Clinical Severity of SARS-CoV-2 Variants during COVID-19 Vaccination: A Systematic Review and Meta-Analysis

The study addresses how clinical severity of COVID-19 varies across SARS-CoV-2 variants during mass vaccination and how this variability affects public health decision-making, resource allocation, and epidemic modeling. Since late 2019, COVID-19 has caused substantial global morbidity and mortality, with multiple variants of concern (Alpha, Beta, Delta, Omicron) exhibiting differing transmissibility and severity profiles across countries. Accurate estimates of clinical severity (cCHR, cCFR, HFR, HIR) are essential for prioritizing interventions and forecasting healthcare needs. Prior studies reported highly variable severity across settings (e.g., Delta cCHR ranging from 1.34% in Norway to 27.27% in Qatar). The objective is to synthesize and compare clinical severity across variants during the vaccination era, assess differences by country and age group, and explore associations with vaccine coverage.

Design: Systematic review and meta-analysis following PRISMA guidelines. Data sources and search: PubMed searched on 1 February 2022 for studies published 1 January 2020 to 1 February 2022 using terms combining severity outcomes (severity, fatality, mortality, death, hospital admission, ICU admission), disease (COVID-19, SARS-CoV-2), and variant descriptors (variant, mutation, lineage, amino acid substitution). Eligibility criteria: Population-based studies with laboratory-confirmed COVID-19 during mass vaccination periods; peer-reviewed; ≥100 confirmed cases; multiple age groups/general population. Excluded: non-variant studies, animal studies, policy/modeling, virology/genome/protein, transmission, detection/sequencing-only, pathology/immunology, treatments, reviews/news/case reports, and studies restricted to special populations. Study selection: Dual screening of titles/abstracts by two authors (Z.Y., Z.S.) with conflicts resolved by coauthors (L.M., R.G.). Full-text review applied inclusion criteria. Data extraction: Independently by two authors (Z.Y., Z.S.). Extracted counts of confirmed cases, hospitalizations, ICU admissions, and deaths; study period/location; variant identification approach; vaccine coverage in general population and elderly (two doses) from studies or official/Our World in Data sources. Calculated Pf (two-dose coverage in total population) and Po (two-dose coverage among elderly >60). Outcomes: Four clinical severity metrics—cCHR (hospitalizations among confirmed), cCFR (deaths among confirmed), HFR (deaths among hospitalized), HIR (ICU among hospitalized). 95% CIs computed assuming binomial distribution. Statistical analysis: Heterogeneity assessed with I2 and Cochran’s Q; fixed- or random-effects models selected accordingly. Meta-analyses produced pooled variant-specific estimates. Mixed-effects meta-regression explored associations between severity metrics and vaccine coverage (Pf, Po) for the Delta variant (where k≈≥10). Analyses performed in R 4.1.2. Study set: 13 studies from nine countries (US, UK, France, Norway, Israel, Qatar, Canada, India, Denmark); 21 results: Alpha (n=5), Beta (n=1), Delta (n=13), Omicron (n=2). Gamma studies focusing only on elderly were excluded.

- Study selection: 3536 records identified; 13 studies included; 9 countries; 21 variant-specific results (Alpha 5, Beta 1, Delta 13, Omicron 2). - Overall pattern across metrics: HIR highest, followed by HFR, cCHR, then cCFR. - Pooled variant-specific estimates (mean %, 95% CI, number of studies): • cCHR: Omicron 1.51% (0.00–6.15; 2), Alpha 4.02% (1.04–6.99; 5), Delta 6.56% (1.50–11.61; 11), Beta 19.96% (16.16–23.75; 1). • cCFR: Omicron 0.04% (0.00–0.61; 2), Beta 0.22% (0.00–0.83; 1), Delta 0.46% (0.20–0.73; 11), Alpha 0.66% (0.00–1.79; 4). • HFR: Beta 1.11% (0.00–4.12; 1), Omicron 3.18% (0.00–31.66; 2), Delta 9.06% (4.63–13.49; 10), Alpha 12.04% (0.36–23.72; 4). • HIR: Omicron 6.01% (0.00–38.05; 2), Beta 15.56% (7.55–23.57; 1), Delta 19.63% (13.22–26.03; 7), Alpha 19.99% (0.00–58.66; 2). - Rank by severity: Delta generally highest; Omicron lowest across metrics (study period covered Omicron BA.1). - Age-specific severity: Adults ≥65 years had substantially higher cCHR, cCFR, HFR, and HIR than younger groups; ages 0–24 had the lowest severity (e.g., Norway Alpha cCHR 0–24: 0.17% vs ≥65: 15.38%). - Country differences: Qatar showed high cCHR for Beta (19.96%) and Delta (27.27%) but no marked increase in HFR/HIR compared with other countries, potentially reflecting healthcare capacity and admission practices. - Meta-regression (Delta): No statistically significant associations between severity metrics (cCHR, cCFR, HFR, HIR) and two-dose vaccine coverage in total population (Pf) or elderly (Po), likely due to heterogeneity in healthcare systems, vaccine strategies, and vaccine products across settings.

The synthesis demonstrates that clinical severity during the vaccination era varies notably by SARS-CoV-2 variant and age. The hierarchy of severity metrics (HIR > HFR > cCHR > cCFR) reflects clinical pathways from hospitalization to intensive care and death. Elderly populations consistently experience greater risk across all metrics, underscoring the need for targeted protection. Delta exhibited the highest pooled severity across metrics, while Omicron (BA.1) showed the lowest, aligning with observed shifts in virulence and population immunity during late 2021. Between-country differences—such as higher cCHR but not proportionally higher HFR/HIR in Qatar—likely reflect differences in healthcare capacity, admission thresholds, and public health policies. Although vaccination likely mitigated severity at population level, meta-regression did not detect significant relationships between severity and two-dose coverage, possibly due to confounding and cross-country heterogeneity in vaccine strategies, products, and prior infection levels. These findings address the research question by quantifying and comparing variant-specific severities to inform public health planning and resource allocation.

This systematic review and meta-analysis of 13 studies across nine countries provides pooled estimates of clinical severity for major SARS-CoV-2 variants during mass vaccination. Delta generally had the highest severity, whereas Omicron (BA.1) had the lowest across cCHR, cCFR, HFR, and HIR. Older adults consistently faced higher risks across all metrics. These results support prioritizing interventions for more severe variants, guiding variant-specific vaccine development and clinical management strategies. Further research should assess later Omicron sublineages (e.g., BA.5, XBB, BQ.1) and incorporate more granular data on prior infection, vaccine type/strategy, and healthcare system factors to refine severity estimates.

- Important covariates potentially affecting severity (healthcare capacity, economic and climatic factors) were not included due to data limitations. - Severity assessment focused on four metrics (cCHR, cCFR, HFR, HIR); other severity measures were not analyzed. - Included studies were predominantly from upper- or middle-income countries (Europe, North America, Asia), limiting generalizability to low-income settings. - Most studies did not account for preexisting immunity from prior infection, which can reduce hospitalization and severe disease risk; thus, Omicron severity at the population level may be underestimated or confounded by immunity. - Only the first Omicron wave (BA.1) was analyzed; later sublineages were not evaluated. - Heterogeneity in variant identification methods and admission criteria across countries may influence pooled estimates.