ABSTRACT
Objectives Sotrovimab 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. Methods We performed a retrospective cohort study of individuals treated with Sotrovimab in the community and either had BA.1 or BA.2 variant classification. Results Using 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). Conclusion These results suggest that the risk of hospital admission is similar between BA.1 and BA.2 cases treated with Sotrovimab in the community.
Subject(s)
COVID-19ABSTRACT
Summary Some COVID-19 patients are unable to clear their infection or are at risk of severe disease, requiring treatment with neutralising monoclonal antibodies (nmAb) and/or antivirals. The rapid roll-out of novel therapeutics means there is limited understanding of the likely genetic barrier to drug resistance. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to the detection of emerging drug resistance. Here we report the accrual of mutations in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the epitopes of the respective nmAbs. For casirivimab+imdevimab these are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum.
Subject(s)
COVID-19ABSTRACT
Purpose The Gamma variant of SARS-CoV-2, first detected in travellers from Brazil, was found to have high transmissibility and virulence; following this finding, this paper aims to describe the epidemiology of Gamma cases in England from its first detection on 12 February 2021 to 31 August 2021. Methods The demographic analysis of Gamma cases was stratified by travel exposure. Travel-associated cases were further analysed by countries travelled from, stratified by categories set in place by the Red (highest risk countries), Amber, Green (lowest risk countries) travel policy, which was implemented from May to October 2021. Results There were 251 confirmed Gamma cases detected in England in the study period. 35.1% were imported, 5.6% were secondary, and 29.5% were not travel associated. Early cases were predominantly travel-associated, with later cases likely obtained through community transmission. 51.0% of travel-related cases were travellers from Amber countries, and 40.2% had at least one Red country in their journey. Conclusion The Gamma variant has not seen the same expansion as other variants such as Delta, most likely due to Delta out-competing community transmission of Gamma. Findings indicate the travel policy requiring quarantine for Red and Amber list travellers may have also contributed to preventing onward transmission of Gamma.
ABSTRACT
The BA.1 sub-lineage of the Omicron (B.1.1.529) variant, first detected in the UK in mid-November 2021, rapidly became the dominant strain partly due to reduced vaccine effectiveness. An increase in a second Omicron sub-lineage BA.2 was observed in early January 2022. In this study we use a test-negative case control study design to estimate vaccine effectiveness against symptomatic disease with BA.1 and BA.2 after one or two doses of BNT162b2, ChAdOx1-S or mRNA-1273, and after booster doses of BNT162b2 or mRNA-1273 during a period of co-circulation. Overall, there was no evidence that vaccine effectiveness against symptomatic disease is reduced following infection with the BA.2 sub-lineage as compared to BA.1. Furthermore, similar rates of waning were observed after the second and booster dose for each sub-lineage. These data provide reassuring evidence of the effectiveness of the vaccines currently in use against symptomatic disease caused by BA.2.
Subject(s)
COVID-19ABSTRACT
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 from a case-number perspective these interventions succeeded in reducing the absolute number of cases of SARS-CoV-2 in the UK, the impact of these non-pharmaceutical interventions was predominantly to drive the decline of those SARS-CoV-2 lineages that 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.
ABSTRACT
Background The SARS-CoV-2 Omicron variant (B.1.1.529) has rapidly replaced the Delta variant (B.1.617.2) to become dominant in England. This epidemiological study assessed differences in transmissibility between the Omicron and Delta using two methods and data sources. Methods Omicron and Delta cases were identified through genomic sequencing, genotyping and S-gene target failure in England from 5-11 December 2021. Secondary attack rates for Omicron and Delta using named contacts and household clustering were calculated using national surveillance and contact tracing data. Logistic regression was used to control for factors associated with transmission. Findings Analysis of contact tracing data identified elevated secondary attack rates for Omicron vs Delta in household (15.0% vs 10.8%) and non-household (8.2% vs 3.7%) settings. The proportion of index cases resulting in residential clustering was twice as high for Omicron (16.1%) compared to Delta (7.3%). Transmission was significantly less likely from cases, or in named contacts, in receipt of three compared to two vaccine doses in household settings, but less pronounced for Omicron (aRR 0.78 and 0.88) compared to Delta (aRR 0.62 and 0.68). In non-household settings, a similar reduction was observed for Delta cases and contacts (aRR 0.84 and 0.51) but only for Omicron contacts (aRR 0.76, 95% CI: 0.58-0.93) and not cases in receipt of three vs two doses (aRR 0.95, 0.77-1.16). Interpretation Our study identified increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta. We identified a reduced effectiveness of vaccination in lowering risk of transmission, a likely contributor for the rapid propagation of Omicron.
ABSTRACT
Abstract Background A 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. Methods We 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. Results Between 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. Conclusions Primary 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.
Subject(s)
COVID-19ABSTRACT
Background: The 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. Methods: A 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. Results: Effectiveness 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). Conclusions: After 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.
Subject(s)
COVID-19ABSTRACT
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.
Subject(s)
COVID-19ABSTRACT
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.