Covid-19 Sentry

Contents

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

From Preprints

• The SARS-CoV-2 Spike S1 Protein Induces Global Proteomic Changes in ATII-Like Rat L2 Cells that are Attenuated by Hyaluronan -
  The COVID-19 pandemic continues to impose a major impact on global health and economy since its identification in early 2020, causing significant morbidity and mortality worldwide. Caused by the SARS-CoV-2 virus, along with a growing number of variants that have been characterized to date, COVID-19 has led to 571,198,904 confirmed cases, and 6,387,863 deaths worldwide (as of July 15th, 2022). Despite tremendous advances in our understanding of COVID19 pathogenesis, the precise mechanism by which SARS-CoV2 causes epithelial injury is incompletely understood. In this current study, robust application of global-discovery proteomics applications combined with systems biology analysis identified highly significant induced changes by the Spike S1 protein of SARS-CoV-2 in an ATII-like Rat L2 cells that include three significant network hubs: E2F1, CREB1/ RelA, and ROCK2/ RhoA. Separately, we found that pre-treatment with High Molecular Weight Hyaluronan (HMW-HA), greatly attenuated the S1 effects. Immuno-targeted studies carried out on E2F1 and Rock2/ RhoA induction and kinase-mediated activation, in addition to cell cycle measurements, validated these observations. Taken as a whole, our discovery proteomics and systems analysis workflow, combined with standard immuno-targeted and cell cycle measurements revealed profound and novel biological changes that contribute to our current understanding of both Spike S1 and Hyaluronan biology. This data shows that the Spike S1 protein may contribute to epithelial injury induced by SARS-CoV-2. In addition, our work supports the potential benefit of HMW-HA in ameliorating SARS CoV2 induced cell injury.
  🖺 Full Text HTML: The SARS-CoV-2 Spike S1 Protein Induces Global Proteomic Changes in ATII-Like Rat L2 Cells that are Attenuated by Hyaluronan
• Prophylactic Treatment of COVID-19 in Care Homes Trial (PROTECT-CH) -

  Background: Coronavirus disease 2019 (COVID-19) is associated with significant mortality and morbidity in care homes. Novel or repurposed antiviral drugs may reduce infection and disease severity through reducing viral replication and inflammation. Objective: To compare the safety and efficacy of antiviral agents (ciclesonide, niclosamide) for preventing SARS-CoV-2 infection and COVID-19 severity in care home residents. Design: Cluster-randomised open-label blinded endpoint platform clinical trial testing antiviral agents in a post-exposure prophylaxis paradigm. Setting: Care homes across all four United Kingdom member countries. Participants: Care home residents 65 years of age or older. Interventions: Care homes were to be allocated at random by computer to 42 days of antiviral agent plus standard care versus standard of care and followed for 60 days after randomisation. Main outcome measures: The primary four-level ordered categorical outcome with participants classified according to the most serious of all-cause mortality, all-cause hospitalisation, SARS-CoV-2 infection and no infection. Analysis using ordinal logistic regression was by intention to treat. Other outcomes included the components of the primary outcome and transmission. Results: Delays in contracting between NIHR and the manufacturers of potential antiviral agents significantly delayed any potential start date. Having set up the trial (protocol, approvals, insurance, website, database, routine data algorithms, training materials), the trial was stopped in September 2021 prior to contracting of care homes and general practitioners in view of the success of vaccination in care homes with significantly reduced infections, hospitalisations and deaths. As a result, the sample size target (based on COVID-19 rates and deaths occurring in February-June 2020) became unfeasible. Limitations: Care home residents were not approached about the trial and so were not consented and did not receive treatment. Hence, the feasibility of screening, consent, treatment and data acquisition, and potential benefit of post exposure prophylaxis were never tested. Further, contracting between the University of Nottingham and the PIs, GPs and care homes was not completed, so the feasibility of contracting with all the different groups at the scale needed was not tested. Conclusions: The role of post exposure prophylaxis of COVID-19 in care home residents was not tested because of changes in COVID-19 incidence, prevalence and virulence as a consequence of the vaccination programme that rendered the study unfeasible. Significant progress was made in describing and developing the infrastructure necessary for a large scale Clinical Trial of Investigational Medicinal Products in care homes in all four UK nations. Future work: The role of post-exposure prophylaxis of COVID-19 in care home residents remains to be defined. Significant logistical barriers to conducting research in care homes during a pandemic need to be removed before such studies are possible in the required short timescale.

  🖺 Full Text HTML: Prophylactic Treatment of COVID-19 in Care Homes Trial (PROTECT-CH)
• Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants -
  Anosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Several studies have focused on the neuropathogenesis of the original SARS-CoV-2, but little is known about the neuropathological potential of the variants. Here, we assessed the clinical, olfactory and inflammatory conditions of golden hamsters infected with the original SARS-CoV-2, its ORF7-deleted mutant, and three variants: Gamma, Delta and Omicron/BA.1. We show that infected animals developed a variant-dependent clinical disease, and that the ORF7 of SARS-CoV-2 contribute to causing olfactory disturbances. Conversely, all SARS-CoV-2 variants were found to be neuroinvasive, regardless of the clinical presentation they induce. With newly-generated nanoluciferase-expressing SARS-CoV-2, we validated the olfactory pathway as a main entry point towards the brain, confirming that neuroinvasion and anosmia are independent phenomena upon SARS-CoV-2 infection.
  🖺 Full Text HTML: Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants
• Impact of reinfection with SARS-CoV-2 Omicron variants in previously infected hamsters -
  The diversity of SARS-CoV-2 mutations raises the possibility of reinfection of individuals previously infected with earlier variants, and this risk is further increased by the emergence of the B.1.1.529 Omicron variant. In this study, we used an in vivo, hamster infection model to assess the potential for individuals previously infected with SARS-CoV-2 to be reinfected with Omicron variant and we also investigated the pathology associated with such infections. Initially, Syrian hamsters were inoculated with a lineage A, B.1.1.7, B.1.351, B.1.617.2 or a subvariant of Omicron, BA.1 strain and then reinfected with the BA.1 strain 5 weeks later. Subsequently, the impact of reinfection with Omicron subvariants (BA.1 and BA.2) in individuals previously infected with the BA.1 strain was examined. Although viral infection and replication were suppressed in both the upper and lower airways, following reinfection, virus-associated RNA was detected in the airways of most hamsters. Viral replication was more strongly suppressed in the lower respiratory tract than in the upper respiratory tract. Consistent amino acid substitutions were observed in the upper respiratory tract of infected hamsters after primary infection with variant BA.1, whereas diverse mutations appeared in hamsters reinfected with the same variant. Histopathology showed no acute pneumonia or disease enhancement in any of the reinfection groups and, in addition, the expression of inflammatory cytokines and chemokines in the airways of reinfected animals was only mildly elevated. These findings are important for understanding the risk of reinfection with new variants of SARS-CoV-2.
  🖺 Full Text HTML: Impact of reinfection with SARS-CoV-2 Omicron variants in previously infected hamsters
• The impact of COVID-19 on prescribing of pancreatic enzyme replacement therapy for people with unresectable pancreatic cancer in England. A cohort study using OpenSafely-TPP -

  Background: Cancer treatments were variably disrupted during the COVID-19 pandemic. Despite UK national guidelines recommending pancreatic enzyme replacement therapy to all people with unresectable pancreatic cancer, observational studies demonstrate under-prescribing. Aim: To investigate the impact of the COVID-19 pandemic on the prescribing of pancreatic enzyme replacement to people with unresectable pancreatic cancer. Methods: With the approval of NHS England, we conducted a cohort study using 24 million health records through the OpenSAFELY-TPP research platform. We modelled the effect of COVID-19 with multivariable linear regression. Results: We found no reduction in pancreatic enzyme replacement therapy during the COVID-19 pandemic. Overall, since 2015, the rates of prescribing increased steadily over time by 1% every year. The national rates ranged from 41% in 2015 to 48% in 2022. There was substantial regional variation. The highest rates of 50% to 60% were in the West Midlands and lowest (20% to 30%) in London. Conclusions: In contrast to many other treatments, prescribing of pancreatic enzyme replacement therapy was not affected during the COVID-19 pandemic. Although overall rates increased over time, substantial under-prescribing existed at the end of this study (March 2022). At just under 50% in 2022, the rates were still below the recommended 100% standard. Prior work evaluating quality of care in this area relied on manual audits which come at increased cost and reduced frequency of updates. With the methodological advantage of OpenSAFELY, we established an automated audit which allows for regular updates.

  🖺 Full Text HTML: The impact of COVID-19 on prescribing of pancreatic enzyme replacement therapy for people with unresectable pancreatic cancer in England. A cohort study using OpenSafely-TPP
• Infectiousness of SARS-CoV-2 breakthrough infections and reinfections during the Omicron wave -

  With more recent SARS-CoV-2 variants, breakthrough infections in vaccinated individuals and reinfections among previously infected individuals are increasingly common, especially during the Omicron wave. Such infections have led to concerns about controlling transmission and underscore a broader need to understand the contribution of vaccination, including booster doses, and natural immunity to the infectiousness of persons with SARS-CoV-2 infections, especially in high-risk populations with intense transmission such as prisons. Here, we show that both vaccine-derived and naturally acquired immunity independently reduce the infectiousness of persons with Omicron variant SARS-CoV-2 infections in a prison setting. Analyzing data from system-wide SARS-CoV-2 surveillance across 35 California state prisons, we estimate that Omicron variant infections among unvaccinated cases had a 36% (95% confidence interval (CI): 30-42%) risk of transmitting to close contacts, as compared to 27% (24-30%) risk among vaccinated cases. In adjusted analyses, we estimated that any vaccination, prior infection alone, and both vaccination and prior infection reduced an index case9s risk of transmitting to close contacts by 24% (9-37%), 21% (4-36%) and 41% (23-54%), respectively. Receipt of booster doses and more recent vaccination further reduced infectiousness among vaccinated cases. These findings suggest that although vaccinated and/or previously infected individuals remain highly infectious upon SARS-CoV-2 infection in this prison setting, their infectiousness is reduced compared to individuals without any history of vaccination or infection.

  🖺 Full Text HTML: Infectiousness of SARS-CoV-2 breakthrough infections and reinfections during the Omicron wave
• Symptoms of depression and anxiety among Vietnamese immigrants in Japan during the COVID-19 pandemic; a cross-sectional web-based study -

  Background: Mental health among immigrants in Japan may be related to aspects of COVID-19 infection as well as pandemic-related lifestyle changes, investigating mental health status among Vietnamese residents remains an important public health concern. The mental health status of Vietnamese immigrants in Japan during the COVID-19 epidemic remains unclear. We aimed to examine the mental health status and related factors among Vietnamese immigrants in Japan during the coronavirus disease 2019 (COVID-19) pandemic using data from an online cross-sectional survey administered from September 21 to October 21, 2021. Methods: Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) scores were considered the main outcome measures. Multivariable logistic regression was used to identify factors related to symptoms of depression and anxiety, and the chosen variables were entered simultaneously in the survey. Results: Among 621 participants (age: 26.0 ± 4.8 years; male: 347 [55.9%]) who completed the questionnaire, 73.7% reported a decrease in income when compared with the period before the COVID-19 pandemic, and 60.4% reported being recently affected by poor socioeconomic status. Moderate to severe symptoms of depression (PHQ-9 score ≥ 10 points) and mild-to-severe symptoms of anxiety (GAD-7 ≥ 5 points) were observed in 203 (32.7%) and 285 (45.9%) individuals, respectively. Factors related to depressive symptoms were age (odds ratio [OR]=0.94, p=0.043), pre-existing health conditions (OR=2.46, p<0.001), and subjective socioeconomic status (OR=2.47, p<0.001). Factors related to anxiety symptoms were being single (OR=1.72, p=0.044), pre-existing health conditions (OR=2.52, p<0.001), subjective socioeconomic status (OR=2.72, p<0.001), and a partner with whom to discuss ones health (OR=1.66, p=0.013). Conclusions: The current findings demonstrate that, when compared with non-Vietnamese Japanese people, people with Vietnamese backgrounds experienced a decrease in income, worsening working conditions, and poor mental health status during the COVID-19 pandemic. These findings highlight the potential contribution of low socioeconomic status and social isolation to poor mental health status.

  🖺 Full Text HTML: Symptoms of depression and anxiety among Vietnamese immigrants in Japan during the COVID-19 pandemic; a cross-sectional web-based study
• Recent SARS-CoV-2 infection abrogates antibody and B-cell responses to booster vaccination -

  SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a two-month period, we evaluated antibody and B-cell responses to a third dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies, and memory B cells. Spike-specific B-cell responses from recent infection were elevated at pre-boost but comparatively less so at 60 days post-boost compared to uninfected individuals, and these differences were linked to baseline frequencies of CD27lo B cells. Day 60 to baseline ratio of BCR signaling measured by phosphorylation of Syk was inversely correlated to days between infection and vaccination. Thus, B-cell responses to booster vaccines are impeded by recent infection.

  🖺 Full Text HTML: Recent SARS-CoV-2 infection abrogates antibody and B-cell responses to booster vaccination
• Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2 -
  Neutralization assays are experimental surrogates for the effectiveness of infection- or vaccine-elicited polyclonal antibodies and therapeutic monoclonal antibodies targeting SARS-CoV-2. However, the measured neutralization can depend on details of the experimental assay. Here we systematically assess how ACE2 expression in target cells affects neutralization by antibodies to different spike epitopes in lentivirus pseudovirus neutralization assays. For high ACE2-expressing target cells, receptor binding domain (RBD) antibodies account for nearly all neutralizing activity in polyclonal human sera. But for lower ACE2-expressing target cells, antibodies targeting regions outside the RBD make a larger (although still modest) contribution to serum neutralization. These serum-level results are mirrored for monoclonal antibodies: N-terminal domain (NTD) antibodies and RBD antibodies that do not compete for ACE2 binding incompletely neutralize on high ACE2-expressing target cells, but completely neutralize on cells with lower ACE2 expression. Our results show that ACE2 expression level in the target cells is an important experimental variable, and that high ACE2 expression emphasizes the role of a subset of RBD-directed antibodies.
  🖺 Full Text HTML: Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2
• Entropic overcompensation of the N501Y mutation on SARS-CoV-2 S binding to ACE2 -
  Recent experimental work has shown that the N501Y mutation in the SARS-CoV-2 S glycoprotein’s receptor binding domain (RBD) increases binding affinity to the angiotensin-converting enzyme 2 (ACE2), primarily by overcompensating for a less favorable enthalpy of binding by a greatly reducing the entropic penalty for complex formation, but the basis for this entropic overcompensation is not clear [Pr’evost et al., J. Biol. Chem. (2021) 297;10115]. We use all-atom molecular dynamics simulations and free-energy calculations to qualitatively assess the impact of the N501Y mutation on enthalpy and entropy of binding of RBD to ACE2. Our calculations correctly predict that N501Y causes a less favorable enthalpy of binding to ACE2 relative to the original strain. Further, we show that this is overcompensated for by a more entropically favorable increase in large-scale quaternary flexibility and intra-protein root-mean squared fluctuations of residue positions upon binding in both RBD and ACE2. The enhanced quaternary flexibility stems from N501Y’s ability to remodel the interresidue interactions between the two proteins away from interactions central to the epitope and toward more peripheral interactions. These findings suggest that an important factor in determining protein-protein binding affinity is the degree to which fluctuations are distributed throughout the complex, and that residue mutations that may seem to result in weaker interactions than their wild-type counterparts may yet result increased binding affinity thanks to their ability to suppress unfavorable entropy changes upon binding.
  🖺 Full Text HTML: Entropic overcompensation of the N501Y mutation on SARS-CoV-2 S binding to ACE2
• Identifying Women with Post-Delivery Posttraumatic Stress Disorder using Natural Language Processing of Personal Childbirth Narratives -

  Background: Maternal mental disorders are considered a leading complication of childbirth and a common contributor to maternal death. In addition to undermining maternal welfare, untreated postpartum psychopathology can result in child emotional and physical neglect, and associated significant pediatric health costs. Some women may experience a traumatic childbirth and develop posttraumatic stress disorder (PTSD) symptoms following delivery (CB-PTSD). Although women are routinely screened for postpartum depression in the U.S., there is no recommended protocol to inform the identification of women who are likely to experience CB-PTSD. Advancements in computational methods of free text has shown promise in informing diagnosis of psychiatric conditions. Although the language in narratives of stressful events has been associated with post-trauma outcomes, whether the narratives of childbirth processed via machine learning can be useful for CB-PTSD screening is unknown. Objective: This study examined the utility of written narrative accounts of personal childbirth experience for the identification of women with provisional CB-PTSD. To this end, we developed a model based on natural language processing (NLP) and machine learning (ML) algorithms to identify CB-PTSD via classification of birth narratives. Study Design: A total of 1,127 eligible postpartum women who enrolled in a study survey during the COVID-19 era provided short written childbirth narrative accounts in which they were instructed to focus on the most distressing aspects of their childbirth experience. They also completed a PTSD symptom screen to determine provisional CB-PTSD. After exclusion criteria were applied, data from 995 participants was analyzed. An ML-based Sentence-Transformer NLP model was used to represent narratives as vectors that served as inputs for a neural network ML model developed in this study to identify participants with provisional CB-PTSD. Results: The ML model derived from NLP of childbirth narratives achieved good performance: AUC 0.75, F1-score 0.76, sensitivity 0.8, and specificity 0.70. Moreover, women with provisional CB-PTSD generated longer narratives (t-test results: t=2.30, p=0.02) and used more negative emotional expressions (Wilcoxon test: 9sadness9: p=8.90e-04, W=31,017; 9anger9: p=1.32e-02, W=35,005.50) and death-related words (Wilcoxon test: p=3.48e-05, W=34,538) in describing their childbirth experience than those with no CB-PTSD. Conclusions: This study provides proof of concept that personal childbirth narrative accounts generated in the early postpartum period and analyzed via advanced computational methods can detect with relatively high accuracy women who are likely to endorse CB-PTSD and those at low risk. This suggests that birth narratives could be promising for informing low-cost, non-invasive tools for maternal mental health screening, and more research that utilizes ML to predict early signs of maternal psychiatric morbidity is warranted.

  🖺 Full Text HTML: Identifying Women with Post-Delivery Posttraumatic Stress Disorder using Natural Language Processing of Personal Childbirth Narratives
• A case-crossover study of the effect of vaccination on SARS-CoV-2 transmission relevant behaviours during a period of national lockdown in England and Wales -

  Background: Studies of COVID-19 vaccine effectiveness show increases in COVID-19 cases within 14 days of a first dose, potentially reflecting post-vaccination behaviour changes associated with SARS-CoV-2 transmission before vaccine protection. However, direct evidence for a relationship between vaccination and behaviour is lacking. We aimed to examine the association between vaccination status and self-reported non-household contacts and non-essential activities during a national lockdown in England and Wales. Methods: Participants (n=1,154) who had received the first dose of a COVID-19 vaccine reported non-household contacts and non-essential activities from February to March 2021 in monthly surveys during a national lockdown in England and Wales. We used a case-crossover study design and conditional logistic regression to examine the association between vaccination status (pre-vaccination vs. 14 days post-vaccination) and self-reported contacts and activities within individuals. Stratified subgroup analyses examined potential effect heterogeneity by sociodemographic characteristics such as sex, household income or age group. Results: 457/1,154 (39.60%) participants reported non-household contacts post-vaccination compared with 371/1,154 (32.15%) participants pre-vaccination. 100/1,154 (8.67%) participants reported use of non-essential shops or services post-vaccination compared with 74/1,154 (6.41%) participants pre-vaccination. Post-vaccination status was associated with increased odds of reporting non-household contacts (OR 1.65, 95% CI 1.31-2.06, p<0.001) and use of non-essential shops or services (OR 1.50, 95% CI 1.03-2.17, p=0.032). This effect varied between men and women and different age groups. Conclusion: Participants had higher odds of reporting non-household contacts and use of non-essential shops or services within 14 days of their first COVID-19 vaccine compared to pre-vaccination. Public health emphasis on maintaining protective behaviours during this post-vaccination time period when individuals have yet to develop full protection from vaccination could reduce risk of SARS-CoV-2 infection.

  🖺 Full Text HTML: A case-crossover study of the effect of vaccination on SARS-CoV-2 transmission relevant behaviours during a period of national lockdown in England and Wales
• Polygenic Risk Scores for Asthma and Allergic Disease Predict COVID-19 Severity in 9/11 Responders -

  Background. Genetic factors contribute to individual differences in the severity of coronavirus disease 2019 (COVID-19). A portion of genetic predisposition can be captured using polygenic risk scores (PRS). Relatively little is known about the associations between PRS and COVID-19 severity or post-acute COVID-19 in community-dwelling individuals. Methods. Participants in this study were 983 World Trade Center responders infected for the first time with SARS-CoV-2 (mean age at infection=56.06, standard deviation [SD]=7.37, 918 (93.4%) male, 813 (82.7%) European ancestry). Seventy-five (7.6%) responders were in the severe COVID-19 category, that included hospitalization and other adverse outcomes; 306 (31.1%) reported at least one post-acute COVID-19 symptom at the 4-week follow-up. Analyses were adjusted for population stratification and demographic covariates. Findings. In responders with European ancestry, the asthma PRS was associated with severe COVID-19 category (odds ratio [OR]=1.61, 95% confidence interval: 1.17-2.21) and more severe COVID-19 symptomatology (β=.09, p=.01), independently of respiratory disease diagnosis. The allergic disease PRS similarly associated with severe COVID-19 category (OR=1.97, [1.26-3.07]). The PRS for COVID-19 hospitalization was associated with the risk of severe COVID-19 category (OR=1.35, [1.01-1.82]), but this association was smaller than for the asthma PRS. PRS for coronary artery disease and type II diabetes were not associated with COVID-19 severity. Interpretation. Taken together, the results indicate that recently developed polygenic biomarkers for asthma, allergic disease, and COVID-19 hospitalization capture some of the individual differences in severity and clinical course of COVID-19 illness in a community population. Funding. National Institute for Occupational Safety and Health, CDC.

  🖺 Full Text HTML: Polygenic Risk Scores for Asthma and Allergic Disease Predict COVID-19 Severity in 9/11 Responders
• Can SARS-CoV-2 transmit from a dead body? -
  Although it has been 2.5 years since the COVID-19 pandemic began, the transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a dead infected body remains unclear, and often, in Japan bereaved family members are not allowed to view in-person a loved one who has died from COVID-19. In this study, we analyzed the possibility of SARS-CoV-2 transmission from a dead body by using the hamster model. We also analyzed the effect of Angel-care–in which the pharynx, nostril, and rectum are plugged–and embalming on reducing transmissibility from dead bodies. We found that SARS-CoV-2 could be transmitted from the body of animals that died within a few days of infection; however, Angel-care and embalming were effective in preventing transmission from the dead body. These results suggest that protection from infection is essential when in contact with a SARS-CoV-2-infected dead body, and that sealing the cavities of a dead body is an important infection control step if embalming is not done.
  🖺 Full Text HTML: Can SARS-CoV-2 transmit from a dead body?
• Molecular fate-mapping of serum antibodies reveals the effects of antigenic imprinting on repeated immunization -
  The ability of serum antibody to protect against pathogens arises from the interplay of antigen-specific B cell clones of different affinities and fine specificities. These cellular dynamics are ultimately responsible for serum-level phenomena such as antibody imprinting or “Original Antigenic Sin” (OAS), a proposed propensity of the immune system to rely repeatedly on the first cohort of B cells that responded to a stimulus upon exposure to related antigens. Imprinting/OAS is thought to pose a barrier to vaccination against rapidly evolving viruses such as influenza and SARS-CoV-2. Precise measurement of the extent to which imprinting/OAS inhibits the recruitment of new B cell clones by boosting is challenging because cellular and temporal origins cannot readily be assigned to antibodies in circulation. Thus, the extent to which imprinting/OAS impacts the induction of new responses in various settings remains unclear. To address this, we developed a “molecular fate-mapping” approach in which serum antibodies derived from specific cohorts of B cells can be differentially detected. We show that, upon sequential homologous boosting, the serum antibody response strongly favors reuse of the first cohort of B cell clones over the recruitment of new, naive-derived B cells. This “primary addiction” decreases as a function of antigenic distance, allowing secondary immunization with divergent influenza virus or SARS-CoV-2 glycoproteins to overcome imprinting/OAS by targeting novel epitopes absent from the priming variant. Our findings have implications for the understanding of imprinting/OAS, and for the design and testing of vaccines aimed at eliciting antibodies to evolving antigens.
  🖺 Full Text HTML: Molecular fate-mapping of serum antibodies reveals the effects of antigenic imprinting on repeated immunization

From Clinical Trials

• A Clinical Study to Evaluate the Efficacy and Safety of SIM0417 Orally Co-Administered With Ritonavir in Symptomatic Adult Participants With Mild to Moderate COVID-19 - Condition:   COVID-19
  Interventions:   Drug: SIM0417;   Drug: Placebo
  Sponsor:   Jiangsu Simcere Pharmaceutical Co., Ltd.
  Not yet recruiting

• Self-management of Post COVID-19 Syndrome Using Wearable Biometric Technology - Condition:   COVID-19
  Intervention:   Other: Self-management of post COVID-19 respiratory outcomes
  Sponsor:   University of Manitoba
  Not yet recruiting

• Booster Study of COVID-19 Protein Subunit Recombinant Vaccine - Condition:   COVID-19
  Interventions:   Biological: SARS-CoV-2 subunit protein recombinant vaccine;   Biological: Active Comparator
  Sponsors:   PT Bio Farma;   Faculty of Medicine Universitas Padjadjaran;   Faculty of Medicine Universitas Udayana
  Recruiting

• A Study to Evaluate the Immunogenicity and Safety of a Recombinant Protein COVID-19 Vaccine SCTV01E-1 in Population Aged Above 18 Years - Conditions:   COVID-19;   SARS-CoV-2 Infection
  Interventions:   Biological: SCTV01E-1 on D0;   Biological: SCTV01E-1 on D28;   Biological: SCTV01E-1 on D150;   Biological: SCTV01E on D0;   Biological: SCTV01E on D28;   Biological: SCTV01E on D150;   Biological: SCTV01E-1 on D120;   Biological: SCTV01E on D120
  Sponsor:   Sinocelltech Ltd.
  Not yet recruiting

• The Role of BCG Vaccine in the Clinical Evolution of COVID-19 and in the Efficacy of Anti-SARS-CoV-2 Vaccines - Condition:   COVID-19
  Interventions:   Biological: BCG (Bacillus Calmette-Guérin) vaccine;   Other: Placebo
  Sponsors:   Oswaldo Cruz Foundation;   University of Sao Paulo;   Federal University of Juiz de Fora
  Recruiting

• Performance Evaluation of LumiraDx COVID-19 (SARS-CoV-2) Ag ULTRA Test (ASPIRE-2) - Condition:   COVID-19
  Interventions:   Diagnostic Test: Nasal Swab;   Diagnostic Test: Nasopharyngeal swab
  Sponsor:   LumiraDx UK Limited
  Recruiting

• A Novel Parameter LIT/N That Predicts Survival in COVID-19 ICU Patients - Condition:   COVID-19 Pneumonia
  Intervention:   Diagnostic Test: the LIT test
  Sponsors:   Gazi University;   Oxford MediStress
  Completed

• Efficacy and Safety of ES16001 in Patients With COVID-19 - Condition:   COVID-19
  Interventions:   Drug: ES16001 40 mg;   Drug: ES16001 80 mg;   Drug: ES16001 160 mg;   Drug: Placebo
  Sponsor:   Genencell Co. Ltd.
  Recruiting

• Phase 2a Trial to Evaluate Safety and Immunogenicity of COVID-19 Vaccine Strategies in HIV-infected/Uninfected Adults. - Condition:   COVID-19
  Intervention:   Drug: Ad26.COV2.S (VAC31518, JNJ-78436735) Vaccine, SARS-CoV-2 rS (CovovaxTM), BNT162b2 (Pfizer)
  Sponsors:   The Aurum Institute NPC;   Coalition for Epidemic Preparedness Innovations
  Recruiting

• UNAIR Inactivated COVID-19 Vaccine Phase III (Immunobridging Study) - Conditions:   COVID-19 Pandemic;   COVID-19 Vaccines
  Interventions:   Biological: Vaksin Merah Putih - UA SARS-CoV-2 (Vero Cell Inactivated) 5 µg;   Biological: CoronaVac Biofarma COVID-19 Vaccine
  Sponsors:   Dr. Soetomo General Hospital;   Indonesia-MoH;   Universitas Airlangga;   Biotis Pharmaceuticals, Indonesia
  Recruiting

• COVID Protection After Transplant - Sanofi GSK (CPAT-SG) Study - Conditions:   COVID-19;   Kidney Transplant
  Intervention:   Biological: Sanofi-GSK monovalent (B.1.351) CoV2 preS dTM-AS03 COVID-19 vaccine
  Sponsors:   National Institute of Allergy and Infectious Diseases (NIAID);   PPD;   Johns Hopkins University;   Sanofi Pasteur, a Sanofi Company
  Not yet recruiting

• Safety and Immunogenicity of COVID-19 Vaccine, AdCLD-CoV19-1 - Conditions:   COVID-19;   Vaccines
  Intervention:   Biological: AdCLD-CoV19-1
  Sponsors:   International Vaccine Institute;   Cellid Co., Ltd.
  Not yet recruiting

• Clinical Trial of Jinzhen Oral Liquid in Treating Children With COVID-19 Infection - Conditions:   COVID-19;   Child, Only
  Intervention:   Drug: Jinzhen oral liquid or Jinhuaqinggan granules
  Sponsor:   The Affiliated Hospital of Qingdao University
  Recruiting

• Smartphone Intervention for Overdose and COVID-19 - Conditions:   Substance Use Disorders;   Overdose;   COVID-19
  Intervention:   Device: iThrive WI Intervention
  Sponsors:   University of Wisconsin, Madison;   National Institute on Drug Abuse (NIDA)
  Not yet recruiting

• Phase 2 Study of the Safety and Immunogenicity of COVID-19 and Influenza Combination Vaccine - Conditions:   COVID-19;   Influenza
  Interventions:   Drug: CIC Vaccine;   Drug: qNIV Vaccine;   Drug: SARS-CoV-2 rS Vaccine;   Drug: Influenza Vaccine
  Sponsor:   Novavax
  Not yet recruiting

From PubMed

• Structural Insights into Binding of Remdesivir Triphosphate within the Replication-Transcription Complex of SARS-CoV-2 - Remdesivir is an adenosine analogue that has a cyano substitution in the C1’ position of the ribosyl moiety and a modified base structure to stabilize the linkage of the base to the C1’ atom with its strong electron-withdrawing cyano group. Within the replication-transcription complex (RTC) of SARS-CoV-2, the RNA-dependent RNA polymerase nsp12 selects remdesivir monophosphate (RMP) over adenosine monophosphate (AMP) for nucleotide incorporation but noticeably slows primer extension after the…

• The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial - CONCLUSIONS: The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.

• Pirfenidone and post-Covid-19 pulmonary fibrosis: invoked again for realistic goals - Pirfenidone (PFN) is an anti-fibrotic drug with significant anti-inflammatory property used for treatment of fibrotic conditions such as idiopathic pulmonary fibrosis (IPF). In the coronavirus disease 2019 (Covid-19) era, severe acute respiratory syndrome 2 (SARS-CoV-2) could initially lead to acute lung injury (ALI) and in severe cases may cause acute respiratory distress syndrome (ARDS) which is usually resolved with normal lung function. However, some cases of ALI and ARDS are progressed to…

• S2 Subunit of SARS-CoV-2 Spike Protein Induces Domain Fusion in Natural Pulmonary Surfactant Monolayers - Pulmonary surfactant has been attempted as a supportive therapy to treat COVID-19. Although it is mechanistically accepted that the fusion peptide in the S2 subunit of the S protein plays a predominant role in mediating viral fusion with the host cell membrane, it is still unknown how the S2 subunit interacts with the natural surfactant film. Using combined bio-physicochemical assays and atomic force microscopy imaging, it was found that the S2 subunit inhibited the biophysical properties of the…

• Synthesis, Molecular Docking, c-Met inhibitions of 2,2,2-Trichloro-ethylidene-cyclohexane-1,3-dione Derivatives Together With Their Application as Target SARS-CoV-2 main Protease (Mpro) And as Potential Anti-Covid-19 - CONCLUSION: The results showed that compounds 10a, 10b, 10c, 10e, 10f, 10g and 10h showed high % inhibitions against SARs-Covnsp 14. Whereas, compounds 5a, 7a, 8b, 10a, 10b, 10c and 10i showed high inhibitions against hRNMT. This study explored the binding affinity of twenty two halogenated compounds to the SARS-CoV-2 MPro and discovered fifteen compounds with higher binding affinity than Nelfinavir, of which three showed remarkable results. c-Met kinase inhibitions of 10a, 10f, 10g and 10h…

• Cannabinoids receptors in Covid-19: Perpetrators and victims - COVID-19 is caused by SARS-CoV-2 and leads to acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations in severely affected cases. However, most of the affected cases are mild or asymptomatic. Cannabinoids (CBs) such as tetrahydrocannabinol (THC) and cannabidiol (CBD), which act on G-protein-coupled receptors called CB1 and CB2, have anti-inflammatory effects. Many published studies show that CBs are effective in various inflammatory disorders, viral…

• Homologous and Heterologous Boosting of the Chadox1-S1-S COVID-19 Vaccine With the SCB-2019 Vaccine Candidate: A Randomized, Controlled, Phase 2 Study - CONCLUSIONS: Boosting ChAdOx1-S-primed adults with SCB-2019 induced higher levels of antibodies against a wild-type strain and SARS-CoV-2 variants than a homologous ChAdOx1-S booster, with the highest responses being with the 30-μg SCB-2019 + CpG + aluminium hydroxide formulation.

• 5-HT/CGRP pathway and Sumatriptan role in Covid-19 - Coronavirus disease 2019 (Covid-19) is a pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In Covid-19, there is uncontrolled activation of immune cells with a massive release of pro-inflammatory cytokines and the development of cytokine storm. These inflammatory changes induce impairment of different organ functions, including the central nervous system (CNS), leading to acute brain injury and substantial changes in the neurotransmitters, including serotonin…

• A potent neutralizing antibody provides protection against SARS-CoV-2 Omicron and Delta variants via nasal delivery - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still rapidly spreading worldwide. Many drugs and vaccines have been approved for clinical use show efficacy in the treatment and prevention of SARS-CoV-2 infections. However, the emergence of SARS-CoV-2 variants of concern (VOCs), such as Delta (B.1.617.2) and the recently emerged Omicron (B.1.1.529), has seriously challenged the application of current therapeutics. Therefore, there is still a pressing need for identification of…

• Brequinar and dipyridamole in combination exhibits synergistic antiviral activity against SARS-CoV-2 in vitro: Rationale for a host-acting antiviral treatment strategy for COVID-19 - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the associated global pandemic resulting in >400 million infections worldwide and several million deaths. The continued evolution of SARS-CoV-2 to potentially evade vaccines and monoclonal antibody (mAb)-based therapies and the limited number of authorized small-molecule antivirals necessitates the need for development of new drug treatments. There remains an unmet…

• Nafamostat Mesylate for Treatment of COVID-19 in Hospitalised Patients: A Structured, Narrative Review - The search for clinically effective antivirals against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is ongoing. Repurposing of drugs licensed for non-coronavirus disease 2019 (COVID-19) indications has been extensively investigated in laboratory models and in clinical studies with mixed results. Nafamostat mesylate (nafamostat) is a drug licensed in Japan and Korea for indications including acute pancreatitis and disseminated intravascular coagulation. It is available only…

• Crystal structure of SARS-CoV-2 nsp10-nsp16 in complex with small molecule inhibitors, SS148 and WZ16 - SARS-CoV-2 nsp10-nsp16 complex is a 2’-O-methyltransferase (MTase) involved in viral RNA capping, enabling the virus to evade the immune system in humans. It has been considered a valuable target in the discovery of antiviral therapeutics, as the RNA cap formation is crucial for viral propagation. Through cross-screening of the inhibitors that we previously reported for SARS-CoV-2 nsp14 MTase activity against nsp10-nsp16 complex, we identified two compounds (SS148 and WZ16) that also inhibited…

• Human Claudin-Derived Peptides Block the Membrane Fusion Process of Zika Virus and Are Broad Flavivirus Inhibitors - Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged in the Pacific islands in 2007 and spread to the Americas in 2015. The infection remains asymptomatic in most cases but can be associated with severe neurological disorders. Despite massive efforts, no specific drug or vaccine against ZIKV infection is available to date. Claudins are tight-junction proteins that favor the entry of several flaviviruses, including ZIKV. In this study, we identified two peptides derived from the…

• Peptidomimetic Small-Molecule Inhibitors of 3CLPro Activity and Spike-ACE2 Interaction: Toward Dual-Action Molecules against Coronavirus Infections - The development of molecules able to target protein-protein interactions (PPIs) is of interest for the development of novel therapeutic agents. Since a high percentage of PPIs are mediated by α-helical structure at the interacting surface, peptidomimetics that reproduce the essential conformational components of helices are useful templates for the development of PPIs inhibitors. In this work, the synthesis of a constrained dipeptide isostere and insertion in the short peptide epitope EDLFYQ of…

• Nonstructural Protein 1 of Variant PEDV Plays a Key Role in Escaping Replication Restriction by Complement C3 - Zoonotic coronaviruses represent an ongoing threat to public health. The classical porcine epidemic diarrhea virus (PEDV) first appeared in the early 1970s. Since 2010, outbreaks of highly virulent PEDV variants have caused great economic losses to the swine industry worldwide. However, the strategies by which PEDV variants escape host immune responses are not fully understood. Complement component 3 (C3) is considered a central component of the three complement activation pathways and plays a…

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