Publications
316 results found
Brown JC, Goldhill DH, Zhou J, et al., 2021, Increased transmission of SARS-CoV-2 lineage B.1.1.7 (VOC 2020212/01) is not accounted for by a replicative advantage in primary airway cells or antibody escape
<jats:title>Abstract</jats:title><jats:p>Lineage B.1.1.7 (Variant of Concern 202012/01) is a new SARS-CoV-2 variant which was first sequenced in the UK in September 2020 before becoming the majority strain in the UK and spreading worldwide. The rapid spread of the B.1.1.7 variant results from increased transmissibility but the virological characteristics which underpin this advantage over other circulating strains remain unknown. Here, we demonstrate that there is no difference in viral replication between B.1.1.7 and other contemporaneous SARS-CoV-2 strains in primary human airway epithelial (HAE) cells. However, B.1.1.7 replication is disadvantaged in Vero cells potentially due to increased furin-mediated cleavage of its spike protein as a result of a P681H mutation directly adjacent to the S1/S2 cleavage site. In addition, we show that B.1.1.7 does not escape neutralisation by convalescent or post-vaccination sera. Thus, increased transmission of B.1.1.7 is not caused by increased replication, as measured on HAE cells, or escape from serological immunity.</jats:p>
Rodriguez-Manzano J, Malpartida-Cardenas K, Moser N, et al., 2021, Handheld point-of-care system for rapid detection of SARS-CoV-2 extracted RNA in under 20 min, ACS Central Science, Vol: 7, Pages: 307-317, ISSN: 2374-7943
The COVID-19 pandemic is a global health emergency characterized by the high rate of transmission and ongoing increase of cases globally. Rapid point-of-care (PoC) diagnostics to detect the causative virus, SARS-CoV-2, are urgently needed to identify and isolate patients, contain its spread and guide clinical management. In this work, we report the development of a rapid PoC diagnostic test (<20 min) based on reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) and semiconductor technology for the detection of SARS-CoV-2 from extracted RNA samples. The developed LAMP assay was tested on a real-time benchtop instrument (RT-qLAMP) showing a lower limit of detection of 10 RNA copies per reaction. It was validated against extracted RNA from 183 clinical samples including 127 positive samples (screened by the CDC RT-qPCR assay). Results showed 91% sensitivity and 100% specificity when compared to RT-qPCR and average positive detection times of 15.45 ± 4.43 min. For validating the incorporation of the RT-LAMP assay onto our PoC platform (RT-eLAMP), a subset of samples was tested (n = 52), showing average detection times of 12.68 ± 2.56 min for positive samples (n = 34), demonstrating a comparable performance to a benchtop commercial instrument. Paired with a smartphone for results visualization and geolocalization, this portable diagnostic platform with secure cloud connectivity will enable real-time case identification and epidemiological surveillance.
Riley S, Walters C, Wang H, et al., 2021, REACT-1 round 9 interim report: downward trend of SARS-CoV-2 in England in February 2021 but still at high prevalence
Background and Methods: England entered its third national lockdown of the COVID-19pandemic on 6th January 2021 with the aim of reducing the daily number of deaths andpressure on healthcare services. The real-time assessment of community transmission study(REACT-1) obtains throat and nose swabs from randomly selected people in England inorder to describe patterns of SARS-CoV-2 prevalence. Here, we report data from round 9aof REACT-1 for swabs collected between 4th and 13th February 2021.Results: Out of 85,473 tested-swabs, 378 were positive. Overall weighted prevalence ofinfection in the community in England was 0.51%, a fall of more than two thirds since our lastreport (round 8) in January 2021 when 1.57% of people tested positive. We estimate ahalving time of 14.6 days and a reproduction number R of 0.72, based on the difference inprevalence between the end of round 8 and the beginning of round 9. Although prevalencefell in all nine regions of England over the same period, there was greater uncertainty in thetrend for North West, North East, and Yorkshire and The Humber. Prevalence fellsubstantially across all age groups with highest prevalence among 18- to 24-year olds at0.89% (0.47%, 1.67%) and those aged 5 to12 years at 0.86% (0.60%, 1.24%). Largehousehold size, living in a deprived neighbourhood, and Asian ethnicity were all associatedwith increased prevalence. Healthcare and care home workers were more likely to testpositive compared to other workers.Conclusions: There is a strong decline in prevalence of SARS-CoV-2 in England among thegeneral population five to six weeks into lockdown, but prevalence remains high: at levelssimilar to those observed in late September 2020. Also, the number of COVID-19 cases inhospitals is higher than at the peak of the first wave in April 2020. The effects of easing ofsocial distancing when we transition out of lockdown need to be closely monitored to avoid aresurgence in infections and renewed pressure on health services.
Ward H, Atchison C, Whitaker M, et al., 2021, SARS-CoV-2 antibody prevalence in England following the first peak of the pandemic., Nature Communications, Vol: 12, Pages: 1-8, ISSN: 2041-1723
England has experienced a large outbreak of SARS-CoV-2, disproportionately affecting people from disadvantaged and ethnic minority communities. It is unclear how much of this excess is due to differences in exposure associated with structural inequalities. Here we report from the REal-time Assessment of Community Transmission-2 (REACT-2) national study of over 100,000 people. After adjusting for test characteristics and re-weighting to the population, overall antibody prevalence is 6.0% (95% CI: 5.8-6.1). An estimated 3.4 million people had developed antibodies to SARS-CoV-2 by mid-July 2020. Prevalence is two- to three-fold higher among health and care workers compared with non-essential workers, and in people of Black or South Asian than white ethnicity, while age- and sex-specific infection fatality ratios are similar across ethnicities. Our results indicate that higher hospitalisation and mortality from COVID-19 in minority ethnic groups may reflect higher rates of infection rather than differential experience of disease or care.
Pillay TD, Kondratiuk A, Davies M, et al., 2021, THE INDUCTION OF EARLY, DYNAMIC AIRWAY MUCOSAL AND SYSTEMIC IMMUNE RESPONSES FOLLOWING RECENT SARS-COV-2 HOUSEHOLD EXPOSURE, Publisher: BMJ PUBLISHING GROUP, Pages: A225-A226, ISSN: 0040-6376
Riley S, Eales O, Walters C, et al., 2021, REACT-1 round 8 final report: high average prevalence with regional heterogeneity of trends in SARS-CoV-2 infection in the community in England during January 2021
In early January 2021, England entered its third national lockdown of the COVID-19 pandemic to reduce numbers of deaths and pressure on healthcare services, while rapidly rolling out vaccination to healthcare workers and those most at risk of severe disease and death. REACT-1 is a survey of SARS-CoV-2 prevalence in the community in England, based on repeated cross-sectional samples of the population. Between 6th and 22nd January 2021, out of 167,642 results, 2,282 were positive giving a weighted national prevalence of infection of 1.57% (95% CI, 1.49%, 1.66%). The R number nationally over this period was estimated at 0.98 (0.92, 1.04). Prevalence remained high throughout, but with suggestion of a decline at the end of the study period. The average national trend masked regional heterogeneity, with robustly decreasing prevalence in one region (South West) and increasing prevalence in another (East Midlands). Overall prevalence at regional level was highest in London at 2.83% (2.53%, 3.16%). Although prevalence nationally was highest in the low-risk 18 to 24 year old group at 2.44% (1.96%, 3.03%), it was also high in those over 65 years who are most at risk, at 0.93% (0.82%, 1.05%). Large household size, living in a deprived neighbourhood, and Black and Asian ethnicity were all associated with higher levels of infections compared to smaller households, less deprived neighbourhoods and other ethnicities. Healthcare and care home workers, and other key workers, were more likely to test positive compared to other workers. If sustained lower prevalence is not achieved rapidly in England, pressure on healthcare services and numbers of COVID-19 deaths will remain unacceptably high.
Riley S, Wang H, Eales O, et al., 2021, REACT-1 round 8 interim report: SARS-CoV-2 prevalence during the initial stages of the third national lockdown in England, Publisher: Imperial College London
BackgroundHigh prevalence of SARS-CoV-2 virus in many northern hemisphere populations is causingextreme pressure on healthcare services and leading to high numbers of fatalities. Eventhough safe and effective vaccines are being deployed in many populations, the majority ofthose most at-risk of severe COVID-19 will not be protected until late spring, even incountries already at a more advanced stage of vaccine deployment.MethodsThe REal-time Assessment of Community Transmission study-1 (REACT-1) obtains throatand nose swabs from between 120,000 and 180,000 people in the community in England atapproximately monthly intervals. Round 8a of REACT-1 mainly covers a period from 6thJanuary 2021 to 15th January 2021. Swabs are tested for SARS-CoV-2 virus and patterns ofswab-positivity are described over time, space and with respect to individual characteristics.We compare swab-positivity prevalence from REACT-1 with mobility data based on the GPSlocations of individuals using the Facebook mobile phone app. We also compare resultsfrom round 8a with those from round 7 in which swabs were collected from 13th Novemberto 24th November (round 7a) and 25th November to 3rd December 2020 (round 7b).ResultsIn round 8a, we found 1,962 positives from 142,909 swabs giving a weighted prevalence of1.58% (95% CI, 1.49%, 1.68%). Using a constant growth model, we found no strongevidence for either growth or decay averaged across the period; rather, based on data froma limited number of days, prevalence may have started to rise at the end of round 8a.Facebook mobility data showed a marked decrease in activity at the end of December 2020,followed by a rise at the start of the working year in January 2021. Between round 7b andround 8a, prevalence increased in all adult age groups, more than doubling to 0.94%(0.83%, 1.07%) in those aged 65 and over. Large household size, living in a deprivedneighbourhood, and Black and Asian ethnicity were all associated with increasedprevalence. Both healthcare
Peacock TP, Penrice-Randal R, Hiscox JA, et al., 2021, SARS-CoV-2 one year on: evidence for ongoing viral adaptation, JOURNAL OF GENERAL VIROLOGY, Vol: 102, ISSN: 0022-1317
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- Citations: 84
Sealy JE, Howard WA, Molesti E, et al., 2021, Amino acid substitutions in the H5N1 avian influenza haemagglutinin alter pH of fusion and receptor binding to promote a highly pathogenic phenotype in chickens, JOURNAL OF GENERAL VIROLOGY, Vol: 102, ISSN: 0022-1317
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Staller E, Sheppard CM, Baillon L, et al., 2021, A natural variant in ANP32B impairs influenza virus replication in human cells, JOURNAL OF GENERAL VIROLOGY, Vol: 102, ISSN: 0022-1317
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- Citations: 4
Riley S, Walters C, Wang H, et al., 2020, REACT-1 round 7 updated report: regional heterogeneity in changes in prevalence of SARS-CoV-2 infection during the second national COVID-19 lockdown in England, REACT-1 round 7 updated report: regional heterogeneity in changes in prevalence of SARS-CoV-2 infection during the second national COVID-19 lockdown in England, London, Publisher: Imperial College London
BackgroundEngland exited a four-week second national lockdown on 2nd December 2020 initiated in response to the COVID-19 pandemic. Prior results showed that prevalence dropped during the first half of lockdown, with greater reductions in higher-prevalence northern regions.MethodsREACT-1 is a series of community surveys of SARS-CoV-2 RT-PCR swab-positivity in England, designed to monitor the spread of the epidemic and thus increase situational awareness. Round 7 of REACT-1 commenced swab-collection on 13th November 2020. A prior interim report included data from 13th to 24th November 2020 for 105,122 participants. Here, we report data for the entire round with swab results obtained up to 3rd December 2020.ResultsBetween 13th November and 3rd December (round 7) there were 1,299 positive swabs out of 168,181 giving a weighted prevalence of 0.94% (95% CI 0.87%, 1.01%) or 94 per 10,000 people infected in the community in England. This compares with a prevalence of 1.30% (1.21%, 1.39%) from 16th October to 2nd November 2020 (round 6), a decline of 28%. Prevalence during the latter half of round 7 was 0.91% (95% CI, 0.81%, 1.03%) compared with 0.96% (0.87%, 1.05%) in the first half. The national R number in round 7 was estimated at 0.96 (0.88, 1.03) with a decline in prevalence observed during the first half of this period no longer apparent during the second half at the end of lockdown. During round 7 there was a marked fall in prevalence in West Midlands, a levelling off in some regions and a rise in London. R numbers at regional level ranged from 0.60 (0.41, 0.80) in West Midlands up to 1.27 (1.04, 1.54) in London, where prevalence was highest in the east and south-east of the city. Nationally, between 13th November and 3rd December, the highest prevalence was in school-aged children especially at ages 13-17 years at 2.04% (1.69%, 2.46%), or approximately 1 in 50.ConclusionBetween the previous round and round 7 (during lockdown), there was a fall in prevalence of SARS-C
Riley S, Eales O, Walters C, et al., 2020, REACT-1 round 7 interim report: fall in prevalence of swab-positivity in England during national lockdown, Publisher: Cold Spring Harbor Laboratory
Background The second wave of the 2020 COVID-19 pandemic in England has been characterized by high growth and prevalence in the North with lower prevalence in the South. High prevalence was first observed at younger adult ages before spreading out to school-aged children and older adults. Local tiered interventions were in place up to 5th November 2020 at which time a second national lockdown was implemented.Methods REACT-1 is a repeated cross-sectional survey of SARS-CoV-2 swab-positivity in random samples of the population of England. The current period of data collection (round 7) commenced on 13th November 2020 and we report interim results here for swabs collected up to and including 24th November 2020. Because there were two distinct periods of growth during the previous round 6, here we compare results from round 7 (mainly) with the second half of round 6, which obtained swabs between 26th October and 2nd November 2020. We report prevalence both unweighted and reweighted to be representative of the population of England. We describe trends in unweighted prevalence with daily growth rates, doubling times, reproduction numbers (R) and splines. We estimated odds ratios for swab-positivity using mutually-adjusted multivariable logistic regression models.Results We found 821 positives from 105,123 swabs giving an unweighted prevalence of 0.78% (95% CI, 0.73%, 0.84%) and a weighted prevalence of 0.96% (0.87%, 1.05%). The weighted prevalence estimate was ∼30% lower than that of 1.32% (1.20%, 1.45%) obtained in the second half of round 6. This decrease corresponds to a halving time of 37 (30, 47) days and an R number of 0.88 (0.86, 0.91). Using only data from the most recent period, we estimate an R number of 0.71 (0.54, 0.90). A spline fit to prevalence showed a rise shortly after the previous period of data collection followed by a fall coinciding with the start of lockdown. The national trends were driven mainly by reductions in higher-prevalence northern regi
Yan AWC, Zhou J, Beauchemin CAA, et al., 2020, Quantifying mechanistic traits of influenza viral dynamics using in vitro data, Publisher: ELSEVIER
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- Citations: 3
Yan AWC, Zhou J, Beauchemin CAA, et al., 2020, Quantifying mechanistic traits of influenza viral dynamics using in vitro data., Epidemics: the journal of infectious disease dynamics, Vol: 33, Pages: 1-10, ISSN: 1755-4365
When analysing in vitro data, growth kinetics of influenza virus strains are often compared by computing their growth rates, which are sometimes used as proxies for fitness. However, analogous to mathematical models for epidemics, the growth rate can be defined as a function of mechanistic traits: the basic reproduction number (the average number of cells each infected cell infects) and the mean generation time (the average length of a replication cycle). Fitting a model to previously published and newly generated data from experiments in human lung cells, we compared estimates of growth rate, reproduction number and generation time for six influenza A strains. Of four strains in previously published data, A/Canada/RV733/2003 (seasonal H1N1) had the lowest basic reproduction number, followed by A/Mexico/INDRE4487/2009 (pandemic H1N1), then A/Indonesia/05/2005 (spill-over H5N1) and A/Anhui/1/2013 (spill-over H7N9). This ordering of strains was preserved for both generation time and growth rate, suggesting a positive biological correlation between these quantities which have not been previously observed. We further investigated these potential correlations using data from reassortant viruses with different internal proteins (from A/England/195/2009 (pandemic H1N1) and A/Turkey/05/2005 (H5N1)), and the same surface proteins (from A/Puerto Rico/8/34 (lab-adapted H1N1)). Similar correlations between traits were observed for these viruses, confirming our initial findings and suggesting that these patterns were related to the degree of human adaptation of internal genes. Also, the model predicted that strains with a smaller basic reproduction number, shorter generation time and slower growth rate underwent more replication cycles by the time of peak viral load, potentially accumulating mutations more quickly. These results illustrate the utility of mathematical models in inferring traits driving observed differences in in vitro growth of influenza strains.
Neil D, Moran L, Horsfield C, et al., 2020, Ultrastructure of cell trafficking pathways and coronavirus: how to recognise the wolf amongst the sheep, JOURNAL OF PATHOLOGY, Vol: 252, Pages: 346-357, ISSN: 0022-3417
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- Citations: 10
Carrique L, Fan H, Walker AP, et al., 2020, Host ANP32A mediates the assembly of the influenza virus replicase, Nature, Vol: 587, Pages: 638-643, ISSN: 0028-0836
Aquatic birds represent a vast reservoir from which new pandemic influenza A viruses can emerge1. Influenza viruses contain a negative-sense segmented RNA genome that is transcribed and replicated by the viral heterotrimeric RNA polymerase (FluPol) in the context of viral ribonucleoprotein complexes2,3. RNA polymerases of avian influenza A viruses (FluPolA) replicate viral RNA inefficiently in human cells because of species-specific differences in acidic nuclear phosphoprotein 32 (ANP32), a family of essential host proteins for FluPol activity4. Host-adaptive mutations, particularly a glutamic-acid-to-lysine mutation at amino acid residue 627 (E627K) in the 627 domain of the PB2 subunit, enable avian FluPolA to overcome this restriction and efficiently replicate viral RNA in the presence of human ANP32 proteins. However, the molecular mechanisms of genome replication and the interplay with ANP32 proteins remain largely unknown. Here we report cryo-electron microscopy structures of influenza C virus polymerase (FluPolC) in complex with human and chicken ANP32A. In both structures, two FluPolC molecules form an asymmetric dimer bridged by the N-terminal leucine-rich repeat domain of ANP32A. The C-terminal low-complexity acidic region of ANP32A inserts between the two juxtaposed PB2 627 domains of the asymmetric FluPolA dimer, suggesting a mechanism for how the adaptive PB2(E627K) mutation enables the replication of viral RNA in mammalian hosts. We propose that this complex represents a replication platform for the viral RNA genome, in which one of the FluPol molecules acts as a replicase while the other initiates the assembly of the nascent replication product into a viral ribonucleoprotein complex.
Riley S, Ainslie K, Eales O, et al., 2020, REACT-1 round 6 updated report: high prevalence of SARS-CoV-2 swab positivity with reduced rate of growth in England at the start of November 2020
BackgroundEngland is now in the midst of its second wave of the COVID-19 pandemic. Multiple regions of the country are at high infection prevalence and all areas experienced rapid recent growth of the epidemic during October 2020.MethodsREACT-1 is a series of community surveys of SARS-CoV-2 RT-PCR swab-positivity in England designed to monitor the spread of the epidemic and thus increase situational awareness. Round 6 of REACT-1 commenced swab-collection on 16th October. A prior interim report included data from 16th to 25th October for 85,971 participants. Here, we report data for the entire round on 160,175 participants with swab results obtained up to 2nd November 2020.ResultsOverall weighted prevalence of infection in the community in England was 1.3% or 130 people per 10,000 infected, up from 60 people per 10,000 in the round 5 report (18th September to 5th October 2020), doubling every 24 days on average since the prior round. The corresponding R number was estimated to be 1.2. Prevalence of infection was highest in North West (2.4%, up from 1.2% ), followed by Yorkshire and The Humber (2.3% up from 0.84%), West Midlands (1.6% up from 0.60%), North East (1.5% up from 1.1%), East Midlands (1.3% up from 0.56%), London (0.97%, up from 0.54%), South West (0.80% up from 0.33%), South East (0.69% up from 0.29%), and East of England (0.69% up from 0.30%). Rapid growth in the South observed in the first half of round 6 was no longer apparent in the second half of round 6. We also observed a decline in prevalence in Yorkshire and The Humber during this period. Comparing the first and second halves of round 6, there was a suggestion of decline in weighted prevalence in participants aged 5 to 12 years and in those aged 25 to 44 years. While prevalence remained high, in the second half of round 6 there was suggestion of a slight fall then rise that was seen nationally and also separately in both the North and the South.ConclusionThe impact of the second national lockdown
Ahmetaj-Shala B, Peacock TP, Baillon L, et al., 2020, Resistance of endothelial cells to SARS-CoV-2 infection <i>in vitro</i>
<jats:title>Abstract</jats:title><jats:sec><jats:title>Rationale</jats:title><jats:p>The secondary thrombotic/vascular clinical syndrome of COVID-19 suggests that SARS-CoV-2 infects not only respiratory epithelium but also the endothelium activating thrombotic pathways, disrupting barrier function and allowing access of the virus to other organs of the body. However, a direct test of susceptibility to SARS-CoV-2 of authentic endothelial cell lines has not been performed.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To determine infectibility of primary endothelial cell lines with live SARS-CoV-2 and pseudoviruses expressing SARS-CoV-2 spike protein.</jats:p></jats:sec><jats:sec><jats:title>Methods and Results</jats:title><jats:p>Expression of ACE2 and BSG pathways genes was determined in three types of endothelial cells; blood outgrowth, lung microvascular and aortic endothelial cells. For comparison nasal epithelial cells, Vero E6 cells (primate kidney fibroblast cell line) and HEK 293T cells (human embryonic kidney cells) transfected with either ACE2 or BSG were used as controls. Endothelial and Vero E6 cells were treated with live SARS-CoV-2 virus for 1 hour and imaged at 24 and 72 hours post infection. Pseudoviruses containing SARS-CoV-2, Ebola and Vesicular Stomatis Virus glycoproteins were generated and added to endothelial cells and HEK 239Ts for 2 hours and infection measured using luminescence at 48 hours post infection. Compared to nasal epithelial cells, endothelial cells expressed low or undetectable levels of ACE2 and TMPRSS2 but comparable levels of BSG, PPIA and PPIB. Endothelial cells showed no susceptibility to live SARS-CoV-2 or SARS-CoV-2 pseudovirus (but showed susceptibility to Ebola and Vesicular Stomatitis Virus). Overexpression of ACE2 but not BSG in HEK 239T cells conferred SARS-CoV-2 pseudovirus entry. Endoth
Riley S, Ainslie KEC, Eales O, et al., 2020, High prevalence of SARS-CoV-2 swab positivity and increasing R number in England during October 2020: REACT-1 round 6 interim report, Publisher: medRxiv
Background REACT-1 measures prevalence of SARS-CoV-2 infection in representative samples of the population in England using PCR testing from self-administered nose and throat swabs. Here we report interim results for round 6 of observations for swabs collected from the 16th to 25th October 2020 inclusive. Methods REACT-1 round 6 aims to collect data and swab results from 160,000 people aged 5 and above. Here we report results from the first 86,000 individuals. We estimate prevalence of PCR-confirmed SARS-CoV-2 infection, reproduction numbers (R) and temporal trends using exponential growth or decay models. Prevalence estimates are presented both unweighted and weighted to be representative of the population of England, accounting for response rate, region, deprivation and ethnicity. We compare these interim results with data from round 5, based on swabs collected from 18th September to 5th October 2020 inclusive. Results Overall prevalence of infection in the community in England was 1.28% or 128 people per 10,000, up from 60 per 10,000 in the previous round. Infections were doubling every 9.0 (6.1, 18) days with a national reproduction number (R) estimated at 1.56 (1.27, 1.88) compared to 1.16 (1.05, 1.27) in the previous round. Prevalence of infection was highest in Yorkshire and The Humber at 2.72% (2.12%, 3.50%), up from 0.84% (0.60%, 1.17%), and the North West at 2.27% (1.90%, 2.72%), up from 1.21% (1.01%, 1.46%), and lowest in South East at 0.55% (0.45%, 0.68%), up from 0.29% (0.23%, 0.37%). Clustering of cases was more prevalent in Lancashire, Manchester, Liverpool and West Yorkshire, West Midlands and East Midlands. Interim estimates of R were above 2 in the South East, East of England, London and South West, but with wide confidence intervals. Nationally, prevalence increased across all age groups with the greatest increase in those aged 55-64 at 1.20% (0.99%, 1.46%), up 3-fold from 0.37% (0.30%, 0.46%). In those aged over 65, prevalence was 0.81% (0.58%, 0
Gibani MM, Toumazou C, Sohbati M, et al., 2020, Assessing a novel, lab-free, point-of-care test for SARS-CoV-2 (CovidNudge): a diagnostic accuracy study., The Lancet Microbe, Vol: 1, Pages: e300-e307, ISSN: 2666-5247
Background: Access to rapid diagnosis is key to the control and management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory RT-PCR testing is the current standard of care but usually requires a centralised laboratory and significant infrastructure. We describe our diagnostic accuracy assessment of a novel, rapid point-of-care real time RT-PCR CovidNudge test, which requires no laboratory handling or sample pre-processing. Methods: Between April and May, 2020, we obtained two nasopharyngeal swab samples from individuals in three hospitals in London and Oxford (UK). Samples were collected from three groups: self-referred health-care workers with suspected COVID-19; patients attending emergency departments with suspected COVID-19; and hospital inpatient admissions with or without suspected COVID-19. For the CovidNudge test, nasopharyngeal swabs were inserted directly into a cartridge which contains all reagents and components required for RT-PCR reactions, including multiple technical replicates of seven SARS-CoV-2 gene targets (rdrp1, rdrp2, e-gene, n-gene, n1, n2 and n3) and human ribonuclease P (RNaseP) as sample adequacy control. Swab samples were tested in parallel using the CovidNudge platform, and with standard laboratory RT-PCR using swabs in viral transport medium for processing in a central laboratory. The primary analysis was to compare the sensitivity and specificity of the point-of-care CovidNudge test with laboratory-based testing. Findings: We obtained 386 paired samples: 280 (73%) from self-referred health-care workers, 15 (4%) from patients in the emergency department, and 91 (23%) hospital inpatient admissions. Of the 386 paired samples, 67 tested positive on the CovidNudge point-of-care platform and 71 with standard laboratory RT-PCR. The overall sensitivity of the point-of-care test compared with laboratory-based testing was 94% (95% CI 86-98) with an overall specificity of 100% (99-100). The sensitivity of the test varied
Riley S, Ainslie KEC, Eales O, et al., 2020, High and increasing prevalence of SARS-CoV-2 swab positivity in England during end September beginning October 2020: REACT-1 round 5 updated report
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>REACT-1 is quantifying prevalence of SARS-CoV-2 infection among random samples of the population in England based on PCR testing of self-administered nose and throat swabs. Here we report results from the fifth round of observations for swabs collected from the 18th September to 5th October 2020. This report updates and should be read alongside our round 5 interim report.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Representative samples of the population aged 5 years and over in England with sample size ranging from 120,000 to 175,000 people at each round. Prevalence of PCR-confirmed SARS-CoV-2 infection, estimation of reproduction number (R) and time trends between and within rounds using exponential growth or decay models.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>175,000 volunteers tested across England between 18th September and 5th October. Findings show a national prevalence of 0.60% (95% confidence interval 0.55%, 0.71%) and doubling of the virus every 29 (17, 84) days in England corresponding to an estimated national R of 1.16 (1.05, 1.27). These results correspond to 1 in 170 people currently swab-positive for the virus and approximately 45,000 new infections each day. At regional level, the highest prevalence is in the North West, Yorkshire and The Humber and the North East with strongest regional growth in North West, Yorkshire and The Humber and West Midlands.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Rapid growth has led to high prevalence of SARS-CoV-2 virus in England, with highest rates in the North of England. Prevalence has increased in all age groups, including those at highest risk. Improved compliance with existing policy and, as necessar
Riley S, Ainslie KEC, Eales O, et al., 2020, High prevalence of SARS-CoV-2 swab positivity in England during September 2020: interim report of round 5 of REACT-1 study, Publisher: Cold Spring Harbor Laboratory Press
Background REACT-1 is a community survey of PCR confirmed swab-positivity for SARS-CoV-2 among random samples of the population in England. This interim report includes data from the fifth round of data collection currently underway for swabs sampled from the 18th to 26th September 2020.Methods Repeated cross-sectional surveys of random samples of the population aged 5 years and over in England with sample size ranging from 120,000 to 160,000 people in each round of data collection. Collection of self-administered nose and throat swab for PCR and questionnaire data. Prevalence of swab-positivity by round and by demographic variables including age, sex, region, ethnicity. Estimation of reproduction number (R) between and within rounds, and time trends using exponential growth or decay model. Assessment of geographical clustering based on boundary-free spatial model.Results Over the 9 days for which data are available, we find 363 positives from 84,610 samples giving a weighted prevalence to date of 0.55% (0.47%, 0.64%) in round 5. This implies that 411,000 (351,000, 478,000) people in England are virus-positive under the assumption that the swab assay is 75% sensitive. Using data from the most recent two rounds, we estimate a doubling time of 10.6 (9.4, 12.0) days covering the period 20th August to 26th September, corresponding to a reproduction number R of 1.47 (1.40, 1.53). Using data only from round 5 we estimate a reproduction number of 1.06 (0.74, 1.46) with probability of 63% that R is greater than 1. Between rounds 4 and 5 there was a marked increase in unweighted prevalence at all ages. In the most recent data, prevalence was highest in the 18 to 24 yrs age group at 0.96% (0.68%, 1.36%). At 65+ yrs prevalence increased 7-fold between rounds 4 and 5 from 0.04% (0.03%, 0.07%) to 0.29% (0.23%, 0.37%). Prevalence increased in all regions between rounds 4 and 5, giving the highest unweighted prevalence in round 5 in the North West at 0.86% (0.69%, 1.06%). In Lond
Hanley B, Naresh KN, Roufosse C, et al., 2020, Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study, The Lancet Microbe, Vol: 1, Pages: e245-e253, ISSN: 2666-5247
BackgroundSevere COVID-19 has a high mortality rate. Comprehensive pathological descriptions of COVID-19 are scarce and limited in scope. We aimed to describe the histopathological findings and viral tropism in patients who died of severe COVID-19.MethodsIn this case series, patients were considered eligible if they were older than 18 years, with premortem diagnosis of severe acute respiratory syndrome coronavirus 2 infection and COVID-19 listed clinically as the direct cause of death. Between March 1 and April 30, 2020, full post-mortem examinations were done on nine patients with confirmed COVID-19, including sampling of all major organs. A limited autopsy was done on one additional patient. Histochemical and immunohistochemical analyses were done, and histopathological findings were reported by subspecialist pathologists. Viral quantitative RT-PCR analysis was done on tissue samples from a subset of patients.FindingsThe median age at death of our cohort of ten patients was 73 years (IQR 52–79). Thrombotic features were observed in at least one major organ in all full autopsies, predominantly in the lung (eight [89%] of nine patients), heart (five [56%]), and kidney (four [44%]). Diffuse alveolar damage was the most consistent lung finding (all ten patients); however, organisation was noted in patients with a longer clinical course. We documented lymphocyte depletion (particularly CD8-positive T cells) in haematological organs and haemophagocytosis. Evidence of acute tubular injury was noted in all nine patients examined. Major unexpected findings were acute pancreatitis (two [22%] of nine patients), adrenal micro-infarction (three [33%]), pericarditis (two [22%]), disseminated mucormycosis (one [10%] of ten patients), aortic dissection (one [11%] of nine patients), and marantic endocarditis (one [11%]). Viral genomes were detected outside of the respiratory tract in four of five patients. The presence of subgenomic viral RNA transcripts provided evidence of
Riley S, Ainslie KEC, Eales O, et al., 2020, Resurgence of SARS-CoV-2 in England: detection by community antigen surveillance
<jats:title>Summary</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Based on cases and deaths, transmission of SARS-CoV-2 in England peaked in late March and early April 2020 and then declined until the end of June. Since the start of July, cases have increased, while deaths have continued to decrease.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We report results from 594,000 swabs tested for SARS-CoV-2 virus obtained from a representative sample of people in England over four rounds collected regardless of symptoms, starting in May 2020 and finishing at the beginning of September 2020. Swabs for the most recent two rounds were taken between 24th July and 11th August and for round 4 between 22nd August and 7th September. We estimate weighted overall prevalence, doubling times between and within rounds and associated reproduction numbers. We obtained unweighted prevalence estimates by sub-groups: age, sex, region, ethnicity, key worker status, household size, for which we also estimated odds of infection. We identified clusters of swab-positive participants who were closer, on average, to other swab-positive participants than would be expected.</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>Over all four rounds of the study, we found that 72% (67%, 76%) of swab-positive individuals were asymptomatic at the time of swab and in the week prior. The epidemic declined between rounds 1 and 2, and rounds 2 and 3. However, the epidemic was increasing between rounds 3 and 4, with a doubling time of 17 (13, 23) days corresponding to an R value of 1.3 (1.2, 1.4). When analysing round 3 alone, we found that the epidemic had started to grow again with 93% probability. Using only the most recent round 4 data, we estimated a doubling time of 7.7 (5.5, 12.7) days, corresponding to an R value of 1.7 (1.4, 2.0). Cy
Seekings AH, Howard WA, Nunez A, et al., 2020, The Emergence of H7N7 Highly Pathogenic Avian Influenza Virus from Low Pathogenicity Avian Influenza Virus Using an in ovo Embryo Culture Model, VIRUSES-BASEL, Vol: 12
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Gibani M, Toumazou C, Sohbati M, et al., 2020, CovidNudge: diagnostic accuracy of a novel lab-free point-of-care diagnostic for SARS-CoV-2, Publisher: Cold Spring Harbor Laboratory
Background Access to rapid diagnosis is key to the control and management of SARS-CoV-2. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) testing usually requires a centralised laboratory and significant infrastructure. We describe the development and diagnostic accuracy assessment of a novel, rapid point-of-care RT-PCR test, the DnaNudge® platform CovidNudge test, which requires no laboratory handling or sample pre-processing.Methods Nasopharyngeal swabs are inserted directly into a cartridge which contains all reagents and components required for RT-PCR reactions, including multiple technical replicates of seven SARS-CoV-2 gene targets (rdrp1, rdrp2, e-gene, n-gene, n1, n2 and n3) and human ribonuclease P (RNaseP) as positive control. Between April and May 2020, swab samples were tested in parallel using the CovidNudge direct-to-cartridge platform and standard laboratory RT-PCR using swabs in viral transport medium. Samples were collected from three groups: self-referred healthcare workers with suspected COVID-19 (Group 1, n=280/386; 73%); patients attending the emergency department with suspected COVID-19 (Group 2, n=15/386; 4%) and hospital inpatient admissions with or without suspected COVID-19 (Group 3, n=91/386; 23%).Results Of 386 paired samples tested across all groups, 67 tested positive on the CovidNudge platform and 71 with standard laboratory RT-PCR. The sensitivity of the test varied by group (Group 1 93% [84-98%], Group 2 100% [48-100%] and Group 3 100% [29-100%], giving an average sensitivity of 94.4% (95% confidence interval 86-98%) and an overall specificity of 100% (95%CI 99-100%; Group 1 100% [98-100%]; Group 2 100% [69-100%] and Group 3 100% [96-100%]). Point of care testing performance was comparable during a period of high (25%) and low (3%) background prevalence. Amplification of the viral nucleocapsid (n1, n2, n3) targets were most sensitive for detection of SARS-CoV2, with the assay able to detect 1×104 viral particles in
Ward H, Atchison C, Whitaker M, et al., 2020, Antibody prevalence for SARS-CoV-2 in England following first peak of the pandemic: REACT2 study in 100,000 adults, Publisher: bioRxiv
Background England, UK has experienced a large outbreak of SARS-CoV-2 infection. As in USA and elsewhere, disadvantaged communities have been disproportionately affected. Methods National REal-time Assessment of Community Transmission-2 (REACT-2) seroprevalence study using self-administered lateral flow immunoassay (LFIA) test for IgG among a random population sample of 100,000 adults over 18 years in England, 20 June to 13 July 2020. Results Completed questionnaires were available for 109,076 participants, yielding 5,544 IgG positive results and adjusted (for test performance), re-weighted (for sampling) prevalence of 6.0% (95% CI: 5.8, 6.1). Highest prevalence was in London (13.0% [12.3, 13.6]), among people of Black or Asian (mainly South Asian) ethnicity (17.3% [15.8, 19.1] and 11.9% [11.0, 12.8] respectively) and those aged 18-24 years (7.9% [7.3, 8.5]). Care home workers with client-facing roles had adjusted odds ratio of 3.1 (2.5, 3.8) compared with non-essential workers. One third (32.2%, [31.0-33.4]) of antibody positive individuals reported no symptoms. Among symptomatic cases, the majority (78.8%) reported symptoms during the peak of the epidemic in England in March (31.3%) and April (47.5%) 2020. We estimate that 3.36 million (3.21, 3.51) people have been infected with SARS-CoV-2 in England to end June 2020, with an overall infection fatality ratio of 0.90% (0.86, 0.94). Conclusion The pandemic of SARS-CoV-2 infection in England disproportionately affected ethnic minority groups and health and care home workers. The higher risk of infection in these groups may explain, at least in part, their increased risk of hospitalisation and mortality from COVID-19.
Atchison C, Pristerà P, Cooper E, et al., 2020, Usability and acceptability of home-based self-testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibodies for population surveillance, Clinical Infectious Diseases, Vol: 2020, Pages: 1-10, ISSN: 1058-4838
BACKGROUND: This study assesses acceptability and usability of home-based self-testing for SARS-CoV-2 antibodies using lateral flow immunoassays (LFIA). METHODS: We carried out public involvement and pilot testing in 315 volunteers to improve usability. Feedback was obtained through online discussions, questionnaires, observations and interviews of people who tried the test at home. This informed the design of a nationally representative survey of adults in England using two LFIAs (LFIA1 and LFIA2) which were sent to 10,600 and 3,800 participants, respectively, who provided further feedback. RESULTS: Public involvement and pilot testing showed high levels of acceptability, but limitations with the usability of kits. Most people reported completing the test; however, they identified difficulties with practical aspects of the kit, particularly the lancet and pipette, a need for clearer instructions and more guidance on interpretation of results. In the national study, 99.3% (8,693/8,754) of LFIA1 and 98.4% (2,911/2,957) of LFIA2 respondents attempted the test and 97.5% and 97.8% of respondents completed it, respectively. Most found the instructions easy to understand, but some reported difficulties using the pipette (LFIA1: 17.7%) and applying the blood drop to the cassette (LFIA2: 31.3%). Most respondents obtained a valid result (LFIA1: 91.5%; LFIA2: 94.4%). Overall there was substantial concordance between participant and clinician interpreted results (kappa: LFIA1 0.72; LFIA2 0.89). CONCLUSION: Impactful public involvement is feasible in a rapid response setting. Home self-testing with LFIAs can be used with a high degree of acceptability and usability by adults, making them a good option for use in seroprevalence surveys.
Flower B, Brown JC, Simmons B, et al., 2020, Clinical and laboratory evaluation of SARS-CoV-2 lateral flow assays for use in a national COVID-19 sero-prevalence survey, Thorax, Vol: 75, Pages: 1082-1088, ISSN: 0040-6376
BackgroundAccurate antibody tests are essential to monitor the SARS-CoV-2 pandemic. Lateral flow immunoassays (LFIAs) can deliver testing at scale. However, reported performance varies, and sensitivity analyses have generally been conducted on serum from hospitalised patients. For use in community testing, evaluation of finger-prick self-tests, in non-hospitalised individuals, is required.MethodsSensitivity analysis was conducted on 276 non-hospitalised participants. All had tested positive for SARS-CoV-2 by RT-PCR and were ≥21d from symptom-onset. In phase I we evaluated five LFIAs in clinic (with finger-prick) and laboratory (with blood and sera) in comparison to a) PCR-confirmed infection and b) presence of SARS-CoV-2 antibodies on two “in-house” ELISAs. Specificity analysis was performed on 500 pre-pandemic sera. In phase II, six additional LFIAs were assessed with serum.Findings95% (95%CI [92.2, 97.3]) of the infected cohort had detectable antibodies on at least one ELISA. LFIA sensitivity was variable, but significantly inferior to ELISA in 8/11 assessed. Of LFIAs assessed in both clinic and laboratory, finger-prick self-test sensitivity varied from 21%-92% vs PCR-confirmed cases and 22%-96% vs composite ELISA positives. Concordance between finger-prick and serum testing was at best moderate (kappa 0.56) and, at worst, slight (kappa 0.13). All LFIAs had high specificity (97.2% - 99.8%).InterpretationLFIA sensitivity and sample concordance is variable, highlighting the importance of evaluations in setting of intended use. This rigorous approach to LFIA evaluation identified a test with high specificity (98.6% (95%CI [97.1, 99.4])), moderate sensitivity (84.4% with fingerprick (95%CI [70.5, 93.5])), and moderate concordance, suitable for seroprevalence surveys.
Riley S, Ainslie KEC, Eales O, et al., 2020, Transient dynamics of SARS-CoV-2 as England exited national lockdown
<jats:title>Abstract</jats:title><jats:p>Control of the COVID-19 pandemic requires a detailed understanding of prevalence of SARS-CoV-2 virus in the population. Case-based surveillance is necessarily biased towards symptomatic individuals and sensitive to varying patterns of reporting in space and time. The real-time assessment of community transmission antigen study (REACT-1) is designed to overcome these limitations by obtaining prevalence data based on a nose and throat swab RT-PCR test among a representative community-based sample in England, including asymptomatic individuals. Here, we describe results comparing rounds 1 and 2 carried out during May and mid June / early July 2020 respectively across 315 lower tier local authority areas. In round 1 we found 159 positive samples from 120,620 tested swabs while round 2 there were 123 positive samples from 159,199 tested swabs, indicating a downwards trend in prevalence from 0.13% (95% CI, 0.11%, 0.15%) to 0.077% (0.065%, 0.092%), a halving time of 38 (28, 58) days, and an R of 0.89 (0.86, 0.93). The proportion of swab-positive participants who were asymptomatic at the time of sampling increased from 69% (61%, 76%) in round 1 to 81% (73%, 87%) in round 2. Although health care and care home workers were infected far more frequently than other workers in round 1, the odds were markedly reduced in round 2. Age patterns of infection changed between rounds, with a reduction by a factor of five in prevalence in 18 to 24 year olds. Our data were suggestive of increased risk of infection in Black and Asian (mainly South Asian) ethnicities. Using regional and detailed case location data, we detected increased infection intensity in and near London. Under multiple sensitivity analyses, our results were robust to the possibility of false positives. At the end of the initial lockdown in England, we found continued decline in prevalence and a shift in the pattern of infection by age and occupation. Community-b
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