Background The Alpha (B.1.1.7) SARS-CoV-2 variant of concern has been associated with increased transmission and increased 28-day mortality. We aimed to investigate the impact of infection on clinical severity of illness, including the need for oxygen or ventilation in a national cohort study. Methods In this prospective clinical cohort study, 1475 SARS-CoV-2 sequences were obtained from patients infected in Scotland, UK between the 1st November 2020 and 30th January 2021 and matched to clinical outcomes as the lineage became dominant in Scotland. We modelled the association between B.1.1.7 infection and severe disease using a cumulative generalised linear mixed model employing a 4-point scale of maximum severity based on requirement of respiratory support at 28 days. We also estimated the growth rate of B.1.1.7-associated infections as it emerged in Scotland using a phylogenetic exponential growth rate population model. Results The B.1.1.7 lineage was responsible for a third wave of SARS-CoV-2 infection in Scotland in association with a transmission rate 5-fold higher than the preceding second wave B.1.177 lineage. Of 1475 patients, 364 were infected with B.1.1.7, 1030 with B.1.177 and 81 with other lineages. Our analysis found a positive association between increased clinical severity and lineage (B.1.1.7 versus non-B.1.1.7; cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93). Viral load was higher in B.1.1.7 samples than in non-B.1.1.7 samples, as measured by cycle threshold (Ct) value (mean Ct change: -2.46, 95% CI: -4.22, -0.70). Conclusions The B.1.1.7 lineage was associated with more severe clinical disease in Scottish patients than co-circulating lineages.

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Objective To determine how the severity of successively dominant SARS-CoV-2 variants has changed over the course of the COVID-19 pandemic. Design Prospective cohort analysis. Setting Community- and hospital- sequenced COVID-19 cases in the NHS Greater Glasgow and Clyde (NHS GG&C) Health Board (1.2 million people). Participants All sequenced non-nosocomial adult COVID-19 cases in NHS GG&C identified to be infected with the relevant SARS-CoV-2 lineage during the following analysis periods. B.1.177/Alpha analysis: 1st November 2020 - 30th January 2021 (n = 1640). Alpha/Delta analysis: 1st April - 30th June 2021 (n = 5552). AY.4.2 Delta/non-AY.4.2 Delta analysis: 1st July - 31st October 2021 (n = 9613). Non-AY.4.2 Delta/Omicron analysis: 1st - 31st December 2021 (n = 3858). Main outcome measures Admission to hospital, admission to ICU, or death within 28 days of first positive COVID-19 test Results In the B.1.177/Alpha analysis, 300 of 807 (37.2%) B.1.177 cases were recorded as hospitalised or having a more severe outcome, compared to 232 of 833 (27.9%) Alpha cases. After adjusting for the following covariates: age, sex, time of positive test, comorbidities and partial postcode, the cumulative odds ratio was 1.51 (95% central credible interval 1.08-2.11) for Alpha versus B.1.177. In the Alpha/Delta analysis, 113 of 2104 (5.4%) Alpha cases were recorded as hospitalised or having a more severe outcome, compared to 230 of 3448 (6.7%) Delta cases. After adjusting for the above covariates plus number of vaccine doses and reinfection, the cumulative odds ratio was 2.09 (95% central credible interval 1.42-3.08) for Delta versus Alpha. In the non-AY.4.2 Delta/AY.4.2 Delta analysis, 845 of 8644 (9.8%) non-AY.4.2 Delta cases were recorded as hospitalised or having a more severe outcome, compared to 101 of 969 (10.4%) AY.4.2 Delta cases. After adjusting for the previously stated covariates, the cumulative odds ratio was 0.99 (95% central credible interval 0.76-1.27) for AY.4.2 Delta versus non-AY.4.2 Delta. In the non-AY.4.2 Delta/Omicron analysis, 30 of 1164 (2.6%) non-AY.4.2 Delta cases were recorded as hospitalised or having a more severe outcome, compared to 26 of 2694 (1.0%) Omicron cases. After adjusting for the previously listed covariates, the median cumulative odds ratio was 0.49 (95% central credible interval 0.22-1.06) for Omicron versus non-AY.4.2 Delta. Conclusions The direction of change in disease severity between successively emerging SARS-CoV-2 variants of concern was inconsistent. This heterogeneity in virulence between variants, coupled with independent evolutionary emergence, demonstrates that severity associated with future SARS-CoV-2 variants is inherently unpredictable.

Our results suggest that early line infection may be protective against CVS. Alternatively, there may be two distinct predisposition states for CVS and line infection. Further studies are needed to confirm our association and investigate causation.

Objectives The SARS-CoV-2 Alpha variant was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between Alpha variant infection and increased hospitalisation and 28-day mortality. However, none have addressed the impact on maximum severity of illness in the general population classified by the level of respiratory support required, or death. We aimed to do this. Methods In this retrospective multi-centre clinical cohort sub-study of the COG-UK consortium, 1475 samples from Scottish hospitalised and community cases collected between 1st November 2020 and 30th January 2021 were sequenced. We matched sequence data to clinical outcomes as the Alpha variant became dominant in Scotland and modelled the association between Alpha variant infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no respiratory support, 2. supplemental oxygen, 3. ventilation and 4. death. Results Our cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (Alpha variant versus pre-Alpha variants). Conclusions The Alpha variant was associated with more severe clinical disease in the Scottish population than co-circulating lineages.