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1.
Preprint in English | medRxiv | ID: ppmedrxiv-22274884

ABSTRACT

Timely and accurate detection of SARS-CoV-2 variants of concern (VOCs) is urgently needed for pandemic surveillance and control. However, current methods are limited by the low sensitivity, long turn-around time or high cost. Here, we report a nucleic acid testing-based method aiming to detect and discriminate SARS-CoV-2 VOCs by combining RT-RPA and CRISPR-Cas12a detecting assays (RRCd). With a detection limit of 10 copies RNA/reaction, RRCd was validated in 204 clinical samples, showing 99% positive predictive agreement and 100% negative predictive agreement, respectively. Critically, using specific crRNAs, representatives of single nucleotide polymorphisms and small deletions in SARS-CoV-2 VOCs including N501Y, T478K and {Delta}H69-V70 were discriminated by RRCd, demonstrating 100% accuracy in clinical samples with Ct < 33. The method completes within 65 min and could offer visible results without using any electrical devices, which may facilitate point-of-care testing of SARS-CoV-2 and its variants.

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-315676

ABSTRACT

Background: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation, however we have previously reported that heterologous schedules incorporating an adenoviral-vectored vaccine (ChAd, Vaxzevria, Astrazeneca) and an mRNA vaccine (BNT, Comirnaty, Pfizer) at a 4-week interval are more reactogenic than homologous schedules. Here we report the immunogenicity of these schedules. Methods: Com-COV (ISRCTN: 69254139, EudraCT: 2020-005085-33) is a participant-blind, non-inferiority trial evaluating vaccine reactogenicity and immunogenicity. Adults ≥ 50 years, including those with well-controlled comorbidities, were randomised across eight groups to receive ChAd/ChAd, ChAd/BNT, BNT/BNT or BNT/ChAd, administered at 28- or 84-day intervals.The primary endpoint is geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG levels (ELISA) at one-month post boost between heterologous and homologous schedules given the same prime vaccine. We tested non-inferiority of GMR using a margin of 0.63. The primary analysis was on a per-protocol population, who were seronegative at baseline. Safety analyses were performed amongst participants receiving at least one dose of study vaccines.Findings: In February 2021, 830 participants were enrolled and randomised, including 463 with a 28-day prime-boost interval whose results are reported in this paper. Participant mean age was 57.8 years, 45.8% were female, and 25.3% from ethnic minorities.The geometric mean concentration (GMC) of day 28 post-boost SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12,906 ELU/ml) was non-inferior to that in ChAd/ChAd recipients (1,392 ELU/ml) with a geometric mean ratio (GMR) of 9.2 (one-sided 97.5% CI: 7.5, ∞). In participants primed with BNT, we failed to show non-inferiority of the heterologous schedule (BNT/ChAd, GMC 7,133 ELU/ml) against the homologous schedule (BNT/BNT, GMC 14,080 ELU/ml) with a GMR of 0.51 (one-sided 97.5% CI: 0.43, ∞). Geometric mean of T cell response at 28 days post boost in the ChAd/BNT group was 185 SFC/106 PBMCs (spot forming cells/106 peripheral blood mononuclear cells) compared to 50, 80 and 99 SFC/106 PBMCs for ChAd/ChAd, BNT/BNT, and BNT/ChAd, respectively. There were four serious adverse events across all groups, none of which were considered related to immunisation.Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the GMCs of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. These data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.Trial Registration: The trial is registered at www.isrctn.com as ISRCTN: 69254139.Funding: Funded by the UK Vaccine Task Force (VTF) and National Institute for Health Research (NIHR)Declaration of Interest: MDS acts on behalf of the University of Oxford as an Investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM vaccines. He receives no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England. AMC and DMF are investigators on studies funded by Pfizer and Unilever. They receive no personal financial payment for this work. AF is a member of the Joint Committee on Vaccination and Immunisation and Chair of the WHO European Technical Advisory Group of Experts (ETAGE) on Immunisation. He is an investigator and/or provides consultative advice on clinical trials and studies of COVID-19 vaccines produced by AstraZeneca, Janssen, Valneva, Pfizer and Sanofi and of other vaccines from these and other manufacturers including GSK, VPI, Takeda and Bionet Asia. He receives no personal remuneration or benefits for any of this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an Inves igator and/or providing consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. PTH acts on behalf of St. George’s University of London as an Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, Novavax and Valneva. He receives no personal financial payment for this work. CAG acts on behalf of University Hospitals Birmingham NHS Foundation Trust as an Investigator on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, Novavax, CureVac, Moderna, and Valneva vaccines, and receives no personal financial payment for this work. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca and Valneva. He receives no personal financial payment for this work. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and is an occasional consultant to Vaccitech unrelated to this work. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19Ethical Approval: The trial was reviewed and approved by the South-Central Berkshire Research Ethics Committee (21/SC/0022), the University of Oxford, and the Medicines and Healthcare Products Regulatory Agency MHRA). An independent data safety monitoring board (DSMB) reviewed safety data, and local trial- site physicians provided oversight of all adverse events in real-time.

3.
Journal of Consumer Behaviour ; 2021.
Article in English | EuropePMC | ID: covidwho-1563849

ABSTRACT

The tourism and hospitality industry has been deeply disrupted by the COVID‐19 pandemic since its inception in December 2019. Many tourists are too anxious to travel. Thus, understanding how travel constraints and perceived travel risk influence travel intention is crucial for many destinations in their post‐crisis recovery. Drawing upon 357 Malaysian respondents, this study finds that structural constraints initiate tourists' negotiation process for travel decisions, which is inconsistent with the original Leisure Constraints Model. Nevertheless, it is reaffirmed that intrapersonal constraints remain the centrality of the negotiation process as they mediate the relationship between structural constraints, perceived travel risk and travel intention. These findings provide some theoretical contributions with regard to the Leisure Constraints Model and perceived travel risk in the context of the COVID‐19. Based on the theoretical contributions, this study also sheds light on tourism revival from a practical perspective. Tourism authorities, destination marketing organizations, and business operators are suggested to take measures to restore tourists' confidence toward travel by reducing structural constraints and mitigating tourists' risk perception in a cooperative manner.

4.
Lancet ; 398(10303): 856-869, 2021 09 04.
Article in English | MEDLINE | ID: covidwho-1397746

ABSTRACT

BACKGROUND: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer-BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. METHODS: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. FINDINGS: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. INTERPRETATION: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. FUNDING: UK Vaccine Task Force and National Institute for Health Research.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , Aged , Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , Equivalence Trials as Topic , Female , Humans , Immunization Schedule , Immunoglobulin G/blood , Intention to Treat Analysis , Male , Middle Aged , Single-Blind Method , Spike Glycoprotein, Coronavirus/immunology
5.
Acta Crystallogr D Struct Biol ; 77(Pt 6): 727-745, 2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-1254969

ABSTRACT

Covalent linkages between constituent blocks of macromolecules and ligands have been subject to inconsistent treatment during the model-building, refinement and deposition process. This may stem from a number of sources, including difficulties with initially detecting the covalent linkage, identifying the correct chemistry, obtaining an appropriate restraint dictionary and ensuring its correct application. The analysis presented herein assesses the extent of problems involving covalent linkages in the Protein Data Bank (PDB). Not only will this facilitate the remediation of existing models, but also, more importantly, it will inform and thus improve the quality of future linkages. By considering linkages of known type in the CCP4 Monomer Library (CCP4-ML), failure to model a covalent linkage is identified to result in inaccurate (systematically longer) interatomic distances. Scanning the PDB for proximal atom pairs that do not have a corresponding type in the CCP4-ML reveals a large number of commonly occurring types of unannotated potential linkages; in general, these may or may not be covalently linked. Manual consideration of the most commonly occurring cases identifies a number of genuine classes of covalent linkages. The recent expansion of the CCP4-ML is discussed, which has involved the addition of over 16 000 and the replacement of over 11 000 component dictionaries using AceDRG. As part of this effort, the CCP4-ML has also been extended using AceDRG link dictionaries for the aforementioned linkage types identified in this analysis. This will facilitate the identification of such linkage types in future modelling efforts, whilst concurrently easing the process involved in their application. The need for a universal standard for maintaining link records corresponding to covalent linkages, and references to the associated dictionaries used during modelling and refinement, following deposition to the PDB is emphasized. The importance of correctly modelling covalent linkages is demonstrated using a case study, which involves the covalent linkage of an inhibitor to the main protease in various viral species, including SARS-CoV-2. This example demonstrates the importance of properly modelling covalent linkages using a comprehensive restraint dictionary, as opposed to just using a single interatomic distance restraint or failing to model the covalent linkage at all.


Subject(s)
Models, Structural , Crystallography, X-Ray , Databases, Protein , Ligands , SARS-CoV-2/chemistry , Viral Proteins/chemistry
6.
Chin Med J (Engl) ; 134(8): 935-943, 2021 Apr 20.
Article in English | MEDLINE | ID: covidwho-1195742

ABSTRACT

BACKGROUND: Since 2019, a novel coronavirus named 2019 novel coronavirus (2019-nCoV) has emerged worldwide. Apart from fever and respiratory complications, acute kidney injury has been observed in a few patients with coronavirus disease 2019. Furthermore, according to recent findings, the virus has been detected in urine. Angiotensin-converting enzyme II (ACE2) has been proposed to serve as the receptor for the entry of 2019-nCoV, which is the same as that for the severe acute respiratory syndrome. This study aimed to investigate the possible cause of kidney damage and the potential route of 2019-nCoV infection in the urinary system. METHODS: We used both published kidney and bladder cell atlas data and new independent kidney single-cell RNA sequencing data generated in-house to evaluate ACE2 gene expression in all cell types in healthy kidneys and bladders. The Pearson correlation coefficients between ACE2 and all other genes were first generated. Then, genes with r values larger than 0.1 and P values smaller than 0.01 were deemed significant co-expression genes with ACE2. RESULTS: Our results showed the enriched expression of ACE2 in all subtypes of proximal tubule (PT) cells of the kidney. ACE2 expression was found in 5.12%, 5.80%, and 14.38% of the proximal convoluted tubule cells, PT cells, and proximal straight tubule cells, respectively, in three published kidney cell atlas datasets. In addition, ACE2 expression was also confirmed in 12.05%, 6.80%, and 10.20% of cells of the proximal convoluted tubule, PT, and proximal straight tubule, respectively, in our own two healthy kidney samples. For the analysis of public data from three bladder samples, ACE2 expression was low but detectable in bladder epithelial cells. Only 0.25% and 1.28% of intermediate cells and umbrella cells, respectively, had ACE2 expression. CONCLUSION: This study has provided bioinformatics evidence of the potential route of 2019-nCoV infection in the urinary system.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Kidney/metabolism , Single-Cell Analysis , Urinary Bladder/metabolism , Gene Expression , Humans , SARS-CoV-2 , Sequence Analysis, RNA
7.
IEEE Access ; 9: 1590-1615, 2021.
Article in English | MEDLINE | ID: covidwho-1066539

ABSTRACT

As a result of the difficulties brought by COVID-19 and its associated lockdowns, many individuals and companies have turned to robots in order to overcome the challenges of the pandemic. Compared with traditional human labor, robotic and autonomous systems have advantages such as an intrinsic immunity to the virus and an inability for human-robot-human spread of any disease-causing pathogens, though there are still many technical hurdles for the robotics industry to overcome. This survey comprehensively reviews over 200 reports covering robotic systems which have emerged or have been repurposed during the past several months, to provide insights to both academia and industry. In each chapter, we cover both the advantages and the challenges for each robot, finding that robotics systems are overall apt solutions for dealing with many of the problems brought on by COVID-19, including: diagnosis, screening, disinfection, surgery, telehealth, care, logistics, manufacturing and broader interpersonal problems unique to the lockdowns of the pandemic. By discussing the potential new robot capabilities and fields they applied to, we expect the robotics industry to take a leap forward due to this unexpected pandemic.

8.
Proc Natl Acad Sci U S A ; 118(7)2021 02 16.
Article in English | MEDLINE | ID: covidwho-1060504

ABSTRACT

The RNA polymerase inhibitor favipiravir is currently in clinical trials as a treatment for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 Å. The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket. Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides. The structure reveals an unusual, nonproductive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp, which explains its low rate of incorporation into the RNA primer strand. Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronaviruses.


Subject(s)
Amides/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Enzyme Inhibitors/pharmacology , Pyrazines/pharmacology , SARS-CoV-2/ultrastructure , Amides/chemistry , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Cryoelectron Microscopy/methods , Enzyme Inhibitors/chemistry , Pyrazines/chemistry , Ribonucleotides/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Single Molecule Imaging/methods
9.
Preprint in English | bioRxiv | ID: ppbiorxiv-347690

ABSTRACT

The RNA polymerase inhibitor, favipiravir, is currently in clinical trials as a treatment for infection with SARS-CoV-2, despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 [A]. The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket. Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides. The structure reveals an unusual, non-productive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp which explains its low rate of incorporation into the RNA primer strand. Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronaviruses.

10.
Front Microbiol ; 11: 1388, 2020.
Article in English | MEDLINE | ID: covidwho-615531

ABSTRACT

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly worldwide, seriously endangering human health. In addition to the typical symptoms of pulmonary infection, patients with COVID-19 have been reported to have gastrointestinal symptoms and/or intestinal flora dysbiosis. It is known that a healthy intestinal flora is closely related to the maintenance of pulmonary and systemic health by regulating the host immune homeostasis. Role of the "gut-lung axis" has also been well-articulated. This review provides a novel suggestion that intestinal flora may be one of the mediators of the gastrointestinal responses and abnormal immune responses in hosts caused by SARS-CoV-2; improving the composition of intestinal flora and the proportion of its metabolites through probiotics, and personalized diet could be a potential strategy to prevent and treat COVID-19. More clinical and evidence-based medical trials may be initiated to determine the strategy.

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