Imperial College London

ProfessorWendyBarclay

Faculty of MedicineDepartment of Infectious Disease

Action Medical Research Chair Virology. Head of Department
 
 
 
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Contact

 

+44 (0)20 7594 5035w.barclay

 
 
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Location

 

416Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

316 results found

Crone MA, Hakki S, Fenn J, Zhou J, Rosadas de Oliveira C, Madon KJ, Koycheva A, Badhan A, Jonnerby J, Nevin S, Conibear E, Derelle R, Varro R, Luca C, Ahmad S, Zambon M, Barclay W, Dunning J, Freemont PS, Taylor GP, Ajit Let al., 2024, Rapid emergence of transmissible SARS-CoV-2 variants in mild community cases, Microbiology Spectrum, ISSN: 2165-0497

Journal article

Michael BD, Dunai C, Needham EJ, Tharmaratnam K, Williams R, Huang Y, Boardman SA, Clark JJ, Sharma P, Subramaniam K, Wood GK, Collie C, Digby R, Ren A, Norton E, Leibowitz M, Ebrahimi S, Fower A, Fox H, Tato E, Ellul MA, Sunderland G, Held M, Hetherington C, Egbe FN, Palmos A, Stirrups K, Grundmann A, Chiollaz A-C, Sanchez J-C, Stewart JP, Griffiths M, Solomon T, Breen G, Coles AJ, Kingston N, Bradley JR, Chinnery PF, Cavanagh J, Irani SR, Vincent A, Baillie JK, Openshaw PJ, Semple MG, ISARIC4C Investigators, COVID-CNS Consortium, Taams LS, Menon DKet al., 2023, Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses, Nature Communications, Vol: 14, ISSN: 2041-1723

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.

Journal article

Styles CT, Zhou J, Flight KE, Brown JC, Lewis C, Wang X, Vanden Oever M, Peacock TP, Wang Z, Millns R, O'Neill JS, Borodavka A, Grove J, Barclay WS, Tregoning JS, Edgar RSet al., 2023, Propylene glycol inactivates respiratory viruses and prevents airborne transmission, EMBO Molecular Medicine, Vol: 15, ISSN: 1757-4676

Viruses are vulnerable as they transmit between hosts, and we aimed to exploit this critical window. We found that the ubiquitous, safe, inexpensive and biodegradable small molecule propylene glycol (PG) has robust virucidal activity. Propylene glycol rapidly inactivates a broad range of viruses including influenza A, SARS-CoV-2 and rotavirus and reduces disease burden in mice when administered intranasally at concentrations commonly found in nasal sprays. Most critically, vaporised PG efficiently abolishes influenza A virus and SARS-CoV-2 infectivity within airborne droplets, potently preventing infection at levels well below those tolerated by mammals. We present PG vapour as a first-in-class non-toxic airborne virucide that can prevent transmission of existing and emergent viral pathogens, with clear and immediate implications for public health.

Journal article

Gonçalves BP, Jassat W, Baruch J, Hashmi M, Rojek A, Dasgupta A, Martin-Loeches I, Reyes LF, Piubelli C, Citarella BW, Kartsonaki C, Lefèvre B, López Revilla JW, Lunn M, Harrison EM, Kraemer MUG, Shrapnel S, Horby P, Bisoffi Z, Olliaro PL, Merson L, ISARIC Clinical Characterisation Groupet al., 2023, A multi-country analysis of COVID-19 hospitalizations by vaccination status., Med, Vol: 4, Pages: 797-812.e2

BACKGROUND: Individuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when infected, can still develop disease that requires hospitalization. It remains unclear whether these patients differ from hospitalized unvaccinated patients with regard to presentation, coexisting comorbidities, and outcomes. METHODS: Here, we use data from an international consortium to study this question and assess whether differences between these groups are context specific. Data from 83,163 hospitalized COVID-19 patients (34,843 vaccinated, 48,320 unvaccinated) from 38 countries were analyzed. FINDINGS: While typical symptoms were more often reported in unvaccinated patients, comorbidities, including some associated with worse prognosis in previous studies, were more common in vaccinated patients. Considerable between-country variation in both in-hospital fatality risk and vaccinated-versus-unvaccinated difference in this outcome was observed. CONCLUSIONS: These findings will inform allocation of healthcare resources in future surges as well as design of longer-term international studies to characterize changes in clinical profile of hospitalized COVID-19 patients related to vaccination history. FUNDING: This work was made possible by the UK Foreign, Commonwealth and Development Office and Wellcome (215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z, and 220757/Z/20/Z); the Bill & Melinda Gates Foundation (OPP1209135); and the philanthropic support of the donors to the University of Oxford's COVID-19 Research Response Fund (0009109). Additional funders are listed in the "acknowledgments" section.

Journal article

Zhou J, Singanayagam A, Barclay WS, 2023, Is it possible to generalise superspreading individuals or events of SARS-CoV-2? - Authors' reply., Lancet Microbe, Vol: 4

Journal article

Meehan GR, Herder V, Allan J, Huang X, Kerr K, Mendonca DC, Ilia G, Wright DW, Nomikou K, Gu Q, Molina Arias S, Hansmann F, Hardas A, Attipa C, De Lorenzo G, Cowton V, Upfold N, Palmalux N, Brown JC, Barclay WS, Filipe ADS, Furnon W, Patel AH, Palmarini Met al., 2023, Phenotyping the virulence of SARS-CoV-2 variants in hamsters by digital pathology and machine learning., PLoS Pathog, Vol: 19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued to evolve throughout the coronavirus disease-19 (COVID-19) pandemic, giving rise to multiple variants of concern (VOCs) with different biological properties. As the pandemic progresses, it will be essential to test in near real time the potential of any new emerging variant to cause severe disease. BA.1 (Omicron) was shown to be attenuated compared to the previous VOCs like Delta, but it is possible that newly emerging variants may regain a virulent phenotype. Hamsters have been proven to be an exceedingly good model for SARS-CoV-2 pathogenesis. Here, we aimed to develop robust quantitative pipelines to assess the virulence of SARS-CoV-2 variants in hamsters. We used various approaches including RNAseq, RNA in situ hybridization, immunohistochemistry, and digital pathology, including software assisted whole section imaging and downstream automatic analyses enhanced by machine learning, to develop methods to assess and quantify virus-induced pulmonary lesions in an unbiased manner. Initially, we used Delta and Omicron to develop our experimental pipelines. We then assessed the virulence of recent Omicron sub-lineages including BA.5, XBB, BQ.1.18, BA.2, BA.2.75 and EG.5.1. We show that in experimentally infected hamsters, accurate quantification of alveolar epithelial hyperplasia and macrophage infiltrates represent robust markers for assessing the extent of virus-induced pulmonary pathology, and hence virus virulence. In addition, using these pipelines, we could reveal how some Omicron sub-lineages (e.g., BA.2.75 and EG.5.1) have regained virulence compared to the original BA.1. Finally, to maximise the utility of the digital pathology pipelines reported in our study, we developed an online repository containing representative whole organ histopathology sections that can be visualised at variable magnifications (https://covid-atlas.cvr.gla.ac.uk). Overall, this pipeline can provide unbiased an

Journal article

Zhou J, Sukhova K, Peacock TP, McKay PF, Brown JC, Frise R, Baillon L, Moshe M, Kugathasan R, Shattock RJ, Barclay WSet al., 2023, Omicron breakthrough infections in vaccinated or previously infected hamsters, Proceedings of the National Academy of Sciences of USA, Vol: 120, ISSN: 0027-8424

The ongoing SARS-CoV-2 epidemic was marked by the repeated emergence and replacement of “variants” with genetic and phenotypic distance from the ancestral strains, the most recent examples being viruses of the Omicron lineage. Here, we describe a hamster direct contact exposure challenge model to assess protection against reinfection conferred by either vaccination or prior infection. We found that two doses of self-amplifying RNA vaccine based on the ancestral Spike ameliorated weight loss following Delta infection and decreased viral loads but had minimal effect on Omicron BA.1 infection. Prior vaccination followed by Delta or BA.1 breakthrough infections led to a high degree of cross-reactivity to all tested variants, suggesting that repeated exposure to antigenically distinct Spikes, via infection and/or vaccination drives a cross-reactive immune response. Prior infection with ancestral or Alpha variant was partially protective against BA.1 infection, whereas all animals previously infected with Delta and exposed to BA.1 became reinfected, although they shed less virus than BA.1-infected naive hamsters. Hamsters reinfected with BA.1 after prior Delta infection emitted infectious virus into the air, indicating that they could be responsible for onwards airborne transmission. We further tested whether prior infection with BA.1 protected from reinfection with Delta or later Omicron sublineages BA.2, BA.4, or BA.5. BA.1 was protective against BA.2 but not against Delta, BA.4, or BA.5 reinfection. These findings suggest that cohorts whose only immune experience of COVID-19 is Omicron BA.1 infection may be vulnerable to future circulation of reemerged Delta-like derivatives, as well as emerging Omicron sublineages.

Journal article

Almond M, Jackson M, Jha A, Katosulis O, Pitts O, Tunstall T, Regis E, Dunning J, Byrne A, Mallia P, Kon OM, Saunders K, Karen S, Snelgrove R, Openshaw P, Edwards M, Barclay W, Heaney L, Johnston S, Singanayagam Aet al., 2023, Obesity dysregulates the pulmonary antiviral immune response, Nature Communications, Vol: 14, ISSN: 2041-1723

Obesity is a well-recognized risk factor for severe influenza infections but the mechanisms underlying susceptibility are poorly understood. Here, we identify that obese individuals have deficient pulmonary antiviral immune responses in bronchoalveolar lavage cells but not in bronchial epithelial cells or peripheral blood dendritic cells. We show that the obese human airway metabolome is perturbed with associated increases in the airway concentrations of the adipokine leptin which correlated negatively with the magnitude of ex vivo antiviral responses. Exogenous pulmonary leptin administration in mice directly impaired antiviral type I interferon responses in vivo and ex vivo in cultured airway macrophages. Obese individuals hospitalised with influenza showed dysregulated upper airway immune responses. These studies provide insight into mechanisms driving propensity to severe influenza infections in obesity and raise the potential for development of leptin manipulation or interferon administration as novel strategies for conferring protection from severe infections in obese higher risk individuals.

Journal article

Sheppard C, Barclay W, Goldhill D, Staller E, Fodor E, Swann O, Penn R, Platt O, Sukhova K, Baillon L, Frise R, Peacock Tet al., 2023, An Influenza A virus can evolve to use human ANP32E through altering polymerase dimerization, Nature Communications, Vol: 14, ISSN: 2041-1723

Human ANP32A and ANP32B are essential but redundant host factors for influenza virus genome replication. While most influenza viruses cannot replicate in edited human cells lacking both ANP32A and ANP32B, some strains exhibit limited growth. Here, we experimentally evolve such an influenza A virus in these edited cells and unexpectedly, after 2 passages, we observe robust viral growth. We find two mutations in different subunits of the influenza polymerase that enable the mutant virus to use a novel host factor, ANP32E, an alternative family member, which is unable to support the wild type polymerase. Both mutations reside in the symmetric dimer interface between two polymerase complexes and reduce polymerase dimerization. These mutations have previously been identified as adapting influenza viruses to mice. Indeed, the evolved virus gains the ability to use suboptimal mouse ANP32 proteins and becomes more virulent in mice. We identify further mutations in the symmetric dimer interface which we predict allow influenza to adapt to use suboptimal ANP32 proteins through a similar mechanism. Overall, our results suggest a balance between asymmetric and symmetric dimers of influenza virus polymerase that is influenced by the interaction between polymerase and ANP32 host proteins.

Journal article

Idoko-Akoh A, Goldhill DH, Sheppard CM, Bialy D, Quantrill JL, Sukhova K, Brown JC, Richardson S, Campbell C, Taylor L, Sherman A, Nazki S, Long JS, Skinner MA, Shelton H, Sang HM, Barclay WS, McGrew MJet al., 2023, Creating resistance to avian influenza infection through genome editing of the ANP32 gene family., Nat Commun, Vol: 14

Chickens genetically resistant to avian influenza could prevent future outbreaks. In chickens, influenza A virus (IAV) relies on host protein ANP32A. Here we use CRISPR/Cas9 to generate homozygous gene edited (GE) chickens containing two ANP32A amino acid substitutions that prevent viral polymerase interaction. After IAV challenge, 9/10 edited chickens remain uninfected. Challenge with a higher dose, however, led to breakthrough infections. Breakthrough IAV virus contained IAV polymerase gene mutations that conferred adaptation to the edited chicken ANP32A. Unexpectedly, this virus also replicated in chicken embryos edited to remove the entire ANP32A gene and instead co-opted alternative ANP32 protein family members, chicken ANP32B and ANP32E. Additional genome editing for removal of ANP32B and ANP32E eliminated all viral growth in chicken cells. Our data illustrate a first proof of concept step to generate IAV-resistant chickens and show that multiple genetic modifications will be required to curtail viral escape.

Journal article

Ward H, Atchison C, Whitaker M, Davies B, Ashby D, Darzi A, Chadeau-Hyam M, Riley S, Donnelly CA, Barclay W, Cooke GS, Elliott Pet al., 2023, Design and implementation of a national program to monitor the prevalence of SARS-CoV-2 IgG antibodies in England using self-testing: the REACT-2 study, American Journal of Public Health, Pages: e1-e9, ISSN: 0090-0036

Data System. The UK Department of Health and Social Care funded the REal-time Assessment of Community Transmission-2 (REACT-2) study to estimate community prevalence of SARS-CoV-2 IgG (immunoglobulin G) antibodies in England. Data Collection/Processing. We obtained random cross-sectional samples of adults from the National Health Service (NHS) patient list (near-universal coverage). We sent participants a lateral flow immunoassay (LFIA) self-test, and they reported the result online. Overall, 905 991 tests were performed (28.9% response) over 6 rounds of data collection (June 2020-May 2021). Data Analysis/Dissemination. We produced weighted estimates of LFIA test positivity (validated against neutralizing antibodies), adjusted for test performance, at local, regional, and national levels and by age, sex, and ethnic group and area-level deprivation score. In each round, fieldwork occurred over 2 weeks, with results reported to policymakers the following week. We disseminated results as preprints and peer-reviewed journal publications. Public Health Implications. REACT-2 estimated the scale and variation in antibody prevalence over time. Community self-testing and -reporting produced rapid insights into the changing course of the pandemic and the impact of vaccine rollout, with implications for future surveillance. (Am J Public Health. Published online ahead of print September 21, 2023:e1-e9. https://doi.org/10.2105/AJPH.2023.307381).

Journal article

Shah N, Xue B, Xu Z, Yang H, Marwali E, Dalton H, Payne PPR, Lu CS, Said Aet al., 2023, Validation of extracorporeal membrane oxygenation mortality prediction and severity of illness scores in an international COVID-19 cohort, ARTIFICIAL ORGANS, Vol: 47, Pages: 1490-1502, ISSN: 0160-564X

Journal article

Whitaker M, Davies B, Atchison C, Barclay W, Ashby D, Darzi A, Riley S, Cooke G, Donnelly C, Chadeau M, Elliott P, Ward Het al., 2023, SARS-CoV-2 rapid antibody test results and subsequent risk of hospitalisation and death in 361,801 people, Nature Communications, Vol: 14, ISSN: 2041-1723

The value of SARS-CoV-2 lateral flow immunoassay (LFIA) tests for estimating individual disease risk is unclear. The REACT-2 study in England, UK, obtained self-administered SARS-CoV-2 LFIA test results from 361,801 adults in January-May 2021. Here, we link to routine data on subsequent hospitalisation (to September 2021), and death (to December 2021). Among those who had received one or more vaccines, a negative LFIA is associated with increased risk of hospitalisation with COVID-19 (HR: 2.73 [95% confidence interval: 1.15,6.48]), death (all-cause) (HR: 1.59, 95% CI:1.07, 2.37), and death with COVID-19 as underlying cause (20.6 [1.83,232]). For people designated at high risk from COVID-19, who had received one or more vaccines, there is an additional risk of all-cause mortality of 1.9 per 1000 for those testing antibody negative compared to positive. However, the LFIA does not provide substantial predictive information over and above that which is available from detailed sociodemographic and health-related variables. Nonetheless, this simple test provides a marker which could be a valuable addition to understanding population and individual-level risk.

Journal article

Zhou J, Singanayagam A, Goonawardane N, Moshe M, Sweeney F, Sukhova K, Killingley B, Kalinova M, Mann A, Catchpole A, Barer MR, Ferguson NM, Chiu C, Barclay WSet al., 2023, Viral emissions into the air and environment after SARS-CoV-2 human challenge: a phase 1, open label, first-in-human study, The Lancet Microbe, Vol: 4, Pages: e579-e590, ISSN: 2666-5247

BackgroundEffectively implementing strategies to curb SARS-CoV-2 transmission requires understanding who is contagious and when. Although viral load on upper respiratory swabs has commonly been used to infer contagiousness, measuring viral emissions might be more accurate to indicate the chance of onward transmission and identify likely routes. We aimed to correlate viral emissions, viral load in the upper respiratory tract, and symptoms, longitudinally, in participants who were experimentally infected with SARS-CoV-2.MethodsIn this phase 1, open label, first-in-human SARS-CoV-2 experimental infection study at quarantine unit at the Royal Free London NHS Foundation Trust, London, UK, healthy adults aged 18–30 years who were unvaccinated for SARS-CoV-2, not previously known to have been infected with SARS-CoV-2, and seronegative at screening were recruited. Participants were inoculated with 10 50% tissue culture infectious dose of pre-alpha wild-type SARS-CoV-2 (Asp614Gly) by intranasal drops and remained in individual negative pressure rooms for a minimum of 14 days. Nose and throat swabs were collected daily. Emissions were collected daily from the air (using a Coriolis μ air sampler and directly into facemasks) and the surrounding environment (via surface and hand swabs). All samples were collected by researchers, and tested by using PCR, plaque assay, or lateral flow antigen test. Symptom scores were collected using self-reported symptom diaries three times daily. The study is registered with ClinicalTrials.gov, NCT04865237.FindingsBetween March 6 and July 8, 2021, 36 participants (ten female and 26 male) were recruited and 18 (53%) of 34 participants became infected, resulting in protracted high viral loads in the nose and throat following a short incubation period, with mild-to-moderate symptoms. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Viral RNA was de

Journal article

Kugathasan R, Sukhova K, Moshe M, Kellam P, Barclay Wet al., 2023, Deep mutagenesis scanning using whole trimeric SARS-CoV-2 spike highlights the importance of NTD-RBD interactions in determining spike phenotype, PLoS Pathogens, Vol: 19, ISSN: 1553-7366

New variants of SARS-CoV-2 are continually emerging with mutations in spike associated with increased transmissibility and immune escape. Phenotypic maps can inform the prediction of concerning mutations from genomic surveillance, however most of these maps currently derive from studies using monomeric RBD, while spike is trimeric, and contains additional domains. These maps may fail to reflect interdomain interactions in the prediction of phenotypes. To try to improve on this, we developed a platform for deep mutational scanning using whole trimeric spike. We confirmed a previously reported epistatic effect within the RBD affecting ACE2 binding, that highlights the importance of updating the base spike sequence for future mutational scanning studies. Using post vaccine sera, we found that the immune response of vaccinated individuals was highly focused on one or two epitopes in the RBD and that single point mutations at these positions can account for most of the immune escape mediated by the Omicron BA.1 RBD. However, unexpectedly we found that the BA.1 RBD alone does not account for the high level of antigenic escape by BA.1 spike. We show that the BA.1 NTD amplifies the immune evasion of its associated RBD. BA.1 NTD reduces neutralistion by RBD directed monoclonal antibodies, and impacts ACE2 interaction. NTD variation is thus an important mechanism of immune evasion by SARS-CoV-2. Such effects are not seen when pre-stabilized spike proteins are used, suggesting the interdomain effects require protein mobility to express their phenotype.

Journal article

McCormack CP, Yan AWC, Brown JC, Sukhova K, Peacock TP, Barclay WS, Dorigatti Iet al., 2023, Modelling the viral dynamics of the SARS-CoV-2 Delta and Omicron variants in different cell types., Journal of the Royal Society Interface, Vol: 20, Pages: 1-12, ISSN: 1742-5662

We use viral kinetic models fitted to viral load data from in vitro studies to explain why the SARS-CoV-2 Omicron variant replicates faster than the Delta variant in nasal cells, but slower than Delta in lung cells, which could explain Omicron's higher transmission potential and lower severity. We find that in both nasal and lung cells, viral infectivity is higher for Omicron but the virus production rate is higher for Delta, with an estimated approximately 200-fold increase in infectivity and 100-fold decrease in virus production when comparing Omicron with Delta in nasal cells. However, the differences are unequal between cell types, and ultimately lead to the basic reproduction number and growth rate being higher for Omicron in nasal cells, and higher for Delta in lung cells. In nasal cells, Omicron alone can enter via a TMPRSS2-independent pathway, but it is primarily increased efficiency of TMPRSS2-dependent entry which accounts for Omicron's increased activity. This work paves the way for using within-host mathematical models to understand the transmission potential and severity of future variants.

Journal article

Eales O, de Oliveira Martins L, Page A, Wang H, Bodinier B, Tang D, Haw D, Jonnerby LJA, Atchison C, Ashby D, Barclay W, Taylor G, Cooke G, Ward H, Darzi A, Riley S, Elliott P, Donnelly C, Chadeau Met al., 2023, Dynamics and scale of the SARS-CoV-2 variant Omicron epidemic in England, Nature Communications, Vol: 13, ISSN: 2041-1723

The SARS-CoV-2 pandemic has been characterised by the regular emergence of genomic variants. With natural and vaccine-induced population immunity at high levels, evolutionary pressure favours variants better able to evade SARS-CoV-2 neutralising antibodies. The Omicron variant (first detected in November 2021) exhibited a high degree of immune evasion, leading to increased infection rates worldwide. However, estimates of the magnitude of this Omicron wave have often relied on routine testing data, which are prone to several biases. Using data from the REal-time Assessment of Community Transmission-1 (REACT-1) study, a series of cross-sectional surveys assessing prevalence of SARS-CoV-2 infection in England, we estimated the dynamics of England’s Omicron wave (from 9 September 2021 to 1 March 2022). We estimate an initial peak in national Omicron prevalence of 6.89% (5.34%, 10.61%) during January 2022, followed by a resurgence in SARS-CoV-2 infections as the more transmissible Omicron sub-lineage, BA.2 replaced BA.1 and BA.1.1. Assuming the emergence of further distinct variants, intermittent epidemics of similar magnitudes may become the ‘new normal’.

Journal article

Peacock TP, Barclay WS, 2023, Mink farming poses risks for future viral pandemics., Proc Natl Acad Sci U S A, Vol: 120

Journal article

Tan C, Trew J, Peacock T, Mok KY, Hart C, Lau K, Ni D, Orme CDL, Ransome E, Pearse W, Coleman C, Bailey D, Thakur N, Quantrill J, Sukhova K, Richard D, Kahane L, Woodward G, Bell T, Worledge L, Nunez-Mino J, Barclay W, van Dorp L, Balloux F, Savolainen Vet al., 2023, Genomic screening of 16 UK native bat species through conservationist networks uncovers coronaviruses with zoonotic potential, Nature Communications, Vol: 14, Pages: 1-13, ISSN: 2041-1723

There has been limited characterisation of bat-borne coronaviruses in Europe. Here, we screened for coronaviruses in 48 faecal samples from 16 of the 17 bat species breeding in the UK, collected through a bat rehabilitation and conservationist network. We recovered nine (two novel) complete genomes across six bat species: four alphacoronaviruses, a MERS-related betacoronavirus, and four closely related sarbecoviruses. We demonstrate that at least one of these sarbecoviruses can bind and use the human ACE2 receptor for infecting human cells, albeit suboptimally. Additionally, the spike proteins of these sarbecoviruses possess an R-A-K-Q motif, which lies only one nucleotide mutation away from a furin cleavage site (FCS) that enhances infectivity in other coronaviruses, including SARS-CoV-2. However, mutating this motif to an FCS does not enable spike cleavage. Overall, while UK sarbecoviruses would require further molecular adaptations to infect humans, their zoonotic risk is unknown and warrants closer surveillance.

Journal article

Atchison C, Whitaker M, Donnelly C, Chadeau-Hyam M, Riley S, Darzi A, Ashby D, Barclay W, Cooke G, Elliott P, Ward Het al., 2023, Characteristics and predictors of persistent symptoms post COVID-19 in children and young people: a large community cross-sectional study in England, Archives of Disease in Childhood, Vol: 108, ISSN: 0003-9888

Objective: To estimate the prevalence of, and associated risk factors for, persistent symptoms post-COVID-19 among children aged 5–17 years in England.Design: Serial cross-sectional study.Setting: Rounds 10–19 (March 2021 to March 2022) of the REal-time Assessment of Community Transmission-1 study (monthly cross-sectional surveys of random samples of the population in England).Study population: Children aged 5–17 years in the community.Predictors: Age, sex, ethnicity, presence of a pre-existing health condition, index of multiple deprivation, COVID-19 vaccination status and dominant UK circulating SARS-CoV-2 variant at time of symptom onset.Main outcome measures: Prevalence of persistent symptoms, reported as those lasting ≥3 months post-COVID-19.Results: Overall, 4.4% (95% CI 3.7 to 5.1) of 3173 5–11 year-olds and 13.3% (95% CI 12.5 to 14.1) of 6886 12–17 year-olds with prior symptomatic infection reported at least one symptom lasting ≥3 months post-COVID-19, of whom 13.5% (95% CI 8.4 to 20.9) and 10.9% (95% CI 9.0 to 13.2), respectively, reported their ability to carry out day-to-day activities was reduced ‘a lot’ due to their symptoms. The most common symptoms among participants with persistent symptoms were persistent coughing (27.4%) and headaches (25.4%) in children aged 5–11 years and loss or change of sense of smell (52.2%) and taste (40.7%) in participants aged 12–17 years. Higher age and having a pre-existing health condition were associated with higher odds of reporting persistent symptoms.Conclusions: One in 23 5–11 year-olds and one in eight 12–17 year-olds post-COVID-19 report persistent symptoms lasting ≥3 months, of which one in nine report a large impact on performing day-to-day activities.

Journal article

Derqui N, Koycheva A, Zhou J, Pillay TD, Crone MA, Hakki S, Fenn J, Kundu R, Varro R, Conibear E, Madon KJ, Barnett JL, Houston H, Singanayagam A, Narean JS, Tolosa-Wright MR, Mosscrop L, Rosadas C, Watber P, Anderson C, Parker E, Freemont PS, Ferguson NM, Zambon M, McClure MO, Tedder R, Barclay WS, Dunning J, Taylor GP, Lalvani A, INSTINCT and ATACCC study groupet al., 2023, Risk factors and vectors for SARS-CoV-2 household transmission: a prospective, longitudinal cohort study, The Lancet Microbe, Vol: 4, Pages: e397-e408, ISSN: 2666-5247

BACKGROUND: Despite circumstantial evidence for aerosol and fomite spread of SARS-CoV-2, empirical data linking either pathway with transmission are scarce. Here we aimed to assess whether the presence of SARS-CoV-2 on frequently-touched surfaces and residents' hands was a predictor of SARS-CoV-2 household transmission. METHODS: In this longitudinal cohort study, during the pre-alpha (September to December, 2020) and alpha (B.1.1.7; December, 2020, to April, 2021) SARS-CoV-2 variant waves, we prospectively recruited contacts from households exposed to newly diagnosed COVID-19 primary cases, in London, UK. To maximally capture transmission events, contacts were recruited regardless of symptom status and serially tested for SARS-CoV-2 infection by RT-PCR on upper respiratory tract (URT) samples and, in a subcohort, by serial serology. Contacts' hands, primary cases' hands, and frequently-touched surface-samples from communal areas were tested for SARS-CoV-2 RNA. SARS-CoV-2 URT isolates from 25 primary case-contact pairs underwent whole-genome sequencing (WGS). FINDINGS: From Aug 1, 2020, until March 31, 2021, 620 contacts of PCR-confirmed SARS-CoV-2-infected primary cases were recruited. 414 household contacts (from 279 households) with available serial URT PCR results were analysed in the full household contacts' cohort, and of those, 134 contacts with available longitudinal serology data and not vaccinated pre-enrolment were analysed in the serology subcohort. Household infection rate was 28·4% (95% CI 20·8-37·5) for pre-alpha-exposed contacts and 51·8% (42·5-61·0) for alpha-exposed contacts (p=0·0047). Primary cases' URT RNA viral load did not correlate with transmission, but was associated with detection of SARS-CoV-2 RNA on their hands (p=0·031). SARS-CoV-2 detected on primary cases' hands, in turn, predicted contacts' risk of infection (adjusted relative risk [aRR]=1·70 [95% CI 1·24-2·3

Journal article

Eales O, Haw D, Wang H, Atchison C, Ashby D, Cooke GS, Barclay W, Ward H, Darzi A, Donnelly CA, Chadeau-Hyam M, Elliott P, Riley Set al., 2023, Dynamics of SARS-CoV-2 infection hospitalisation and infection fatality ratios over 23 months in England, PLoS Biology, Vol: 21, Pages: 1-21, ISSN: 1544-9173

The relationship between prevalence of infection and severe outcomes such as hospitalisation and death changed over the course of the COVID-19 pandemic. Reliable estimates of the infection fatality ratio (IFR) and infection hospitalisation ratio (IHR) along with the time-delay between infection and hospitalisation/death can inform forecasts of the numbers/timing of severe outcomes and allow healthcare services to better prepare for periods of increased demand. The REal-time Assessment of Community Transmission-1 (REACT-1) study estimated swab positivity for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in England approximately monthly from May 2020 to March 2022. Here, we analyse the changing relationship between prevalence of swab positivity and the IFR and IHR over this period in England, using publicly available data for the daily number of deaths and hospitalisations, REACT-1 swab positivity data, time-delay models, and Bayesian P-spline models. We analyse data for all age groups together, as well as in 2 subgroups: those aged 65 and over and those aged 64 and under. Additionally, we analysed the relationship between swab positivity and daily case numbers to estimate the case ascertainment rate of England's mass testing programme. During 2020, we estimated the IFR to be 0.67% and the IHR to be 2.6%. By late 2021/early 2022, the IFR and IHR had both decreased to 0.097% and 0.76%, respectively. The average case ascertainment rate over the entire duration of the study was estimated to be 36.1%, but there was some significant variation in continuous estimates of the case ascertainment rate. Continuous estimates of the IFR and IHR of the virus were observed to increase during the periods of Alpha and Delta's emergence. During periods of vaccination rollout, and the emergence of the Omicron variant, the IFR and IHR decreased. During 2020, we estimated a time-lag of 19 days between hospitalisation and swab positivity, and 26 days between deaths

Journal article

Peacock T, Sheppard C, Lister M, Staller E, Frise R, Swann O, Goldhill D, Long J, Barclay Wet al., 2023, Mammalian ANP32A and ANP32B proteins drive differential polymerase adaptations in avian influenza virus, Journal of Virology, Vol: 97, Pages: 1-13, ISSN: 0022-538X

ANP32 proteins, which act as influenza polymerase cofactors, vary between birds and mammals. In mammals, ANP32A and ANP32B have been reported to serve essential but redundant roles to support influenza polymerase activity. The well-known mammalian adaptation PB2-E627K enables influenza polymerase to use mammalian ANP32 proteins. However, some mammalian-adapted influenza viruses do not harbor this substitution. Here, we show that alternative PB2 adaptations, Q591R and D701N, also allow influenza polymerase to use mammalian ANP32 proteins, whereas other PB2 mutations, G158E, T271A, and D740N, increase polymerase activity in the presence of avian ANP32 proteins as well. Furthermore, PB2-E627K strongly favors use of mammalian ANP32B proteins, whereas D701N shows no such bias. Accordingly, PB2-E627K adaptation emerges in species with strong pro-viral ANP32B proteins, such as humans and mice, while D701N is more commonly seen in isolates from swine, dogs, and horses, where ANP32A proteins are the preferred cofactor. Using an experimental evolution approach, we show that the passage of viruses containing avian polymerases in human cells drove acquisition of PB2-E627K, but not in the absence of ANP32B. Finally, we show that the strong pro-viral support of ANP32B for PB2-E627K maps to the low-complexity acidic region (LCAR) tail of ANP32B.IMPORTANCE Influenza viruses naturally reside in wild aquatic birds. However, the high mutation rate of influenza viruses allows them to rapidly and frequently adapt to new hosts, including mammals. Viruses that succeed in these zoonotic jumps pose a pandemic threat whereby the virus adapts sufficiently to efficiently transmit human-to-human. The influenza virus polymerase is central to viral replication and restriction of polymerase activity is a major barrier to species jumps. ANP32 proteins are essential for influenza polymerase activity. In this study, we describe how avian influenza viruses can adapt in several different ways to use ma

Journal article

Goldswain H, Dong X, Penrice-Randal R, Alruwaili M, Shawli GT, Prince T, Williamson MK, Raghwani J, Randle N, Jones B, Donovan-Banfield I, Salguero FJ, Tree JA, Hall Y, Hartley C, Erdmann M, Bazire J, Jearanaiwitayakul T, Semple MG, Openshaw PJM, Baillie JK, ISARIC4C Investigators, Emmett SR, Digard P, Matthews DA, Turtle L, Darby AC, Davidson AD, Carroll MW, Hiscox JAet al., 2023, The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection, Genome Biology, Vol: 24, ISSN: 1474-7596

BACKGROUND: The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. RESULTS: Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. CONCLUSIONS: These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.

Journal article

Elliott P, Whitaker M, Tang D, Eales O, Steyn N, Bodinier B, Wang H, Elliott J, Atchison C, Ashby D, Barclay W, Taylor G, Darzi A, Cooke G, Ward H, Donnelly C, Riley S, Chadeau Met al., 2023, Design and implementation of a national SARS-CoV-2 monitoring programme in England: REACT-1 Study, American Journal of Public Health, ISSN: 0090-0036

Data System. The REal-time Assessment of Community Transmission-1 (REACT-1) Study was funded by the Department of Health and Social Care in England to provide reliable and timely estimates of prevalence of SARS-CoV-2 infection by time, person and place.Data Collection/Processing. The data were obtained by writing to named individuals aged 5 years and above in random cross-sections of the population of England, using the National Health Service (NHS) list of patients registered with a general practitioner (>99% coverage) as sampling frame. Data were collected 2-3 weekly approximately every month across 19distinct rounds of data collection from May 1, 2020 to March 31, 2022.Data Analysis/Dissemination. The data and study materials are widely disseminated via the study website, preprints, publications in peer-reviewed journals and the media. Data tabulations suitably anonymised to protect participant confidentiality are available on request to the study’s Data Access Committee.Implications. The study provided inter alia real-time data on SARS-CoV-2 prevalence over time, by area, and by socio-demographic variables; estimates of vaccine effectiveness; symptom profiles and detected emergence of new variants based on viral genome sequencing.

Journal article

Carabelli AM, Peacock TP, Thorne LG, Harvey WT, Hughes J, COVID-19 Genomics UK Consortium, Peacock SJ, Barclay WS, de Silva TI, Towers GJ, Robertson DLet al., 2023, SARS-CoV-2 variant biology: immune escape, transmission and fitness, Nature Reviews Microbiology, Vol: 21, Pages: 162-177, ISSN: 1740-1526

In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. These highly mutated forms of SARS-CoV-2 had enhanced rates of transmission relative to previous variants and were termed 'variants of concern' (VOCs). Designated Alpha, Beta, Gamma, Delta and Omicron, the VOCs emerged independently from one another, and in turn each rapidly became dominant, regionally or globally, outcompeting previous variants. The success of each VOC relative to the previously dominant variant was enabled by altered intrinsic functional properties of the virus and, to various degrees, changes to virus antigenicity conferring the ability to evade a primed immune response. The increased virus fitness associated with VOCs is the result of a complex interplay of virus biology in the context of changing human immunity due to both vaccination and prior infection. In this Review, we summarize the literature on the relative transmissibility and antigenicity of SARS-CoV-2 variants, the role of mutations at the furin spike cleavage site and of non-spike proteins, the potential importance of recombination to virus success, and SARS-CoV-2 evolution in the context of T cells, innate immunity and population immunity. SARS-CoV-2 shows a complicated relationship among virus antigenicity, transmission and virulence, which has unpredictable implications for the future trajectory and disease burden of COVID-19.

Journal article

Siggins MK, Davies K, Fellows R, Thwaites RS, Baillie JK, Semple MG, Openshaw PJM, Zelek WM, Harris CL, Morgan BP, ISARIC4C Investigatorset al., 2023, Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19, Immunology, Vol: 168, Pages: 473-492, ISSN: 0019-2805

Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID-19. Complement activation products are detected in plasma and tissues and complement blockade considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in an COVID-19 to date, a comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalised COVID-19 patients collected across the hospitalisation period as part of the UK ISARIC4C study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to heathy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID-19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID-19 disease severity and death. The data demonstrate that early-onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID-19, further exacerbated in severe disease. These findings provide novel insights into COVID-19 immunopathogenesis and inform strategies for therapeutic intervention.

Journal article

Atchison C, Moshe M, Brown J, Whitaker M, Wong N, Bharath A, Mckendry R, Darzi A, Ashby D, Donnelly C, Riley S, Elliott P, Barclay W, Cooke G, Ward Het al., 2023, Validity of self-testing at home with rapid SARS-CoV-2 antibody detection by lateral flow immunoassay, Clinical Infectious Diseases, Vol: 76, Pages: 658-666, ISSN: 1058-4838

Background: We explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow immunoassay (LFIA) performance under field conditions compared to laboratory-based ELISA and live virus neutralisation. Methods: In July 2021, 3758 participants performed, at home, a self-administered LFIA on finger-prick blood, reported and submitted a photograph of the result, and provided a self-collected capillary blood sample for assessment of IgG antibodies using the Roche Elecsys® Anti-SARS-CoV-2 assay. We compared the self-reported LFIA result to the quantitative Roche assay and checked the reading of the LFIA result with an automated image analysis (ALFA). In a subsample of 250 participants, we compared the results to live virus neutralisation. Results: Almost all participants (3593/3758, 95.6%) had been vaccinated or reported prior infection. Overall, 2777/3758 (73.9%) were positive on self-reported LFIA, 2811/3457 (81.3%) positive by LFIA when ALFA-reported, and 3622/3758 (96.4%) positive on Roche (using the manufacturer reference standard threshold for positivity of 0.8 U ml−1). Live virus neutralisation was detected in 169 of 250 randomly selected samples (67.6%); 133/169 were positive with self-reported LFIA (sensitivity 78.7%; 95% CI 71.8, 84.6), 142/155 (91.6%; 86.1, 95.5) with ALFA, and 169 (100%; 97.8, 100.0) with Roche. There were 81 samples with no detectable virus neutralisation; 47/81 were negative with self-reported LFIA (specificity 58.0%; 95% CI 46.5, 68.9), 34/75 (45.3%; 33.8, 57.3) with ALFA, and 0/81 (0%; 0.0, 4.5) with Roche. Conclusions: Self-administered LFIA is less sensitive than a quantitative antibody test, but the positivity in LFIA correlates better than the quantitative ELISA with virus neutralisation.

Journal article

Eales O, Page AJ, Tang SN, Walters CE, Wang H, Haw D, Trotter AJ, Le Viet T, Foster-Nyarko E, Prosolek S, Atchison C, Ashby D, Cooke G, Barclay W, Donnelly CA, O'Grady J, Volz E, The Covid-Genomics Uk Cog-Uk Consortium, Darzi A, Ward H, Elliott P, Riley Set al., 2023, The use of representative community samples to assess SARS-CoV-2 lineage competition: Alpha outcompetes Beta and wild-type in England from January to March 2021., Microbial Genomics, Vol: 9, Pages: 1-14, ISSN: 2057-5858

Genomic surveillance for SARS-CoV-2 lineages informs our understanding of possible future changes in transmissibility and vaccine efficacy and will be a high priority for public health for the foreseeable future. However, small changes in the frequency of one lineage over another are often difficult to interpret because surveillance samples are obtained using a variety of methods all of which are known to contain biases. As a case study, using an approach which is largely free of biases, we here describe lineage dynamics and phylogenetic relationships of the Alpha and Beta variant in England during the first 3 months of 2021 using sequences obtained from a random community sample who provided a throat and nose swab for rt-PCR as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Overall, diversity decreased during the first quarter of 2021, with the Alpha variant (first identified in Kent) becoming predominant, driven by a reproduction number 0.3 higher than for the prior wild-type. During January, positive samples were more likely to be Alpha in those aged 18 to 54 years old. Although individuals infected with the Alpha variant were no more likely to report one or more classic COVID-19 symptoms compared to those infected with wild-type, they were more likely to be antibody-positive 6 weeks after infection. Further, viral load was higher in those infected with the Alpha variant as measured by cycle threshold (Ct) values. The presence of infections with non-imported Beta variant (first identified in South Africa) during January, but not during February or March, suggests initial establishment in the community followed by fade-out. However, this occurred during a period of stringent social distancing. These results highlight how sequence data from representative community surveys such as REACT-1 can augment routine genomic surveillance during periods of lineage diversity.

Journal article

Swann O, Rasmussen A, Peacock T, Sheppard C, Barclay Wet al., 2023, Avian Influenza A Virus polymerase can utilise human ANP32 proteins to support cRNA but not vRNA synthesis, mBio, Vol: 14, Pages: 1-14, ISSN: 2150-7511

Host restriction limits the emergence of novel pandemic strains from the influenza A virus avian reservoir. For efficient replication in mammalian cells, the avian influenza RNA-dependent RNA polymerase must adapt to use human orthologues of the host factor ANP32, which lack a 33-amino-acid insertion relative to avian ANP32A. Here, we find that influenza polymerase requires ANP32 proteins to support both steps of genome replication: cRNA and vRNA synthesis. However, avian strains are only restricted in vRNA synthesis in human cells. Therefore, avian influenza polymerase can use human ANP32 orthologues to support cRNA synthesis, without acquiring mammalian adaptations. This implies a fundamental difference in the mechanism by which ANP32 proteins support cRNA versus vRNA synthesis.IMPORTANCE To infect humans and cause a pandemic, avian influenza must first adapt to use human versions of the proteins the virus hijacks for replication, instead of the avian orthologues found in bird cells. One critical host protein is ANP32. Understanding the details of how host proteins such as ANP32 support viral activity may allow the design of new antiviral strategies that disrupt these interactions. Here, we use cells that lack ANP32 to unambiguously demonstrate ANP32 is needed for both steps of influenza genome replication. Unexpectedly, however, we found that avian influenza can use human ANP32 proteins for the first step of replication, to copy a complementary strand, without adaptation but can only utilize avian ANP32 for the second step of replication that generates new genomes. This suggests ANP32 may have a distinct role in supporting the second step of replication, and it is this activity that is specifically blocked when avian influenza infects human cells.

Journal article

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