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BackgroundAntigen lateral flow devices (LFDs) have been widely used to control SARS-CoV-2. Changes in LFD sensitivity and detection of infectious individuals during the pandemic with successive variants, vaccination, and changes in LFD use are incompletely understood. MethodsPaired LFD and PCR tests were collected from asymptomatic and symptomatic participants, across multiple settings in the UK between 04-November-2020 and 21-March-2022. Multivariable logistic regression was used to analyse LFD sensitivity and specificity, adjusting for viral load, LFD manufacturer, setting, age, sex, assistance, symptoms, vaccination, and variant. National contact tracing data were used to estimate the proportion of transmitting index cases (with [≥]1 PCR/LFD-positive contact) potentially detectable by LFDs over time, accounting for viral load, variant, and symptom status. Findings4131/75,382 (5.5%) participants were PCR-positive. Sensitivity vs. PCR was 63.2% (95%CI 61.7-64.6%) and specificity 99.71% (99.66-99.74%). Increased viral load was independently associated with being LFD-positive. There was no evidence LFD sensitivity differed between Delta vs. Alpha/pre-Alpha infections, but Omicron infections were more likely to be LFD positive. Sensitivity was higher in symptomatic participants, 68.7% (66.9-70.4%) than in asymptomatic participants, 52.8% (50.1-55.4%). 79.4% (68.6-81.3%) of index cases resulting in probable onward transmission with were estimated to have been detectable using LFDs, this proportion was relatively stable over time/variants, but lower in asymptomatic vs. symptomatic cases. InterpretationLFDs remained able to detect most SARS-CoV-2 infections throughout vaccine roll-out and different variants. LFDs can potentially detect most infections that transmit to others and reduce risks. However, performance is lower in asymptomatic compared to symptomatic individuals. FundingUK Government. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSLateral flow devices (LFDs; i.e. rapid antigen detection devices) have been widely used for SARS-CoV-2 testing. However, due to their imperfect sensitivity when compared to PCR and a lack of a widely available gold standard proxy for infectiousness, the performance and use of LFDs has been a source of debate. We conducted a literature review in PubMed and bioRxiv/medRxiv for all studies examining the performance of lateral flow devices between 01 January 2020 and 31 October 2022. We used the search terms SARS-CoV-2/COVID-19 and antigen/lateral flow test/lateral flow device. Multiple studies have examined the sensitivity and specificity of LFDs, including several systematic reviews. However, the majority of the studies are based on pre-Alpha infections. Large studies examining the test accuracy for different variants, including Delta and Omicron, and following vaccination are limited. Added value of this studyIn this large national LFD evaluation programme, we compared the performance of three different LFDs relative to PCR in various settings. Compared to PCR testing, sensitivity was 63.2% (95%CI 61.7-64.6%) overall, and 71.6% (95%CI 69.8-73.4%) in unselected communitybased testing. Specificity was 99.71% (99.66-99.74%). LFDs were more likely to be positive as viral loads increased. LFD sensitivity was similar during Alpha/pre-Alpha and Delta periods but increased during the Omicron period. There was no association between sensitivity and vaccination status. Sensitivity was higher in symptomatic participants, 68.7% (66.9-70.4%) than in asymptomatic participants, 52.8% (50.1-55.4%). Using national contact tracing data, we estimated that 79.4% (68.6-81.3%) of index cases resulting in probable onward transmission (i.e. with [≥]1 PCR/LFD-positive contact) were detectable using LFDs. Symptomatic index cases were more likely to be detected than asymptomatic index cases due to higher viral loads and better LFD performance at a given viral load. The proportion of index cases detected remained relatively stable over time and with successive variants, with a slight increase in the proportion of asymptomatic index cases detected during Omicron. Implications of all the available evidenceOur data show that LFDs detect most SARS-CoV-2 infections, with findings broadly similar to those summarised in previous meta-analyses. We show that LFD performance has been relatively consistent throughout different variant-dominant phases of the pandemic and following the roll-out of vaccination. LFDs can detect most infections that transmit to others and can therefore be used as part of a risk reduction strategy. However, performance is lower in asymptomatic compared to symptomatic individuals and this needs to be considered when designing testing programmes.
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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.
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BackgroundMonitoring infection trends is vital to informing public health strategy. Detecting and quantifying changes in growth rates can inform policymakers rationale for implementing or continuing interventions aimed at reducing impact. Substantial changes in SARS-CoV-2 prevalence with emergence of variants provides opportunity to investigate different methods to do this. MethodsWe included PCR results from all participants in the UKs COVID-19 Infection Survey between 1 August 2020-30 June 2022. Change-points for growth rates were identified using iterative sequential regression (ISR) and second derivatives of generalised additive models (GAMs). Consistency between methods and timeliness of detection were compared. FindingsOf 8,799,079 visits, 147,278 (1{middle dot}7%) were PCR-positive. Over the time period, change-points associated with emergence of major variants were estimated to occur a median 4 days earlier (IQR 0-8) in GAMs versus ISR, with only 2/48 change-points identified by only one method. Estimating recent change-points using successive data periods, four change-points (4/96) identified by GAMs were not found when adding later data or by ISR; 77% (74/96) of change-points identified by successive GAMs were identified by ISR. Change-points were detected 3-5 weeks after they occurred in both methods but could be detected earlier within specific subgroups. InterpretationChange-points in growth rates of SARS-CoV-2 can be detected in near real-time using ISR and second derivatives of GAMs. To increase certainty about changes in epidemic trajectories both methods could be run in parallel. Running either method in near real-time on different infection surveillance data streams could provide timely warnings of changing underlying epidemiology. FundingUK Health Security Agency, Department of Health and Social Care (UK), Welsh Government, Department of Health (on behalf of the Northern Ireland Government), Scottish Government, National Institute for Health Research.
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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.
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Both infection and vaccination, alone or in combination, generate antibody and T cell responses against SARSCoV2. However, the maintenance of such responses, and hence protection from disease, requires careful characterisation. In a large prospective study of UK healthcare workers (Protective immunity from T cells in Healthcare workers (PITCH), within the larger SARSCoV2 immunity and reinfection evaluation (SIREN) study) we previously observed that prior infection impacted strongly on subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. Here, we report longer follow up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. We make three observations: Firstly, the dynamics of humoral and cellular responses differ; binding and neutralising antibodies declined whereas T and memory B cell responses were maintained after the second vaccine dose. Secondly, vaccine boosting restored IgG levels, broadened neutralising activity against variants of concern including omicron BA.1, BA.2 and BA.5, and boosted T cell responses above the 6 month level post dose 2. Thirdly, prior infection maintained its impact driving larger as well as broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. In conclusion, broadly cross-reactive T cell responses are well maintained over time, especially in those with combined vaccine and infection-induced immunity (hybrid immunity), and may contribute to continued protection against severe disease.
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BackgroundUnderstanding immunological responses to SARS-CoV-2 vaccinations is integral to the management of SARS-CoV-2. We aimed to investigate determinants of antibody response to the BNT162b2 vaccine. MethodsA cross-sectional analysis of anti-spike binding antibodies in serum samples from healthcare workers after one or two doses. Post-vaccination interval was restricted to [≥]21 days after dose 1, [≥]14 days after dose 2. The primary outcome was anti-S titres with explanatory variables dose, previous infection, dosing interval, age, ethnicity, and comorbidities. Multivariable linear regression was also conducted. ResultsParticipants (n=5,871) included 3,989 post-dose 1, 1,882 post-dose 2. In SARS-CoV-2 infection naive, 99.65% seroconverted after dose 1 and >99.9% seroconverted after dose 2. Geometric mean anti-S titre in the naive cohort was 75.48 Binding Antibody Units/ml after dose 1, 7,049 BAU/ml after dose 2. Anti-S titres were higher in those with previous infection (2,111 BAU/ml post-dose 1, 16,052 BAU/ml post-dose 2), and increased with time between infection and vaccination: 3 months 1,970 (1,506-2,579) vs 9 months; 13,759 (8,097-23,379). Longer dosing intervals increased antibody response post-dose 2: 11-fold higher with a longer interval (>10 weeks) than those with shorter intervals, across all age-groups. Younger participants had higher mean titres (>2.2-fold higher). Multivariable regression modelling corroborated the above associations, and also found higher titres associated with being female or from an ethnic minority but lower titres among immunocompromised participants. ConclusionThe number of antigen exposures and timing between vaccinations plays a significant role in the magnitude of the post-vaccination antibody response, with implications for long-term protection and post-booster antibody responses.
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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.
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BackgroundUnderstanding the duration and effectiveness of infection and vaccine-acquired SARS-CoV-2 immunity is essential to inform pandemic policy interventions, including the timing of vaccine-boosters. We investigated this in our large prospective cohort of UK healthcare workers undergoing routine asymptomatic PCR testing. MethodsWe assessed vaccine effectiveness (VE) (up to 10-months after first dose) and infection-acquired immunity by comparing time to PCR-confirmed infection in vaccinated and unvaccinated individuals using a Cox regression-model, adjusted by prior SARS-CoV-2 infection status, vaccine-manufacturer/dosing-interval, demographics and workplace exposures. ResultsOf 35,768 participants, 27% (n=9,488) had a prior SARS-CoV-2 infection. Vaccine coverage was high: 97% had two-doses (79% BNT162b2 long-interval, 8% BNT162b2 short-interval, 8% ChAdOx1). There were 2,747 primary infections and 210 reinfections between 07/12/2020 and 21/09/2021. Adjusted VE (aVE) decreased from 81% (95% CI 68%-89%) 14-73 days after dose-2 to 46% (95% CI 22%-63%) >6-months; with no significant difference for short-interval BNT162b2 but significantly lower aVE (50% (95% CI 18%-70%) 14-73 days after dose-2 from ChAdOx1. Protection from infection-acquired immunity showed evidence of waning in unvaccinated follow-up but remained consistently over 90% in those who received two doses of vaccine, even in those infected over 15-months ago. ConclusionTwo doses of BNT162b2 vaccination induce high short-term protection to SARS-CoV-2 infection, which wanes significantly after six months. Infection-acquired immunity boosted with vaccination remains high over a year after infection. Boosters will be essential to maintain protection in vaccinees who have not had primary infection to reduce infection and transmission in this population. Trial registration numberISRCTN11041050
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BackgroundThe COVID-19 pandemic is rapidly evolving, with emerging variants and fluctuating control policies. Real-time population screening and identification of groups in whom positivity is highest could help monitor spread and inform public health messaging and strategy. MethodsTo develop a real-time screening process, we included results from nose and throat swabs and questionnaires taken 19 July 2020-17 July 2021 in the UKs national COVID-19 Infection Survey. Fortnightly, associations between SARS-CoV-2 positivity and 60 demographic and behavioural characteristics were estimated using logistic regression models adjusted for potential confounders, considering multiple testing, collinearity, and reverse causality. FindingsOf 4,091,537 RT-PCR results from 482,677 individuals, 29,903 (0{middle dot}73%) were positive. As positivity rose September-November 2020, rates were independently higher in younger ages, and those living in Northern England, major urban conurbations, more deprived areas, and larger households. Rates were also higher in those returning from abroad, and working in healthcare or outside of home. When positivity peaked December 2020-January 2021 (Alpha), high positivity shifted to southern geographical regions. With national vaccine roll-out from December 2020, positivity reduced in vaccinated individuals. Associations attenuated as rates decreased between February-May 2021. Rising positivity rates in June-July 2021 (Delta) were independently higher in younger, male, and unvaccinated groups. Few factors were consistently associated with positivity. 25/45 (56%) confirmed associations would have been detected later using 28-day rather than 14-day periods. InterpretationPopulation-level demographic and behavioural surveillance can be a valuable tool in identifying the varying characteristics driving current SARS-CoV-2 positivity, allowing monitoring to inform public health policy. FundingDepartment of Health and Social Care (UK), Welsh Government, Department of Health (on behalf of the Northern Ireland Government), Scottish Government, National Institute for Health Research.
ABSTRACT
Quarantining close contacts of individuals infected with SARS-CoV-2 for 10 to 14 days is a key strategy in reducing transmission. However, quarantine requirements are often unpopular, with low adherence, especially when a large fraction of the population has been vaccinated. Daily contact testing (DCT), in which contacts are required to isolate only if they test positive, is an alternative to quarantine for mitigating the risk of transmission from traced contacts. In this study, we developed an integrated model of COVID-19 transmission dynamics and compared the strategies of quarantine and DCT with regard to reduction in transmission and social/economic costs (days of quarantine/self-isolation). Specifically, we compared 10-day quarantine to 7 days of self-testing using rapid lateral flow antigen tests, starting 3 days after exposure to a case. We modelled both incomplete adherence to quarantine and incomplete adherence to DCT. We found that DCT reduces transmission from contacts with similar effectiveness, at much lower social/economic costs, especially for highly vaccinated populations. The findings were robust across a spectrum of scenarios with varying assumptions on the speed of contact tracing, sensitivity of lateral flow antigen tests, adherence to quarantine and uptake of testing. Daily tests would also allow rapid initiation of a new round of tracing from infected contacts.
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BackgroundSchool-based COVID-19 contacts in England are asked to self-isolate at home. However, this has led to large numbers of missed school days. Therefore, we trialled daily testing of contacts as an alternative, to investigate if it would affect transmission in schools. MethodsWe performed an open-label cluster randomised controlled trial in students and staff from secondary schools and further education colleges in England (ISRCTN18100261). Schools were randomised to self-isolation of COVID-19 contacts for 10 days (control) or to voluntary daily lateral flow device (LFD) testing for school contacts with LFD-negative contacts remaining at school (intervention). Household contacts were excluded from participation. Co-primary outcomes in all students and staff were symptomatic COVID-19, adjusted for community case rates, to estimate within-school transmission (non-inferiority margin: <50% relative increase), and COVID-19-related school absence. Analyses were performed on an intention to treat (ITT) basis using quasi-Poisson regression, also estimating complier average causal effects (CACE). Secondary outcomes included participation rates, PCR results in contacts and performance characteristics of LFDs vs. PCR. FindingsOf 99 control and 102 intervention schools, 76 and 86 actively participated (19-April-2021 to 27-June-2021); additional national data allowed most non-participating schools to be included in the co-primary outcomes. 2432/5763(42.4%) intervention arm contacts participated. There were 657 symptomatic PCR-confirmed infections during 7,782,537 days-at-risk (59.1/100k/week) and 740 during 8,379,749 days-at-risk (61.8/100k/week) in the control and intervention arms respectively (ITT adjusted incidence rate ratio, aIRR=0.96 [95%CI 0.75-1.22;p=0.72]) (CACE-aIRR=0.86 [0.55-1.34]). There were 55,718 COVID-related absences during 3,092,515 person-school-days (1.8%) and 48,609 during 3,305,403 person-school-days(1.5%) in the control and intervention arms (ITT-aIRR=0.80 [95%CI 0.53-1.21;p=0.29]) (CACE-aIRR 0.61 [0.30-1.23]). 14/886(1.6%) control contacts providing an asymptomatic PCR sample tested positive compared to 44/2981(1.5%) intervention contacts (adjusted odds ratio, aOR=0.73 [95%CI 0.33-1.61;p=0.44]). Rates of symptomatic infection in contacts were 44/4665(0.9%) and 79/5955(1.3%), respectively (aOR=1.21 [0.82-1.79;p=0.34]). InterpretationDaily contact testing of school-based contacts was non-inferior to self-isolation for control of COVID-19 transmission. COVID-19 rates in school-based contacts in both intervention and control groups were <2%. Daily contact testing is a safe alternative to home isolation following school-based exposures.
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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.
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BackgroundHow SARS-CoV-2 infectivity varies with viral load is incompletely understood. Whether rapid point-of-care antigen lateral flow devices (LFDs) detect most potential transmission sources despite imperfect sensitivity is unknown. MethodsWe combined SARS-CoV-2 testing and contact tracing data from England between 01-September-2020 and 28-February-2021. We used multivariable logistic regression to investigate relationships between PCR-confirmed infection in contacts of community-diagnosed cases and index case viral load, S gene target failure (proxy for B.1.1.7 infection), demographics, SARS-CoV-2 incidence, social deprivation, and contact event type. We used LFD performance to simulate the proportion of cases with a PCR-positive contact expected to be detected using one of four LFDs. Results231,498/2,474,066 (9%) contacts of 1,064,004 index cases tested PCR-positive. PCR-positive results in contacts independently increased with higher case viral loads (lower Ct values) e.g., 11.7%(95%CI 11.5-12.0%) at Ct=15 and 4.5%(4.4-4.6%) at Ct=30. B.1.1.7 infection increased PCR-positive results by [~]50%, (e.g. 1.55-fold, 95%CI 1.49-1.61, at Ct=20). PCR-positive results were most common in household contacts (at Ct=20.1, 8.7%[95%CI 8.6-8.9%]), followed by household visitors (7.1%[6.8-7.3%]), contacts at events/activities (5.2%[4.9-5.4%]), work/education (4.6%[4.4-4.8%]), and least common after outdoor contact (2.9%[2.3-3.8%]). Contacts of children were the least likely to test positive, particularly following contact outdoors or at work/education. The most and least sensitive LFDs would detect 89.5%(89.4-89.6%) and 83.0%(82.8-83.1%) of cases with PCR-positive contacts respectively. ConclusionsSARS-CoV-2 infectivity varies by case viral load, contact event type, and age. Those with high viral loads are the most infectious. B.1.1.7 increased transmission by [~]50%. The best performing LFDs detect most infectious cases. Key pointsIn 2,474,066 contacts of 1,064,004 SARS-CoV-2 cases, PCR-positive tests in contacts increased with higher index case viral loads, the B.1.1.7 variant and household contact. Children were less infectious. Lateral flow devices can detect 83.0-89.5% of infections leading to onward transmission.
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BackgroundTesting asymptomatic contacts of confirmed COVID-19 cases for the presence of SARS-CoV-2 could reduce onward transmission by improving case ascertainment and lessen the impact of self-isolation on un-infected individuals. This study investigated the feasibility and acceptability of implementing a test to enable approach as part of Englands tracing strategy. MethodsContacts of confirmed COVID-19 cases were offered serial testing as an alternative to self-isolation using daily self-performed lateral flow device (LFD) tests for the first 7 days post exposure. Asymptomatic participants with a negative LFD result were given 24 hours of freedom from self-isolation between each test. A self-collected confirmatory PCR test was performed on testing positive or at the end of the LFD testing period. ResultsOf 1,760 contacts, 882 consented to daily testing, with 812 within 48 hours of exposure sent testing packs. Of those who declined to participate, 39.1% stated they had already accessed PCR testing. Of the 812 who were sent packs, 570 (70.2%) reported one or more LFD results; 102 (17.9%) tested positive. Concordance between reported LFD result and a supplied LFD image was 97.1%. 82.8% of PCR positive samples and 99.6% of PCR negative samples were correctly detected by LFD. The proportion of secondary cases from contacts of those who participated in the study and tested positive (6.3%; 95% CI: 3.4-11.1%) were comparable to a comparator group who self-isolated (7.6%; 95% CI: 7.3-7.8%). ConclusionThis study shows a high acceptability, compliance and positivity rates when using self-administered LFDs among contacts of confirmed COVID-19 cases. Offering routine testing as a structured part of the contact tracing process is likely to be an effective method of case ascertainment.
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BackgroundNatural and vaccine-induced immunity will play a key role in controlling the SARS-CoV-2 pandemic. SARS-CoV-2 variants have the potential to evade natural and vaccine-induced immunity. MethodsIn a longitudinal cohort study of healthcare workers (HCWs) in Oxfordshire, UK, we investigated the protection from symptomatic and asymptomatic PCR-confirmed SARS-CoV-2 infection conferred by vaccination (Pfizer-BioNTech BNT162b2, Oxford-AstraZeneca ChAdOx1 nCOV-19) and prior infection (determined using anti-spike antibody status), using Poisson regression adjusted for age, sex, temporal changes in incidence and role. We estimated protection conferred after one versus two vaccinations and from infections with the B.1.1.7 variant identified using whole genome sequencing. Results13,109 HCWs participated; 8285 received the Pfizer-BioNTech vaccine (1407 two doses) and 2738 the Oxford-AstraZeneca vaccine (49 two doses). Compared to unvaccinated seronegative HCWs, natural immunity and two vaccination doses provided similar protection against symptomatic infection: no HCW vaccinated twice had symptomatic infection, and incidence was 98% lower in seropositive HCWs (adjusted incidence rate ratio 0.02 [95%CI <0.01-0.18]). Two vaccine doses or seropositivity reduced the incidence of any PCR-positive result with or without symptoms by 90% (0.10 [0.02-0.38]) and 85% (0.15 [0.08-0.26]) respectively. Single-dose vaccination reduced the incidence of symptomatic infection by 67% (0.33 [0.21-0.52]) and any PCR-positive result by 64% (0.36 [0.26-0.50]). There was no evidence of differences in immunity induced by natural infection and vaccination for infections with S-gene target failure and B.1.1.7. ConclusionNatural infection resulting in detectable anti-spike antibodies and two vaccine doses both provide robust protection against SARS-CoV-2 infection, including against the B.1.1.7 variant. SummaryNatural infection resulting in detectable anti-spike antibodies and two vaccine doses both provided [≥] 85% protection against symptomatic and asymptomatic SARS-CoV-2 infection in healthcare workers, including against the B.1.1.7 variant. Single dose vaccination reduced symptomatic infection by 67%.
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ObjectivesNosocomial transmission was an important aspect of SARS-CoV-1 and MERS-CoV outbreaks. Healthcare-associated SARS-CoV-2 infection has been reported in single and multi-site hospital-based studies in England, but not nationally. MethodsAdmission records for all hospitals in England were linked to SARS-CoV-2 national test data for the period 01/03/2020 to 31/08/2020. Case definitions were: community-onset community-acquired (CO.CA), first positive test (FPT) <14 days pre-admission, up to day 2 of admission; hospital-onset indeterminate healthcare-associated (HO.iHA), FPT on day 3-7; hospital-onset probable healthcare-associated (HO.pHA), FPT on day 8-14; hospital-onset definite healthcare-associated (HO.HA), FPT from day 15 of admission until discharge; community-onset possible healthcare-associated (CO.pHA), FPT [≤]14 days post-discharge. ResultsOne-third (34.4%, 100,859/293,204) of all laboratory-confirmed COVID-19 cases were linked to a hospital record. HO.pHA and HO.HA cases represented 5.3% (15,564/293,204) of all laboratory-confirmed cases and 15.4% (15,564/100,859) of laboratory-confirmed cases among hospital patients. CO.CA and CO.pHA cases represented 86.5% (253,582/293,204) and 5.1% (14,913/293,204) of all laboratory-confirmed cases, respectively. ConclusionsUp to 1 in 6 SARS-CoV-2 infections among hospitalised patients with COVID-19 in England during the first 6 months of the pandemic could be attributed to nosocomial transmission, but these represent less than 1% of the estimated 3 million COVID-19 cases in this period.
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BackgroundThere is an urgent need to better understand whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection. MethodsA large multi-centre prospective cohort was recruited from publicly funded hospital staff in the UK. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed fortnightly questionnaires on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive or prior PCR/antibody test positive) or negative cohort (antibody negative, not previously known to be PCR/antibody positive). Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, possible (subdivided by symptom-status)) depending on hierarchy of evidence. Individuals in the primary infection were excluded from this analysis if infection was confirmed by antibody only. Reinfection rates in the positive cohort were compared against new PCR positives in the negative cohort using a mixed effective multivariable logistic regression analysis. FindingsBetween 18 June and 09 November 2020, 44 reinfections (2 probable, 42 possible) were detected in the baseline positive cohort of 6,614 participants, collectively contributing 1,339,078 days of follow-up. This compares with 318 new PCR positive infections and 94 antibody seroconversions in the negative cohort of 14,173 participants, contributing 1,868,646 days of follow-up. The incidence density per 100,000 person days between June and November 2020 was 3.3 reinfections in the positive cohort, compared with 22.4 new PCR confirmed infections in the negative cohort. The adjusted odds ratio was 0.17 for all reinfections (95% CI 0.13-0.24) compared to PCR confirmed primary infections. The median interval between primary infection and reinfection was over 160 days. InterpretationA prior history of SARS-CoV-2 infection was associated with an 83% lower risk of infection, with median protective effect observed five months following primary infection. This is the minimum likely effect as seroconversions were not included. FundingDepartment of Health and Social Care and Public Health England, with contributions from the Scottish, Welsh and Northern Irish governments.
ABSTRACT
BackgroundA new variant of SARS-CoV-2, B.1.1.7/VOC202012/01, was identified in the UK in December-2020. Direct estimates of its potential to enhance transmission are limited. MethodsNose and throat swabs from 28-September-2020 to 2-January-2021 in the UKs nationally representative surveillance study were tested by RT-PCR for three genes (N, S and ORF1ab). Those positive only on ORF1ab+N, S-gene target failures (SGTF), are compatible with B.1.1.7/VOC202012/01. We investigated cycle threshold (Ct) values (a proxy for viral load), percentage of positives, population positivity and growth rates in SGTF vs non-SGTF positives. Results15,166(0.98%) of 1,553,687 swabs were PCR-positive, 8,545(56%) with three genes detected and 3,531(23%) SGTF. SGTF comprised an increasing, and triple-gene positives a decreasing, percentage of infections from late-November in most UK regions/countries, e.g. from 15% to 38% to 81% over 1.5 months in London. SGTF Ct values correspondingly declined substantially to similar levels to triple-gene positives. Population-level SGTF positivity remained low (<0.25%) in all regions/countries until late-November, when marked increases with and without self-reported symptoms occurred in southern England (to 1.5-3%), despite stable rates of non-SGTF cases. SGTF positivity rates increased on average 6% more rapidly than rates of non-SGTF positives (95% CI 4-9%) supporting addition rather than replacement with B.1.1.7/VOC202012/01. Excess growth rates for SGTF vs non-SGTF positives were similar in those up to high school age (5% (1-8%)) and older individuals (6% (4-9%)). ConclusionsDirect population-representative estimates show that the B.1.1.7/VOC202012/01 SARS-CoV-2 variant leads to higher infection rates, but does not seem particularly adapted to any age group.
ABSTRACT
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.
ABSTRACT
BackgroundThe overall risk of reinfection in individuals who have previously had COVID-19 is unknown. To determine if prior SARS-CoV-2 infection (as determined by at least one positive commercial antibody test performed in a laboratory) in healthcare workers confers future immunity to reinfection, we are undertaking a large-scale prospective longitudinal cohort study of healthcare staff across the United Kingdom. MethodsPopulation and Setting: staff members of healthcare organisations working in hospitals in the UK At recruitment, participants will have their serum tested for anti-SARS-CoV-2 at baseline and using these results will be initially allocated to either antibody positive or antibody negative cohorts. Participants will undergo antibody and viral RNA testing at 1-4 weekly intervals throughout the study period, and based on these results may move between cohorts. Any results from testing undertaken for other reasons (e.g. symptoms, contact tracing etc.) or prior to study entry will also be included. Individuals will complete enrolment and fortnightly questionnaires on exposures and symptoms. Follow-up will be for at least 12 months from study entry. OutcomeThe primary outcome of interest is a reinfection with SARS -CoV-2 during the study period. Secondary outcomes will include incidence and prevalence (both RNA and antibody) of SARS-CoV-2, viral genomics, viral culture, symptom history and antibody/neutralising antibody titres. ConclusionThis large study will help us to understand the impact of the presence of antibodies on the risk of reinfection with SARS-CoV-2; the results will have substantial implications in terms of national and international policy, as well as for risk management of contacts of COVID-19 cases. Trial RegistrationIRAS ID 284460, HRA and Health and Care Research Wales approval granted 22 May 2020.