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<meta content="width=device-width, initial-scale=1.0, user-scalable=yes" name="viewport"/>
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<title>01 December, 2022</title>
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<title>Covid-19 Sentry</title><meta content="width=device-width, initial-scale=1.0" name="viewport"/><link href="styles/simple.css" rel="stylesheet"/><link href="../styles/simple.css" rel="stylesheet"/><link href="https://unpkg.com/aos@2.3.1/dist/aos.css" rel="stylesheet"/><script src="https://unpkg.com/aos@2.3.1/dist/aos.js"></script></head>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
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<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
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<ul>
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<li><a href="#from-preprints">From Preprints</a></li>
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<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
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<li><a href="#from-pubmed">From PubMed</a></li>
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<li><a href="#from-patent-search">From Patent Search</a></li>
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</ul>
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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>The imprinting effect of COVID-19 vaccines: an expected selection bias in observational studies</strong> -
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Findings of recent observational studies have been interpreted as supporting immune imprinting of COVID-19 vaccines. In this work, we clarify that the current discussion can be mapped to an attempt to estimate the direct effect of vaccine boosters on SARS-CoV-2 reinfections, and that such direct effect cannot be correctly estimated with observational data. We conclude that recent observational estimates regarding immune imprinting are fundamentally biased, and that the increased risk of reinfection in individuals vaccinated with a vaccine booster compared to no booster is expected even if the immune imprinting hypothesis is false. We use graphical methods (directed acyclic graphs), data simulations and analysis of real-life data to illustrate the mechanism and magnitude of this bias.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.11.30.22282923v1" target="_blank">The imprinting effect of COVID-19 vaccines: an expected selection bias in observational studies</a>
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</div></li>
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<li><strong>A Transformer-Based Model Trained on Large Scale Claims Data for Prediction of Severe COVID-19 Disease Progression</strong> -
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In situations like the COVID-19 pandemic, healthcare systems are under enormous pressure as they can rapidly collapse under the burden of the crisis. Machine learning (ML) based risk models could lift the burden by identifying patients with high risk of severe disease progression. Electronic Health Records (EHRs) provide crucial sources of information to develop these models because they rely on routinely collected healthcare data. However, EHR data is challenging for training ML models because it contains irregularly timestamped diagnosis, prescription, and procedure codes. For such data, transformer-based models are promising. We extended the previously published Med-BERT model by including age, sex, medications, quantitative clinical measures, and state information. After pre-training on approximately 988 million EHRs from 3.5 million patients, we developed models to predict Acute Respiratory Manifestations (ARM) risk using the medical history of 80,211 COVID-19 patients. Compared to XGBoost and Random Forests, our transformer-based models more accurately forecast the risk of developing ARM after COVID-19 infection. We used Integrated Gradients and Bayesian networks to understand the link between the essential features of our model. Finally, we evaluated adapting our model to Austrian in-patient data. Our study highlights the promise of predictive transformer-based models for precision medicine.
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</p>
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.11.29.22282632v1" target="_blank">A Transformer-Based Model Trained on Large Scale Claims Data for Prediction of Severe COVID-19 Disease Progression</a>
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<li><strong>Clinical, imaging, serological, and histopathological features of pulmonary post-acute sequelae after mild COVID-19 (PASC)</strong> -
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Background: A significant proportion of patients experience prolonged pulmonary, cardiocirculatory or neuropsychiatric symptoms after Coronavirus disease 2019 (COVID-19), termed post-acute sequelae of COVID (PASC). Lung manifestations of PASC include cough, dyspnea on exertion and persistent radiologic abnormalities and have been linked to viral persistence, ongoing inflammation and immune dysregulation. So far, there is limited data on lung histopathology and tissue-based immune cell subtyping in PASC. Methods: 51 unvaccinated patients (median age, 40 years; 43% female) with a median of 17 weeks (range, 2-55 weeks) after mild SARS-CoV-2 infection (without hospitalization) underwent full clinical evaluation including high-resolution computed tomography (HR-CT) and transbronchial biopsy. We used RT-PCR/FISH and immunohistochemistry (nucleocapsid/spike/CD3/CD4/CD8) for residual SARS-CoV-2 detection and T lymphocyte subtyping, respectively. We assessed interstitial fibrosis and macrophage profiles by transmission electron microscopy (TEM) and immunofluorescence multiplex staining, while cytokine profiling in broncho-alveolar lavage (BAL) fluid was performed by legendplex immunoassay. Results: Dyspnea on exertion was the leading symptom of pulmonary PASC in our cohort. In 16% and 42.9% of patients, FEV1 and MEF50 were ≤80% and 35.3% showed low attenuation volume (LAV) in >5% of lung area, in line with airflow obstruction. There was a significant correlation between oxygen pulse and time since COVID (p=0.009). Histopathologically, PASC manifested as organizing pneumonia (OP), fibrinous alveolitis and increased CD4+ T cell infiltrate predominantly around airways (bronchiolitis), while the residual virus components were detectable in only a single PASC patient (2%). T cell infiltrates around small airways were inversely correlated with time since COVID, however, this trend failed to reach statistical significance. We identified discrete interstitial fibrosis and a pro-fibrotic macrophage subtype (CD68/CD163/S100A9) as well as significantly elevated interleukin 1β in BAL fluid from PASC patients (p=0.01), but H-scores for fibrotic macrophage population did not correlate with severity of clinical symptoms or T cell infiltration. Interpretation: We show decreased FEV1/MEF50 and increased LAV in line with obstructive lung disease due to CD4+ T cell-predominant bronchiolitis as well as evidence of pro-fibrotic signaling in a subset of unvaccinated PASC patients. Since our results point towards self-limiting inflammation of small airways without detectable viral reservoirs, it remains unclear whether pulmonary symptoms in PASC are SARS-CoV-2-specific or represent a general response to viral infection. Still, evidence of pro-fibrotic signaling should warrant clincal follow-up and further research into possible long-time fibrotic remodeling in PASC patients.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.11.29.22282913v1" target="_blank">Clinical, imaging, serological, and histopathological features of pulmonary post-acute sequelae after mild COVID-19 (PASC)</a>
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<li><strong>SARS-CoV-2 Envelope-mediated Golgi pH dysregulation interferes with ERAAP retention in cells</strong> -
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Endoplasmic reticulum (ER) aminopeptidase associated with antigen processing (ERAAP) trims peptide precursors in the ER for presentation by major histocompatibility (MHC)-I molecules to surveying CD8+T-cells. This function allows ERAAP to regulate the nature and quality of the peptide repertoire and, accordingly, the resulting immune responses. We recently showed that infection with murine cytomegalovirus leads to a dramatic loss of ERAAP levels in infected cells. In mice, this loss is associated with the activation of QFL T-cells, a subset of T-cells that monitor ERAAP integrity and eliminate cells experiencing ERAAP dysfunction. In this study, we aimed to identify host factors that regulate ERAAP expression level and determine whether these could be manipulated during viral infections. We performed a CRISPR knockout screen and identified ERp44 as a factor promoting ERAAP retention in the ER. ERp44’s interaction with ERAAP is dependent on the pH gradient between the ER and Golgi. We hypothesized that viruses that disrupt the pH of the secretory pathway interfere with ERAAP retention. Here, we demonstrate that expression of the Envelope (E) protein from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) leads to Golgi pH neutralization and consequently decrease of ERAAP intracellular levels. Furthermore, SARS-CoV-2-induced ERAAP loss correlates with its release into the extracellular environment. ERAAP’s reliance on ERp44 and a functioning ER/Golgi pH gradient for proper localization and function led us to propose that ERAAP serves as a sensor of disturbances in the secretory pathway during infection and disease.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.11.29.518257v1" target="_blank">SARS-CoV-2 Envelope-mediated Golgi pH dysregulation interferes with ERAAP retention in cells</a>
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<li><strong>Targeted photodynamic neutralization of SARS-CoV-2 mediated by singlet oxygen</strong> -
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The SARS-CoV-2 virus has been on a rampage for more than two years. Vaccines in combination with neutralizing antibodies (NAbs) against SARS-CoV-2 carry great hope in the treatment and final elimination of COVID-19. However, the relentless emergence of variants of concern (VOC), including the most recent Omicron variants, presses for novel measures to counter these variants that often show immune evasion. Hereby we developed a targeted photodynamic approach to neutralize SARS-CoV-2 by engineering a genetically encoded photosensitizer (SOPP3) to a diverse list of antibodies targeting the WT spike protein, including human antibodies isolated from a 2003 SARS patient, potent monomeric and multimeric nanobodies targeting RBD, and non-neutralizing antibodies (non-NAbs) targeting the more conserved NTD region. As confirmed by pseudovirus neutralization assay, this targeted photodynamic approach significantly increased the efficacy of these antibodies, especially that of non-NAbs, against not only the WT but also the Delta strain and the heavily immune escape Omicron strain (BA.1). Subsequent measurement of infrared phosphorescence at 1270 nm confirmed the generation of singlet oxygen (1O2) in the photodynamic process. Mass spectroscopy assay uncovered amino acids in the spike protein targeted by 1O2. Impressively, Y145 and H146 form an oxidization hotspot, which overlaps with the antigenic supersite in NTD. Taken together, our study established a targeted photodynamic approach against the SARS-CoV-2 virus and provided mechanistic insights into the photodynamic modification of protein molecules mediated by 1O2.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.11.29.518438v1" target="_blank">Targeted photodynamic neutralization of SARS-CoV-2 mediated by singlet oxygen</a>
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<li><strong>Effect of COVID-19 during pregnancy: Studying the maternal and neonatal outcomes and assessing the placental changes related to SARS-CoV-2</strong> -
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Abstract: Background: Pregnant females affected with COVID-19 are reported to have poorer disease outcomes as compared to non-pregnant females of a similar age group. COVID-19 may lead to adverse changes in the placenta, which needs to be studied. Methods: This is a case series of 63 pregnant women hospitalized with COVID-19 from May 2020 to February 2021.The primary outcomes were maternal death or complications. Results: 63 women were studied. 83.3% of women were in the age group of 26 to 35 years. 33% women had associated comorbidities. 68.3% of women tested positive in their third trimester, 15.9% and 11% tested positive in their second and first trimesters respectively. 73% women had mild disease and 27% women required oxygen support. 3/63 women died. One woman in the second and two women in the third trimester died respectively. Histopathological examination in 13 placentae (of 19 placentae examined) were suggestive of maternal and fetal malperfusion. Conclusion: Pregnant COVID-19 women may develop disease-related as well as obstetric complications.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.11.29.22282903v1" target="_blank">Effect of COVID-19 during pregnancy: Studying the maternal and neonatal outcomes and assessing the placental changes related to SARS-CoV-2</a>
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<li><strong>Continuous Positive Airway Pressure (CPAP) in Covid 19 Acute Respiratory Distress Syndrome (ARDS): A Systematic Review</strong> -
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Introduction: Acute Respiratory Distress Syndrome (ARDS) is a feared consequence of Covid 19 Pneumonia. Traditional guidance was for ARDS to be treated with Intubation and Mechanical Ventilation (IMV), when failing simple oxygen. However globally numbers of patients with Covid 19 ARDS (CARDS) quickly overwhelmed IMV capacity, with Continuous Positive Airway Pressure (CPAP) has been used as a bridge or alternative to IMV. However, the evidence base remains limited in quality despite widespread adoption in guidelines. Methods: Pubmed (15.6.2022), Embase (30.7.2022) and Google Scholar (4.8.2022) were searched to identify studies with the primary outcome of IMV free survival in patients with CARDS receiving CPAP, ideally with simple oxygen as a comparator. Secondary outcomes were overall survival with CPAP, length of stay and adverse events. All studies were assessed by the relevant Critical Appraisal Skills Programme Tool (CASP). Results: 13 studies were identified, out of which only 1 was a Randomised Control Trial (RCT) with simple oxygen as a comparator. There were 11 Cohort studies and one Systematic review. Discussion: There is much heterogeneity in CPAP success rates (50 to 70%), which may be linked to variation in candidate selection, resource setting, application protocols and combined use with other respiratory support modalities (Non Invasive Ventilation: NIV, and High Flow Nasal Oxygen: HFNO). Adverse events and economic data such as length of stay are under reported. Conclusion: CPAP is an effective respiratory support in CARDS particularly in resource poor settings. However further research is needed to refine optimum candidate selection, application protocols and any added benefit from combination with NIV or HFNO. No funding was received for this study. This review was not registered.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.11.29.22282819v1" target="_blank">Continuous Positive Airway Pressure (CPAP) in Covid 19 Acute Respiratory Distress Syndrome (ARDS): A Systematic Review</a>
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<li><strong>Correlates of protection against SARS-CoV-2 Omicron variant and anti-spike antibody responses after a third/booster vaccination or breakthrough infection in the UK general population</strong> -
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Following primary SARS-CoV-2 vaccination, understanding the relative extent of protection against SARS-CoV-2 infection from boosters or from breakthrough infections (i.e. infection in the context of previous vaccination) has important implications for vaccine policy. In this study, we investigated correlates of protection against Omicron BA.4/5 infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults ≥18y from the United Kingdom general population. We found that higher anti-spike IgG antibody levels were associated with increased protection against Omicron BA.4/5 infection and that breakthrough infections were associated with higher levels of protection at any given antibody level than booster vaccinations. Breakthrough infections generated similar antibody levels to third/booster vaccinations, and the subsequent declines in antibody levels were similar to or slightly slower than those after third/booster vaccinations. Taken together our findings show that breakthrough infection provides longer lasting protection against further infections than booster vaccinations. For example, considering antibody levels associated with 67% protection against infection, a third/booster vaccination did not provide long-lasting protection, while a Delta/Omicron BA.1 breakthrough infection could provide 5-10 months of protection against Omicron BA.4/5 reinfection. 50-60% of the vaccinated UK population with a breakthrough infection would still be protected by the end of 2022, compared to <15% of the triple-vaccinated UK population without previous infection. Although there are societal impacts and risks to some individuals associated with ongoing transmission, breakthrough infection could be an efficient immune-boosting mechanism for subgroups of the population, including younger healthy adults, who have low risks of adverse consequences from infection.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.11.29.22282916v1" target="_blank">Correlates of protection against SARS-CoV-2 Omicron variant and anti-spike antibody responses after a third/booster vaccination or breakthrough infection in the UK general population</a>
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<li><strong>Mental Health, Substance Use, and the Importance of Religion during the COVID-19 Pandemic</strong> -
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COVID-19 impacted multiple facets of life, with implications on physical, mental, and societal health. Specifically, long COVID and related losses have exacerbated complex and prolonged grief responses and mental disorders including depression and anxiety. These mental health concerns are in turn associated with increased detrimental coping strategies including substance use disorders (SUD). The social and interpersonal implications of SUD are varied. Secondary data analyses from the National Survey on Drug Use and Health (NSDUH) collected during the COVID-19 pandemic revealed an increase in substance use behaviors and mental health problems. Self-reported religious activities had a positive meditating effect on reducing substance use behaviors. Accordingly, we explored the importance of one9s religion and faith in coping with stress, grief, and mental health challenges during the COVID-19 pandemic, highlighting the impact of religion and faith in bringing hope and purpose during periods of loss, grief, mental health challenges, and SUD.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.11.29.22282907v1" target="_blank">Mental Health, Substance Use, and the Importance of Religion during the COVID-19 Pandemic</a>
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<li><strong>An Optimized Circular Polymerase Extension Reaction-based Method for Functional Analysis of SARS-CoV-2</strong> -
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Reverse genetics systems have been crucial for studying specific viral genes and their relevance in the virus lifecycle, and become important tools for the rational attenuation of viruses and thereby for vaccine design. Recent rapid progress has been made in the establishment of reverse genetics systems for functional analysis of SARS-CoV-2, a coronavirus that causes the ongoing COVID-19 pandemic that has resulted in detrimental public health and economic burden. Among the different reverse genetics approaches, CPER (circular polymerase extension reaction) has become one of the leading methodologies to generate recombinant SARS-CoV-2 infectious clones due to its accuracy, efficiency, and flexibility. Here, we report an optimized CPER methodology which, through the use of a modified linker plasmid and by performing DNA nick ligation and direct transfection of permissive cells, overcomes certain intrinsic limitations of the “traditional” CPER approaches for SARS-CoV-2, allowing for efficient virus rescue. This optimized CPER system may facilitate research studies to assess the contribution of SARS-CoV-2 genes and individual motifs or residues to virus replication, pathogenesis and immune escape, and may also be adapted to other viruses.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.11.26.518005v1" target="_blank">An Optimized Circular Polymerase Extension Reaction-based Method for Functional Analysis of SARS-CoV-2</a>
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<li><strong>Proteomic profiling identifies biomarkers of COVID-19 severity</strong> -
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SARS-CoV-2 infection remains a major public health concern, particularly for the aged and those individuals with co-morbidities at risk for developing severe COVID-19. Understanding the pathogenesis and biomarkers associated with responses to SARS-CoV-2 infection remain critical components in developing effective therapeutic approaches, especially in cases of severe and long-COVID-19. In this study blood plasma protein expression was compared in subjects with mild, moderate, and severe COVID-19 disease. Evaluation of an inflammatory protein panel confirms upregulation of proteins including TNF{beta}, IL-6, IL-8, IL-12, already associated with severe cytokine storm and progression to severe COVID-19. Importantly, we identify several proteins not yet associated with COVID-19 disease, including mesothelin (MSLN), that are expressed at significantly higher levels in severe COVID-19 subjects. In addition, we find a subset of markers associated with T-cell and dendritic cell responses to viral infection that are significantly higher in mild cases and decrease in expression as severity of COVID-19 increases, suggesting that an immediate and effective activation of T-cells is critical in modulating disease progression. Together, our findings identify new targets for further investigation as therapeutic approaches for the treatment of SARS-CoV-2 infection and prevention of complications of severe COVID-19.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.11.29.518411v1" target="_blank">Proteomic profiling identifies biomarkers of COVID-19 severity</a>
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<li><strong>DAPTEV: Deep aptamer evolutionary modelling for COVID-19 drug design</strong> -
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Typical drug discovery and development processes are costly, time consuming and often biased by expert opinion. Aptamers are short, single-stranded oligonucleotides (RNA/DNA) that bind to target proteins and other types of biomolecules. Compared with small-molecule drugs, aptamers can bind to their targets with high affinity (binding strength) and specificity (uniquely interacting with the target only). The conventional development process for aptamers utilizes a manual process known as Systematic Evolution of Ligands by Exponential Enrichment (SELEX), which is costly, slow, dependent on library choice and often produces aptamers that are not optimized. To address these challenges, in this research, we create an intelligent approach, named DAPTEV, for generating and evolving aptamer sequences to support aptamer-based drug discovery and development. Using the COVID-19 spike protein as a target, our computational results suggest that DAPTEV is able to produce structurally complex aptamers with strong binding affinities.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.11.30.518473v1" target="_blank">DAPTEV: Deep aptamer evolutionary modelling for COVID-19 drug design</a>
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<li><strong>Epidemiological impact of a large number of incorrect negative SARS-CoV-2 test results in South West England during September and October 2021</strong> -
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Background In England, free testing for COVID-19 was widely available from early in the pandemic until 1 April 2022. Based on apparent differences in the rate of positive PCR tests at a single laboratory compared to the rest of the laboratory network, we hypothesised that a substantial number of UK PCR tests processed during September and October 2021 may have been incorrectly reported as negative, compared with the rest of the laboratory network. We investigate the epidemiological impact of this incident. Methods We estimate the additional number of COVID-19 cases that would have been reported had the sensitivity of the laboratory test procedure not dropped for the period 2 September to 12 October. In addition, by making comparisons between the most affected local areas and comparator populations, we estimate the number of additional infections, cases, hospitalisations and deaths that could have occurred as a result of increased transmission due to the misclassification of tests. Results We estimate that around 39,000 tests may have been incorrectly classified during this period and, as a direct result of this incident, the most affected areas in the South West could have experienced between 6,000 and 34,000 additional reportable cases, with a central estimate of around 24,000 additional reportable cases. Using modelled relationships between key variables, we estimate that this central estimate could have translated to approximately 55,000 additional infections, which means that each incorrect negative test likely led to just over two additional infections. In those same geographical areas, our results also suggest an increased number of admissions and deaths. Conclusion The incident is likely to have had a measurable impact on cases and infections in the affected areas in the South West of England.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.11.30.22282922v1" target="_blank">Epidemiological impact of a large number of incorrect negative SARS-CoV-2 test results in South West England during September and October 2021</a>
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<li><strong>Vaccine hesitancy, reactogenicity and immunogenicity of BNT162b2 and CoronaVac in pediatric patients with neuromuscular diseases</strong> -
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Introduction COVID-19 causes global health and psychosocial devastation, particularly to high-risk patients such as those with neuromuscular diseases (NMDs). The mRNA-based BNT162b2 and inactivated whole-virus CoronaVac are two novel COVID-19 vaccines widely used across the world that confer immune protection to healthy individuals. However, hesitancy towards COVID-19 vaccination was common for patients with NMDs early in the pandemic due to the paucity of data on the safety and efficacy in this specific patient population. Therefore, we examined the underlying factors associated with vaccine hesitancy across time for these patients and included the assessment of the reactogenicity and immunogenicity of these two vaccines. Methods Pediatric patients were screened from our NMD registry. For the vaccine hesitancy arm, those aged 8-18 years with no cognitive delay were invited to complete surveys in January and April 2022. For the reactogenicity and immunogenicity arm, patients aged 2-21 years were enrolled for COVID-19 vaccination between June 2021 to April 2022. Participants recorded adverse reactions (ARs) for 7 days after vaccination. Peripheral blood was obtained before BNT162b2 or CoronaVac and within 49 days after vaccination to measure their serological antibody responses as compared to healthy children and adolescents. Results Forty-one patients completed vaccine hesitancy surveys for both timepoints, and 22 joined our reactogenicity and immunogenicity arm of the study. Two or more family members vaccinated against COVID-19 was positively associated with intention of vaccination (odds ratio 11.7, 95% CI 1.81-75.1, p=0.010). Pain at the injection site, fatigue and myalgia were the commonest ARs. Most ARs were mild (75.5%, n=71/94). All 19 patients seroconverted against the wildtype SARS-CoV-2 after two doses of BNT162b2 or CoronaVac, although there was lower neutralization against the Omicron BA.1 variant. Discussion This study demonstrated vaccine hesitancy amongst patients with NMDs was influenced by family members and changed across time. BNT162b2 and CoronaVac were safe and immunogenic even for patients on low-dose corticosteroids. Future research is required to assess the durability of the COVID-19 vaccines, the effectiveness of booster doses and other routes of administration against emerging SARS-CoV-2 variants for these patients.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.11.29.22282857v1" target="_blank">Vaccine hesitancy, reactogenicity and immunogenicity of BNT162b2 and CoronaVac in pediatric patients with neuromuscular diseases</a>
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<li><strong>Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.</strong> -
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We and others have previously shown that the SARS-CoV-2 accessory protein ORF6 is a powerful antagonist of the interferon (IFN) signaling pathway by directly interacting with Nup98-Rae1 at the nuclear pore complex (NPC) and disrupting bidirectional nucleo-cytoplasmic trafficking. In this study, we further assessed the role of ORF6 during infection using recombinant SARS-CoV-2 viruses carrying either a deletion or a well characterized M58R loss-of-function mutation in ORF6. We show that ORF6 plays a key role in the antagonism of IFN signaling and in viral pathogenesis by interfering with karyopherin(importin)-mediated nuclear import during SARS-CoV-2 infection both in vitro, and in the Syrian golden hamster model in vivo. In addition, we found that ORF6-Nup98 interaction also contributes to inhibition of cellular mRNA export during SARS-CoV-2 infection. As a result, ORF6 expression significantly remodels the host cell proteome upon infection. Importantly, we also unravel a previously unrecognized function of ORF6 in the modulation of viral protein expression, which is independent of its function at the nuclear pore. Lastly, we characterized the ORF6 D61L mutation that recently emerged in Omicron BA.2 and BA.4 and demonstrated that it is able to disrupt ORF6 protein functions at the NPC and to impair SARS-CoV-2 innate immune evasion strategies. Importantly, the now more abundant Omicron BA.5 lacks this loss-of-function polymorphism in ORF6. Altogether, our findings not only further highlight the key role of ORF6 in the antagonism of the antiviral innate immune response, but also emphasize the importance of studying the role of non-spike mutations to better understand the mechanisms governing differential pathogenicity and immune evasion strategies of SARS-CoV-2 and its evolving variants.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.10.18.512708v2" target="_blank">Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.</a>
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<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>CareSuperb COVID-19 Antigen Test Usability</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Device: CareSuperb COVID-19 Antigen Home Test Kit<br/><b>Sponsor</b>: AccessBio, Inc.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Feasibility and Usability of COVID-19 Antigen RDTs in Uganda</strong> - <b>Condition</b>: COVID-19 Pandemic<br/><b>Interventions</b>: Diagnostic Test: PMC Sure Status COVID-19 Antigen Test; Diagnostic Test: Acon Flowflex COVID-19 Antigen Home Test<br/><b>Sponsor</b>: PATH<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>SUNRISE-3: Efficacy and Safety of Bemnifosbuvir in High-Risk Outpatients With COVID-19</strong> - <b>Conditions</b>: SARS CoV 2 Infection; COVID-19<br/><b>Interventions</b>: Drug: Bemnifosbuvir (BEM); Drug: Placebo<br/><b>Sponsor</b>: Atea Pharmaceuticals, Inc.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study to Learn About Bivalent COVID-19 RNA Vaccine Candidate(s) in Healthy Infants and Children</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: Bivalent BNT162b2 (original/Omicron BA.4/BA.5) 3 microgram dose; Biological: Bivalent BNT162b2 (original/Omicron BA.4/BA.5) 6 microgram dose; Biological: Bivalent BNT162b2 (original/Omicron BA.4/BA.5) 10 microgram dose; Biological: Bivalent BNT162b2 (original/Omicron BA.4/BA.5) 1 microgram dose<br/><b>Sponsors</b>: BioNTech SE; Pfizer<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Study of RAY1216 Tablets Compared With Placebo in Patients With Mild to Moderate COVID-19</strong> - <b>Condition</b>: Mild to Moderate COVID-19<br/><b>Interventions</b>: Drug: RAY1216; Drug: Placebo<br/><b>Sponsor</b>: Guangdong Raynovent Biotech Co., Ltd<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Evaluation of an Integrative Medicine Outpatient Clinical Setting for Post-COVID-19 Patients</strong> - <b>Conditions</b>: COVID-19; Fatigue<br/><b>Interventions</b>: Behavioral: outpatient clinic with multimodal integrative medicine and naturopathy for post-COVID-19 patients; Other: waiting group<br/><b>Sponsor</b>: Universität Duisburg-Essen<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Acute Rehabilitation in Patients With COVID-19 Pneumonia</strong> - <b>Conditions</b>: COVID-19; Rehabilitation; Physical Medicine<br/><b>Intervention</b>: Procedure: Acute rehabilitation program<br/><b>Sponsor</b>: Institut za Rehabilitaciju Sokobanjska Beograd<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Clinical Evaluation of the Panbio™ COVID-19/Flu A&B Rapid Panel Professional Use Product Using Mid-Turbinate Nasal Swabs</strong> - <b>Conditions</b>: COVID-19; Influenza A; Influenza Type B<br/><b>Intervention</b>: Diagnostic Test: Panbio™<br/><b>Sponsor</b>: Abbott Rapid Dx<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Efficacy of a Physical and Respiratory Rehabilitation Program for Patients With Persistent COVID-19 (SARS-CoV-2).</strong> - <b>Conditions</b>: SARS-CoV-2 Infection; COVID-19 Recurrent; Cognitive Dysfunction; Fatigue<br/><b>Intervention</b>: Other: COPERIA-REHAB<br/><b>Sponsors</b>: Fundacin Biomedica Galicia Sur; University of Vigo; Galician South Health Research Institute<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Message Communicating Latest Data on COVID Transmission in Patient’s Area</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Behavioral: COVID Booster text messages<br/><b>Sponsor</b>: University of Pennsylvania<br/><b>Enrolling by invitation</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>VNS for Long-COVID-19</strong> - <b>Conditions</b>: Post-COVID-19 Syndrome; Postural Tachycardia Syndrome; Dysautonomia<br/><b>Interventions</b>: Device: Non-invasive vagus nerve stimulation; Device: Sham Intervention<br/><b>Sponsor</b>: Icahn School of Medicine at Mount Sinai<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Differential Diagnosis of Persistent COVID-19 by Artificial Intelligence</strong> - <b>Conditions</b>: COVID-19; Fatigue; Distress Respiratory Syndrome; Cognitive Dysfunction; COVID-19 Recurrent; SARS CoV 2 Infection<br/><b>Intervention</b>: Other: Experimental tests<br/><b>Sponsors</b>: Fundacin Biomedica Galicia Sur; University of Vigo; Galician South Health Research Institute<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Dietary Modulation of Gut Microbiota in Overweight/Obese Adolescents and COVID-19 Infection</strong> - <b>Conditions</b>: Health Behavior; Child Development; Adolescent Obesity<br/><b>Interventions</b>: Dietary Supplement: Probiotics; Behavioral: Counselling on healthy eating, physical activity, and psychosocial stimulation; Dietary Supplement: Placebo probiotics<br/><b>Sponsors</b>: Indonesia University; Gadjah Mada University; Universitas Airlangga; University of Melbourne; The Indonesia Endowment Funds for Education, Ministry of Finance Indonesia<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>MT Combined With XKSA for Depressive Symptoms During COVID-19</strong> - <b>Condition</b>: Depression, Anxiety<br/><b>Interventions</b>: Other: MT Combined With XKSA; Other: MT<br/><b>Sponsor</b>: Renrong Wu<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Phonation Therapy to Improve Symptoms and Lung Physiology in Patients Referred for Pulmonary Rehabilitation</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Behavioral: Tonation Breathing Techniques; Behavioral: Music Driven Vocal Exercises; Behavioral: Silent Breathing<br/><b>Sponsor</b>: MetroHealth Medical Center<br/><b>Recruiting</b></p></li>
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</ul>
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<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Combining Computational and Experimental Evidence on the Activity of Antimalarial Drugs on Papain-Like Protease of SARS-CoV-2: A Repurposing Study</strong> - The development of inhibitors that target the papain-like protease (PLpro) has the potential to counteract the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent causing coronavirus disease 2019 (COVID-19). Based on a consideration of its several downstream effects, interfering with PLpro would both revert immune suppression exerted by the virus and inhibit viral replication. By following a repurposing strategy, the current study evaluates the potential of…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Paxlovid<sup>TM</sup> Information From FDA and Guidance for AES Members</strong> - This American Epilepsy Society (AES) official statement provides information and preliminary guidance to Society members related to the U.S. Food & Drug Administration (FDA) December 22, 2021 Emergency Use Authorization for Paxlovid™ for the oral treatment of mild to moderate COVID-19 in adults and children (≥12 years and weighing ≥40 kg). Paxlovid is likely to be widely prescribed, and important considerations for patients on antiseizure medications (ASMs) include key contraindications and…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Platelet in thrombo-inflammation: Unraveling new therapeutic targets</strong> - In the broad range of human diseases, thrombo-inflammation appears as a clinical manifestation. Clinically, it is well characterized in context of superficial thrombophlebitis that is recognized as thrombosis and inflammation of superficial veins. However, it is more hazardous when developed in the microvasculature of injured/inflamed/infected tissues and organs. Several diseases like sepsis and ischemia-reperfusion can cause formation of microvascular thrombosis subsequently leading to…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Recombinant proteins of spike protein of SARS-CoV-2 with the Omicron receptor-binding domain induce production of highly Omicron-specific neutralizing antibodies</strong> - Various vaccines have been developed to fight severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 pandemic. However, new variants of SARS-CoV-2 undermine the effort to fight SARS-CoV-2. Here, we produced S proteins harboring the receptor-binding domain (RBD) of the Omicron variant in plants. Plant-produced S proteins together with adjuvant CIA09A triggered strong immune responses in mice. Antibodies in serum inhibited interaction…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>B-cell lymphoma-2 family proteins-activated proteases as potential therapeutic targets for influenza A virus and severe acute respiratory syndrome coronavirus-2: Killing two birds with one stone?</strong> - The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a global health emergency. There are many similarities between SARS-CoV-2 and influenza A virus (IAV); both are single-stranded RNA viruses infecting airway epithelial cells and have similar modes of replication and transmission. Like IAVs, SARS-CoV-2 infections poses serious challenges due to the lack of effective therapeutic interventions, frequent appearances of new strains of the virus,…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Common and rare variant associations with clonal haematopoiesis phenotypes</strong> - Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes^(1-5). Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Essential oils block cellular entry of SARS-CoV-2 delta variant</strong> - Aiming to fill a gap in the literature, we aimed to identify the most promising EOs blocking in vitro cellular entry of SARS-CoV-2 delta variant without conferring human cytotoxicity and provide insights into the influence of their composition on these activities. Twelve EOs were characterized by gas chromatography coupled to mass spectrometry. The antiviral and cytotoxicity activities were determined using the cell-based pseudoviral entry with SARS-CoV-2 delta pseudovirus and the XTT assay in…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Comparison of RT-dPCR and RT-qPCR and the effects of freeze-thaw cycle and glycine release buffer for wastewater SARS-CoV-2 analysis</strong> - Public health efforts to control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic rely on accurate information on the spread of the disease in the community. Acute and surveillance testing has been primarily used to characterize the extent of the disease. However, obtaining a representative sample of the human population is challenging because of limited testing capacity and incomplete testing compliance. Wastewater-based epidemiology is an agnostic alternative to…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Meet changes with constancy: Defence, antagonism, recovery, and immunity roles of extracellular vesicles in confronting SARS-CoV-2</strong> - Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has wrought havoc on the world economy and people’s daily lives. The inability to comprehensively control COVID-19 is due to the difficulty of early and timely diagnosis, the lack of effective therapeutic drugs, and the limited effectiveness of vaccines. The body contains billions of extracellular vesicles (EVs), which have shown remarkable potential in disease diagnosis, drug…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Protocol for a 30-day randomised, parallel-group, non-inferiority, controlled trial investigating the effects of discontinuing renin-angiotensin system inhibitors in patients with and without COVID-19: the RASCOVID-19 trial</strong> - INTRODUCTION: The COVID-19 pandemic caused by the virus SARS-CoV has spread rapidly and caused damage worldwide. Data suggest a major overrepresentation of hypertension and diabetes among patients experiencing severe courses of COVID-19 including COVID-19-related deaths. Many of these patients receive renin-angiotensin system (RAS) inhibiting therapy, and evidence suggests that treatment with angiotensin II receptor blockers (ARBs) could attenuate SARS-CoV-induced acute respiratory distress…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Plantaricin NC8 αβ rapidly and efficiently inhibits flaviviruses and SARS-CoV-2 by disrupting their envelopes</strong> - Potent broad-spectrum antiviral agents are urgently needed to combat existing and emerging viral infections. This is particularly important considering that vaccine development is a costly and time consuming process and that viruses constantly mutate and render the vaccine ineffective. Antimicrobial peptides (AMP), such as bacteriocins, are attractive candidates as antiviral agents against enveloped viruses. One of these bacteriocins is PLNC8 αβ, which consists of amphipathic peptides with…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Characterizing the ligand-binding affinity toward SARS-CoV-2 Mpro <em>via</em> physics- and knowledge-based approaches</strong> - Computational approaches, including physics- and knowledge-based methods, have commonly been used to determine the ligand-binding affinity toward SARS-CoV-2 main protease (Mpro or 3CLpro). Strong binding ligands can thus be suggested as potential inhibitors for blocking the biological activity of the protease. In this context, this paper aims to provide a short review of computational approaches that have recently been applied in the search for inhibitor candidates of Mpro. In particular,…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Neuromasts and Olfactory Organs of Zebrafish Larvae Represent Possible Sites of SARS-CoV-2 Pseudovirus Host Cell Entry</strong> - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the acute respiratory disease coronavirus disease 2019 (COVID-19), which has resulted in millions of deaths globally. Here, we explored the mechanism of host cell entry of a luciferase-ZsGreen spike (SARS-CoV-2)-pseudotyped lentivirus using zebrafish embryos/larvae as an in vivo model. Successful pseudovirus entry was demonstrated via the expression of the luciferase (luc) gene, which was validated by reverse…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A multi-reference poly-conformational method for <em>in silico</em> design, optimization, and repositioning of pharmaceutical compounds illustrated for selected SARS-CoV-2 ligands</strong> - BACKGROUND: This work presents a novel computational multi-reference poly-conformational algorithm for design, optimization, and repositioning of pharmaceutical compounds.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong><em>In silico</em> analysis of the antidepressant fluoxetine and similar drugs as inhibitors of the human protein acid sphingomyelinase: a related SARS-CoV-2 inhibition pathway</strong> - Acid Sphingomyelinase (ASM) is a human phosphodiesterase that catalyzes the metabolism of sphingomyelin (SM) to ceramide and phosphocholine. ASM is involved in the plasma membrane cell repair and is associated with the lysosomal inner lipid membrane by nonbonding interactions. The disruption of those interaction would result in ASM release into the lysosomal lumen and consequent degradation of its structure. Furthermore, SARS-CoV-2 infection has been linked with ASM activation and with a…</p></li>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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