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OBJECTIVES: To determine how the intrinsic severity of successively dominant SARS-CoV-2 variants changed over the course of the pandemic. METHODS: A retrospective cohort analysis in the NHS Greater Glasgow and Clyde (NHS GGC) Health Board. All sequenced non-nosocomial adult COVID-19 cases in NHS GGC with relevant SARS-CoV-2 lineages (B.1.177/Alpha, Alpha/Delta, AY.4.2 Delta/non-AY.4.2 Delta, non-AY.4.2 Delta/Omicron, and BA.1 Omicron/BA.2 Omicron) during analysis periods were included. Outcome measures were hospital admission, ICU admission, or death within 28 days of positive COVID-19 test. We report the cumulative odds ratio; the ratio of the odds that an individual experiences a severity event of a given level vs all lower severity levels for the resident and the replacement variant after adjustment. RESULTS: After adjustment for covariates, the cumulative odds ratio was 1.51 (95% CI: 1.08-2.11) for Alpha versus B.1.177, 2.09 (95% CI: 1.42-3.08) for Delta versus Alpha, 0.99 (95% CI: 0.76-1.27) for AY.4.2 Delta versus non-AY.4.2 Delta, 0.49 (95% CI: 0.22-1.06) for Omicron versus non-AY.4.2 Delta, and 0.86 (95% CI: 0.68-1.09) for BA.2 Omicron versus BA.1 Omicron. CONCLUSIONS: The direction of change in intrinsic severity between successively emerging SARS-CoV-2 variants was inconsistent, reminding us that the intrinsic severity of future SARS-CoV-2 variants remains uncertain.

Background: The SARS-CoV-2 omicron variant (B.1.1.529) is highly transmissible, but disease severity appears to be reduced compared with previous variants such as alpha and delta. We investigated the risk of severe outcomes following infection in residents of long-term care facilities. Methods: We did a prospective cohort study in residents of long-term care facilities in England who were tested regularly for SARS-CoV-2 between Sept 1, 2021, and Feb 1, 2022, and who were participants of the VIVALDI study. Residents were eligible for inclusion if they had a positive PCR or lateral flow device test during the study period, which could be linked to a National Health Service (NHS) number, enabling linkage to hospital admissions and mortality datasets. PCR or lateral flow device test results were linked to national hospital admission and mortality records using the NHS-number-based pseudo-identifier. We compared the risk of hospital admission (within 14 days following a positive SARS-CoV-2 test) or death (within 28 days) in residents who had tested positive for SARS-CoV-2 in the period shortly before omicron emerged (delta-dominant) and in the omicron-dominant period, adjusting for age, sex, primary vaccine course, past infection, and booster vaccination. Variants were confirmed by sequencing or spike-gene status in a subset of samples. Results: 795 233 tests were done in 333 long-term care facilities, of which 159 084 (20·0%) could not be linked to a pseudo-identifier and 138 012 (17·4%) were done in residents. Eight residents had two episodes of infection (>28 days apart) and in these cases the second episode was excluded from the analysis. 2264 residents in 259 long-term care facilities (median age 84·5 years, IQR 77·9–90·0) were diagnosed with SARS-CoV-2, of whom 253 (11·2%) had a previous infection and 1468 (64·8%) had received a booster vaccination. About a third of participants were male. Risk of hospital admissions was markedly lower in the 1864 residents infected in the omicron-period (4·51%, 95% CI 3·65–5·55) than in the 400 residents infected in the pre-omicron period (10·50%, 7·87–13·94), as was risk of death (5·48% [4·52–6·64] vs 10·75% [8·09–14·22]). Adjusted hazard ratios (aHR) also indicated a reduction in hospital admissions (0·64, 95% CI 0·41–1·00; p=0·051) and mortality (aHR 0·68, 0·44–1·04; p=0·076) in the omicron versus the pre-omicron period. Findings were similar in residents with a confirmed variant. Interpretation: Observed reduced severity of the omicron variant compared with previous variants suggests that the wave of omicron infections is unlikely to lead to a major surge in severe disease in long-term care facility populations with high levels of vaccine coverage or natural immunity. Continued surveillance in this vulnerable population is important to protect residents from infection and monitor the public health effect of emerging variants. Funding: UK Department of Health and Social Care.

Funder: COG-UK, 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.

Pathogen sequencing guided understanding of SARS-CoV-2 evolution during the COVID-19 pandemic. Many health systems developed pathogen genomics services to monitor SARS-CoV-2. There are no agreed guidelines about how pathogen genomic information should be used in public health practice. We undertook a modified Delphi study in three rounds to develop expert consensus statements about how genomic information should be used. Our aim was to inform health protection policy, planning and practice. Participants were from organisations that produced or used pathogen genomics information in the United Kingdom. The first round posed questions derived from a rapid literature review. Responses informed statements for the subsequent rounds. Consensus was accepted when 70 % or more of the responses were strongly agree/agree, or 70 % were disagree/strongly disagree on the five-point Likert scale. Consensus was achieved in 26 (96 %) of 27 statements. We grouped the statements into six categories: monitoring the emergence of new variants; understanding the epidemiological context of genomic data; using genomic data in outbreak risk assessment and risk management; prioritising the use of limited sequencing capacity; sequencing service performance; and sequencing service capability. The expert consensus statements will help guide public health authorities and policymakers to integrate pathogen genomics in health protection practice.

BACKGROUND: Barriers to rapid return of sequencing results can affect the utility of sequence data for infection prevention and control decisions. AIM: To undertake a mixed-methods analysis to identify challenges that sites faced in achieving a rapid turnaround time (TAT) in the COVID-19 Genomics UK Hospital-Onset COVID-19 Infection (COG-UK HOCI) study. METHODS: For the quantitative analysis, timepoints relating to different stages of the sequencing process were extracted from both the COG-UK HOCI study dataset and surveys of study sites. Qualitative data relating to the barriers and facilitators to achieving rapid TATs were included from thematic analysis. FINDINGS: The overall TAT, from sample collection to receipt of sequence report by infection control teams, varied between sites (median 5.1 days, range 3.0-29.0 days). Most variation was seen between reporting of a positive COVID-19 polymerase chain reaction (PCR) result to sequence report generation (median 4.0 days, range 2.3-27.0 days). On deeper analysis, most of this variability was accounted for by differences in the delay between the COVID-19 PCR result and arrival of the sample at the sequencing laboratory (median 20.8 h, range 16.0-88.7 h). Qualitative analyses suggest that closer proximity of sequencing laboratories to diagnostic laboratories, increased staff flexibility and regular transport times facilitated a shorter TAT. CONCLUSION: Integration of pathogen sequencing into diagnostic laboratories may help to improve sequencing TAT to allow sequence data to be of tangible value to infection control practice. Adding a quality control step upstream to increase capacity further down the workflow may also optimize TAT if lower quality samples are removed at an earlier stage.

Background\ud Advances in SARS-CoV-2 sequencing have enabled identification of new variants, tracking of its evolution, and monitoring of its spread. We aimed to use whole genome sequencing to describe the molecular epidemiology of the SARS-CoV-2 outbreak and to inform the implementation of effective public health interventions for control in Zimbabwe.\ud \ud Methods\ud We performed a retrospective study of nasopharyngeal samples collected from nine laboratories in Zimbabwe between March 20 and Oct 16, 2020. Samples were taken as a result of quarantine procedures for international arrivals or to test for infection in people who were symptomatic or close contacts of positive cases. Samples that had a cycle threshold of less than 30 in the diagnostic PCR test were processed for sequencing. We began our analysis in July, 2020 (120 days since the first case), with a follow-up in October, 2020 (at 210 days since the first case). The phylogenetic relationship of the genome sequences within Zimbabwe and global samples was established using maximum likelihood and Bayesian methods.\ud \ud Findings\ud Of 92 299 nasopharyngeal samples collected during the study period, 8099 were PCR-positive and 328 were available for sequencing, with 156 passing sequence quality control. 83 (53%) of 156 were from female participants. At least 26 independent introductions of SARS-CoV-2 into Zimbabwe in the first 210 days were associated with 12 global lineages. 151 (97%) of 156 had the Asp614Gly mutation in the spike protein. Most cases, 93 (60%), were imported from outside Zimbabwe. Community transmission was reported 6 days after the onset of the outbreak.\ud \ud Interpretation\ud Initial public health interventions delayed onset of SARS-CoV-2 community transmission after the introduction of the virus from international and regional migration in Zimbabwe. Global whole genome sequence data are essential to reveal major routes of spread and guide intervention strategies.\ud \ud Funding\ud WHO, Africa CDC, Biotechnology and Biological Sciences Research Council, Medical Research Council, National Institute for Health Research, and Genome Research Limited.

Funder: Trinidad and Tobago - UWI Research Development Impact Fund, The scale of data produced during the SARS-CoV-2 pandemic has been unprecedented, with more than 13 million sequences shared publicly at the time of writing. This wealth of sequence data provides important context for interpreting local outbreaks. However, placing sequences of interest into national and international context is difficult given the size of the global dataset. Often outbreak investigations and genomic surveillance efforts require running similar analyses again and again on the latest dataset and producing reports. We developed civet (cluster investigation and virus epidemiology tool) to aid these routine analyses and facilitate virus outbreak investigation and surveillance. Civet can place sequences of interest in the local context of background diversity, resolving the query into different 'catchments' and presenting the phylogenetic results alongside metadata in an interactive, distributable report. Civet can be used on a fine scale for clinical outbreak investigation, for local surveillance and cluster discovery, and to routinely summarise the virus diversity circulating on a national level. Civet reports have helped researchers and public health bodies feedback genomic information in the appropriate context within a timeframe that is useful for public health.

The raw material for viral evolution is provided by intra-host mutations occurring during replication, transcription or post-transcription. Replication and transcription of Coronaviridae proceed through the synthesis of negative-sense 'antigenomes' acting as templates for positive-sense genomic and subgenomic RNA. Hence, mutations in the genomes of SARS-CoV-2 and other coronaviruses can occur during (and after) the synthesis of either negative-sense or positive-sense RNA, with potentially distinct patterns and consequences. We explored for the first time the mutational spectrum of SARS-CoV-2 (sub)genomic and anti(sub)genomic RNA. We use a high-quality deep sequencing dataset produced using a quantitative strand-aware sequencing method, controlled for artefacts and sequencing errors, and scrutinized for accurate detection of within-host diversity. The nucleotide differences between negative- and positive-sense strand consensus vary between patients and do not show dependence on age or sex. Similarities and differences in mutational patterns between within-host minor variants on the two RNA strands suggested strand-specific mutations or editing by host deaminases and oxidative damage. We observe generally neutral and slight negative selection on the negative strand, contrasting with purifying selection in ORF1a, ORF1b and S genes of the positive strand of the genome.

BACKGROUND: Most patients with SARS-CoV-2 are non-infectious within 2 weeks, though viral RNA may remain detectable for weeks. However there are reports of persistent SARS-CoV-2 infection, with viable virus and ongoing infectivity months after initial detection. Beyond individuals, viral evolution during persistent infections may be accelerated, driving emergence of mutations associated with viral variants of concern. These patients often do not meet inclusion criteria for clinical trials, meaning clinical and virologic characteristics, and optimal management strategies are poorly evidence-based. METHODS: We analysed cases of SARS-CoV-2 infection from a regional testing laboratory in South-West England between March 2020 and December 2021, with at least two SARS-CoV-2 positive samples separated by ≥ 56 days were identified. Excluding those with confirmed or likely re-infection, we identified patients with persistent infection, characterised by an ongoing clinical syndrome consistent with COVID-19 alongside monophyletic viral lineage of SARS-CoV-2. We examined clinical and virologic characteristics, treatment, and outcome. We further performed a literature review investigating cases of persistent SARS-CoV-2 infection, reviewing patient characteristics and treatment. RESULTS: We identified six patients with persistent SARS-CoV-2 infection. All were hypogammaglobulinaemic and had underlying haematological malignancy, with four having received B-cell depleting therapy. Evidence of viral evolution, including accrual of mutations associated with variants of concern, was demonstrated in five cases. Four patients ultimately cleared SARS-CoV-2. In two patients, clearance followed treatment with casirivimab/imdevimab. Both survived beyond thirty days following viral clearance, having experienced infections of 305- and 269-days duration respectively, after failed attempts at clearance with alternative therapies. We found 60 cases of confirmed persistent infection in the literature, with a further 31 probable cases. Of those, 80% of patients treated with monoclonal antibodies cleared SARS-CoV-2, and none died. CONCLUSION: Haematological malignancy and patients receiving B-cell depleting therapies represent key groups at risk of persistent SARS-CoV-2 infection. Throughout persistent infection, SARS-CoV-2 can evolve rapidly, giving rise to significant mutations, including those implicated in variants of concern. Monoclonal antibodies appear to be a promising therapeutic option, potentially in combination with antivirals, crucial for individuals, and for public health.

Monoclonal antibodies (mAbs) offer a treatment option for individuals with severe COVID-19 and are especially important in high-risk individuals where vaccination is not an option. Given the importance of understanding the evolution of resistance to mAbs by SARS-CoV-2, we reviewed the available in vitro neutralization data for mAbs against live variants and viral constructs containing spike mutations of interest. Unfortunately, evasion of mAb-induced protection is being reported with new SARS-CoV-2 variants. The magnitude of neutralization reduction varied greatly among mAb-variant pairs. For example, sotrovimab retained its neutralization capacity against Omicron BA.1 but showed reduced efficacy against BA.2, BA.4 and BA.5, and BA.2.12.1. At present, only bebtelovimab has been reported to retain its efficacy against all SARS-CoV-2 variants considered here. Resistance to mAb neutralization was dominated by the action of epitope single amino acid substitutions in the spike protein. Although not all observed epitope mutations result in increased mAb evasion, amino acid substitutions at non-epitope positions and combinations of mutations also contribute to evasion of neutralization. This Review highlights the implications for the rational design of viral genomic surveillance and factors to consider for the development of novel mAb therapies.

Genomic surveillance of SARS-CoV-2 has provided a critical evidence base for public health decisions throughout the pandemic. Sequencing data from clinical cases has helped to understand disease transmission and the spread of novel variants. Genomic wastewater surveillance can offer important, complementary information by providing frequency estimates of all variants circulating in a population without sampling biases. Here we show that genomic SARS-CoV-2 wastewater surveillance can detect fine-scale differences within urban centres, specifically within the city of Liverpool, UK, during the emergence of Alpha and Delta variants between November 2020 and June 2021. Furthermore, wastewater and clinical sequencing match well in the estimated timing of new variant rises and the first detection of a new variant in a given area may occur in either clinical or wastewater samples. The study's main limitation was sample quality when infection prevalence was low in spring 2021, resulting in a lower resolution of the rise of the Delta variant compared to the rise of the Alpha variant in the previous winter. The correspondence between wastewater and clinical variant frequencies demonstrates the reliability of wastewater surveillance. However, discrepancies in the first detection of the Alpha variant between the two approaches highlight that wastewater monitoring can also capture missing information, possibly resulting from asymptomatic cases or communities less engaged with testing programmes, as found by a simultaneous surge testing effort across the city.

Peer reviewed: True, Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265, BACKGROUND: Viral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings. METHODS: We conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data collection period, followed by intervention periods comprising 8 weeks of 'rapid' (

The SARS-CoV-2 epidemic has been extended by the evolution of more transmissible viral variants. In autumn 2020, the B.1.177 lineage became the dominant variant in England, before being replaced by the B.1.1.7 (Alpha) lineage in late 2020, with the sweep occurring at different times in each region. This period coincided with a large number of non-pharmaceutical interventions (e.g. lockdowns) to control the epidemic, making it difficult to estimate the relative transmissibility of variants. In this paper, we model the spatial spread of these variants in England using a meta-population agent-based model which correctly characterizes the regional variation in cases and distribution of variants. As a test of robustness, we additionally estimated the relative transmissibility of multiple variants using a statistical model based on the renewal equation, which simultaneously estimates the effective reproduction number R. Relative to earlier variants, the transmissibility of B.1.177 is estimated to have increased by 1.14 (1.12-1.16) and that of Alpha by 1.71 (1.65-1.77). The vaccination programme starting in December 2020 is also modelled. Counterfactual simulations demonstrate that the vaccination programme was essential for reopening in March 2021, and that if the January lockdown had started one month earlier, up to 30 k (24 k-38 k) deaths could have been prevented. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

The SARS-CoV-2 Delta (Pango lineage 8.1.617.2) variant of concern spread globally, causing resurgences of COVID-19 worldwide(1,2). The emergence of the Delta variant in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 SARS-CoV-2 genomes from England together with 93,649 genomes from the rest of the world to reconstruct the emergence of Delta and quantify its introduction to and regional dissemination across England in the context of changing travel and social restrictions. Using analysis of human movement, contact tracing and virusgenomic data, we find that the geographic focus of the expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced more than 1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers reduced onward transmission from importations; however, the transmission chainsthat later dominated the Delta wave in England were seeded before travel restrictions were introduced. Increasing inter-regional travel within England drove the nationwide dissemination of Delta, with some cities receiving more than 2,000 observable lineage introductions from elsewhere. Subsequently, increased levels of local population mixing-and not the number of importations-were associated with the faster relative spread of Delta. The invasion dynamics of Delta depended on spatial heterogeneity in contact patterns, and our findings will inform optimal spatial interventionsto reduce the transmission of current and future variants of concern, such as Omicron (Pango lineage B.1.1.529)., Nature, 610, ISSN:0028-0836, ISSN:1476-4687

Nosocomial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have severely affected bed capacity and patient flow. We utilized whole-genome sequencing (WGS) to identify outbreaks and focus infection control resources and intervention during the United Kingdom’s second pandemic wave in late 2020. Phylogenetic analysis of WGS and epidemiological data pinpointed an initial transmission event to an admission ward, with immediate prior community infection linkage documented. High incidence of asymptomatic staff infection with genetically identical viral sequences was also observed, which may have contributed to the propagation of the outbreak. WGS allowed timely nosocomial transmission intervention measures, including admissions ward point-of-care testing and introduction of portable HEPA14 filters. Conversely, WGS excluded nosocomial transmission in 2 instances with temporospatial linkage, conserving time and resources. In summary, WGS significantly enhanced understanding of SARS-CoV-2 clusters in a hospital setting, both identifying high-risk areas and conversely validating existing control measures in other units, maintaining clinical service overall.

Background: Viral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings. Methods: We conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data-collection period, followed by intervention periods comprising 8 weeks of 'rapid' (

BACKGROUND: Since the emergence of SARS-CoV-2, evolutionary pressure has driven large increases in the transmissibility of the virus. However, with increasing levels of immunity through vaccination and natural infection the evolutionary pressure will switch towards immune escape. Genomic surveillance in regions of high immunity is crucial in detecting emerging variants that can more successfully navigate the immune landscape. METHODS: We present phylogenetic relationships and lineage dynamics within England (a country with high levels of immunity), as inferred from a random community sample of individuals who provided a self-administered throat and nose swab for rt-PCR testing as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. During round 14 (9 September-27 September 2021) and 15 (19 October-5 November 2021) lineages were determined for 1322 positive individuals, with 27.1% of those which reported their symptom status reporting no symptoms in the previous month. RESULTS: We identified 44 unique lineages, all of which were Delta or Delta sub-lineages, and found a reduction in their mutation rate over the study period. The proportion of the Delta sub-lineage AY.4.2 was increasing, with a reproduction number 15% (95% CI 8-23%) greater than the most prevalent lineage, AY.4. Further, AY.4.2 was less associated with the most predictive COVID-19 symptoms (p = 0.029) and had a reduced mutation rate (p = 0.050). Both AY.4.2 and AY.4 were found to be geographically clustered in September but this was no longer the case by late October/early November, with only the lineage AY.6 exhibiting clustering towards the South of England. CONCLUSIONS: As SARS-CoV-2 moves towards endemicity and new variants emerge, genomic data obtained from random community samples can augment routine surveillance data without the potential biases introduced due to higher sampling rates of symptomatic individuals.

Funder: Medical Research Council, Funder: Wellcome Trust, This paper uses a robust method of spatial epidemiological analysis to assess the spatial growth rate of multiple lineages of SARS-CoV-2 in the local authority areas of England, September 2020-December 2021. Using the genomic surveillance records of the COVID-19 Genomics UK (COG-UK) Consortium, the analysis identifies a substantial (7.6-fold) difference in the average rate of spatial growth of 37 sample lineages, from the slowest (Delta AY.4.3) to the fastest (Omicron BA.1). Spatial growth of the Omicron (B.1.1.529 and BA) variant was found to be 2.81× faster than the Delta (B.1.617.2 and AY) variant and 3.76× faster than the Alpha (B.1.1.7 and Q) variant. In addition to AY.4.2 (a designated variant under investigation, VUI-21OCT-01), three Delta sublineages (AY.43, AY.98 and AY.120) were found to display a statistically faster rate of spatial growth than the parent lineage and would seem to merit further investigation. We suggest that the monitoring of spatial growth rates is a potentially valuable adjunct to outbreak response procedures for emerging SARS-CoV-2 variants in a defined population.

The English SARS-CoV-2 epidemic has been affected by the emergence of new viral variants such as B.1.177, Alpha and Delta, and changing restrictions. We used statistical models and the agent-based model Covasim, in June 2021, to estimate B.1.177 to be 20% more transmissible than the wild type, Alpha to be 50–80% more transmissible than B.1.177 and Delta to be 65–90% more transmissible than Alpha. Using these estimates in Covasim (calibrated 1 September 2020 to 20 June 2021), in June 2021, we found that due to the high transmissibility of Delta, resurgence in infections driven by the Delta variant would not be prevented, but would be strongly reduced by delaying the relaxation of restrictions by one month and with continued vaccination. The English SARS-CoV-2 epidemic has been affected by the emergence of new viral variants such as B.1.177, Alpha and Delta, and changing restrictions. We used statistical models and the agent-based model Covasim, in June 2021, to estimate B.1.177 to be 20% more transmissible than the wild type, Alpha to be 50-80% more transmissible than B.1.177 and Delta to be 65-90% more transmissible than Alpha. Using these estimates in Covasim (calibrated 1 September 2020 to 20 June 2021), in June 2021, we found that due to the high transmissibility of Delta, resurgence in infections driven by the Delta variant would not be prevented, but would be strongly reduced by delaying the relaxation of restrictions by one month and with continued vaccination. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

B.1.1.7 lineage SARS-CoV-2 is more transmissible, leads to greater clinical severity, and results in modest reductions in antibody neutralization. Subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome. Applying our tool (periscope) to ARTIC Network Oxford Nanopore Technologies genomic sequencing data from 4400 SARS-CoV-2 positive clinical samples, we show that normalised sgRNA is significantly increased in B.1.1.7 (alpha) infections (n = 879). This increase is seen over the previous dominant lineage in the UK, B.1.177 (n = 943), which is independent of genomic reads, E cycle threshold and days since symptom onset at sampling. A noncanonical sgRNA which could represent ORF9b is found in 98.4% of B.1.1.7 SARS-CoV-2 infections compared with only 13.8% of other lineages, with a 16-fold increase in median sgRNA abundance. We demonstrate that ORF9b protein levels are increased 6-fold in B.1.1.7 compared to a B lineage virus in vitro. We hypothesise that increased ORF9b in B.1.1.7 is a direct consequence of a triple nucleotide mutation in nucleocapsid (28280:GAT > CAT, D3L) creating a transcription regulatory-like sequence complementary to a region 3' of the genomic leader. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles to evaluate emerging potential variants of concern.

We studied the prevalent cytotoxic CD8 T cell response mounted against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein269-277 epitope (sequence YLQPRTFLL) via the most frequent human leukocyte antigen (HLA) class I worldwide, HLA A∗02. The Spike P272L mutation that has arisen in at least 112 different SARS-CoV-2 lineages to date, including in lineages classified as "variants of concern," was not recognized by the large CD8 T cell response seen across cohorts of HLA A∗02+ convalescent patients and individuals vaccinated against SARS-CoV-2, despite these responses comprising of over 175 different individual T cell receptors. Viral escape at prevalent T cell epitopes restricted by high frequency HLAs may be particularly problematic when vaccine immunity is focused on a single protein such as SARS-CoV-2 Spike, providing a strong argument for inclusion of multiple viral proteins in next generation vaccines and highlighting the need for monitoring T cell escape in new SARS-CoV-2 variants.

Background Since the emergence of SARS-CoV-2, evolutionary pressure has driven large increases in the transmissibility of the virus. However, with increasing levels of immunity through vaccination and natural infection the evolutionary pressure will switch towards immune escape. Genomic surveillance in regions of high immunity is crucial in detecting emerging variants that can more successfully navigate the immune landscape. Methods We present phylogenetic relationships and lineage dynamics within England (a country with high levels of immunity), as inferred from a random community sample of individuals who provided a self-administered throat and nose swab for rt-PCR testing as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. During round 14 (9 September–27 September 2021) and 15 (19 October–5 November 2021) lineages were determined for 1322 positive individuals, with 27.1% of those which reported their symptom status reporting no symptoms in the previous month. Results We identified 44 unique lineages, all of which were Delta or Delta sub-lineages, and found a reduction in their mutation rate over the study period. The proportion of the Delta sub-lineage AY.4.2 was increasing, with a reproduction number 15% (95% CI 8–23%) greater than the most prevalent lineage, AY.4. Further, AY.4.2 was less associated with the most predictive COVID-19 symptoms (p = 0.029) and had a reduced mutation rate (p = 0.050). Both AY.4.2 and AY.4 were found to be geographically clustered in September but this was no longer the case by late October/early November, with only the lineage AY.6 exhibiting clustering towards the South of England. Conclusions As SARS-CoV-2 moves towards endemicity and new variants emerge, genomic data obtained from random community samples can augment routine surveillance data without the potential biases introduced due to higher sampling rates of symptomatic individuals.

Genome sequencing is a powerful tool for identifying SARS-CoV-2 variant lineages; however, there can be limitations due to sequence dropout when used to identify specific key mutations. Recently, ThermoFisher Scientific has developed genotyping assays to help bridge the gap between testing capacity and sequencing capability to generate real-time genotyping results based on specific variants. Over a 6-week period during the months of April and May 2021, we set out to assess the ThermoFisher TaqMan mutation panel genotyping assay, initially for three mutations of concern and then for an additional two mutations of concern, against SARS-CoV-2-positive clinical samples and the corresponding COVID-19 Genomics UK Consortium (COG-UK) sequencing data. We demonstrate that genotyping is a powerful in-depth technique for identifying specific mutations, is an excellent complement to genome sequencing, and has real clinical health value potential, allowing laboratories to report and take action on variants of concern much more quickly.

COG-UK Mutation Explorer (COG-UK-ME, https://sars2.cvr.gla.ac.uk/cog-uk/-last accessed date 16 March 2022) is a web resource that displays knowledge and analyses on SARS-CoV-2 virus genome mutations and variants circulating in the UK, with a focus on the observed amino acid replacements that have an antigenic role in the context of the human humoral and cellular immune response. This analysis is based on more than 2 million genome sequences (as of March 2022) for UK SARS-CoV-2 data held in the CLIMB-COVID centralised data environment. COG-UK-ME curates these data and displays analyses that are cross-referenced to experimental data collated from the primary literature. The aim is to track mutations of immunological importance that are accumulating in current variants of concern and variants of interest that could alter the neutralising activity of monoclonal antibodies (mAbs), convalescent sera, and vaccines. Changes in epitopes recognised by T cells, including those where reduced T cell binding has been demonstrated, are reported. Mutations that have been shown to confer SARS-CoV-2 resistance to antiviral drugs are also included. Using visualisation tools, COG-UK-ME also allows users to identify the emergence of variants carrying mutations that could decrease the neutralising activity of both mAbs present in therapeutic cocktails, e.g. Ronapreve. COG-UK-ME tracks changes in the frequency of combinations of mutations and brings together the curated literature on the impact of those mutations on various functional aspects of the virus and therapeutics. Given the unpredictable nature of SARS-CoV-2 as exemplified by yet another variant of concern, Omicron, continued surveillance of SARS-CoV-2 remains imperative to monitor virus evolution linked to the efficacy of therapeutics., COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) (MC_PC_19027), and Genome Research Limited, operating as the Wellcome Sanger Institute. WTH and TPP are supported by the G2P-UK National Virology Consortium (MR/W005611/1) and WTH by the MRC (MR/R024758/1). DLR, DW and JH are funded by the MRC (MC_UU_12014/12) and DLR by the Wellcome Trust (220977/Z/20/Z).

BACKGROUND: The omicron variant (B.1.1.529) of SARS-CoV-2 has demonstrated partial vaccine escape and high transmissibility, with early studies indicating lower severity of infection than that of the delta variant (B.1.617.2). We aimed to better characterise omicron severity relative to delta by assessing the relative risk of hospital attendance, hospital admission, or death in a large national cohort. METHODS: Individual-level data on laboratory-confirmed COVID-19 cases resident in England between Nov 29, 2021, and Jan 9, 2022, were linked to routine datasets on vaccination status, hospital attendance and admission, and mortality. The relative risk of hospital attendance or admission within 14 days, or death within 28 days after confirmed infection, was estimated using proportional hazards regression. Analyses were stratified by test date, 10-year age band, ethnicity, residential region, and vaccination status, and were further adjusted for sex, index of multiple deprivation decile, evidence of a previous infection, and year of age within each age band. A secondary analysis estimated variant-specific and vaccine-specific vaccine effectiveness and the intrinsic relative severity of omicron infection compared with delta (ie, the relative risk in unvaccinated cases). FINDINGS: The adjusted hazard ratio (HR) of hospital attendance (not necessarily resulting in admission) with omicron compared with delta was 0·56 (95% CI 0·54-0·58); for hospital admission and death, HR estimates were 0·41 (0·39-0·43) and 0·31 (0·26-0·37), respectively. Omicron versus delta HR estimates varied with age for all endpoints examined. The adjusted HR for hospital admission was 1·10 (0·85-1·42) in those younger than 10 years, decreasing to 0·25 (0·21-0·30) in 60-69-year-olds, and then increasing to 0·47 (0·40-0·56) in those aged at least 80 years. For both variants, past infection gave some protection against death both in vaccinated (HR 0·47 [0·32-0·68]) and unvaccinated (0·18 [0·06-0·57]) cases. In vaccinated cases, past infection offered no additional protection against hospital admission beyond that provided by vaccination (HR 0·96 [0·88-1·04]); however, for unvaccinated cases, past infection gave moderate protection (HR 0·55 [0·48-0·63]). Omicron versus delta HR estimates were lower for hospital admission (0·30 [0·28-0·32]) in unvaccinated cases than the corresponding HR estimated for all cases in the primary analysis. Booster vaccination with an mRNA vaccine was highly protective against hospitalisation and death in omicron cases (HR for hospital admission 8-11 weeks post-booster vs unvaccinated: 0·22 [0·20-0·24]), with the protection afforded after a booster not being affected by the vaccine used for doses 1 and 2. INTERPRETATION: The risk of severe outcomes following SARS-CoV-2 infection is substantially lower for omicron than for delta, with higher reductions for more severe endpoints and significant variation with age. Underlying the observed risks is a larger reduction in intrinsic severity (in unvaccinated individuals) counterbalanced by a reduction in vaccine effectiveness. Documented previous SARS-CoV-2 infection offered some protection against hospitalisation and high protection against death in unvaccinated individuals, but only offered additional protection in vaccinated individuals for the death endpoint. Booster vaccination with mRNA vaccines maintains over 70% protection against hospitalisation and death in breakthrough confirmed omicron infections. FUNDING: Medical Research Council, UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research, Community Jameel, and Engineering and Physical Sciences Research Council., UKRI Medical Research Council (MRC) ([MR/R015600/1]; [Unit Programme number MC/UU/00002/11]; [Unit Programme number MC/UU/00002/10]); MRC UKRI/DHSC NIHR COVID-19 rapid response call ([MR/V038109/1]; [MC/PC/19074]); NIHR Health Protection Units in: Modelling and Health Economics, Behavioural Science and Evaluation, Respiratory Infections; the NIHR Cambridge Biomedical Research Centre ([BRC-1215-20014]); Wellcome Trust ([210758/Z/18/Z]); Community Jameel; UKRI Engineering and Physical Sciences Research Council.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.

Understanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics., Nature Communications, 13, ISSN:2041-1723

Hospital outbreaks of COVID19 result in considerable mortality and disruption to healthcare services and yet little is known about transmission within this setting. We characterise within hospital transmission by combining viral genomic and epidemiological data using Bayesian modelling amongst 2181 patients and healthcare workers from a large UK NHS Trust. Transmission events were compared between Wave 1 (1st March to 25th July 2020) and Wave 2 (30th November 2020 to 24th January 2021). We show that staff-to-staff transmissions reduced from 31.6% to 12.9% of all infections. Patient-to-patient transmissions increased from 27.1% to 52.1%. 40%-50% of hospital-onset patient cases resulted in onward transmission compared to 4% of community-acquired cases. Control measures introduced during the pandemic likely reduced transmissions between healthcare workers but were insufficient to prevent increasing numbers of patient-to-patient transmissions. As hospital-acquired cases drive most onward transmission, earlier identification of nosocomial cases will be required to break hospital transmission chains.

Funder: Biotechnology and Biological Sciences Research Council, We reviewed all genomic epidemiology studies on COVID-19 in long-term care facilities (LTCFs) that had been published to date. We found that staff and residents were usually infected with identical, or near identical, SARS-CoV-2 genomes. Outbreaks usually involved one predominant cluster, and the same lineages persisted in LTCFs despite infection control measures. Outbreaks were most commonly due to single or few introductions followed by a spread rather than a series of seeding events from the community into LTCFs. The sequencing of samples taken consecutively from the same individuals at the same facilities showed the persistence of the same genome sequence, indicating that the sequencing technique was robust over time. When combined with local epidemiology, genomics allowed probable transmission sources to be better characterised. The transmission between LTCFs was detected in multiple studies. The mortality rate among residents was high in all facilities, regardless of the lineage. Bioinformatics methods were inadequate in a third of the studies reviewed, and reproducing the analyses was difficult because sequencing data were not available in many facilities.

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16-20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement., We thank members of the COVID-19 Genomics Consortium UK and Test and Trace contact tracers for their contributions to generating the data used in this study. We thank the Sanger Covid Team for assisting with Samples and Logistics. We thank Sarah Mitchell from the Department of Plant Sciences, University of Cambridge, for direction on statistical analysis. DA is a Clinical PhD Fellow and gratefully supported by the Wellcome Trust (Grant number: 222903/Z/21/Z). EMH is supported by a UK Research and Innovation (UKRI) Fellowship: MR/S00291X/1. AJP, TLV, GMS gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); their research was funded by the BBSRC Institute Strategic Programme Microbes in the Food Chain BB/R012504/1 and its constituent project BBS/E/F/000PR10352, also Quadram Institute Bioscience BBSRC funded Core Capability Grant (project number BB/CCG1860/1). The COVID-19 Genomics UK (COG-UK) Consortium 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background: England has experienced a third wave of the COVID-19 epidemic since the end of May, 2021, coinciding with the rapid spread of the delta (B.1.617.2) variant, despite high levels of vaccination among adults. Vaccination rates (single dose) in England are lower among children aged 16–17 years and 12–15 years, whose vaccination in England commenced in August and September, 2021, respectively. We aimed to analyse the underlying dynamics driving patterns in SARS-CoV-2 prevalence during September, 2021, in England. Methods: The REal-time Assessment of Community Transmission-1 (REACT-1) study, which commenced data collection in May, 2020, involves a series of random cross-sectional surveys in the general population of England aged 5 years and older. Using RT-PCR swab positivity data from 100 527 participants with valid throat and nose swabs in round 14 of REACT-1 (Sept 9–27, 2021), we estimated community-based prevalence of SARS-CoV-2 and vaccine effectiveness against infection by combining round 14 data with data from round 13 (June 24 to July 12, 2021; n=172 862). Findings: During September, 2021, we estimated a mean RT-PCR positivity rate of 0·83% (95% CrI 0·76–0·89), with a reproduction number (R) overall of 1·03 (95% CrI 0·94–1·14). Among the 475 (62·2%) of 764 sequenced positive swabs, all were of the delta variant; 22 (4·63%; 95% CI 3·07–6·91) included the Tyr145His mutation in the spike protein associated with the AY.4 sublineage, and there was one Glu484Lys mutation. Age, region, key worker status, and household size jointly contributed to the risk of swab positivity. The highest weighted prevalence was observed among children aged 5–12 years, at 2·32% (95% CrI 1·96–2·73) and those aged 13–17 years, at 2·55% (2·11–3·08). The SARS-CoV-2 epidemic grew in those aged 5–11 years, with an R of 1·42 (95% CrI 1·18–1·68), but declined in those aged 18–54 years, with an R of 0·81 (0·68–0·97). At ages 18–64 years, the adjusted vaccine effectiveness against infection was 62·8% (95% CI 49·3–72·7) after two doses compared to unvaccinated people, for all vaccines combined, 44·8% (22·5–60·7) for the ChAdOx1 nCov-19 (Oxford–AstraZeneca) vaccine, and 71·3% (56·6–81·0) for the BNT162b2 (Pfizer–BioNTech) vaccine. In individuals aged 18 years and older, the weighted prevalence of swab positivity was 0·35% (95% CrI 0·31–0·40) if the second dose was administered up to 3 months before their swab but 0·55% (0·50–0·61) for those who received their second dose 3–6 months before their swab, compared to 1·76% (1·60–1·95) among unvaccinated individuals. Interpretation: In September, 2021, at the start of the autumn school term in England, infections were increasing exponentially in children aged 5–17 years, at a time when vaccination rates were low in this age group. In adults, compared to those who received their second dose less than 3 months ago, the higher prevalence of swab positivity at 3–6 months following two doses of the COVID-19 vaccine suggests an increased risk of breakthrough infections during this period. The vaccination programme needs to reach children as well as unvaccinated and partially vaccinated adults to reduce SARS-CoV-2 transmission and associated disruptions to work and education. Funding: Department of Health and Social Care, England.

Background: The SARS-CoV-2 Delta variant (B.1.617.2), first detected in India, has rapidly become the dominant variant in England. Early reports suggest this variant has an increased growth rate suggesting increased transmissibility. This study indirectly assessed differences in transmissibility between the emergent Delta variant compared to the previously dominant Alpha variant (B.1.1.7). Methods: A matched case-control study was conducted to estimate the odds of household transmission (≥ 2 cases within 14 days) for Delta variant index cases compared with Alpha cases. Cases were derived from national surveillance data (March to June 2021). One-to-two matching was undertaken on geographical location of residence, time period of testing and property type, and a multivariable conditional logistic regression model was used for analysis. Findings: In total 5,976 genomically sequenced index cases in household clusters were matched to 11,952 sporadic index cases (single case within a household). 43.3% (n=2,586) of cases in household clusters were confirmed Delta variant compared to 40.4% (n= 4,824) of sporadic cases. The odds ratio of household transmission was 1.70 among Delta variant cases (95% CI 1.48-1.95, p

OBJECTIVES: To analyse nosocomial transmission in the early stages of the coronavirus 2019 (COVID-19) pandemic at a large multisite healthcare institution. Nosocomial incidence is linked with infection control interventions. METHODS: Viral genome sequence and epidemiological data were analysed for 574 consecutive patients, including 86 nosocomial cases, with a positive PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first 19 days of the pandemic. RESULTS: Forty-four putative transmission clusters were found through epidemiological analysis; these included 234 cases and all 86 nosocomial cases. SARS-CoV-2 genome sequences were obtained from 168/234 (72%) of these cases in epidemiological clusters, including 77/86 nosocomial cases (90%). Only 75/168 (45%) of epidemiologically linked, sequenced cases were not refuted by applying genomic data, creating 14 final clusters accounting for 59/77 sequenced nosocomial cases (77%). Viral haplotypes from these clusters were enriched 1-14x (median 4x) compared to the community. Three factors implicated unidentified cases in transmission: (a) community-onset or indeterminate cases were absent in 7/14 clusters (50%), (b) four clusters (29%) had additional evidence of cryptic transmission, and (c) in three clusters (21%) diagnosis of the earliest case was delayed, which may have facilitated transmission. Nosocomial cases decreased to low levels (0-2 per day) despite continuing high numbers of admissions of community-onset SARS-CoV-2 cases (40-50 per day) and before the impact of introducing universal face masks and banning hospital visitors. CONCLUSION: Genomics was necessary to accurately resolve transmission clusters. Our data support unidentified cases-such as healthcare workers or asymptomatic patients-as important vectors of transmission. Evidence is needed to ascertain whether routine screening increases case ascertainment and limits nosocomial transmission.

BACKGROUND: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. METHODS: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. FINDINGS: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17-43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32-3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08-1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47-8·05] and for hospital admission or emergency care attendance 1·58 [0·69-3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29-4·16] and 1·43 [1·04-1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. INTERPRETATION: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. FUNDING: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

Nosocomial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have severely affected bed capacity and patient flow. We utilized whole-genome sequencing (WGS) to identify outbreaks and focus infection control resources and intervention during the United Kingdom's second pandemic wave in late 2020. Phylogenetic analysis of WGS and epidemiological data pinpointed an initial transmission event to an admission ward, with immediate prior community infection linkage documented. High incidence of asymptomatic staff infection with genetically identical viral sequences was also observed, which may have contributed to the propagation of the outbreak. WGS allowed timely nosocomial transmission intervention measures, including admissions ward point-of-care testing and introduction of portable HEPA14 filters. Conversely, WGS excluded nosocomial transmission in 2 instances with temporospatial linkage, conserving time and resources. In summary, WGS significantly enhanced understanding of SARS-CoV-2 clusters in a hospital setting, both identifying high-risk areas and conversely validating existing control measures in other units, maintaining clinical service overall.