Inconsistent directions of change in case severity across successive SARS-CoV-2 variant waves suggests an unpredictable future (preprint)

ObjectiveTo determine how the severity of successively dominant SARS-CoV-2 variants changed over the course of the COVID-19 pandemic. DesignRetrospective cohort analysis. SettingCommunity- and hospital-sequenced COVID-19 cases in the NHS Greater Glasgow and Clyde (NHS GG&C) Health Board. ParticipantsAll sequenced non-nosocomial adult COVID-19 cases in NHS GG&C infected with the relevant SARS-CoV-2 lineages during analysis periods. B.1.177/Alpha: 1st November 2020 - 30th January 2021 (n = 1640). Alpha/Delta: 1st April - 30th June 2021 (n = 5552). AY.4.2 Delta/non-AY.4.2 Delta: 1st July - 31st October 2021 (n = 9613). Non-AY.4.2 Delta/Omicron: 1st - 31st December 2021 (n = 3858). Main outcome measuresAdmission to hospital, ICU, or death within 28 days of positive COVID-19 test ResultsFor B.1.177/Alpha, 300 of 807 B.1.177 cases were recorded as hospitalised or worse, compared to 232 of 833 Alpha cases. After adjustment, the cumulative odds ratio was 1.51 (95% CI: 1.08-2.11) for Alpha versus B.1.177. For Alpha/Delta, 113 of 2104 Alpha cases were recorded as hospitalised or worse, compared to 230 of 3448 Delta cases. After adjustment, the cumulative odds ratio was 2.09 (95% CI: 1.42-3.08) for Delta versus Alpha. For non-AY.4.2 Delta/AY.4.2 Delta, 845 of 8644 non-AY.4.2 Delta cases were recorded as hospitalised or worse, compared to 101 of 969 AY.4.2 Delta cases. After adjustment, the cumulative odds ratio was 0.99 (95% CI: 0.76-1.27) for AY.4.2 Delta versus non-AY.4.2 Delta. For non-AY.4.2 Delta/Omicron, 30 of 1164 non-AY.4.2 Delta cases were recorded as hospitalised or worse, compared to 26 of 2694 Omicron cases. After adjustment, the median cumulative odds ratio was 0.49 (95% CI: 0.22-1.06) for Omicron versus non-AY.4.2 Delta. ConclusionsThe direction of change in disease severity between successively emerging SARS-CoV-2 variants of concern was inconsistent. This heterogeneity demonstrates that severity associated with future SARS-CoV-2 variants is unpredictable.

The SARS-CoV-2 Alpha variant is associated with increased clinical severity of disease (preprint)

BackgroundThe B.1.1.7 (Alpha) SARS-CoV-2 variant of concern was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between the B.1.1.7 lineage infection and increased 28-day mortality. However, to date none have addressed the impact of infection on severity of illness or the need for oxygen or ventilation. MethodsIn this prospective clinical cohort sub-study of the COG-UK consortium, 1475 samples from hospitalised and community cases collected between the 1st November 2020 and 30th January 2021 were collected. These samples were sequenced in local laboratories and analysed for the presence of B.1.1.7-defining mutations. We prospectively matched sequence data to clinical outcomes as the lineage became dominant in Scotland and modelled the association between B.1.1.7 infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no support, 2. oxygen, 3. ventilation and 4. death. Additionally, we calculated an estimate of the growth rate of B.1.1.7-associated infections following introduction into Scotland using phylogenetic data. ResultsB.1.1.7 was responsible for a third wave of SARS-CoV-2 in Scotland, and rapidly replaced the previously dominant second wave lineage B.1.177) due to a significantly higher transmission rate ([~]5 fold). Of 1475 patients, 364 were infected with B.1.1.7, 1030 with B.1.177 and 81 with other lineages. 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 (B.1.1.7 versus non-B.1.1.7). 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). ConclusionsThe B.1.1.7 lineage was associated with more severe clinical disease in Scottish patients than co-circulating lineages. FundingCOG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute. Funding was also provided by UKRI through the JUNIPER consortium (grant number MR/V038613/1). Sequencing and bioinformatics support was funded by the Medical Research Council (MRC) core award (MC UU 1201412).

Early epidemiological signatures of novel SARS-CoV-2 variants: establishment of B.1.617.2 in England (preprint)

The rapid emergence of SARS-CoV-2 mutants with new phenotypic properties is a critical challenge to the control of the ongoing pandemic. B.1.1.7 was monitored in the UK through routine testing and S-gene target failures (SGTF), comprising over 90% of cases by March 2021. Now, the reverse is occurring: SGTF cases are being replaced by an S-gene positive variant, which we associate with B.1.617.2. Evidence from the characteristics of S-gene positive cases demonstrates that, following importation, B.1.617.2 is transmitted locally, growing at a rate higher than B.1.1.7 and a doubling time between 5-14 days. S-gene positive cases should be prioritised for sequencing and aggressive control in any countries in which this variant is newly detected.

The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity (preprint)

SARS-CoV-2 can mutate to evade immunity, with consequences for the efficacy of emerging vaccines and antibody therapeutics. Herein we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is the most divergent region of S, and provide epidemiological, clinical, and molecular characterization of a prevalent RBM variant, N439K. We demonstrate that N439K S protein has enhanced binding affinity to the hACE2 receptor, and that N439K virus has similar clinical outcomes and in vitro replication fitness as compared to wild- type. We observed that the N439K mutation resulted in immune escape from a panel of neutralizing monoclonal antibodies, including one in clinical trials, as well as from polyclonal sera from a sizeable fraction of persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.

Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity (preprint)

Global dispersal and increasing frequency of the SARS-CoV-2 Spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of Spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large data set, well represented by both Spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the Spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant.