clinical results were available (5 Alpha, 1 Beta, 13 Delta, 2 Omicron). Across all variants, HIR was the highest, followed by HFR, cCHR, and cCFR. Delta consistently showed the highest severity among the variants, while Omicron exhibited the lowest. Specifically: * **cCHR:** Omicron (1.51%), Alpha (4.02%), Delta (6.56%), Beta (19.96%) * **cCFR:** Omicron (0.04%), Beta (0.22%), Delta (0.46%), Alpha (0.66%) * **HFR:** Omicron (3.18%), Beta (1.11%), Delta (9.06%), Alpha (12.04%) * **HIR:** Omicron (6.01%), Beta (15.56%), Delta (19.63%), Alpha (19.99%) Analysis by age group showed significantly higher severity levels for all four metrics in adults over 65. Younger individuals (0-24) showed the lowest severity. Meta-regression analysis of Delta variant data did not reveal a significant association between vaccination rates and clinical severity, possibly due to variations in healthcare systems and vaccine strategies across countries.

This study provides comprehensive estimates of COVID-19 severity for various SARS-CoV-2 variants during mass vaccination. The findings confirm Delta's high severity and Omicron's comparatively lower severity (though only the BA.1 Omicron variant was considered). The higher severity observed in older adults highlights the importance of targeted interventions for this vulnerable population. The lack of a significant association between vaccination rates and severity underscores the complexity of factors influencing clinical outcomes, such as healthcare infrastructure, public health policies, and underlying health conditions. The study's findings support the need for variant-specific interventions, including vaccine development and treatment strategies.

This meta-analysis, based on 13 studies from nine countries, provides crucial insights into the clinical severity of different SARS-CoV-2 variants during mass vaccination. Delta and Omicron variants demonstrated the highest and lowest severity, respectively. The higher severity in older adults emphasizes the need for targeted public health strategies. Future research should investigate the impact of other Omicron subvariants and explore the interplay between vaccination, pre-existing immunity, and other factors influencing clinical outcomes.

Several limitations should be noted. Data on factors such as healthcare conditions, climate, and economic conditions were unavailable and couldn't be incorporated into the analysis. The study primarily focused on cCHR, cCFR, HFR, and HIR, excluding other potential severity metrics. The study's data primarily came from high- and middle-income countries, potentially underrepresenting severity in low-income settings. Furthermore, most studies did not account for pre-existing immunity from prior infection.