SARS-CoV2 Infection Research Articles

518. Newborn immune transcriptome changes rapidly and is shaped by maternal SARS-CoV-2 infection and/or vaccination

Abstract Background SARS-CoV-2 infection during pregnancy is associated with adverse maternal effects, but its impact on infant’s immune development is not well defined. Using transcriptional profiles we analyzed the impact of SARS-CoV2 infection and/or vaccination in pregnant people and their infants longitudinally Transcriptome changes in pregnant people with SARS-CoV-2 infection and/or vaccination Modular analysis of pregnant people with SARS-CoV-2 infection and/or vaccination compared with healthy uninfected controls. Red dot: overexpression, blue dot: underexpression, white/empty space no difference vs controls Methods Multicenter observational study of SARS-CoV-2-infected and/or vaccinated pregnant people and their infants. Pregnant people (infected [n=91], vaccinated [n=42], infected-and-vaccinated [n=14], controls [n=22]) and their infants (n=81, 38,14, 11, respectively) were included. Maternal blood samples were collected during different trimesters and at delivery. Infant blood samples were collected longitudinally from birth (< 72 hours), at 1 week and 1, 3 and 6 months of age. Whole blood RNA was extracted for RNA-sequencing and transcriptomic data analyzed with R Transcriptional analysis of immune system development in early life Modular gene expression scores were analyzed longitudinally of individual infant samples. Red: higher expression, white: lower expression. D1-3: days 1 to 3, W1: week 1, M1: month 1, M3: month 3, M6: month 6 Results Compared with uninfected controls, interferon and plasma cells genes were overexpressed in pregnant people with acute infection (< 14 days), but underexpressed with earlier infection or vaccination during pregnancy (Figure 1). Newborns < 72 h of age (from all groups) showed significantly increased expression of erythrocytes, neutrophils, and inflammation genes. Expression of T/cytotoxic cell genes started to be observed at 1 week, while expression of B cells, plasma cells and interferon genes was observed at 3 months of age (Figure 2). Quantitative gene set enrichment analysis showed that compared to controls, infants from infected and/or vaccinated mothers had increased expression of interferon, while neutrophil, and adaptive immunity genes were decreased (Figure 3) SARS-CoV-2 infection and/or vaccination of pregnant people shaped immune profiles of their infants Fold changes of gene sets in infants compared to controls are shown (adjusted p-value <0.01) from quantitative gene set enrichment (QuSAGE) analysis. Red: overexpression, blue: underexpression. Infant groups are defined by maternal infection and/or vaccination status at delivery. Conclusion Interferon and plasma cells related pathways were overexpressed in pregnant people with acute COVID-19, while vaccination and SARS-CoV-2 infection earlier in pregnancy were associated with under-expression of both innate and adaptive immunity genes. The infant immune system changed rapidly in the first few days of life, as different immune programs followed separate time trajectories. Maternal SARS-CoV-2 infection and/or vaccination shaped the immune profiles of their newborns, suggesting a potential impact on their immune development Disclosures Rodrigo DeAntonio, MD, MSc, DrPH, GSK: Grant/Research Support|Moderna: Grant/Research Support|Sanofi: Grant/Research Support Asuncion Mejias, MD, PhD, MsCS, Astra-Zeneca: Advisor/Consultant|Astra-Zeneca: Honoraria|Enanta: Advisor/Consultant|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Sanofi-Pasteur: Advisor/Consultant|Sanofi-Pasteur: Honoraria Octavio Ramilo, MD, Pfizer, Sanofi, Gates Foundation, NIH, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Advisor/Consultant|Pfizer, Sanofi, Gates Foundation, NIH, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Grant/Research Support|Pfizer, Sanofi, Gates Foundation, NIH, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): Honoraria|Pfizer, Sanofi, Gates Foundation, NIH, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD): SAC member for MSD

Post COVID-19 infection and quality of life of healthcare workers at Sahloul University Hospital of Sousse in Tunisia.

Since the COVID-19 pandemic, health care workers (HCWs) faced an enormous physical and mental burden, sometimes altering their quality of life due mainly to persistent challenges stemming from their frontline position. Todetermine the prevalence of post-COVID-19 syndrome, and its impact on the Health-Related Quality of Life (HRQoL) among HCWs. This is an exhaustive cross-sectional study with analytical scope, conducted among all HCWs of the University Hospital Sahloul of Sousse, Tunisia, who have contracted COVID-19 between September 2020 and 30 March 2021 (N=529 cases).The post-covid medical check-up was carried out three months after the acute phase of the COVID-19 infection (December 2020 to June 2021). HRQoL was assessed using the SF-12 (12-item Short Form Health Survey) questionnaire. Bivariate study and multiple linear regressions were performed to identify the different factors influencing the quality of life of HCWs. During the study period, 529 HCWs were diagnosed with SARS CoV-2 infection, out of them 249 participants were included (47% participation rate). Post covid-19 syndrome was reported in 65% of cases. A low overall quality of life (QoL) score was reported in 28.6% of cases. Low physical and mental composite scores were reported in 34.3% and 29.4% of cases respectively. In the multiple linear regression analysis, gender, post COVID-19 syndrome and time off work were significantly associated with SF12 scores. In our study, HCWs experienced a significant deterioration in HRQoL after COVID-19 with a high incidence of post-COVID-19 syndrome. The need of long-term follow-up after SARS-CoV-2 infection remains essential to support HCWs and mitigate long-term impacts.

89. First-in-human study of a novel half-life extended monoclonal antibody (GB-0669) against SARS-CoV2 and related sarbecoviruses

Abstract Background GB-0669 is a novel half-life extended monoclonal antibody for the prophylaxis of SARS-CoV2 infection and is one of the first biologics designed using artificial intelligence/machine learning to reach clinical development and the first against SARS-CoV2. GB-0669 targets the previously undruggable S2 domain of the SARS-CoV2 spike protein, which contains the fusion peptide and stem-helix peptides, and was selected because the S2 domain is conserved across all SARS-CoV2 variants to-date. The S2 domain is not immunodominant and is therefore not subject to selective pressure from natural infection or vaccine induced immunity. This suggesting GB-0669 will maintain its activity, unlike monoclonal antibodies directed against the SARS-CoV2 receptor-binding domain. GB-0669 is also able to neutralize other sarbecoviruses, such as SARS-CoV2 and WIV1 (Table).Table:GB-0669 EC50 against SARS-CoV2 variants and other sarbecoviruses in a VSV pseudoneutralisation assay Methods In this single-ascending dose study, healthy volunteers aged 18–55 years were administered either GB-0669 or placebo intravenously. There were five sequential dosing cohorts 100 mg, 300 mg, 600 mg, 1200 mg, 2400 mg and each cohort was randomized to receive either GB-0669 or placebo in ratios of 3:3, 3:3, 10:3, 10:3, 10:3 respectively. Total follow-up will be 43 weeks; although dosing is now complete, follow-up is ongoing.Figure:Simulated GB-0669 drug concentrations over 43 weeks (plasma and lung) following a single dose of 1200 mg Results No dose-limiting toxicity has been observed to date and all treatment-related adverse reactions observed were mild (grade 1 or 2) at all doses. Preliminary pharmacokinetic data shows dose-proportionality up to 2400 mg the highest dose tested, with a half-life of approximately 70 days. An exploratory analysis of live virus neutralization shows a clear dose response and separation from placebo at 600 and 1200 mg. Limited anti-drug antibodies were observed in a few participants, but had no observable impact on PK or viral neutralization titers. Simulated PK of GB-0669 confirmed with observed data (assuming 10% lung penetration) are at levels anticipated to protect against COVID-19 for at least 150 days (Figure). Conclusion The preliminary data support the hypothesis that GB-0669 will be able to provide a six-month duration of prophylactic efficacy against currently circulating viral variants when administered as part of a combination. Disclosures Dinesh De Alwis, PhD, Generate Biomedicines: Stocks/Bonds (Private Company) Iñaki F. Troconiz, Pharmacy, Generate Biomedicines: Advisor/Consultant Daria Hazuda, PhD, Generate Biomedicines: Stocks/Bonds (Private Company) Gavin CKW Koh, PhD, AstraZeneca: Stocks/Bonds (Public Company)|Generate:Biomedicines: Stocks/Bonds (Private Company)|GlaxoSmithKline: Stocks/Bonds (Public Company) Alexandra Snyder, MD, Generate Biomedicines: employee

Effect of SARS-CoV2 Infection on Endovascular Thrombectomy Outcomes - Data from the Florida Stroke Registry.

Endovascular thrombectomy outcomes are impacted by changes in stroke systems of care. During the pandemic, SARS-CoV2 positive status had major implications on hospital arrival and treatment models of non-COVID related hospital admissions. Using the Florida Stroke Registry, we compared the rates of in-hospital death and discharge outcomes of patients treated with endovascular thrombectomy who tested positive for SARS-CoV2 infection during their hospitalization. Data from Get with the Guidelines-Stroke hospitals participating in the Florida Stroke Registry during the COVID pandemic from March 2020 to December 2022 were reviewed to identify endovascular thrombectomy patients with coding for SARS-CoV2 testing during their hospital stay. Associations between SARS-CoV2 status and favorable endovascular thrombectomy outcomes of mRS (0-2) at discharge, discharge to home or rehabilitation centre, symptomatic intracerebral hemorrhage, in-hospital mortality, and independent ambulation at discharge were examined using multivariate logistic regression modeling adjusting for demographics, vascular risk factors, and clinical characteristics. Temporal analyses were used to compare outcomes across the study period. A total of 8,184 patients underwent endovascular thrombectomy (median age 71.1 years, female 50%, mean NIHSS 14), of these, 180 (2.2%) were SARS-CoV2 positive. Compared to SARS-CoV2 negative endovascular thrombectomy patients, those who tested positive were younger, more frequently male, but with comparable stroke severity at presentation. In multivariable analysis, adjusting for baseline differences and confounding variables, there was a 33% lower likelihood of being discharged to home/inpatient rehab (OR=0.67, 95% CI=(0.49-0.93)), 65% higher odds of in-hospital death (OR=1.65, 95% CI=(1.06-2.58)), as well as a 85% less chance of having a high mRS (>2) at discharge (OR=0.15, 95% CI=(0.04-0.60)) for patients with positive SARS-CoV2 infection. However, a similar risk of symptomatic intracerebral hemorrhage was present compared to SARS-CoV2 negative patients (OR=0.97, 95% CI=(0.501.88)). Temporal analysis of SARS-CoV2 positive patients showed no significant differences. In this large multicenter stroke registry, despite comparable clinical presentation and in-hospital treatment timelines, SARS-CoV2 positive status negatively impacted thrombectomy outcomes. AIS = acute ischemic stroke; LVO = large vessel occlusion; EVT = endovascular thrombectomy; FSR = Florida Stroke Registry; sICH = symptomatic intracerebral hemorrhage.

Long-term effects of SARS-CoV-2 infection and vaccination in a population-based pediatric cohort

During the omicron wave of the COVID-19 pandemic and with SARS-CoV-2 vaccines becoming available, seroprevalence rates rose in children and adolescents. This study investigated the impact of both SARS-CoV-2 infections and vaccinations on the incidence of acute and prolonged symptoms in real-world conditions during the transition from the pandemic to the endemic phase. Participants from a pediatric population based seroprevalence study (CorKID study) were followed up at least two and for almost four years by survey of health status features and symptoms suggestive of post-COVID syndrome (PCS). In a subgroup (n = 259) SARS-CoV-2 antibody serology was further investigated. 789 participants of the original CorKID study cohort (n = 2.121; 37.2%) were included. 67.9% reported at least one SARS-CoV2 infection. 46.6% had received one or more SARS-CoV-2 vaccinations. In the vast majority of serologically tested participants antibodies again SARS-CoV-2 spike (98.9%) or nucleocapsid (93.3%) antigen were detected following infection and/or vaccination. At least 30% experienced one unrecognized SARS-CoV-2 infection. The overall health status was comparable between children, irrespective of SARS-CoV-2 infections and similar to pre-pandemic assessment. However, a subset of young adolescents exhibited a decline in physical performance compared to pre-pandemic conditions. After infection, PCS-like symptoms persisted in 7% of the respondents for more than three months and up to four years. SARS-CoV-2 vaccinated participants (47%) reported 12% less acute flu-like infections other than SARS-CoV-2. Nearly all participants developed SARS-CoV-2 antibodies in this longitudinal study through either vaccination or infection during the Omicron wave. About 7% of participants suffered from PCS symptoms, predominately fatigue and exhaustion. Furthermore, participants who received vaccinations against SARS-CoV-2 reported a lower frequency of acute infections during follow-up.

Regulatory T Cell Phenotype Related to Cytokine Expression Patterns in Post-COVID-19 Pulmonary Fibrosis and Idiopathic Pulmonary Fibrosis.

Post-coronavirus disease 19 lung fibrosis (PCLF) shares common immunological abnormalities with idiopathic pulmonary fibrosis (IPF), characterized by an unbalanced cytokine profile being associated with the development of lung fibrosis. The aim of the present study was to analyze and compare the different subsets of CD4- and CD8-T cells, along with specific cytokine expression patterns, in peripheral blood (PB) from patients affected by PCLF and IPF and healthy controls (HCs). One-hundred patients followed at the Rare Lung Disease Center of Siena University Hospital were enrolled. Eight HCs were recruited. PB samples were collected, and CD4- and CD8-T subsets were analyzed through flow cytometry. Multiplex bead-based LEGENDplex™ were used for cytokine quantification. Higher CD8 percentages were observed in IPF than in HCs and PCLF (p = 0.020 and p = 0.007, respectively). PCLF subgroup showed higher Th-naïve, Th-effector, Tc-naïve, and Tc-reg percentages than IPF (p < 0.001; p = 0.018; p = 0.005; p = 0.017, respectively). Th-naïve and Tc-naïve inversely correlated with Tc-reg (p < 0.0001, r = -0.61 and p = 0.005, r = -0.39, respectively). Tc-naïve-PD1 and Tc-effector-PD1 percentages were higher in PCLF than IPF (p < 0.001), while Tfh-reg and Tfc-reg were significantly higher in IPF than PCLF (p < 0.001). IL-4, IL-2, TNF-α, and IL-17A were more expressed in PCLF than IPF (p < 0.001). IL-8 directly correlated with Tc-naïve percentages in PCLF (p = 0.018, r = 0.35). A variety of immune cells is involved in the development and progression of pulmonary fibrosis confirming an immunological similarity between IPF and PCLF. T-reg cells play a key role in the worsening of the disease. High cytokine values showed a pro-fibrotic environment in PCLF patients, suggesting dysregulation of the immune system of these patients. Moreover, the immunological similarity between IPF and PCLF patients suggests that SARS-CoV2 infection may trigger the activation of biological pathways common with IPF.

A comparison of CXR-CAD software to radiologists in identifying COVID-19 in individuals evaluated for Sars CoV-2 infection in Malawi and Zambia.

AI based software, including computer aided detection software for chest radiographs (CXR-CAD), was developed during the pandemic to improve COVID-19 case finding and triage. In high burden TB countries, the use of highly portable CXR and computer aided detection software has been adopted more broadly to improve the screening and triage of individuals for TB, but there is little evidence in these settings regarding COVID-19 CAD performance. We performed a multicenter, retrospective cross-over study evaluating CXRs from individuals at risk for COVID-19. We evaluated performance of CAD software and radiologists in comparison to COVID-19 laboratory results in 671 individuals evaluated for COVID-19 at sites in Zambia and Malawi between January 2021 and June 2022. All CXRs were interpreted by an expert radiologist and two commercially available COVID-19 CXR-CAD software. Radiologists interpreted CXRs for COVID-19 with a sensitivity of 73% (95% CI: 69%- 76%) and specificity of 49% (95% CI: 40%-58%). One CAD software (CAD2) showed performance in diagnosing COVID-19 that was comparable to that of radiologists, (AUC-ROC of 0.70 (95% CI: 0.65-0.75)), while a second (CAD1) showed inferior performance (AUC-ROC of 0.57 (95% CI: 0.52-0.63)). Agreement between CAD software and radiologists was moderate for diagnosing COVID-19, and agreement was very good in differentiating normal and abnormal CXRs in this high prevalent population. The study highlights the potential of CXR-CAD as a tool to support effective triage of individuals in Malawi and Zambia during the pandemic, particularly for distinguishing normal from abnormal CXRs. These findings suggest that while current AI-based diagnostics like CXR-CAD show promise, their effectiveness varies significantly. In order to better prepare for future pandemics, there is a need for representative training data to optimize performance in key populations, and ongoing data collection to maintain diagnostic accuracy, especially as new disease strains emerge.

Safety of two-dose schedule of COVID-19 adsorbed inactivated vaccine (CoronaVac; Sinovac/Butantan) and heterologous additional doses of mRNA BNT162b2 (Pfizer/BioNTech) in immunocompromised and immunocompetent individuals.

Immunocompromised individuals were considered high-risk for severe disease due to SARS COV-2 infection. This study aimed to describe the safety of two doses of COVID-19 adsorbed inactivated vaccine (CoronaVac; Sinovac/Butantan), followed by additional doses of mRNA BNT162b2 (Pfizer/BioNTech) in immunocompromised (IC) adults, compared to immunocompetent/healthy (H) individuals. This phase 4, multicenter, open label study included solid organ transplant and hematopoietic stem cell transplant recipients, cancer patients and people with inborn errors of immunity with defects in antibody production, rheumatic, end-stage chronic kidney or liver disease, who were enrolled in the IC group. Participants received two doses of CoronaVac and additional doses of mRNA BNT162b2. Adverse reactions (AR) data were collected within seven days after each vaccination. Serious adverse events and of special interest (AESI) were monitored throughout the study. We included 241 immunocompromised and 100 immunocompetent subjects. Arthralgia, fatigue, myalgia, and nausea were more frequent in the IC group after CoronaVac. Following the first additional dose of mRNA BNT162, pain, induration, and tenderness at injection site, fatigue and myalgia were more frequent in the H group. A heart transplant recipient had a graft rejection temporally associated with the second CoronaVac dose, but there was no literature evidence of causal association. Four cases of AESI were considered related to the vaccine: three erythema multiforme after CoronaVac, all in IC participants, and one paresthesia after mRNA, in a H participant. Our findings were comparable to other studies that evaluated the safety of COVID-19 vaccines in different immunocompromised populations. Both vaccines were safe for immunocompromised participants.

A Prospective Hospital Based Study of Placental Changes to Identify Antenatal and Perinatal Transmission of Sars CoV2 Infection

A Prospective Hospital Based Study of Placental Changes to Identify Antenatal and Perinatal Transmission of Sars CoV2 Infection

The association between different timeframes of air pollution exposure and COVID-19 incidence, morbidity and mortality in German counties in 2020

BackgroundAmbient air pollution is a known risk factor for several chronic health conditions, including pulmonary dysfunction. In recent years, studies have shown a positive association between exposure to air pollutants and the incidence, morbidity, and mortality of a COVID-19 infection, however the time period for which air pollution exposure is most relevant for the COVID-19 outcome is still not defined. The aim of this study was to analyze the difference in association when varying the time period of air pollution exposure considered on COVID-19 infection within the same cohort during the first wave of the pandemic in 2020.MethodsWe conducted a cross-sectional study analyzing the association between long- (10- and 2-years) and short-term (28 days, 7 days, and 2 days) exposure to NO2 and PM2.5 on SARS-CoV-2 incidence, morbidity, and mortality at the level of county during the first outbreak of the pandemic in spring 2020. Health data were extracted from the German national public health institute (Robert-Koch-Institute) and from the German Interdisciplinary Association for Intensive Care and Emergency Medicine. Air pollution data were taken from the APExpose dataset (version 2.0). We used negative binomial models, including adjustment for risk factors (age, sex, days since first COVID-19 case, population density, socio-economic and health parameters).ResultsWe found that PM2.5 and NO2 exposure 28 days before COVID-19 infection had the highest association with infection, morbidity as well as mortality, as compared to long-term or short-term (2 or 7 days) air pollutant exposure. A 1 μg/m3 increase in PM2.5 was associated with a 31.7% increase in incidence, a 20.6% need for ICU treatment, a 23.1% need for mechanical ventilation, and a 55.3% increase in mortality; an increase of 1 μg/m3 of NO2 was associated with an increase for all outcomes by 25.2 – 29.4%.ConclusionsOur findings show a positive association between PM2.5 and NO2 exposure and the clinical course of a SARS-CoV2 infection, with the strongest association to 28 days of exposure to air pollution. This finding provides an indication as to the primary underlying pathophysiology, and can therefore help to improve the resilience of societies by implementing adequate measures to reduce the air pollutant impact on health outcomes.Trial registrationNot applicable.

Subset of DN Memory B Cells Expressing Low Levels of Inhibitory Receptor BTLA Is Enriched in SLE Patients.

The dialogue between T and B cells can be regulated by different mechanisms, such as co-inhibitory receptors, which therefore play a crucial role in preventing autoimmune diseases such as systemic lupus erythematosus (SLE). B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor expressed on many myeloid and lymphoid cells. Although peripheral B cells express a very high amount of BTLA, previous works in the context of autoimmunity mainly focused on T cells, and whether BTLA expression on B cells plays a role in the lupus pathogenesis is still unclear. In the present study, we examine the expression of BTLA, as well as its ligand HVEM (Herpesvirus Entry Mediator), on various B cell subsets in lupus patients compared to healthy controls (HCs). We evidenced the existence of double-negative (DN; IgD-CD27-) memory B cells expressing very low levels of BTLA, which are enhanced in active lupus patients. An in-depth analysis revealed that these BTLAlow DN cells mainly correspond to the newly reported DN3 B cell subset, originally described in the context of SARS-CoV2 infection. These cells display an activated and antibody-secreting cell phenotype, and we propose that their low BTLA expression may favor their expansion and rapid differentiation into plasmablasts in lupus patients.

Predictors of sepsis in hospitalized COVID-19 patients

BackgroundViral sepsis has been suggested as a precise term to define multisystem dysregulated immune response and clinical sequelae in severe and critical COVID-19 cases. This work aimed to determine predictors of sepsis in those patients and to report their outcomes.MethodologyThis prospective observational clinical study took place on 120 patients aged more than 18 years old, both genders, and hospitalized patients with laboratory-verified SARS CoV-2 infection. Enrolled patients were allocated into two groups: sepsis group (n = 49) and no sepsis group (n = 71).ResultsCOVID-19 severity, National Early Warning Score (NEWS) risk, and Quick Sepsis-related Organ Failure Assessment (qSOFA) score were significantly elevated in sepsis group. Glasgow Coma Scale was significantly reduced in sepsis group (P < 0.05). Mortality, length of hospital stay, ICU admission, and ventilatory support were significantly higher in sepsis group (P < 0.05). Serum procalcitonin was significantly elevated in sepsis group (P < 0.05). Serum procalcitonin can significantly predict sepsis at cutoff > 0.5 µg/L with 89.8% sensitivity and 90% specificity. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and pH (decreased in sepsis group), heart rate (HR), platelets count, lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), qSOFA score, serum procalcitonin, and duration of hospitalization (increased in sepsis group) were independent predictors of sepsis.ConclusionsIn COVID-19 patients, decreased SBP, DBP, MAP, and pH while increased HR, respiratory rate, platelets, LDH, ESR, qSOFA score, serum procalcitonin, and duration of hospitalization were found to be independent predictors of sepsis.

Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. The rapid development of highly effective vaccines2,3 against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics4 have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity5. Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S-adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant (Kd) of 61 pM and a half-maximal effective concentration (EC50) of 11 nM, inhibiting virus infection in a cell-based system. TDI-015051 also inhibited viral replication in primary small airway epithelial cells and in a transgenic mouse model of SARS CoV-2 infection with an efficacy comparable with the FDA-approved reversible covalent protease inhibitor nirmatrelvir6. The inhibition of viral cap methylases as an antiviral strategy is also adaptable to other pandemic viruses.

Early combination of sotrovimab with nirmatrelvir/ritonavir or remdesivir is associated with low rate of persisting SARS CoV-2 infection in immunocompromised outpatients with mild-to-moderate COVID-19: a prospective single-centre study

Background Immunocompromised patients are at high risk of developing persisting/prolonged COVID-19. Data on the early combined use of antivirals and monoclonal antibodies in this population are scarce. Research design and methods We performed an observational, prospective study, enrolling immunocompromised outpatients with mild-to-moderate COVID-19, treated with a combination of sotrovimab plus one antiviral (remdesivir or nirmatrelvir/ritonavir) within 7 days from symptom onset. Primary outcome was hospitalization within 30 days. Secondary outcomes were: needing for oxygen therapy; development of persistent infection; death within 60 days and reinfection or relapse within 90 days. Results We enrolled 52 patients. No patient was hospitalized within 30 days of disease onset, required oxygen administration, died within 60 days, or experienced a reinfection or clinical relapse within 90 days. The clearance rates were 67% and 97% on the 14th day after the end of therapy and at the end of the follow-up period, respectively. Factors associated with longer infection were initiation of therapy 3 days after symptom onset and enrollment for more than 180 days from the beginning of the study. However, only the latter factor was independently associated with a longer SARS-CoV-2 infection, suggesting a loss of efficacy of this strategy with the evolution of SARS-CoV-2 variants. Conclusions Early administration of combination therapy with a direct antiviral and sotrovimab seems to be effective in preventing hospitalization, progression to severe COVID-19, and development of prolonged/persisting SARS-CoV-2 infection in immunocompromised patients.

Altered plasma levels of the SARS-CoV-2-related proteins ACE2 and TMPRSS2 in patients with Crohn’s disease

The SARS-CoV-2 coronavirus infects cells through the cellular receptor angiotensin-converting enzyme 2 (ACE2), and the protease TMPRSS2 for the priming of viral spike protein. Thus, changes in these key proteins due to chronic conditions can increase risk for SARS-CoV2 infection; but significance of changes may differ is these changes correspond to full-length species or proteolytic fragments. Here, we determined that full-length ACE2 decreased in the plasma of uninfected Crohn’s disease (CD) patients before treatment onset compared to controls. TMPRSS2 is mostly presented in plasma as full-length species and as an active peptidase fragment, but also as a prodomain fragment, which is the unique species remarkably decreased in plasma from CD patients. Patients treated with the anti-TNFα adalimumab showed recovery in ACE2 levels, while those treated with infliximab, or with the anti-IL-12/23 ustekinumab, still displayed a decrease in full-length species, as well as in cleaved fragments. Patients treated with azathioprine displayed similar ACE2 levels to that of controls, except a decrease in one of the ACE2 fragments. Uniquely, patients treated with azathioprine or with ustekinumab showed partial recovery in the reduction of the TMPRSS2-prodomain fragment characterized in treatment-naïve patients. Our data suggest that CD and common therapies are not related to increased susceptibility for SARS-CoV-2.

Features of chronic urticaria after COVID-19 mRNA vaccine over time

BackgroundNew onsets of chronic urticaria (CU) have been reported after repeated immunizations, mainly with the Moderna mRNA-1273 vaccine (Spikevax). This study aims to evaluate patients with CU after COVID-19 mRNA vaccination. The contribution of SARS-Cov2 infection, atopy and IgE against the vaccine was analyzed.MethodsWe monitored the features of patients who developed CU after vaccination through two surveys conducted in 2022 and 2023. Fifty individuals with CU underwent blood tests, and their results were compared with individuals without a history of urticaria (N = 135). The presence of anti-vaccine IgE was tested in 185 individuals with basophil activation tests (BAT). We assessed anti-SARS-Cov2 humoral response, and the presence of IgEs against common respiratory allergens (Phadiatop) as a surrogate for atopy.ResultsPost-vaccination CU occurs after a median interval of 10 days and significantly more after the Spikevax booster, affecting middle-aged individuals (median 41, 66% females). In 2023, CU was still active in 53% of the cases. Inducible forms of CU, primarily dermographism, are reported in 54% (2022) and 61% (2023) of the cases. BAT positivity is not specific to CU, anti-nucleocapsid positivity, or atopy but is significantly associated with higher anti-spike neutralizing activities and younger age. Four CU patients tolerate an additional dose of mRNA vaccine with no disease exacerbation/recurrence.ConclusionsThe spikevax booster induces anti-vaccine IgE independently of CU, the latter being not directly associated with COVID-19 infection nor atopy. The tolerance to a new booster in 4/4 patients suggests that the Spikevax vaccine indirectly triggers CU in predisposed individuals.

Neurological Sequelae of Post-COVID-19 Fatigue: A Narrative Review of Dipeptidyl Peptidase IV-Mediated Cerebrovascular Complications.

Coronavirus disease 2019 (COVID-19) has been a global pandemic affecting millions of people's lives, which has led to 'post-COVID-19 fatigue'. Alarmingly, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) not only infects the lungs but also influences the heart and brain. Endothelial cell dysfunction and hypercoagulation, which we know occur with this infection, lead to thrombo-inflammation that can manifest as many myriad cardio-cerebrovascular disorders, such as brain fog, fatigue, cognitive dysfunction, etc. Additionally, SARS-CoV-2 has been associated with oxidative stress, protein aggregation, cytokine storm, and mitochondrial dysfunction in neurodegenerative diseases. Accordingly, the identification of molecular targets involved in these actions could provide strategies for preventing and treating this disease. In particular, the very common enzyme dipeptidyl peptidase IV (DPPIV) has recently been identified as a candidate co-receptor for the cell entry of the SARS-CoV-2 virus with its involvement in infection. In addition, DPPIV has been reported as a co-receptor for some viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV). It mediates immunologic reactions and diseases such as type 2 diabetes mellitus, obesity, and hypertension, which have been considered the prime risk factors for stroke among other types of cardio-cerebrovascular diseases. Unlike angiotensin-converting enzyme 2 (ACE2), DPPIV has been implicated in aggravating the course of infection due to its disruptive effect on inflammatory signaling networks and the neuro-glia-vascular unit. Regarding the neurological, physiological, and molecular grounds governing post-COVID-19 fatigue, this review focuses on DPPIV as one of such reasons that progressively establishes cerebrovascular grievances following SARS-CoV infection.

A critical analysis of UK media characterisations of Long Covid in children and young people.

Long Covid is the continuation or development of symptoms related to a SARSCoV2 infection. Those with Long Covid may face epistemic injustice, where they are unjustifiably viewed as unreliable evaluators of their own illness experiences. Media articles both reflect and influence perception and subsequently how people regard children and young people (CYP) with Long Covid, and may contribute to epistemic injustice. We aimed to explore how the UK media characterises Long Covid in CYP through examining three key actor groups: parents, healthcare professionals, and CYP with Long Covid, through the lens of epistemic injustice. A systematic search strategy resulted in the inclusion of 103 UK media articles. We used an adapted corpus-assisted Critical Discourse Analysis in tandem with thematic analysis. Specifically, we utilised search terms to locate concordances of key actor groups. In the corpus, parents highlighted minimisation of Long Covid, barriers to care, and experiences of personal attacks. Mothers were presented as also having Long Covid. Fathers were unmentioned. Healthcare professionals emphasised the rarity of Long Covid in CYP, avoided pathologising Long Covid, and overemphasised psychological components. CYP were rarely consulted in media articles but were presented as formerly very able. Manifestations of Long Covid in CYP were validated or invalidated in relation to adults. Media characterisations contributed to epistemic injustice. The disempowering portrayal of parents promotes stigma and barriers to care. Healthcare professionals' narratives often contributed to negative healthcare experiences and enacted testimonial injustice, where CYP and parents' credibility was diminished due to unfair identity prejudice, in their invalidation of Long Covid. Media characterisations reveal and maintain a lack of societal framework for understanding Long Covid in CYP. The findings of this study illustrate the discursive practices employed by journalists that contribute to experiences of epistemic injustice. Based on our findings, we propose recommendations for journalists.

Anosmia and homoeopathy

Anosmia is a commonly reported symptom in COVID-19 patients that frequently occurs early in the course of the disease &amp; may persist as a long term symptom. SARS-COV2 infection has been suggested to cause the death of support cells in the olfactory epithelium with consequences for neuronal function.The article focuses on the age old concept of Ayurveda where it is advised to start feeling the senses as the day starts &amp; be aware of any changes with the comeback of Communicable Diseases (CD) such as the COVID 19 pandemic. As the CDs surged, the concept of eating while smelling the food emerged since the process of anosmia led to definitive changes in the nasal cavity that are definitive signs of COVID 19 infection. The current article sees the role of Homoeopathy of the AYUSH system in the process of anosmia due to COVID 19. Those adopting the process of healthy nasal health may use the therapeutic system of homeopathy to optimize the benefits of a healthy olfaction.After discussing the various modalities of anosmia, a homoeopathic treatment protocol is suggested on the lines of the markers mentioned above. The article aspires that this integration will help the nation to deal with the current &amp; future menace of CDs.

Abstract 4138507: Uncovering Risk Factors for Myocarditis and Cardiac Arrhythmia in Youth Post-SARS-CoV-2 Infection: Insights from the N3C Database and Advanced Machine Learning

Background: SARS-CoV2 infection has been associated with cardiovascular consequences, including myocarditis and cardiac arrhythmias. Myocarditis secondary to SARS-CoV2 infection and cardiac arrhythmias may often go unrecognized and can present with late and nonspecific symptoms. Predicting those at risk allows for prompt treatment and prevention of their potentially life-threatening consequences. Methods: The National COVID Cohort Collaborative (N3C) database was used to identify patients aged 0-30 years with COVID-19 index date between 1/1/2020 and 3/31/2022, whose sites provided data for at least six months beyond the index date. Outcomes included myocarditis and new arrythmias within 6 months of the index visit. Patients with known cardiac comorbidities were excluded. Predictors included gender, race, COVID severity as an ordinal scale, vaccination status, clinical comorbidities, and Area Deprivation Index (ADI). The data were stratified by age groups (0-4, 5-17, 18-30). Random forest models were used for data analysis and SHapley Additive exPlanations (SHAP) method was applied to optimize results. These analyses were conducted using the NCATS N3C Data Enclave. Results: Of the 1,487,741 patients in our study population, 4,105 (0.28%) had the measured outcomes; 404 had myocarditis only, 3,634 had arrhythmia only and 67 had both. Severity of COVID (SHAP 0.2344 for 0-4 years, 0.2114 for 5-17, 0.1370 for 18-30) was identified as the most important risk factor for de-novo myocarditis and arrhythmias overall. Increase in ADI (indicating lower socioeconomic status) was the second most important risk factor for the 0-4 and 5-17 age groups (SHAP: 0.0370, 0.0223). Among the 18-30 age group, race (SHAP 0.0321) and gender (SHAP 0.0289) were the second and third most important risk factors, with White and Black patients more likely to develop an event and Hispanic patients less likely. Women were less likely to develop a cardiac outcome than men. Conclusion: The severity of COVID was identified as the most important risk factor for the occurrence of myocarditis or cardiac arrhythmia within 6 months of infection. ADI, race, and gender were also identified as important, though less influential, risk factors.