ABSTRACT
Testing has been central to our response to the COVID-19 pandemic. However, the accuracy of testing relies on standards, including reference materials, proficiency testing schemes, and information and reporting guidelines. The use of standards is a simple, inexpensive, and effective method to ensure reliable test results that inform clinical and public health decisions. Here we describe the central role of standards during the COVID-19 pandemic, where they have enabled population-scale screening, genomic surveillance and measures of immune protection measures. Given these benefits, the Coronavirus Standards Working Group (CSWG) was formed to coordinate standards in SARS-CoV-2 testing. This network of scientists has developed best-practices, reference materials, and conducted proficiency studies to harmonize laboratory performance. We propose that this coordinated development of standards should be prioritized as a key early step in the public health response to future pandemics that is necessary for reliable, large-scale testing for infectious disease.
Subject(s)
COVID-19ABSTRACT
During the summer months food insecurity increases for some children because many youth who receive meals during the academic year do not receive meals during the summer. Federal summer feeding program data suggest that recreation providers play a role in addressing summertime food insecurity, butfew targeted studies have been conducted. This study assessed South Carolina recreation provider participation in programs addressing summertime food insecurity as well as challenges associated with summer feeding program implementation. Data were collected from 58 South Carolina recreation providers (i.e., summer camps and parks and recreation agencies) via an online questionnaire. Provider-reported quantitative, qualitative, and spatial data were analyzed. Findings were visualized using concept mapping and ArcGIS Pro mapping. Twenty-three of the 58 (39.6%) responding organizations participated in a summer feeding program. Transportation of youth to a feeding site was the most salient challenge. Spatial analyses suggest that communities with the greatest economic needs are underserved by recreation providers in this study sample. Recreation providers are important community-based intermediaries between federal, state, and local food suppliers and youth/families in need, with food distribution via recreation providers occurring through diverse youth program mechanisms (i.e., camp sessions, parks, recreation centers, and after school program sites). However, more recreation providers can be engaged as summer feeding sponsors or sites. Future research examining summertimefood insecurity following the onset of COVID-19 as well as the ways in which summer feeding program recipients are engaging with recreation providers is needed.
ABSTRACT
BackgroundDoctors report that collecting equipment for intravenous (IV) cannulation from the treatment room (TR) was a time-consuming and inconsistent process. Delays in this common paediatric procedure can prolong medical interventions resulting in sub-standard care and negatively impacting patient safety.ObjectivesTo reduce the time for HCPs to collect essential IV cannulation items from the TR by 25% over a 5 month period.MethodsHCPs, including doctors, nurses and healthcare assistants (HCA) helped to brainstorm factors contributing to the delay in collecting cannulation equipment which were collated into a ‘Cause and Effect’ diagram. Using a Plan-Do-Study-Act approach, the following interventions were derived:To reorganise and re-label the IV cannulation trolley in the TR and create a ‘how to stock’ card;To introduce a ‘stocking request whiteboard’ into the TR to ease communication of missing items between staff.The primary outcome was the time taken to collect IV cannulation items, measured using weekly time trials based on a pre-designed scenario. Questionnaires of different HCPs were conducted following each intervention.ResultsAt baseline, the median time to collect IV cannulation equipment was 302 seconds (range 155–374 seconds). A run chart demonstrated a sustained reduction in median time taken to collect items over 5 months. Post-intervention 1, the median time was 111 seconds (range 50–309 seconds), a decrease of 63% from baseline. Post-intervention 2, the median time was 83 seconds (range 77–142 seconds), an overall decrease of 73% from baseline.Feedback from questionnaires was universally positive. Following both interventions, HCPs were 33.4% more likely to find all required items in the TR and reported an increase in knowing what to do when items were missing (positivity score increased by 66.7%). The HCA reported an increase in knowing which items were out stock (positivity score increased by 150%) and where to stock them (positive score increased by 33%).ConclusionsSimplifying the process of restocking the IV cannulation trolley and implementing a system of communicating missing items reduced the median time taken for HCPs to collect essential IV cannulation items by more than half. The sustained reduction suggests simple interventions can improve efficiency, crucial at a time when staff are overstretched during the COVID-19 pandemic.There are many confounding factors in this study which could have affected the time trials including the unfamiliarity of new HCPs with the TR and staff redeployment and sickness affecting re-stocking of items. As a result, we liaised with the ward matron to identify a designated person to regularly stock the TR which will be key to sustainability. Other institutions report similar results in improving efficiency of collecting items through disseminating standardised cannulation trolleys.1 Other wards in the hospital could replicate our interventions to improve efficiency.ReferenceFonfe A, Lotha K, Rance T. G85 Improving cannulation efficiency in leeds children’s hospital (LCH). In: Archives of Disease in Childhood. BMJ 2020:A27.2-A27.
ABSTRACT
Background: Although 6 COVID-19 vaccines have been approved by the World Health Organisation as of 7th June 2021, global supply remains limited. An understanding of the immune response associated with protection could facilitate rapid licensure of new vaccines. Methods: Data from a randomised efficacy trial of ChAdOx1 nCoV-19 (AZD1222) vaccine in the UK was analysed to determine the antibody levels associated with protection against SARS-CoV-2. Anti-spike and anti-RBD IgG by multiplex immunoassay, pseudovirus and live neutralizing antibody at 28 days after the second dose were measured in infected and non-infected vaccine recipients. Weighted generalised additive models for binary data were applied to outcome. Cubic spline smoothed log antibody levels, and baseline risk of exposure were the predictor variables with weights applied to account for selection bias in sample processing. Results: Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. Vaccine efficacy of 80% against primary symptomatic COVID-19 was achieved with antibody level of 40923 (95% CI: 16748, 125017) and 63383 (95% CI: 16903, not computed (NC)) for anti-spike and anti-RBD, and 185 (95% CI: NC, NC) and 247 (95% CI: 101, NC) for pseudo- and live-neutralisation assays respectively. Antibody responses did not correlate with overall protection against asymptomatic infection. Conclusions: Correlates of protection can be used to bridge to new populations using validated assays. The data can be used to extrapolate efficacy estimates for new vaccines where large efficacy trials cannot be conducted. More work is needed to assess correlates for emerging variants.
Subject(s)
COVID-19ABSTRACT
Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, MHRA, with a regimen of two standard doses given with an interval of between 4 and 12 weeks. The planned rollout in the UK will involve vaccinating people in high risk categories with their first dose immediately, and delivering the second dose 12 weeks later.Here we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.Methods: We present data from phase III efficacy trials of ChAdOx1 nCoV-19 in the United Kingdom and Brazil, and phase I/II clinical trials in the UK and South Africa, against symptomatic disease caused by SARS-CoV-2. The data cut-off date for these analyses was 7th December 2020. The accumulated cases of COVID-19 disease at this cut-off date exceeds the number required for a pre-specified final analysis, which is also presented. As previously described, individuals over 18 years of age were randomised 1:1 to receive two standard doses (SD) of ChAdOx1 nCoV-19 (5x1010 viral particles) or a control vaccine/saline placebo. In the UK trial efficacy cohort a subset of participants received a lower dose (LD, 2.2x1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. All cases with a nucleic acid amplification test (NAAT) were adjudicated for inclusion in the analysis, by a blinded independent endpoint review committee. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov; NCT04324606, NCT04400838, and NCT04444674.Findings: 17,177 baseline seronegative trial participants were eligible for inclusion in the efficacy analysis, 8948 in the UK, 6753 in Brazil and 1476 in South Africa, with 619 documented NAAT +ve infections of which 332 met the primary endpoint of symptomatic infection >14 days post dose 2.The primary analysis of overall vaccine efficacy >14 days after the second dose including LD/SD and SD/SD groups, based on the prespecified criteria was 66.7% (57.4%, 74.0%). There were no hospitalisations in the ChAdOx1 nCoV-19 group after the initial 21 day exclusion period, and 15 in the control group.Vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 post vaccination was 76% (59%, 86%), and modelled analysis indicated that protection did not wane during this initial 3 month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 day (GMR 0.66, 95% CI 0.59, 0.74).In the SD/SD group, after the second dose, efficacy was higher with a longer prime-boost interval: VE 82.4% 95%CI 62.7%, 91.7% at 12+ weeks, compared with VE 54.9%, 95%CI 32.7%, 69.7% at <6 weeks. These observations are supported by immunogenicity data which showed binding antibody responses more than 2-fold higher after an interval of 12 or more weeks compared with and interval of less than 6 weeks GMR 2.19 (2.12, 2.26) in those who were 18-55 years of age.Interpretation: ChAdOx1 nCoV-19 vaccination programmes aimed at vaccinating a large proportion of the population with a single dose, with a second dose given after a 3 month period is an effective strategy for reducing disease, and may be the optimal for rollout of a pandemic vaccine when supplies are limited in the short term.Trial Registration: Studies are registered at ISRCTN89951424 and ClinicalTrials.gov; NCT04324606, NCT04400838, and NCT04444674.Funding: UKRI, NIHR, CEPI, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D’OR, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and Astra Zeneca.Conflict of Interest: Oxford University has entered into a partnership with Astra Zeneca for further development of ChAdOx1 nCoV-19. SCG is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine. TL is named as aninventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project. PMF is a consultant to Vaccitech. AJP is Chair of UK Dept.Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in discussions on COVID-19 vaccines, and is a member of the WHO’sSAGE. AJP and SNF are NIHR Senior Investigator. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, NIHR or WHO. AVSH reports personal feesfrom Vaccitech, outside the submitted work and has a patent on ChAdOx1 licensed to Vaccitech, and may benefit from royalty income to the University of Oxford from sales of this vaccine by AstraZeneca and sublicensees. MS reports grants from NIHR, non-financial support fromAstraZeneca, during the conduct of the study; grants from Janssen, grants fromGlaxoSmithKline, grants from Medimmune, grants from Novavax, grants and non-financialsupport from Pfizer, grants from MCM, outside the submitted work. CG reports personal fees from the Duke Human Vaccine Institute, outside of the submitted work. SNF reports grants from Janssen and Valneva, outside the submitted work. ADD reports grants and personal fees from AstraZeneca, outside of the submitted work. In addition, ADD has a patent manufacturingprocess for ChAdOx vectors with royalties paid to AstraZeneca, and a patent ChAdOx2 vector with royalties paid to AstraZeneca. The other authors declare no competing interests.
Subject(s)
COVID-19 , Hepatitis DABSTRACT
Birmingham University Turnkey laboratory is part of the Lighthouse network responsible for testing clinical samples under the UK government ‘ Test & Trace’ scheme. Samples are analysed for the presence of SARS-CoV-2 in respiratory samples using the Thermofisher TaqPath RT-QPCR test, which is designed to co-amplify sections of three SARS-CoV-2 viral genes. Since more recent information became available regarding the presence of SARS-CoV-2 variants of concern (S-VoC), which can show a suboptimal profile in RT-QPCR tests such as the ThermoFisher TaqPath used at the majority of Lighthouse laboratories, we analysed recently published data for trends and significance of the S-gene ‘dropout’ variant. Results: showed that: the population of S-gene dropout samples had significantly lower median Ct values of ORF and N-gene targets compared to samples where S-gene was detected on a population basis, S-gene dropout samples clustered around very low Ct values for ORF and N targets linked Ct values for individual samples showed that a low Ct for ORF and N were clearly associated with an S-dropout characteristic when conservatively inferring relative viral load from Ct values, approximately 35% of S-dropout samples had high viral loads between 10 and 10,000-fold greater than 1 × 10 6 , compared to 10% of S-positive samples. This analysis suggests that patients whose samples exhibit the S-dropout profile in the TaqPath test are more likely to have high viral loads at the time of sampling. The relevance of this to epidemiological reports of fast spread of the SARS-CoV-2 in regions of the UK is discussed.
ABSTRACT
Lateral flow devices are quickly being implemented for use in large scale population surveillance programs for SARS-CoV-2 infection in the United Kingdom. These programs have been piloted in city wide screening in the city of Liverpool, and are now being rolled out to support care home visits and the return home of University students for the Christmas break. Very little data exists comparing the performance of the UK lateral flow tests with gold standard PCR diagnostics, especially against comparable test populations such as the national Pillar 2 testing program in the United Kingdom. Here we utilise thousands of pillar 2 test data from our University of Birmingham test lab, and by extrapolation against the validate limit-of-detection of the lateral flow assay, provide a potential sensitivity for the test in a comparable low prevalence population captured in the pillar 2 program. Our data suggests the lateral flow assay should successfully capture around 85% of all PCR positive tests performed in our pillar 2 laboratory, and that a fully designed comparative study of lateral flow versus PCR testing is merited in a real life testing environment
Subject(s)
COVID-19ABSTRACT
SARS-CoV-2 has become a major problem across the globe, with approximately 50 million cases and more than 1 million deaths and currently no approved treatment or vaccine. Chronic obstructive pulmonary disease (COPD) is one of the underlying conditions in adults of any age that place them at risk for developing severe illness associated with COVID-19. We established an airway epithelium model to study SARS-CoV-2 infection in healthy and COPD lung cells. We found that both the entry receptor ACE2 and the co-factor transmembrane protease TMPRSS2 are expressed at higher levels on nonciliated goblet cell, a novel target for SARS-CoV-2 infection. We observed that SARS-CoV-2 infected goblet cells and induced syncytium formation and cell sloughing. We also found that SARS-CoV-2 replication was increased in the COPD airway epithelium likely due to COPD associated goblet cell hyperplasia. Our results reveal goblet cells play a critical role in SARS-CoV-2 infection in the lung.
Subject(s)
Pulmonary Disease, Chronic Obstructive , Carcinoid Tumor , COVID-19ABSTRACT
By late 2020, the coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 has caused tens of millions of infections and over 1 million deaths worldwide. A protective vaccine and more effective therapeutics are urgently needed. We evaluated a new PARP inhibitor, stenoparib, which was recently advanced to Stage II clinical trials for treatment of ovarian cancer. This is an initial report on the activity of stenoparib against human respiratory coronaviruses, including SARS-CoV-2, in vitro. Stenoparib exhibits dose-dependent suppression of SARS-CoV-2 multiplication and spread in Vero E6 monkey kidney and Calu-3 human lung adenocarcinoma cells. Stenoparib was also strongly inhibitory to multiplication of the HCoV-NL63 human seasonal respiratory coronavirus. Compared to remdesivir, which inhibits the viral replicon subsequent to cell entry, stenoparib is inhibitory to virus entry and post-entry processes as determined by time-of-addition (TOA) experiments. Moreover, a 10 M dosage of stenoparib, which is far below its 25.5 M half-maximally effective concentration (EC50), when combined with 0.5 M remdesivir suppressed coronavirus growth by 90.7%, indicating a potentially synergistic effect for this drug combination. Thus, stenoparib as a standalone or as a component of combinatorial therapy with remdesivir may be a valuable addition to the arsenal against COVID-19.
Subject(s)
Coronavirus Infections , COVID-19 , Ovarian NeoplasmsABSTRACT
Personal protective equipment (PPE) remains in short supply. Current decontamination methods are complex, slow, expensive and particularly ill-suited for low to middle income nations where the need is greatest. We propose a low temperature, ambient humidity decontamination method (WASP-D) based on the thirty minute or less half-life of Sars-CoV-2 (and other common pathogens) at temperatures above 45C, combined with the observation that most PPE are designed to be safely transported and stored at temperatures below 50C. Decontamination at 12 hours, 46C (115F) and ambient humidity should consistently reduce SARS-CoV-2 viral load by a factor of 10-6, without negatively affecting PPE materials or performance.
ABSTRACT
SARS-CoV-2 is the causative agent for the COVID-19 pandemic and there is an urgent need to understand the cellular response to SARS-CoV-2 infection. Beclin-1 is an essential scaffold autophagy protein that forms two distinct subcomplexes with modulators Atg14 and UVRAG, responsible for autophagosome formation and maturation, respectively. In the present study, we found that SARS-CoV-2 infection triggers an incomplete autophagy response, elevated autophagosome formation but impaired autophagosome maturation, and declined autophagy by genetic knockout of essential autophagic genes reduces SARS-CoV-2 replication efficiency. By screening 28 viral proteins of SARS-CoV-2, we demonstrated that expression of ORF3a alone is sufficient to induce incomplete autophagy. Mechanistically, SARS-CoV-2 ORF3a interacts with autophagy regulator UVRAG to facilitate Beclin-1-Vps34-Atg14 complex but selectively inhibit Beclin-1-Vps34-UVRAG complex. Interestingly, although SARS-CoV ORF3a shares 72.7% amino acid identity with the SARS-CoV-2 ORF3a, the former had no effect on cellular autophagy response. Thus, our findings provide the mechanistic evidence of possible takeover of host autophagy machinery by ORF3a to facilitate SARS-CoV-2 replication and raises the possibility of targeting the autophagic pathway for the treatment of COVID-19.
Subject(s)
COVID-19ABSTRACT
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for the virus replication and, thus, a potent drug target. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.