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Following primary SARS-CoV-2 vaccination, understanding the relative extent of protection against SARS-CoV-2 infection from boosters or from breakthrough infections (i.e. infection in the context of previous vaccination) has important implications for vaccine policy. In this study, we investigated correlates of protection against Omicron BA.4/5 infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults [≥]18y from the United Kingdom general population. We found that higher anti-spike IgG antibody levels were associated with increased protection against Omicron BA.4/5 infection and that breakthrough infections were associated with higher levels of protection at any given antibody level than booster vaccinations. Breakthrough infections generated similar antibody levels to third/booster vaccinations, and the subsequent declines in antibody levels were similar to or slightly slower than those after third/booster vaccinations. Taken together our findings show that breakthrough infection provides longer lasting protection against further infections than booster vaccinations. For example, considering antibody levels associated with 67% protection against infection, a third/booster vaccination did not provide long-lasting protection, while a Delta/Omicron BA.1 breakthrough infection could provide 5-10 months of protection against Omicron BA.4/5 reinfection. 50-60% of the vaccinated UK population with a breakthrough infection would still be protected by the end of 2022, compared to <15% of the triple-vaccinated UK population without previous infection. Although there are societal impacts and risks to some individuals associated with ongoing transmission, breakthrough infection could be an efficient immune-boosting mechanism for subgroups of the population, including younger healthy adults, who have low risks of adverse consequences from infection.
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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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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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COVID-19 is unlikely to be the last pandemic that we face. According to an analysis of a global dataset of historical pandemics from 1600 to the present, the risk of a COVID-like pandemic has been estimated as 2.63% annually or a 38% lifetime probability. This rate may double over the coming decades. While we may be unable to prevent future pandemics, we can reduce their impact by investing in preparedness. In this study, we propose RapiD_AI : a framework to guide the use of pretrained neural network models as a pandemic preparedness tool to enable healthcare system resilience and effective use of ML during future pandemics. The RapiD_AI framework allows us to build high-performing ML models using data collected in the first weeks of the pandemic and provides an approach to adapt the models to the local populations and healthcare needs. The motivation is to enable healthcare systems to overcome data limitations that prevent the development of effective ML in the context of novel diseases. We digitally recreated the first 20 weeks of the COVID-19 pandemic and experimentally demonstrated the RapiD_AI framework using domain adaptation and inductive transfer. We (i) pretrain two neural network models (Deep Neural Network and TabNet) on a large Electronic Health Records dataset representative of a general in-patient population in Oxford, UK, (ii) fine-tune using data from the first weeks of the pandemic, and (iii) simulate local deployment by testing the performance of the models on a held-out test dataset of COVID-19 patients. Our approach has demonstrated an average relative/absolute gain of 4.92/4.21% AUC compared to an XGBoost benchmark model trained on COVID-19 data only. Moreover, we show our ability to identify the most useful historical pretraining samples through clustering and to expand the task of deployed models through inductive transfer to meet the emerging needs of a healthcare system without access to large historical pretraining datasets.
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BackgroundThe SARS-CoV-2 Delta variant has been replaced by the highly transmissible Omicron BA.1 variant, and subsequently by Omicron BA.2. It is important to understand how these changes in dominant variants affect reported symptoms, while also accounting for symptoms arising from other co-circulating respiratory viruses. MethodsIn a nationally representative UK community study, the COVID-19 Infection Survey, we investigated symptoms in PCR-positive infection episodes vs. PCR-negative study visits over calendar time, by age and vaccination status, comparing periods when the Delta, Omicron BA.1 and BA.2 variants were dominant. ResultsBetween October-2020 and April-2022, 120,995 SARS-CoV-2 PCR-positive episodes occurred in 115,886 participants, with 70,683 (58%) reporting symptoms. The comparator comprised 4,766,366 PCR-negative study visits (483,894 participants); 203,422 (4%) reporting symptoms. Symptom reporting in PCR-positives varied over time, with a marked reduction in loss of taste/smell as Omicron BA.1 dominated, maintained with BA.2 (44%/45% 17 October 2021, 16%/13% 2 January 2022, 15%/12% 27 March 2022). Cough, fever, shortness of breath, myalgia, fatigue/weakness and headache also decreased after Omicron BA.1 dominated, but sore throat increased, the latter to a greater degree than concurrent increases in PCR-negatives. Fatigue/weakness increased again after BA.2 dominated, although to a similar degree to concurrent increases in PCR-negatives. Symptoms were consistently more common in adults aged 18-65 years than in children or older adults. ConclusionsIncreases in sore throat (also common in the general community), and a marked reduction in loss of taste/smell, make Omicron harder to detect with symptom-based testing algorithms, with implications for institutional and national testing policies. SummaryIn a UK community study, loss of taste/smell was markedly less commonly reported with Omicron BA.1/BA.2 than Delta SARS-CoV-2 infections, with smaller declines in reported shortness of breath, myalgia and fatigue/weakness, but increases in sore throat, challenging symptom-based testing algorithms.
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Given high SARS-CoV-2 incidence, coupled with slow and inequitable vaccine roll-out, there is an urgent need for evidence to underpin optimum vaccine deployment, aiming to maximise global population immunity at speed. We evaluate whether a single vaccination in previously infected individuals generates similar initial and subsequent antibody responses to two vaccinations in those without prior infection. We compared anti-spike IgG antibody responses after a single dose of ChAdOx1, BNT162b2, or mRNA-1273 SARS-CoV-2 vaccines in the COVID-19 Infection Survey in the UK general population. In 100,849 adults who received at least one vaccination, 13,404 (13.3%) had serological and/or PCR evidence of prior infection. Prior infection significantly boosted antibody responses for all three vaccines, producing a higher peak level and longer half-life, and a response comparable to those without prior infection receiving two vaccinations. In those with prior infection, median time above the positivity threshold was estimated to last for >1 year after the first dose. Single-dose vaccination targeted to those previously infected may provide protection in populations with high rates of previous infection faced with limited vaccine supply, as an interim measure while vaccine campaigns are scaled up.
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The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis with unprecedented challenges for public health. Vaccinations against SARS-CoV-2 have slowed the incidence of new infections and reduced disease severity. As the time-of-day of vaccination has been reported to influence host immune responses to multiple pathogens, we quantified the influence of SARS-CoV-2 vaccination time, vaccine type, age, sex, and days post-vaccination on anti-Spike antibody responses in healthcare workers. The magnitude of the anti-Spike antibody response associated with the time-of-day of vaccination, vaccine type, participant age, sex, and days post vaccination. These results may be relevant for optimizing SARS-CoV-2 vaccine efficacy.
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There is substantial interest regarding the perceived risk that immunomodulator and biologic therapy could have on COVID-19 disease severity among patients with inflammatory bowel disease (IBD) and clinicians. In this study, we show that infliximab/thiopurine combination therapy is associated with significantly lower IgA, a range of lower IgG responses as well as impaired neutralising antibody responses, compared to responses observed in healthy individuals. We also demonstrate that whilst IgG responses were significantly reduced in individuals with IBD treated with infliximab or vedolizumab monotherapy compared to healthy controls, there was no significant reduction in IgA and neutralising antibody responses. As neutralising antibody responses correlate with protection, this observation may provide the mechanistic explanation for the observation reported by the SECURE-IBD study that individuals on infliximab/thiopurine combination therapy were at greater risk of severe COVID-19 outcomes than patients on monotherapy.
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ObjectiveTo describe the impact of the SARS-CoV-2 pandemic on the incidence of paediatric viral respiratory tract infection in Oxfordshire, UK. MethodsData on paediatric Emergency Department (ED) attendances (0-15 years inclusive), respiratory virus testing, vital signs and mortality at Oxford University Hospitals were summarised using descriptive statistics. ResultsBetween 1-March-2016 and 30-July-2021, 155,056 ED attendances occurred and 7,195 respiratory virus PCRs were performed. Detection of all pathogens was suppressed during the first national lockdown. Rhinovirus and adenovirus rates increased when schools reopened September-December 2020, then fell, before rising in March-May 2021. The usual winter RSV peak did not occur in 2020/21, with an inter-seasonal rise (32/1,000 attendances in 0-3yr olds) in July 2021. Influenza remained suppressed throughout. A higher Paediatric Early Warning Score (PEWS) was seen for attendees with adenovirus during the pandemic compared to pre-pandemic (p=0.04, Mann-Witney U test), no other differences in PEWS were seen. ConclusionsSARS-CoV-2 caused major changes in the incidence of paediatric respiratory viral infection in Oxfordshire, with implications for clinical service demand, testing strategies, timing of palivizumab RSV prophylaxis, and highlighting the need to understand which public health interventions are most effective for preventing respiratory virus infections.
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BackgroundPre-Delta, vaccination reduced SARS-CoV-2 transmission from individuals infected despite vaccination, potentially via reducing viral loads. While vaccination still lowers the risk of infection, similar viral loads in vaccinated and unvaccinated individuals infected with Delta question how much vaccination prevents transmission. MethodsWe performed a retrospective observational cohort study of adult contacts of SARS-CoV-2-infected adult index cases using English contact testing data. We used multivariable Poisson regression to investigate associations between transmission and index case and contact vaccination, and how these vary with Alpha and Delta variants (classified using S-gene detection/calendar trends) and time since second vaccination. Results54,667/146,243(37.4%) PCR-tested contacts of 108,498 index cases were PCR-positive. Two doses of BNT162b2 or ChAdOx1 vaccines in Alpha index cases were independently associated with reduced PCR-positivity in contacts (aRR, adjusted rate ratio vs. unvaccinated=0.32[95%CI 0.21-0.48] and 0.48[0.30-0.78] respectively). The Delta variant attenuated vaccine-associated reductions in transmission: two BNT162b2 doses reduced Delta transmission (aRR=0.50[0.39-0.65]), more than ChAdOx1 (aRR=0.76[0.70-0.82]). Variation in Ct values (indicative of viral load) explained 7-23% of vaccine-associated transmission reductions. Transmission reductions declined over time post-second vaccination, for Delta reaching similar levels to unvaccinated individuals by 12 weeks for ChAdOx1 and attenuating substantially for BNT162b2. Protection in contacts also declined in the 3 months post-second vaccination. ConclusionsVaccination reduces transmission of Delta, but by less than the Alpha variant. The impact of vaccination decreased over time. Factors other than PCR Ct values at diagnosis are important in understanding vaccine-associated transmission reductions. Booster vaccinations may help control transmission together with preventing infections.
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We investigated anti-spike IgG antibody responses and correlates of protection following second doses of ChAdOx1 or BNT162b2 SARS-CoV-2 vaccines in the UK general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, while declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2-3 months after two ChAdOx1 doses and 5-8 months after two BNT162b2 doses in those without prior infection, and 1-2 years for those unvaccinated after natural infection. A third booster dose may be needed, prioritised to ChAdOx1 recipients and those more clinically vulnerable.
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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.
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BackgroundUncertainty in patients COVID-19 status contributes to treatment delays, nosocomial transmission, and operational pressures in hospitals. However, typical turnaround times for batch-processed laboratory PCR tests remain 12-24h. Although rapid antigen lateral flow testing (LFD) has been widely adopted in UK emergency care settings, sensitivity is limited. We recently demonstrated that AI-driven triage (CURIAL-1.0) allows high-throughput COVID-19 screening using clinical data routinely available within 1h of arrival to hospital. Here we aimed to determine operational and safety improvements over standard-care, performing external/prospective evaluation across four NHS trusts with updated algorithms optimised for generalisability and speed, and deploying a novel lab-free screening pathway in a UK emergency department. MethodsWe rationalised predictors in CURIAL-1.0 to optimise separately for generalisability and speed, developing CURIAL-Lab with vital signs and routine laboratory blood predictors (FBC, U&E, LFT, CRP) and CURIAL-Rapide with vital signs and FBC alone. Models were calibrated during training to 90% sensitivity and validated externally for unscheduled admissions to Portsmouth University Hospitals, University Hospitals Birmingham and Bedfordshire Hospitals NHS trusts, and prospectively during the second-wave of the UK COVID-19 epidemic at Oxford University Hospitals (OUH). Predictions were generated using first-performed blood tests and vital signs and compared against confirmatory viral nucleic acid testing. Next, we retrospectively evaluated a novel clinical pathway triaging patients to COVID-19-suspected clinical areas where either model prediction or LFD results were positive, comparing sensitivity and NPV with LFD results alone. Lastly, we deployed CURIAL-Rapide alongside an approved point-of-care FBC analyser (OLO; SightDiagnostics, Israel) to provide lab-free COVID-19 screening in the John Radcliffe Hospitals Emergency Department (Oxford, UK), as trust-approved service improvement. Our primary improvement outcome was time-to-result availability; secondary outcomes were sensitivity, specificity, PPV, and NPV assessed against a PCR reference standard. We compared CURIAL-Rapides performance with clinician triage and LFD results within standard-care. Results72,223 patients met eligibility criteria across external and prospective validation sites. Model performance was consistent across trusts (CURIAL-Lab: AUROCs range 0.858-0.881; CURIAL-Rapide 0.836-0.854), with highest sensitivity achieved at Portsmouth University Hospitals (CURIAL-Lab:84.1% [95% Wilsons score CIs 82.5-85.7]; CURIAL-Rapide:83.5% [81.8 - 85.1]) at specificities of 71.3% (95% Wilsons score CIs: 70.9 - 71.8) and 63.6% (63.1 - 64.1). For 3,207 patients receiving LFD-triage within routine care for OUH admissions between December 23, 2021 and March 6, 2021, a combined clinical pathway increased sensitivity from 56.9% for LFDs alone (95% CI 51.7-62.0) to 88.2% with CURIAL-Rapide (84.4-91.1; AUROC 0.919) and 85.6% with CURIAL-Lab (81.6-88.9; AUROC 0.925). 520 patients were prospectively enrolled for point-of-care FBC analysis between February 18, 2021 and May 10, 2021, of whom 436 received confirmatory PCR testing within routine care and 10 (2.3%) tested positive. Median time from patient arrival to availability of CURIAL-Rapide result was 45:00 min (32-64), 16 minutes (26.3%) sooner than LFD results (61:00 min, 37-99; log-rank p<0.0001), and 6:52 h (90.2%) sooner than PCR results (7:37 h, 6:05-15:39; p<0.0001). Sensitivity and specificity of CURIAL-Rapide were 87.5% (52.9-97.8) and 85.4% (81.3-88.7), therefore achieving high NPV (99.7%, 98.2-99.9). CURIAL-Rapide correctly excluded COVID-19 for 58.5% of negative patients who were triaged by a clinician to COVID-19-suspected (amber) areas. ImpactCURIAL-Lab & CURIAL-Rapide are generalisable, high-throughput screening tests for COVID-19, rapidly excluding the illness with higher NPV than LFDs. CURIAL-Rapide can be used in combination with near-patient FBC analysis for rapid, lab-free screening, and may reduce the number of COVID-19-negative patients triaged to enhanced precautions ( amber) clinical areas.
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The effectiveness of BNT162b2, ChAdOx1, and mRNA-1273 vaccines against new SARS-CoV-2 infections requires continuous re-evaluation, given the increasingly dominant Delta variant. We investigated the effectiveness of the vaccines in a large community-based survey of randomly selected households across the UK. We found that the effectiveness of BNT162b2 and ChAd0x1 against any infections (new PCR positives) and infections with symptoms or high viral burden is reduced with the Delta variant. A single dose of the mRNA-1273 vaccine had similar or greater effectiveness compared to a single dose of BNT162b2 or ChAdOx1. Effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity following second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positives but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher among those vaccinated following a prior infection and younger adults. With Delta, infections occurring following two vaccinations had similar peak viral burden to those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with Delta.
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BackgroundSeveral community-based studies have assessed the ability of different symptoms to identify COVID-19 infections, but few have compared symptoms over time (reflecting SARS-CoV-2 variants) and by vaccination status. MethodsUsing data and samples collected by the COVID-19 Infection Survey at regular visits to representative households across the UK, we compared symptoms in new PCR-positives and comparator test-negative controls. ResultsFrom 26/4/2020-7/8/2021, 27,869 SARS-CoV-2 PCR-positive episodes occurred in 27,692 participants (median 42 years (IQR 22-58)); 13,427 (48%) self-reported symptoms ("symptomatic positive episodes"). The comparator group comprised 3,806,692 test-negative visits (457,215 participants); 130,612 (3%) self-reported symptoms ("symptomatic negative visit"). Reporting of any symptoms in positive episodes varied over calendar time, reflecting changes in prevalence of variants, incidental changes (e.g. seasonal pathogens, schools re-opening) and vaccination roll-out. There was a small increase in sore throat reporting in symptomatic positive episodes and negative visits from April-2021. After May-2021 when Delta emerged there were substantial increases in headache and fever in positives, but not in negatives. Although specific symptom reporting in symptomatic positive episodes vs. negative visits varied by age, sex, and ethnicity, only small improvements in symptom-based infection detection were obtained; e.g. adding fatigue/weakness or all eight symptoms to the classic four symptoms (cough, fever, loss of taste/smell) increased sensitivity from 74% to 81% to 90% but tests per positive from 4.6 to 5.3 to 8.7. ConclusionsWhilst SARS-CoV-2-associated symptoms vary by variant, vaccination status and demographics, differences are modest and do not warrant large-scale changes to targeted testing approaches given resource implications. SummaryWithin the COVID-19 Infection Survey, recruiting representative households across the UK general population, SARS-CoV-2-associated symptoms varied by viral variant, vaccination status and demographics. However, differences are modest and do not currently warrant large-scale changes to targeted testing approaches.
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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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We estimated the duration and determinants of antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as non-responders not developing anti-spike antibodies. These seronegative non-responders were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.
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BackgroundDespite robust efforts, patients and staff acquire SARS-CoV-2 infection in hospitals. In this retrospective cohort study, we investigated whether whole-genome sequencing (WGS) could enhance the epidemiological investigation of healthcare-associated SARS-CoV-2 acquisition. Methods and findingsFrom 17-November-2020 to 5-January-2021, 803 inpatients and 329 staff were diagnosed with SARS-CoV-2 infection across four teaching hospitals in Oxfordshire, UK. We classified cases according to epidemiological definitions, sought epidemiological evidence of a potential source for each nosocomial infection, and evaluated if epidemiologically-linked cases had genomic evidence supporting transmission. We compared epidemiological and genomic outbreak identification. Using national epidemiological definitions, 109/803 (14%) inpatient infections were classified as definite/probable nosocomial, 615 (77%) as community-acquired and 79 (10%) as indeterminate. There was strong epidemiological evidence to support definite/probable cases as nosocomial: 107/109 (98%) had a prior-negative PCR in the same hospital stay before testing positive, and 101(93%) shared time and space with known infected patients/staff. Many indeterminate cases were likely infected in hospital: 53/79 (67%) had a prior-negative PCR and 75 (95%) contact with a potential source. 89/615 (11% of all 803 patients) with apparent community-onset had a recent hospital exposure. WGS highlighted SARS-CoV-2 is mainly imported into hospitals: within 764 samples sequenced 607 genomic clusters were identified (>1 SNP distinct). Only 43/607 (7%) clusters contained evidence of onward transmission (subsequent cases within [≤]1 SNP). 20/21 epidemiologically-identified outbreaks contained multiple genomic introductions. Most (80%) nosocomial acquisition occurred in rapid super-spreading events in settings with a mix of COVID-19 and non-COVID-19 patients. Hospitals not routinely admitting COVID-19 patients had low rates of transmission. Undiagnosed/unsequenced individuals prevent genomic data from excluding nosocomial acquisition. ConclusionsOur findings suggest current surveillance definitions underestimate nosocomial acquisition and reveal most nosocomial transmission occurs from a relatively limited number of highly infectious individuals.
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It is unclear whether prior endemic coronavirus infections affect COVID-19 severity. Here, we show that in cases of fatal COVID-19, antibody responses to the SARS-COV-2 spike are directed against epitopes shared with endemic beta-coronaviruses in the S2 subunit of the SARS-CoV-2 spike protein. This immune response is associated with the compromised production of a de novo SARS-CoV-2 spike response among individuals with fatal COVID-19 outcomes.
RESUMEN
BackgroundSARS-CoV-2 can spread efficiently in hospitals, but the transmission pathways amongst patients and healthcare workers are unclear. MethodsWe analysed data from four teaching hospitals in Oxfordshire, UK, from January to October 2020. Associations between infectious SARS-CoV-2 individuals and infection risk were quantified using logistic, generalised additive and linear mixed models. Cases were classified as community- or hospital-acquired using likely incubation periods. ResultsNine-hundred and twenty of 66184 patients who were hospitalised during the study period had a positive SARS-CoV-2 PCR test within the same period (1%). Out of these, 571 patients had their first positive PCR tests while hospitalised (62%), and 97 of these occurred at least seven days after admission (11%). Amongst the 5596 healthcare workers, 615 (11%) tested positive during the study period using PCR or serological tests. For susceptible patients, one day in the same ward with another patient with hospital-acquired SARS-CoV-2 was associated with an additional eight infections per 1000 susceptible patients (95%CrI 6-10). Exposure to an infectious patient with community-acquired COVID-19 or to an infectious healthcare worker was associated with substantially lower infection risks (2/1000 susceptible patients/day, 95%CrI 1-2). As for healthcare worker infections, exposure to an infectious patient with hospital-acquired SARS-CoV-2 or to an infectious healthcare worker were both associated with an additional one infection per 1000 susceptible healthcare workers per day (95%CrI 1-2). Exposure to an infectious patient with community-acquired SARS-CoV-2 was associated with half this risk (0.5/1000 susceptible healthcare workers/day, 95%CrI 0.3-0.7). InterpretationExposure to patients with hospital-acquired SARS-CoV-2 poses a substantial infection risk. Infection control measures to limit nosocomial transmission must be optimised to protect both staff and patients from SARS-CoV-2 infection. FundingNational Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University in partnership with Public Health England (PHE) (NIHR200915). Medical Research Council, Nosocomial transmission of SARS-CoV-2 (MR/V028456/1). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched the PubMed database using the search terms ("COVID-19" OR "SARS-CoV-2") AND ("nosocomial" OR "hospital") AND ("transmission") in either the abstracts or titles, for English-language articles published up to March 31, 2021. This returned 748 results, out of which ten reported transmission events in the hospital setting quantitatively. These publications can be broadly categorised to epidemiological descriptions of isolated outbreaks (5) or contact tracing of patients exposed to infected healthcare workers (1), retrospective cohort studies involving a particular group of patients, e.g., patients who underwent surgical procedures (2), and using genomic sequencing to identify transmission clusters (2). None of the studies reported the comparative transmission rates of SARS-CoV-2 amongst patients and staff. Added value of this studyThis study reports the analysis of a large observational dataset collected from a group of hospitals in the UK over eight months, consisting of both hospitalised patients and healthcare workers. Based on these detailed individual-level data, we quantified the associations between patient and healthcare worker characteristics and risks for acquiring nosocomial SARS-CoV-2 infection after adjusting for their exposures to SARS-CoV-2. Over the study period, we describe how risk of acquisition changes both with calendar time and over a patients hospital stay. By linking the presence of infected and susceptible patients and healthcare workers by time and ward locations, we quantify the relative importance of the transmission pathways for both the susceptible patients and healthcare workers. Implications of all the available evidenceNosocomial transmission of SARS-CoV-2 is common. Identifying the drivers of SARS-CoV-2 transmissions in the hospital setting is essential for designing infection prevention and control policies to minimise the added pressure from such events on our health systems. We found that newly infected patients who acquired SARS-CoV-2 in the hospital pose the highest risk of onward transmission to other patients and healthcare workers. Infection control and prevention efforts need to be enhanced around these patients to prevent further transmissions and studies assessing the effectiveness of these policies are needed.