Covid-19 Sentry

Contents

• From Preprints
• From Clinical Trials
• From PubMed
• From Patent Search

From Preprints

• Robust immunogenicity of a third BNT162b2 vaccination against SARS-CoV-2 Omicron variant in a naive New Zealand cohort -

  The ability of a third dose of the Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine to stimulate immune responses against subvariants, including Omicron BA.1, has not been assessed in New Zealand populations. Unlike many overseas populations, New Zealanders were largely infection naive at the time they were boosted. This adult cohort of 298 participants, oversampled for at-risk populations, was composed of 29% Māori and 28% Pacific peoples, with 40% of the population aged 55+. A significant proportion of the cohort was obese and presented with at least one comorbidity. Sera were collected 28 days and 6 months post second vaccination and 28 days post third vaccination. SARS-CoV-2 anti-S IgG titres and neutralising capacity using surrogate viral neutralisation assays against variants of concern, including Omicron BA.1, were investigated. The incidence of SARS-CoV-2 infection, within our cohort, prior to third vaccination was very low (<6%). This study found a third vaccine significantly increased the mean SARS-CoV-2 anti-S IgG titres, for every demographic subgroup, by a minimum of 1.5-fold compared to titres after two doses. Diabetic participants experienced a greater increase (~4-fold) in antibody titres after their third vaccination, compared to non-diabetics (increase of ~2-fold). This corrected for the deficiency in antibody titres within diabetic participants which was observed following two doses. A third dose also induced a neutralising response against Omicron variant BA.1, which was absent after two doses. This neutralising response improved regardless of age, BMI, ethnicity, or diabetes status. Participants aged >75 years consistently had the lowest SARS-CoV-2 anti-S IgG titres at each timepoint, however experienced the greatest improvement after three doses compared to younger participants. This study shows that in the absence of prior SARS-CoV-2 infection, a third Pfizer-BioNTech BNT162b2 vaccine enhances immunogenicity, including against Omicron BA.1, in a cohort representative of at-risk groups in the adult New Zealand population.

  🖺 Full Text HTML: Robust immunogenicity of a third BNT162b2 vaccination against SARS-CoV-2 Omicron variant in a naive New Zealand cohort
• Blood biomarkers-defined subgroups show heterogeneity in post-acute COVID-19 syndrome: a rationale for precision medicine. -

  Acute COVID-19 can cause a post-infectious syndrome in a significant percentage of patients, with multifacted and long lasting symptoms. We hypothesized that this Post-Acute COVID syndrome (PASC) could result from various underlying causes, which may compromise the demonstration of efficacy for treatments evaluated on cohorts of heterogeneous patients. To assess the feasibility of stratifying or characterizing subgroups of post-COVID-19 patients consistent with different indications in a precision medicine perspective, we tested serum biomarkers in a pilot cross-sectional study of patients with neuro-cognitive symptoms from the Northwestern University post-COVID-19 clinic (Chicago,USA). Patient health status was evaluated with the use of standardized PROMIS questionnaires and underwent validated cognitive tests with the NIH Toolbox. Serum biomarkers were chosen as proteins known to be involved in the pathogenic features of a neuro-inflammatory disease, i.e., multiple sclerosis, with a final selection of the most discriminant ones. A multi-isotypes serology against SARS-CoV-2 spike and nucleocapsid antigens was performed to allow detailed analyses of the humoral immune status. Despite the limited numbers of this feasibility study, results showed that clinical data could not differentiate PASC patients with persisting neuro-cognitive impairment, while three major PASC subgroups were identified with serum biomarkers according to the presence or absence of the HERV-W ENV soluble protein combined with neurofilaments light chains and, to a lesser extent, with elevated levels of IL-6. SARS-CoV-2 serological results in PASC compared to healthy controls also revealed a significant increase of anti-Spike and/or Nucleocapsid IgM, IgA and, unexpectedly, IgE. For IgG, a significant difference was observed with Nucleocapsid only since anti-Spike IgG titers were normally elevated in vaccinated controls. This multi-Ig isotypes serology may provide additional information on the infectious and immunological status of individual patients and should be considered in face of a potential viral persistence in some individuals. Altogether the results show the feasibility of using serum biomarkers to discriminate relevant subgroups or individual patients for precision medicine indications in post-COVID syndromes. This pilot study paves the way to further exploring biological assays for the definition of subtypes of PASC, also called long COVID, useful for the choice of relevant therapeutic strategies.

  🖺 Full Text HTML: Blood biomarkers-defined subgroups show heterogeneity in post-acute COVID-19 syndrome: a rationale for precision medicine.
• Covid-19 and post-acute sick leave: a hybrid register and questionnaire study in the adult Danish population -

  Long covid follows 10-20% of first-time SARS-CoV-2 infections, but the societal burden of long covid and risk factors for the condition are not well-understood. Here, we report findings about self-reported sick leave and risk factors thereof from a hybrid survey and register study, which included 37,482 RT-PCR confirmed SARS-CoV-2 cases and 51,336 test-negative controls who were tested during the index and alpha waves. An additional 33 individuals per 1000 took substantial sick leave following acute infection compared to persons with no known history of infection, where substantial sick leave was defined as >1 month of sick leave within the period 1-9 months after the RT-PCR test date. Being female, ≥50 years, and having certain pre-existing conditions such as fibromyalgia increased risks for taking substantial sick leave. Further research exploring this heterogeneity is urgently needed and may provide important evidence for more targeted preventative strategies.

  🖺 Full Text HTML: Covid-19 and post-acute sick leave: a hybrid register and questionnaire study in the adult Danish population
• miRNA binding pressure channels evolution of SARS-CoV-2 genomes -
  In somatic cells, microRNAs (miRNAs) bind to the genomes of RNA viruses and influence their translation and replication. Here we demonstrate that a significant number of miRNA binding sites locate in the NSP4 region of the SARS-CoV-2 genome, and the intestinal human miRNAs exert evolutionary pressure on this region. Notably, in infected cells, NSP4 promotes the formation of double-membrane vesicles, which serve as the scaffolds for replication-transcriptional complexes and protect viral RNA from intracellular destruction. In three years of selection, the loss of many miRNA binding sites, in particular, those within the NSP4, has shaped the SARS-CoV-2 genomes to promote the descendants of the BA.2 variants as the dominant strains and define current momentum of the pandemics.
  🖺 Full Text HTML: miRNA binding pressure channels evolution of SARS-CoV-2 genomes
• Mechanistic investigation of SARS-CoV-2 Omicron variant spike mutants via full quantum mechanical modeling -
  Ab initio quantum mechanical models can characterize and predict intermolecular binding, but only recently have models including more than a few hundred atoms gained traction. Here, we simulate ~13,000 atoms to predict and characterize binding of SARS-CoV-2 spike variants to the human receptor ACE2 (hACE2). We compare four spike variants in our analysis: Wuhan, Omicron, and two Omicron-based variants. To assess binding, we mechanistically characterize the energetic contribution of each amino acid involved, and predict the effect of select single point mutations. We validate our computational predictions experimentally by comparing binding efficacy of spike variants to cells expressing hACE2. We argue that this computational model, QM-CR, can identify mutations critical for intermolecular interactions and inform the engineering of high-specificity interactors.
  🖺 Full Text HTML: Mechanistic investigation of SARS-CoV-2 Omicron variant spike mutants via full quantum mechanical modeling
• Trends in serotype distribution and disease severity in adults hospitalised with Streptococcus pneumoniae infection in Bristol and Bath: a retrospective cohort study, 2006-2022 -

  Background Paediatric pneumococcal conjugate vaccination (PCV) has reduced adult PCV-serotype disease: PCV7 has greater indirect effects than PCV13. Ongoing surveillance is required to evaluate current vaccine usage and inform future vaccine deployment, particularly with respiratory infection epidemiology changing following SARS-CoV-2 emergence. Methods and Findings A retrospective cohort study, all adults >16 years admitted to three UK hospitals, 2006-2022, with pneumococcal disease. Medical records were reviewed for each clinical episode and serotype data were obtained from the UK Health Security Agency national reference laboratory. We identified 1,501 (40.3%) cases of invasive pneumococcal disease (IPD) with known serotype, 134 (3.6%) IPD cases without serotype data, and 2,084 (56.0%) non-IPD cases, which are typically missed in national surveillance. Disease incidence increased progressively from 2006-2020, followed by a sudden decline after COVID-19 emergence and then a gradual increase to pre-pandemic levels. Paediatric PCV7 introduction reduced adult PCV7 serotype IPD from 29.4% [24.1-35.4] of IPD in 2006-09 to 7.0% [3.7-12.7] in 2021-22. PCV13 introduction also decreased adult vaccine serotype IPD, but considerable residual adult disease remains, causing 34.3% [28.6-40.4] of IPD in 2006-09 and 21.7% [15.5-29.6] 9 in 2021-22, respectively. Serotype replacement diminished the benefits of PCV introduction: PCV20-13 and non-PCV serotypes represented 27.0% [21.9-32.9] and 9.3% [6.3-13.5] of disease in 2006-2009, and 39.5% [31.5-48.2] and 31.8% [24.4-40.2] in 2021-2022, respectively. Serotype shifts have resulted in increasing disease caused by serotype 3 and 8, and the re-emergence of serotype 19F and 19A. These serotype shifts occurred as clinical disease severity changed, and whilst the COVID-19 pandemic disrupted disease severity trends, these have now largely reverted to previous trajectories. Patient age trended upwards and although CURB65 severity decreased there were increased ICU admission rates. Overall, inpatient mortality decreased and hospitalisation duration remained stable. Conclusions After 17 years of PCV use, residual pneumococcal disease due to the vaccine serotypes among hospitalised adults remains. The sharp decline in pneumococcal disease during the COVID-19 pandemic has now reversed, with increasing cases due to vaccine serotypes, especially serotype 3. Around 68.2% of cases in 2022 were potentially covered by the recently licensed 20-valent PCV.

  🖺 Full Text HTML: Trends in serotype distribution and disease severity in adults hospitalised with Streptococcus pneumoniae infection in Bristol and Bath: a retrospective cohort study, 2006-2022
• The Unexpected Protective Role of Thrombosis in Sepsis-Induced Inflammatory Lung Injury Via Endothelial Alox15 -

  Background. Patients with sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) commonly suffer from severe pulmonary thrombosis, but clinical trials of anti-coagulant therapies in sepsis and ARDS patients have failed. ARDS patients with thrombocytopenia also exhibit increased mortality, and widespread pulmonary thrombosis is often seen in coronavirus disease 2019 (COVID-19) ARDS patients. Methods. Employing different amounts of microbeads to induce various levels of pulmonary thrombosis. Acute lung injury was induced by either lipopolysaccharide i.p. or cecal ligation and puncture. Endothelial cell (EC)-targeted nanoparticle coupled with CDH5 promoter was employed to delivery plasmid DNA expressing the CRISPR/Cas9 system for EC-specific gene knockout or expressing Alox15 for EC-specific overexpression. Additionally, thrombocytopenia was induced by genetic depletion of platelets using DTRPf4Cre mice by breeding Pf4Cre mice into the genetic background of DTR mice. Results. We show that while severe pulmonary thrombosis or thrombocytopenia augments sepsis-induced ALI, the induction of mild pulmonary thrombosis conversely reduces endothelial cell (EC) apoptosis, ALI, and mortality via sustained expression of endothelial arachidonate 15-lipoxygenase (Alox15). Endothelial Alox15 knockout via EC-targeted nanoparticle delivery of CRISPR/Cas9 plasmid DNA in adult mice abolished the protective impact of mild lung thrombosis. Conversely, overexpression of endothelial Alox15 inhibited the increases in ALI caused by severe pulmonary thrombosis. The clinical relevance of the findings was validated by the observation of reduced ALOX15-expressing ECs in lung autopsy samples of ARDS patients. Additionally, restoration of pulmonary thrombosis in thrombocytopenic mice also normalized endotoxemia-induced ALI. Conclusion. We have demonstrated that moderate levels of thrombosis protect against sepsis-induced inflammatory lung injury via endothelial Alox15. Overexpression of Alox5 inhibits severe pulmonary thrombosis-induced increase of ALI. Thus, activation of ALOX15 signaling represents a promising therapeutic strategy for treatment of ARDS, especially in sub-populations of patients with thrombocytopenia and/or severe pulmonary thrombosis.

  🖺 Full Text HTML: The Unexpected Protective Role of Thrombosis in Sepsis-Induced Inflammatory Lung Injury Via Endothelial Alox15
• Disparities in Mortality Associated with Acute Myocardial Infarction and COVID-19 in the United States: A Nationwide Analysis -

  Background: The impact of the COVID-19 pandemic on potential racial disparities in acute myocardial infarction (AMI) management and outcomes is unclear. We examined AMI patient management and outcomes during the pandemic9s initial nine months, comparing COVID-19 and non-COVID-19 cases. Methods: We identified all patients hospitalized for AMI in 2020 using the National Inpatient Sample (NIS), identifying those with or without concurrent COVID-19. Logistic and linear regression was used for analyses of associations, with adjustment for potential confounders. Results: Patients with both AMI and COVID-19 had higher in-hospital mortality rates (aOR 3.19, 95% CI 2.63-3.88), mechanical ventilation (aOR 1.90, 95% CI 1.54-2.33), and hemodialysis (aOR 1.38, 95% CI 1.05-1.89) compared to those without COVID-19. Black and Asian/Pacific Islander patients had higher in-hospital mortality than White patients, (aOR 2.13, 95% CI 1.35-3.59) and (aOR 3.41, 95% CI 1.5-8.37). Moreover, Black, Hispanic, and Asian/Pacific Islander patients had higher odds of initiating hemodialysis, (aOR 5.48, 95% CI 2.13-14.1), (aOR 2.99, 95% CI 1.13-7.97), and (aOR 7.84, 95% CI 1.55-39.5) and were less likely to receive PCI for AMI, (aOR 0.71, 95% CI 0.67-0.74), (aOR 0.81, 95% CI 0.77-0.86), and (aOR 0.82, 95% CI 0.75-0.90). Additionally, Black patients had a lower likelihood of undergoing CABG surgery for AMI (aOR 0.55, 95% CI 0.49-0.61). Conclusion: Our study revealed increased mortality and complications in COVID-19 patients with AMI, highlighting significant racial disparities. Urgent measures addressing healthcare disparities, such as enhancing access and promoting culturally sensitive care, are needed to improve health equity.

  🖺 Full Text HTML: Disparities in Mortality Associated with Acute Myocardial Infarction and COVID-19 in the United States: A Nationwide Analysis
• The Breadth of the Neutralizing Antibody Response to Original SARS-CoV-2 Infection is Linked to the Presence of Long COVID Symptoms -

  Background: The associations between longitudinal dynamics and the breadth of SARS-CoV-2 neutralizing antibody response with various Long COVID (LC) phenotypes prior to vaccination are not known. The capacity of antibodies to cross neutralize a variety of viral variants may be associated with ongoing pathology and persistent symptoms. Methods: We measured longitudinal neutralizing and cross-neutralizing antibody responses to pre- and post-SARS-CoV-2 Omicron variants in participants infected during the early waves of the COVID-19 pandemic, prior to wide-spread rollout of SARS-CoV-2 vaccines. Cross sectional regression models adjusted for various clinical covariates and longitudinal mixed effects models were used to determine the impact of the breadth and rate of decay of neutralizing responses on the development of Long COVID symptoms in general, as well as LC phenotypes. Results: We identified several novel relationships between SARS-CoV-2 antibody neutralization and the presence of LC symptoms. Specifically, we show that, although neutralizing antibody responses to the original, infecting strain of SARS-CoV-2 were not associated with LC in cross-sectional analyses, cross-neutralization ID50 levels to the Omicron BA.5 variant approximately 4 months following acute infection was independently and significantly associated with greater odds of LC and with persistent gastrointestinal and neurological symptoms. Longitudinal modeling demonstrated significant associations in the overall levels and rates of decay of neutralization capacity with LC phenotypes. A higher proportion of participants had antibodies capable of neutralizing Omicron BA.5 compared with BA.1 or XBB.1.5 variants. Conclusions: Our findings suggest that relationships between various immune responses and LC are likely complex but may involve the breadth of antibody neutralization responses.

  🖺 Full Text HTML: The Breadth of the Neutralizing Antibody Response to Original SARS-CoV-2 Infection is Linked to the Presence of Long COVID Symptoms
• S:D614G and S:H655Y are gateway mutations that act epistatically to promote SARS-CoV-2 variant fitness -
  SARS-CoV-2 variants bearing complex combinations of mutations have been associated with increased transmissibility, COVID-19 severity, and immune escape. S:D614G may have facilitated emergence of such variants since they appeared after S:D614G had gone to fixation. To test this hypothesis, Spike sequences from an immunocompromised individual with prolonged infection, and from the major SARS-CoV-2 variants of concern, were reverted to the ancestral S:D614. In all cases, infectivity of the revertants was compromised. Rare SARS-CoV-2 lineages that lack S:D614G were identified and the infectivity of these was dependent upon S:Q613H or S:H655Y. Notably, Gamma and Omicron variants possess both S:D614G and S:H655Y, each of which contributed to infectivity of these variants. All three mutations, S:Q613H, S:D614G, and S:H655Y, stabilized Spike on virions, consistent with selection of these mutations by a common molecular mechanism. Among sarbecoviruses, S:Q613H, S:D614G, and S:H655Y are only detected in SARS-CoV-2, which uniquely possesses a polybasic S1/S2 cleavage site. Results of genetic and biochemical experiments here demonstrated that S:D614G and S:H655Y are likely adaptations to the cleavage site. CryoEM revealed that both mutations shift the Spike receptor binding domain towards the open conformation required for ACE2-binding and Spikes bearing either S:D614G or S:H655Y spontaneously mimic the smFRET signal that ACE2 induces in the parental molecule. Data from these orthogonal experiments demonstrate that S:D614G and S:H655Y are convergent adaptations to the polybasic S1/S2 cleavage site, which stabilize S1 on the virion in the open RBD conformation that is on-pathway for target cell fusion, and thereby act epistatically to promote the fitness of variants bearing complex combinations of clinically significant mutations.
  🖺 Full Text HTML: S:D614G and S:H655Y are gateway mutations that act epistatically to promote SARS-CoV-2 variant fitness
• Determinants of species-specific utilization of ACE2 by human and animal coronaviruses -
  Utilization of human ACE2 allowed several bat coronaviruses (CoVs), including the causative agent of COVID-19, to infect humans either directly or via intermediate hosts. Here, we analyzed the ability of Spike proteins from 24 human or animal CoVs to use ACE2 receptors across nine reservoir, potential intermediate and human hosts. We show that overall SARS-CoV-2 Omicron variants evolved more efficient ACE2 usage but mutation of R493Q in BA.5 Spike disrupts utilization of ACE2 from Greater horseshoe bats. Spikes from most CoVs showed species-specific differences in ACE2 usage, partly due to variations in ACE2 residues 31, 41 or 354. Mutation of T403R allowed the RaTG13 bat CoV Spike to use all ACE2 orthologs analysed for viral entry. Sera from COVID-19 vaccinated individuals neutralized the Spike proteins of a range of bat Sarbecoviruses. Our results define determinants of ACE2 receptor usage of diverse CoVs and suggest that COVID-19 vaccination may protect against future zoonoses of SARS-CoV-related bat viruses.
  🖺 Full Text HTML: Determinants of species-specific utilization of ACE2 by human and animal coronaviruses
• Spatiotemporally organized immunomodulatory response to SARS-CoV-2 virus in primary human broncho-alveolar epithelia -
  The COVID-19 pandemic continues to be a health crisis with major unmet medical needs. The early responses from airway epithelial cells, the first target of the virus regulating the progression towards severe disease, are not fully understood. Primary human air-liquid interface cultures representing the broncho-alveolar epithelia were used to study the kinetics and dynamics of SARS-CoV-2 variants infection. The infection measured by nucleoprotein expression, was a late event appearing between day 4-6 post infection for Wuhan-like virus. Other variants demonstrated increasingly accelerated timelines of infection. All variants triggered similar transcriptional signatures, an early inflammatory/immune signature preceding a late type I/III IFN, but differences in the quality and kinetics were found, consistent with the timing of nucleoprotein expression. Response to virus was spatially organized: CSF3 expression in basal cells and CCL20 in apical cells. Thus, SARS-CoV-2 virus triggers specific responses modulated over time to engage different arms of immune response.
  🖺 Full Text HTML: Spatiotemporally organized immunomodulatory response to SARS-CoV-2 virus in primary human broncho-alveolar epithelia
• Explicit Modelling of Antibody Levels for Infectious Disease Simulations in the Context of SARS-CoV-2 -
  Measurable levels of immunoglobulin G antibodies develop after infections with and vaccinations against SARS-CoV-2. These antibodies are temporarily dynamic; due to waning, antibody levels will drop below detection thresholds over time. As a result, epidemiological studies could underestimate population protection, given that antibodies are a marker for protective immunity. During the COVID-19 pandemic, multiple models predicting infection dynamics were used by policymakers to plan public health policies. Explicitly integrating antibody and waning effects into the models is crucial for reliable calculations of individual infection risk. However, only few approaches have been suggested that explicitly treat these effects. This paper presents a methodology that explicitly models antibody levels and the resulting protection against infection for individuals within an agent-based model. This approach can be integrated in general frameworks, allowing complex population studies with explicit antibody and waning effects. We demonstrate the usefulness of our model in two use cases.
  🖺 Full Text HTML: Explicit Modelling of Antibody Levels for Infectious Disease Simulations in the Context of SARS-CoV-2
• Risk averse reproduction numbers improve resurgence detection -

  The effective reproduction number R is a prominent statistic for inferring the transmissibility of infectious diseases and effectiveness of interventions. R purportedly provides an easy-to-interpret threshold for deducing whether an epidemic will grow (R>1) or decline (R<1). We posit that this interpretation can be misleading and statistically overconfident when applied to infections accumulated from groups featuring heterogeneous dynamics. These groups may be delineated by geography, infectiousness or sociodemographic factors. In these settings, R implicitly weights the dynamics of the groups by their number of circulating infections. We find that this weighting can cause delayed detection of outbreak resurgence and premature signalling of epidemic control because it underrepresents the risks from highly transmissible groups. Applying E-optimal experimental design theory, we develop a weighting algorithm to minimise these issues, yielding the risk averse reproduction number E. Using simulations, analytic approaches and real-world COVID-19 data stratified at the city and district level, we show that E meaningfully summarises transmission dynamics across groups, balancing bias from the averaging underlying R with variance from directly using local group estimates. An E>1generates timely resurgence signals (upweighting risky groups), while an E<1ensures local outbreaks are under control. We propose E as an alternative to R for informing policy and assessing transmissibility at large scales (e.g., state-wide or nationally), where R is commonly computed but well-mixed or homogeneity assumptions break down.

  🖺 Full Text HTML: Risk averse reproduction numbers improve resurgence detection
• What is stopping us to get vaccinated? The role of optimism-pessimism, information sources, trust, conspiracy theories, and fear in the willingness to get vaccinated -
  The aim of this study was to check the role of optimism-pessimism, information sources, trust in information sources, and conspiracy theories regarding COVID-19 vaccines in the willingness to get vaccinated. The convenience sample was used (N = 2291) from Serbia. Instruments were used in this study: The Life Orientation Test-Revised; information sources and trust in information sources; fears regarding COVID-19; items on conspiracy theories on COVID-19 vaccines, and items measuring willingness to get vaccinated. SEM confirms the role of optimism-pessimism in COVID-19-related feelings, the relation between trust in information sources and the information gathered from them, the role of information in the fear for oneself and close to others, the negative role of conspiracy and the positive role of fear in vaccination intention.
  🖺 Full Text HTML: What is stopping us to get vaccinated? The role of optimism-pessimism, information sources, trust, conspiracy theories, and fear in the willingness to get vaccinated

From Clinical Trials

• Evaluation of Safety & Efficacy of MIR 19 ® Inhalation Solution in Patients With Mild COVID-19 - Condition:   COVID-19
  Interventions:   Drug: MIR 19 ®;   Combination Product: Standard therapy
  Sponsor:   National Research Center - Institute of Immunology Federal Medical-Biological Agency of Russia
  Completed

• LACTYFERRIN™ Forte and ZINC Defense™ and Standard of Care (SOC) vs SOC in the Treatment of Non-hospitalized Patients With COVID-19 - Condition:   COVID-19
  Interventions:   Drug: Sesderma LACTYFERRIN™ Forte and Sesderma ZINC Defense™;   Drug: Placebo
  Sponsors:   Jose David Suarez, MD;   Sesderma S.L.;   Westchester General Hospital Inc. DBA Keralty Hospital Miami;   MGM Technology Corp
  Not yet recruiting

• MP0420 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial) - Condition:   COVID-19
  Interventions:   Drug: MP0420;   Drug: Placebo;   Biological: Remdesivir
  Sponsors:   National Institute of Allergy and Infectious Diseases (NIAID);   International Network for Strategic Initiatives in Global HIV Trials (INSIGHT);   University of Copenhagen;   Medical Research Council;   Kirby Institute;   Washington D.C. Veterans Affairs Medical Center;   AIDS Clinical Trials Group;   National Heart, Lung, and Blood Institute (NHLBI);   US Department of Veterans Affairs;   Prevention and Early Treatment of Acute Lung Injury (PETAL);   Cardiothoracic Surgical Trials Network (CTSN);   Molecular Partners AG;   University of Minnesota
  Active, not recruiting

• AZD7442 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial) - Condition:   COVID-19
  Interventions:   Biological: AZD7442;   Biological: Placebo;   Biological: Remdesivir
  Sponsors:   National Institute of Allergy and Infectious Diseases (NIAID);   International Network for Strategic Initiatives in Global HIV Trials (INSIGHT);   University of Copenhagen;   Medical Research Council;   Kirby Institute;   Washington D.C. Veterans Affairs Medical Center;   AIDS Clinical Trials Group;   National Heart, Lung, and Blood Institute (NHLBI);   US Department of Veterans Affairs;   Prevention and Early Treatment of Acute Lung Injury (PETAL);   Cardiothoracic Surgical Trials Network (CTSN);   AstraZeneca;   University of Minnesota
  Active, not recruiting

• VIR-7831 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial) - Condition:   COVID-19
  Interventions:   Biological: VIR-7831;   Biological: Placebo;   Biological: Remdesivir
  Sponsors:   National Institute of Allergy and Infectious Diseases (NIAID);   International Network for Strategic Initiatives in Global HIV Trials (INSIGHT);   University of Copenhagen;   Medical Research Council;   Kirby Institute;   Washington D.C. Veterans Affairs Medical Center;   AIDS Clinical Trials Group;   National Heart, Lung, and Blood Institute (NHLBI);   US Department of Veterans Affairs;   Prevention and Early Treatment of Acute Lung Injury (PETAL);   Cardiothoracic Surgical Trials Network (CTSN);   Vir Biotechnology, Inc.;   GlaxoSmithKline;   University of Minnesota
  Completed

• PF-07304814 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial) - Condition:   COVID-19
  Interventions:   Drug: PF-07304814;   Drug: Placebo;   Biological: Remdesivir
  Sponsors:   National Institute of Allergy and Infectious Diseases (NIAID);   International Network for Strategic Initiatives in Global HIV Trials (INSIGHT);   University of Copenhagen;   Medical Research Council;   Kirby Institute;   Washington D.C. Veterans Affairs Medical Center;   AIDS Clinical Trials Group;   National Heart, Lung, and Blood Institute (NHLBI);   US Department of Veterans Affairs;   Prevention and Early Treatment of Acute Lung Injury (PETAL);   Cardiothoracic Surgical Trials Network (CTSN);   Pfizer;   University of Minnesota
  Suspended

• BRII-196/BRII-198 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial) - Condition:   COVID-19
  Interventions:   Biological: BRII-196;   Biological: BRII-198;   Biological: Placebo;   Biological: Remdesivir
  Sponsors:   National Institute of Allergy and Infectious Diseases (NIAID);   International Network for Strategic Initiatives in Global HIV Trials (INSIGHT);   University of Copenhagen;   Medical Research Council;   Kirby Institute;   Washington D.C. Veterans Affairs Medical Center;   AIDS Clinical Trials Group;   National Heart, Lung, and Blood Institute (NHLBI);   US Department of Veterans Affairs;   Prevention and Early Treatment of Acute Lung Injury (PETAL);   Cardiothoracic Surgical Trials Network (CTSN);   Brii Biosciences Limited;   University of Minnesota
  Completed

• LY3819253 (LY-CoV555) for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial) - Condition:   COVID-19
  Interventions:   Biological: LY3819253;   Biological: Placebo;   Biological: Remdesivir
  Sponsors:   National Institute of Allergy and Infectious Diseases (NIAID);   International Network for Strategic Initiatives in Global HIV Trials (INSIGHT);   University of Copenhagen;   Medical Research Council;   Kirby Institute;   Washington D.C. Veterans Affairs Medical Center;   AIDS Clinical Trials Group;   National Heart, Lung, and Blood Institute (NHLBI);   US Department of Veterans Affairs;   Prevention and Early Treatment of Acute Lung Injury (PETAL);   Cardiothoracic Surgical Trials Network (CTSN);   Eli Lilly and Company;   University of Minnesota
  Completed

• RCT for Yinqiaosan-Maxingganshitang in the Treatment of COVID-19 - Condition:   COVID-19
  Interventions:   Drug: Chinese Herb;   Diagnostic Test: Placebo
  Sponsor:   Chinese University of Hong Kong
  Not yet recruiting

• Effect of a Health Pathway for People With Persistent Symptoms Covid-19 - Condition:   COVID-19
  Interventions:   Other: usual care and follow-up by a nurse;   Other: Personalized Multifactorial Intervention (IMP)
  Sponsor:   Centre Hospitalier Universitaire de Saint Etienne
  Not yet recruiting

• A Clinical Study on Safety and Effectiveness of Mesenchymal Stem Cell Exosomes for the Treatment of COVID-19. - Condition:   COVID-19 Pneumonia
  Intervention:   Biological: Extracellular Vesicles from Mesenchymal Stem Cells
  Sponsor:   First Affiliated Hospital of Wenzhou Medical University
  Recruiting

• Teletechnology-assisted Home-based Exercise Program for Severe COVID-19 - Conditions:   COVID-19;   Telerehabilitation
  Intervention:   Behavioral: Teletechnology-assisted home-based pulmonary rehabilitation
  Sponsor:   National Taiwan University Hospital
  Not yet recruiting

• Study of the Safety, Tolerability and Efficacy of NP-101 in Treating High Risk Participants Who Are Covid-19 Positive. - Condition:   COVID-19
  Interventions:   Drug: NP-101;   Other: Placebo
  Sponsor:   Novatek Pharmaceuticals
  Recruiting

• Cluster-Randomized Trial of Air Filtration and Ventilation to Reduce Covid19 Spread in Homes - Condition:   Covid19
  Interventions:   Device: Filtration Fan;   Behavioral: Safe-home pamphlet;   Behavioral: Mid-week phone call
  Sponsor:   Stanford University
  Enrolling by invitation

• Zinc Supplementation Impact in Acute COVID-19 Clinical Outcomes - Conditions:   Zinc Deficiency;   Sars-CoV-2 Infection
  Intervention:   Dietary Supplement: Zinc Acetate
  Sponsors:   Parc de Salut Mar;   Universitat Pompeu Fabra
  Completed

From PubMed

• Defibrotide mitigates endothelial cell injury induced by plasmas from patients with COVID-19 and related vasculopathies - CONCLUSION: Our data, in the context of a recent clinical trial in severe COVID-19, suggest benefits to further exploration of defibrotide and these pathways in COVID-19 and related endotheliopathies.

• Efficacy and Safety of Garadacimab in Combination with Standard of Care Treatment in Patients with Severe COVID-19 - CONCLUSION: In patients with severe COVID-19, garadacimab did not confer a clinical benefit over placebo. Transient aPTT prolongation and suppressed FXIIa-mKA showed target engagement of garadacimab that was not associated with bleeding events even with concomitant anticoagulant use. The safety profile of garadacimab was consistent with previous studies in patients with hereditary angioedema.

• The Potential Effect of Dapsone on the Inflammatory Reactions in Covid-19: Staggering view - Severe SARS-CoV-2 infection is linked with an overstated immune response with the succeeding release of pro-inflammatory cytokines and progression of the cytokine storm. In addition, severe SARS-CoV-2 infection is associated with the development of oxidative stress and coagulopathy. Dapsone (DPS) is a bacteriostatic antibiotic that has a potent anti-inflammatory effect. Thus, this mini-review aimed to elucidate the potential role of DPS in mitigating inflammatory disorders in Covid-19 patients….

• Hyper-inflammation and complement in COVID-19 - COVID-19 is a complex disease manifesting in a broad severity spectrum and involving distinct organs and systems. Hyperinflammation, including complement over-activation, has a pivotal role in severe COVID-19 pathobiology, stimulating the inflammatory response, causing microangiopathy, platelet-neutrophil activation, and hypercoagulability. SARS-CoV-2 can directly activate the complement system by the classic, alternative, and lectin pathways, and infected cells can produce intracellular…

• Susceptibility of SARS COV-2 nucleocapsid and spike proteins to reactive oxygen species and role in inflammation - Chemiluminescence was used to test the susceptibility of the SARS-CoV-2 N and S proteins to oxidation by reactive oxygen species (ROS) at pH7.4 and pH8.5. The Fenton’s system generates various ROS (H(2)O(2), ·OH, -OH, ·OOH). All proteins were found to significantly suppress oxidation (the viral proteins exhibited 25-60% effect compared to albumin). In the second system, H(2)O(2)was used both as a strong oxidant and as a ROS. A similar effect was observed (30-70%); N protein approached the effect…

• Antimycotic effect of 3-phenyllactic acid produced by probiotic bacterial isolates against Covid-19 associated mucormycosis causing fungi - The Covid-19 associated mucormycosis (CAM) is an emerging disease affecting immunocompromised patients. Prevention of such infections using probiotics and their metabolites persist as effective therapeutic agents. Therefore, the present study emphasizes on assessment of their efficacy and safety. Samples from different sources like human milk, honey bee intestine, toddy, and dairy milk were collected, screened and characterized for potential probiotic lactic acid bacteria (LAB) and their…

• Two Resveratrol Oligomers Inhibit Cathepsin L Activity to Suppress SARS-CoV-2 Entry - Cell entry of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) depends on specific host cell proteases, which are the key targets for preventing and treating viral infections. Herein, we describe miyabenol C and trans-ε-viniferin, two resveratrol oligomers that specifically inhibit SARS-CoV-2 entry by targeting host protease cathepsin L. Several cell-based assays were used to demonstrate the effect of resveratrol oligomers, and their target was identified via screening of antiviral…

• Amuvatinib Blocks SARS-CoV-2 Infection at the Entry Step of the Viral Life Cycle - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2 propagation is mediated by the protein interaction between viral proteins and host cells. Tyrosine kinase has been implicated in viral replication, and hence, it has become a target for developing antiviral drugs. We have previously reported that receptor tyrosine kinase inhibitor blocks the replication of hepatitis C virus (HCV). In the present study, we…

• Investigating the potential of natural compounds as novel inhibitors of SARS-CoV-2 RdRP using computational approaches - COVID-19 is a highly contagious disease caused by SARS-CoV-2. Currently, no vaccines or antiviral treatments are available to combat this deadly virus; however, precautions and some repurposed medicines are available to contain COVID-19. RNA-dependent RNA polymerase (RdRP) plays an important role in the replication or transcription of viral mechanisms. Approved antiviral drug such as Remdesivir has shown inhibitory activity against SARS-CoV-2 RdRP. The purpose of this study was to carry out a…

• Multifaceted involvements of Paneth cells in various diseases within intestine and systemically - Serving as the guardians of small intestine, Paneth cells (PCs) play an important role in intestinal homeostasis maintenance. Although PCs uniquely exist in intestine under homeostasis, the dysfunction of PCs is involved in various diseases not only in intestine but also in extraintestinal organs, suggesting the systemic importance of PCs. The mechanisms under the participation of PCs in these diseases are multiple as well. The involvements of PCs are mostly characterized by limiting intestinal…

• Synthesis, molecular docking, and binding Gibbs free energy calculation of β-nitrostyrene derivatives: Potential inhibitors of SARS-CoV-2 3CL protease - The outbreak of novel coronavirus disease 2019 (COVID-19), caused by the novel coronavirus (SARS-CoV-2), has had a significant impact on human health and the economic development. SARS-CoV-2 3CL protease (3CLpro) is highly conserved and plays a key role in mediating the transcription of virus replication. It is an ideal target for the design and screening of anti-coronavirus drugs. In this work, seven β-nitrostyrene derivatives were synthesized by Henry reaction and β-dehydration reaction, and…

• Engineering Nanomolar Potent Protein-based Inhibitors for Papain-like Protease Guided by Residue Correlation Network - We developed a rational protocol with a minimal number of mutated residues to create highly potent and selective protein-based inhibitors. Guided by an interaction and dihedral correlation network of ubiquitin (Ub) and MERS coronaviral papain-like protease (PLpro) complex, our designed ubiquitin variant (UbV) with 3 mutated residues (A46F, K48E, and E64Y) resulted in a ~3,500-fold increase in functional inhibition as compared with the wildtype Ub (wtUb). Further optimization with C-terminal R74N…

• Development of monoclonal antibody-based blocking ELISA for detecting SARS-CoV-2 exposure in animals - The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant threat to public health. Besides humans, SARS-CoV-2 can infect several animal species. Highly sensitive and specific diagnostic reagents and assays are urgently needed for rapid detection and implementation of strategies for prevention and control of the infection in animals. In this study, we initially developed a panel of monoclonal antibodies (mAbs) against SARS-CoV-2 nucleocapsid (N)…

• Cell Surface Nucleocapsid Protein Expression: A Betacoronavirus Immunomodulatory Strategy - We recently reported that SARS-CoV-2 Nucleocapsid (N) protein is abundantly expressed on the surface of both infected and neighboring uninfected cells, where it enables activation of Fc receptor-bearing immune cells with anti-N antibodies (Abs) and inhibits leukocyte chemotaxis by binding chemokines (CHKs). Here, we extend these findings to N from the seasonal human coronavirus (HCoV)-OC43, which is also robustly expressed on the surface of infected and non-infected cells by binding…

• Totally-green cellulosic fiber with prominent sustained antibacterial and antiviral properties for potential use in spunlaced non-woven fabric production - The worldwide spread of COVID-19 has put a higher requirement for personal medical protective clothing, developing protective clothing with sustained antibacterial and antiviral performance is the priority for safe and sustaining application. For this purpose, we develop a novel cellulose based material with sustained antibacterial and antiviral properties. In the proposed method, the chitosan oligosaccharide (COS) was subjected to a guanylation reaction with dicyandiamide in the presence of…

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