Comparison of the risk of hospitalisation among BA.1 and BA.2 COVID-19 cases treated with Sotrovimab in the community in England

ObjectivesSotrovimab is one of several therapeutic agents that have been licensed to treat people at risk of severe outcomes following COVID-19 infection. However, there are concerns that it has reduced efficacy to treat people with the BA.2 sub-lineage of the Omicron (B.1.1.529) SARS-CoV-2 variant. We compared individuals with the BA.1 or BA.2 sub-lineage of the Omicron variant treated Sotrovimab in the community to assess their risk of hospital admission. MethodsWe performed a retrospective cohort study of individuals treated with Sotrovimab in the community and either had BA.1 or BA.2 variant classification. ResultsUsing a Stratified Cox regression model it was estimated that the hazard ratios (HR) of hospital admission with a length of stay of two or more days was 1.17 for BA.2 compared to BA.1 (95% CI 0.74-1.86) and for such admissions where COVID-19 ICD-10 codes was recorded the HR was 0.98 (95% CI 0.58-1.65). ConclusionThese results suggest that the risk of hospital admission is similar between BA.1 and BA.2 cases treated with Sotrovimab in the community.

The origins and molecular evolution of SARS-CoV-2 lineage B.1.1.7 in the UK

The first SARS-CoV-2 variant of concern (VOC) to be designated was lineage B.1.1.7, later labelled by the World Health Organisation (WHO) as Alpha. Originating in early Autumn but discovered in December 2020, it spread rapidly and caused large waves of infections worldwide. The Alpha variant is notable for being defined by a long ancestral phylogenetic branch with an increased evolutionary rate, along which only two sequences have been sampled. Alpha genomes comprise a well-supported monophyletic clade within which the evolutionary rate is more typical of SARS-CoV-2. The Alpha epidemic continued to grow despite the continued restrictions on social mixing across the UK, and the imposition of new restrictions, in particular the English national lockdown in November 2020. While these interventions succeeded in reducing the absolute number of cases, the impact of these non-pharmaceutical interventions was predominantly to drive the decline of the SARS-CoV-2 lineages which preceded Alpha. We investigate the only two sampled sequences that fall on the branch ancestral to Alpha. We find that one is likely to be a true intermediate sequence, providing information about the order of mutational events that led to Alpha. We explore alternate hypotheses that can explain how Alpha acquired a large number of mutations yet remained largely unobserved in a region of high genomic surveillance: an under-sampled geographical location, a non-human animal population, or a chronically-infected individual. We conclude that the last hypothesis provides the best explanation of the observed behaviour and dynamics of the variant, although we find that the individual need not be immunocompromised, as persistently-infected immunocompetent hosts also display a higher within-host rate of evolution. Finally, we compare the ancestral branches and mutation profiles of other VOCs to each other, and identify that Delta appears to be an outlier both in terms of the genomic locations of its defining mutations, and its lack of rapid evolutionary rate on the ancestral branch. As new variants, such as Omicron, continue to evolve (potentially through similar mechanisms) it remains important to investigate the origins of other variants to identify ways to potentially disrupt their evolution and emergence.

Context-specific emergence and growth of the SARS-CoV-2 Delta variant

The Delta variant of concern of SARS-CoV-2 has spread globally causing large outbreaks and resurgences of COVID-19 cases1-3. The emergence of Delta in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions4,5. Here we analyse 52,992 Delta genomes from England in combination with 93,649 global genomes 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. Through analysis of human movement, contact tracing, and virus genomic data, we find that the focus of geographic expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced >1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers from India reduced onward transmission from importations; however the transmission chains that later dominated the Delta wave in England had been already seeded before restrictions were introduced. In England, increasing inter-regional travel drove Deltas nationwide dissemination, with some cities receiving >2,000 observable lineage introductions from other regions. Subsequently, increased levels of local population mixing, not the number of importations, was associated with faster relative growth of Delta. Among US states, we find that regions that previously experienced large waves also had faster Delta growth rates, and a model including interactions between immunity and human behaviour could accurately predict the rise of Delta there. Deltas invasion dynamics depended on fine scale spatial heterogeneity in immunity and contact patterns and our findings will inform optimal spatial interventions to reduce transmission of current and future VOCs such as Omicron.

Effectiveness of COVID-19 vaccines against the Omicron (B.1.1.529) variant of concern

BackgroundA rapid increase in cases due to the SARS-CoV-2 Omicron (B.1.1.529) variant in highly vaccinated populations has raised concerns about the effectiveness of current vaccines. MethodsWe used a test-negative case-control design to estimate vaccine effectiveness (VE) against symptomatic disease caused by the Omicron and Delta variants in England. VE was calculated after primary immunisation with two BNT162b2 or ChAdOx1 doses, and at 2+ weeks following a BNT162b2 booster. ResultsBetween 27 November and 06 December 2021, 581 and 56,439 eligible Omicron and Delta cases respectively were identified. There were 130,867 eligible test-negative controls. There was no effect against Omicron from 15 weeks after two ChAdOx1 doses, while VE after two BNT162b2 doses was 88.0% (95%CI: 65.9 to 95.8%) 2-9 weeks after dose 2, dropping to between 34 and 37% from 15 weeks post dose 2.From two weeks after a BNT162b2 booster, VE increased to 71.4% (95%CI: 41.8 to 86.0%) for ChAdOx1 primary course recipients and 75.5% (95%CI: 56.1 to 86.3%) for BNT162b2 primary course recipients. For cases with Delta, VE was 41.8% (95%CI: 39.4-44.1%) at 25+ weeks after two ChAdOx1 doses, increasing to 93.8% (95%CI: 93.2-94.3%) after a BNT162b2 booster. With a BNT162b2 primary course, VE was 63.5% (95%CI: 61.4 to 65.5%) 25+ weeks after dose 2, increasing to 92.6% (95%CI: 92.0-93.1%) two weeks after the booster. ConclusionsPrimary immunisation with two BNT162b2 or ChAdOx1 doses provided no or limited protection against symptomatic disease with the Omicron variant. Boosting with BNT162b2 following either primary course significantly increased protection.

Effectiveness of COVID-19 vaccines against the B.1.617.2 variant

BackgroundThe B.1.617.2 COVID-19 variant has contributed to the surge in cases in India and has now been detected across the globe, including a notable increase in cases in the UK. We estimate the effectiveness of the BNT162b2 and ChAdOx1 COVID-19 vaccines against this variant. MethodsA test negative case control design was used to estimate the effectiveness of vaccination against symptomatic disease with both variants over the period that B.1.617.2 began circulating with cases identified based on sequencing and S-gene target status. Data on all symptomatic sequenced cases of COVID-19 in England was used to estimate the proportion of cases with B.1.617.2 compared to the predominant strain (B.1.1.7) by vaccination status. ResultsEffectiveness was notably lower after 1 dose of vaccine with B.1.617.2 cases 33.5% (95%CI: 20.6 to 44.3) compared to B.1.1.7 cases 51.1% (95%CI: 47.3 to 54.7) with similar results for both vaccines. With BNT162b2 2 dose effectiveness reduced from 93.4% (95%CI: 90.4 to 95.5) with B.1.1.7 to 87.9% (95%CI: 78.2 to 93.2) with B.1.617.2. With ChAdOx1 2 dose effectiveness reduced from 66.1% (95% CI: 54.0 to 75.0) with B.1.1.7 to 59.8% (95%CI: 28.9 to 77.3) with B.1.617.2. Sequenced cases detected after 1 or 2 doses of vaccination had a higher odds of infection with B.1.617.2 compared to unvaccinated cases (OR 1.40; 95%CI: 1.13-1.75). ConclusionsAfter 2 doses of either vaccine there were only modest differences in vaccine effectiveness with the B.1.617.2 variant. Absolute differences in vaccine effectiveness were more marked with dose 1. This would support maximising vaccine uptake with two doses among vulnerable groups.

An integrated analysis of contact tracing and genomics to assess the efficacy of travel restrictions on SARS-CoV-2 introduction and transmission in England from June to September, 2020

BackgroundMitigation of SARS-CoV-2 transmission from international travel is a priority. Travellers from countries with travel restrictions (closed travel-corridors) were required to quarantine for 14 days over Summer 2020 in England. We describe the genomic epidemiology of travel-related cases in England and evaluate the effectiveness of this travel policy. MethodsBetween 27/05/2020 and 13/09/2020, probable travel-related SARS-CoV-2 cases and their contacts were identified and combined with UK SARS-CoV-2 sequencing data. The epidemiology and demographics of cases was identified, and the number of contacts per case modelled using negative binomial regression to estimate the effect of travel restriction, and any variation by age, sex and calendar date. Unique travel-related SARS-CoV-2 genomes in the COG-UK dataset were identified to estimate the effect travel restrictions on cluster size generated from these. The Polecat Clustering Tool was used to identify a travel-related SARS-CoV-2 cluster of infection. Findings4,207 travel-related SARS-CoV-2 cases are identified. 51.2% (2155/4207) of cases reported travel to one of three countries; 21.0% (882) Greece, 16.3% (685) Croatia and 14.0% (589) Spain. Median number of contacts per case was 3 (IQR 1-5), and greatest for the 16-20 age-group (9.0, 95% C.I.=5.6-14.5), which saw the largest attenuation by travel restriction. Travel restriction was associated with a 40% (rate ratio=0.60, 95% C.I.=0.37-0.95) lower rate of contacts. 827/4207 (19.7%) of cases had high-quality SARS-CoV-2 genomes available. Fewer genomically-linked cases were observed for index cases related to countries with travel restrictions compared to cases from non-travel restriction countries (rate ratio=0.17, 95% C.I.=0.05-0.52). A large travel-related cluster dispersed across England is identified through genomics, confirmed with contact-tracing data. InterpretationThis study demonstrates the efficacy of travel restriction policy in reducing the onward transmission of imported cases. FundingWellcome Trust, Biotechnology and Biological Sciences Research Council, UK Research & Innovation, National Institute of Health Research, Wellcome Sanger Institute. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed, medRxiv, bioRxiv, Web of Science and Scopus for the terms (COVID-19 OR SARS-COV-2) AND (imported or importation) AND (sequenc* OR genom* or WGS). We filtered the 55 articles identified through this search and rejected any that did not undertake SARS-CoV-2 sequencing as part of an epidemiological investigation for importation into a different country. The remaining 20 papers were reviewed in greater detail to understand the patterns of importation and the methods used in each case. Added value of this studyThis is the first published study on importations of SARS-CoV-2 into England using genomics. Plessis et al., (2021) used a predictive model to infer the number of importations in to the UK from all SARS-CoV-2 genomes generated before 26th June 2020. The current study assesses the period 27/05/2020 to 13/09/2020 and presents findings of case-reported travel linked to genomic data. Two unpublished reports exist for Wales and Scotland, although only examine a comparatively small number of importations. Implications of all the available evidenceThis large-scale study has a number of findings that are pertinent to public health and of global significance, not available from prior evidence to our knowledge. The study demonstrates travel restrictions, through the implementation of travel-corridors, are effective in reducing the number of contacts per case based on observational data. Age has a significant effect on the number of contacts and this can be mitigated with travel restrictions. Analysis of divergent clusters indicates travel restrictions can reduce the number of onwards cases following a travel-associated case. Analysis of divergent clusters can allow for importations to be identified from genomics, as subsequently evidenced by cluster characteristics derived from contact tracing. The majority of importations of SARS-CoV-2 in England over Summer 2020 were from coastal European countries. The highest number of cases and onward contacts were from Greece, which was largely exempt from self-isolation requirements (bar some islands in September at the end of the study period). Systematic monitoring of imported SARS-CoV-2 cases would help refine implementation of travel restrictions. Finally, along with multiple studies, this study highlights the use of genomics to monitor and track importations of SARS-CoV-2 mutations of interest; this will be of particular use as the repertoire of clinically relevant SARS-CoV-2 variants expand over time and globally.

Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: Insights from linking epidemiological and genetic data

The SARS-CoV-2 lineage B.1.1.7, now designated Variant of Concern 202012/01 (VOC) by Public Health England, originated in the UK in late Summer to early Autumn 2020. We examine epidemiological evidence for this VOC having a transmission advantage from several perspectives. First, whole genome sequence data collected from community-based diagnostic testing provides an indication of changing prevalence of different genetic variants through time. Phylodynamic modelling additionally indicates that genetic diversity of this lineage has changed in a manner consistent with exponential growth. Second, we find that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S-gene target failures (SGTF) in community-based diagnostic PCR testing. Third, we examine growth trends in SGTF and non-SGTF case numbers at local area level across England, and show that the VOC has higher transmissibility than non-VOC lineages, even if the VOC has a different latent period or generation time. Available SGTF data indicate a shift in the age composition of reported cases, with a larger share of under 20 year olds among reported VOC than non-VOC cases. Fourth, we assess the association of VOC frequency with independent estimates of the overall SARS-CoV-2 reproduction number through time. Finally, we fit a semi-mechanistic model directly to local VOC and non-VOC case incidence to estimate the reproduction numbers over time for each. There is a consensus among all analyses that the VOC has a substantial transmission advantage, with the estimated difference in reproduction numbers between VOC and non-VOC ranging between 0.4 and 0.7, and the ratio of reproduction numbers varying between 1.4 and 1.8. We note that these estimates of transmission advantage apply to a period where high levels of social distancing were in place in England; extrapolation to other transmission contexts therefore requires caution.

Research Priorities in Light of Current Trends in Microsurgical Training: Revalidation, Simulation, Cross-Training, and Standardisation

Plastic surgery training worldwide has seen a thorough restructuring over the past decade, with the introduction of formal training curricula and work-based assessment tools. Part of this process has been the introduction of revalidation and a greater use of simulation in training delivery. Simulation is an increasingly important tool for educators because it provides a way to reduce risks to both trainees and patients, whilst facilitating improved technical proficiency. Current microsurgery training interventions are often predicated on theories of skill acquisition and development that follow a 'practice makes perfect' model. Given the changing landscape of surgical training and advances in educational theories related to skill development, research is needed to assess the potential benefits of alternative models, particularly cross-training, a model now widely used in non-medical areas with significant benefits. Furthermore, with the proliferation of microsurgery training interventions and therefore diversity in length, cost, content and models used, appropriate standardisation will be an important factor to ensure that courses deliver consistent and effective training that achieves appropriate levels of competency. Key research requirements should be gathered and used in directing further research in these areas to achieve on-going improvement of microsurgery training.

Microsurgery Training for the Twenty-First Century

Current educational interventions and training courses in microsurgery are often predicated on theories of skill acquisition and development that follow a 'practice makes perfect' model. Given the changing landscape of surgical training and advances in educational theories related to skill development, research is needed to assess current training tools in microsurgery education and devise alternative methods that would enhance training. Simulation is an increasingly important tool for educators because, whilst facilitating improved technical proficiency, it provides a way to reduce risks to both trainees and patients. The International Microsurgery Simulation Society has been founded in 2012 in order to consolidate the global effort in promoting excellence in microsurgical training. The society's aim to achieve standarisation of microsurgical training worldwide could be realised through the development of evidence based educational interventions and sharing best practices.

A Systematic Review of Evidence for Education and Training Interventions in Microsurgery

Over the past decade, driven by advances in educational theory and pressures for efficiency in the clinical environment, there has been a shift in surgical education and training towards enhanced simulation training. Microsurgery is a technical skill with a steep competency learning curve on which the clinical outcome greatly depends. This paper investigates the evidence for educational and training interventions of traditional microsurgical skills courses in order to establish the best evidence practice in education and training and curriculum design. A systematic review of MEDLINE, EMBASE, and PubMed databases was performed to identify randomized control trials looking at educational and training interventions that objectively improved microsurgical skill acquisition, and these were critically appraised using the BestBETs group methodology. The databases search yielded 1,148, 1,460, and 2,277 citations respectively. These were then further limited to randomized controlled trials from which abstract reviews reduced the number to 5 relevant randomised controlled clinical trials. The best evidence supported a laboratory based low fidelity model microsurgical skills curriculum. There was strong evidence that technical skills acquired on low fidelity models transfers to improved performance on higher fidelity human cadaver models and that self directed practice leads to improved technical performance. Although there is significant paucity in the literature to support current microsurgical education and training practices, simulated training on low fidelity models in microsurgery is an effective intervention that leads to acquisition of transferable skills and improved technical performance. Further research to identify educational interventions associated with accelerated skill acquisition is required.