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Background: SARS-CoV-2 variants resistant to monoclonal antibodies, and drug-drug interactions and potential mutagenicity of direct acting antivirals, heightens the need for additional therapeutics to prevent progression to severe COVID-19. Exogenous interferon beta is a promising therapeutic option against SARS-CoV-2 given its broad-spectrum antiviral activity and data suggesting impaired endogenous IFN production in individuals with severe disease. Method(s): The safety and efficacy of orally inhaled nebulized interferon-beta1a (SNG001) was evaluated in a Phase II randomized controlled trial on the ACTIV-2/ A5401 platform (NCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized to SNG001 once daily for 14 days or blinded pooled placebo. Primary outcomes included treatment-emergent Grade >=3 adverse event (TEAE) through day 28;time to symptom improvement of 13 targeted COVID-19 symptoms collected by daily study diary through day 28;and SARS-CoV-2 RNA < lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs at days 3, 7, and 14. All-cause hospitalization or death through day 28 was a key secondary outcome. Result(s): Of 221 participants enrolled at 25 US sites between February and August 2021, 220 (110 SNG001, 110 placebo) initiated study intervention, with a median age of 40 years, 55% female, and 20% SARS-CoV-2 vaccinated. There was no significant difference between SNG001 and placebo in Grade >=3 TEAEs (4% vs 8%, Fisher's exact test p=0.25). Median time to symptom improvement was 13 days for SNG001 and 9 days for placebo (Gehan-Wilcoxon test p=0.17). There was no difference in the proportion of participants with SARS-CoV-2 RNA < LLoQ at day 3, 7 or 14 (SNG001 vs placebo, Day 3: 28% vs. 39%;Day 7: 65% vs. 66%;Day 10: 91% vs. 91%;joint Wald test p=0.41). There were fewer hospitalizations with SNG001 (n=1;1%) compared with placebo (n=7;6%), but this difference was not statistically significant (Fisher's exact test p=0.07;Figure). All hospitalizations were due to COVID-19 and occurred among unvaccinated participants without protocol-defined high-risk factors. Conclusion(s): Inhaled nebulized SNG001 was safe and well tolerated but did not reduce SARS-CoV-2 RNA levels in the nasopharynx nor decrease time to improvement of COVID-19 symptoms in outpatients with mild-to-moderate COVID-19. The non-statistically significant decrease in hospitalizations among SNG001 participants warrants further investigation in a phase 3 clinical trial. Cumulative incidence of hospitalization or death comparing SNG001 vs. placebo.
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Background: Given effectiveness of SARS-CoV-2 vaccines and outpatient antiviral and monoclonal antibody therapy for reducing progression to severe COVID-19, we sought to estimate the impact of these interventions on risk of hospitalization following SARS-CoV-2 infection in a large US healthcare system. Method(s): All patients >=18 of age in the UNC Health system, with first positive SARS-CoV-2 RT-PCR test or U07.1 ICD-10-CM (diagnosis date) during 07/01/2021- 05/31/2022, were included. The outcome was first hospitalization with U07.1 ICD-10-CM primary diagnosis <=14 days after SARS-CoV-2 diagnosis date. SARS-CoV-2 vaccinations were included if received >=14 days prior to diagnosis. Outpatient therapies were included if administered after diagnosis date and before hospital admission. Age, gender, race, ethnicity, and comorbidities associated with COVID-19 (using ICD-10-CM, if documented >=14 days prior to diagnosis date) were also evaluated. Risk ratios for hospitalization were estimated using generalized linear models, and predictors identified using extreme gradient boosting using feature influence with Shapley additive explanations algorithm. Result(s): The study population included 54,886 patients, 41% men and 27% >=60 years of age. One-third of SARS-CoV-2 diagnoses occurred July-December 2021 and 67% December-May 2022 (predominantly Delta and Omicron variants, respectively). Overall 7.0% of patients were hospitalized for COVID-19, with median hospitalization stay of 5 days (IQR: 3-9). 32% and 12% of patients received >=1 SARS-CoV-2 vaccine dose and outpatient therapy, respectively. Unadjusted and age-adjusted hospitalization risk decreased with vaccination and outpatient therapy (TABLE). Comparing patients who received 3 vaccine doses versus none we observed a 66% relative reduction in risk, with stronger association for more recent vaccination. For patients who received nirmatrelvir/ ritonavir versus no therapy we observed a 99% relative reduction in risk. In predictive models, older age was the most influential predictor of being hospitalized with COVID-19, while vaccination and outpatient therapy were the most influential factors predicting non-hospitalization. Conclusion(s): The impact of recent SARS-CoV-2 vaccination and outpatient antiviral and monoclonal antibody therapy on reducing COVID-19 hospitalization risk was striking in this large healthcare system covering Delta and Omicron variant timeframes. SARS-CoV-2 vaccinations and outpatient therapeutics are critical for preventing severe COVID-19. Unadjusted and age-adjusted risk ratios for hospitalization among patients with SARS-CoV-2.
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Background. Data are currently limited on the performance of SARS-CoV-2 RNA levels as predictors or surrogate markers for clinical outcomes in outpatients with mild-to-moderate COVID-19. Methods. This exploratory analysis used data from 2205 non-hospitalized adults who enrolled between August 2020 and July 2021 and participated in placebocontrolled evaluations of two monoclonal antibody (mAb) agents (bamlanivimab [n=317] or amubarvimab/romlusevimab [n=837]), and an open-label cohort of bamlanivimab recipients [n=1051] as part of the ACTIV-2/A5401 platform trial. SARS-CoV-2 RNA levels were measured in anterior nasal (AN) swabs and plasma at day 0 (pre-treatment) and AN at day 3. We fit regression models to estimate the association between RNA level or detection and subsequent hospitalization/death within 28 days of enrollment. Results. One-hundred four participants (53/571 [9%] on placebo and 51/ 1634 [3%] on mAb) died or were hospitalized through day 28. Median AN RNA levels were lower at day 3 compared to day 0 in both placebo (2.5 vs 4.0 log10 copies/mL [cp/mL]) and mAb (2.3 vs 4.9) groups. For placebo recipients, higher Day 0 AN RNA was associated with an increasing risk of hospitalization/ death, ranging from 3% to 16% for < 2 and >= 6 log10 cp/mL, respectively. Although only 1% had quantifiable plasma SARS-CoV-2 RNA, there was a similar trend for day 0 plasma RNA: 5% hospitalizations/death for undetectable RNA, 16% for detectable but not quantifiable RNA, and 80% for >= 2 log10 cp/mL. Among 485 placebo recipients with days 0 and 3 ANRNA results, the risk of subsequent hospitalization/death was highest among those with >= 5.0 log10 cp/mL at both days [8/78;10%] and lowest for those with unquantifiable levels at both days [0/124;0%]. Higher AN RNA at day 3 (adjusted for day 0 RNA) was associated with subsequent hospitalization/death among placebo recipients (relative risk (RR): 1.4 per log10 cp/mL;95%CI: 1.0, 2.1), but not mAb recipients (RR: 1.0;95%CI: 0.7, 1.6). Conclusion. These findings suggest that AN and plasma SARS-CoV-2 RNA levels are predictive of hospitalization/death in the natural history setting. However, different associations for mAb and placebo recipients raises concerns for using AN RNA as a surrogate for clinical outcomes in mAb trials. (Table Presented).
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The initial step of interaction of some pathogens with the host is driven by the interaction of glycoproteins of either side via endcaps of their glycans. These end caps consist of sialic acids or sugar molecules. Coronaviruses (CoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are found to use this route of interaction. The strength and spatial interactions on the single molecule level of sialic acids with either the spike (S) protein of SARS coronaviruses, or human angiotensin-converting enzyme 2 (ACE2) and furin are probed and compared to the binding modes of those sugar molecules which are present in glycans of glycoproteins. The protocol of using single molecules is seen as a simplified but effective mimic of the complex mode of interaction of the glycans. Averaged estimated binding energies from a docking approach result in preferential binding of the sialic acids to a specific binding site of the S protein of human coronavirus OC43 (HCoV-OC43). Furin is proposed to provide better binding sites for sialic acids than ACE2, albeit outweighed by sites for other sugar molecules. Absolute minimal estimated binding energies indicate weak binding affinities and are indifferent to the type of sugar molecules and the proteins. Neither the proposed best binding sites of the sialic acids nor those of the sugar molecules overlap with any of the cleavage sites at the S protein and the active sites of the human proteins. © 2021, AIMS Biophysics. All rights reserved.
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An algorithm is applied to propose a sequence-function correlation of the transmembrane domains (TMDs) of the non-structural protein 4B (NS4B) of hepatitis C virus (HCV). The putative sequence of the TMDs is obtained using 20 available secondary structure prediction programs (SSPPs) with different lengths of the overall amino acid sequence of the protein as input. The results support the notion of four helical TMDs. Whilst the region of the first TMDs leaves room for speculation about an additional TMD, the other three TMDs are consistently predicted. Structural features and the role of each of the TMDs is proposed by applying pairwise sequence alignment using BLAST on the level (i) protein sequence alignment and consequent (ii) function-related alignment. Sequence identity with those TMDs of proteins involved in Ca-homeostasis and generation of replication vesicles, such as Nsp3 of corona viruses, murine coronavirus especially mouse hepatitis virus (MEW), middle east respiratory syndrome coronavirus (MERS), severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2, are suggested. Focusing the search on those proteins in particular and their TMDs playing an active role in their mechanism of function, such as transporters, pumps, viral channel forming protein Vpu of human immunodeficiency virus type 1 (HIV-1) and mediators, suggests TMDs 2 and 4 to have functional roles in NS4B, as well as additionally TMD1 and 3 in case of vesicle formation.
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Background: The emergence of SARS-CoV-2 viral variants threatens current anti-viral and preventative strategies, including monoclonal antibodies and vaccines. Critically, the limited supply of vaccines and the complex logistics surrounding the delivery of infusion-based therapies herald the need for an easily produced, distributed, and specific direct-acting antiviral for COVID-19 that limits progression of illness and ideally prevents transmission. Methods: The efficacy of molnupiravir was evaluated in a double-blind, randomized, placebo-controlled, Phase 2 dose-range finding study using realtime polymerase chain reaction (RT-PCR) and virus isolation was conducted at 11 study sites in the U.S. Participants were randomized if they had signs or symptoms of COVID-19 within 7 days, and a positive SARS-CoV-2 RT-PCR within 4 days of enrollment. Initially, participants were randomized in a 1:1 ratio to receive 200 mg molnupiravir or placebo twice daily for 5 days. Subsequently, in the dose-range finding portion of the study, participants were randomized in a 3:1 ratio to receive 200, 400, or 800 mg molnupiravir or placebo twice daily for 5 days. Nasopharyngeal swabs were analyzed from 175 subjects at enrollment, Day 3, and Day 5 for SARS-CoV-2 infectivity. Samples were stored at 4°C for up to 72 hours, shipped refrigerated, aliquoted, and stored at -80°C until testing. Vero E6 cell monolayers were infected with the sample for 1 hour. Culture medium was analyzed for viral load at 2 and 5 days post-infection by RT-PCR. Results: Seventy-eight (45%) participants, median 4.62 days (min. 1.40, max. 7.54) from symptom onset, had a positive SARS-CoV-2 culture at enrollment (52 on active and 26 on placebo). The percentage of participants with a positive viral culture at enrollment who were positive on Day 3 was 20.4% on active and 28% on placebo (p = 0.56). At day 5, 24% of placebo participants were culturethe positive compared to none treated with molnupiravir (p = 0.001). Between treatment, comparisons were performed using Fisher's exact test. Conclusion: This is the first demonstration of reduced infectiousness by antiviral therapy in people with SARS-2 infection. This simple, short-course oral therapy may benefit individuals and public health and is unlikely to be impacted by spike-protein variants.
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INTRODUCTION: Severe acute respiratory failure is a common complication of COVID-19, with refractory hypoxemia being a hallmark finding in severe illness and a common cause of mortality. With limited therapeutic strategies, management centers on good supportive care. Prone positioning has been shown to improve oxygenation and survival in patients with moderate-to-severe acute respiratory distress syndrome (ARDS) but the impact of prone positioning in COVID-19 with severe hypoxemia is unknown. This study aims to examine the response to proning as a predictor of COVID-19 related mortality. METHODS: This is a single-center, retrospective analysis of critically ill patients with COVID-19 confirmed by PCR. Patients were included if they were invasively ventilated, and if supportive care included prone positioning for management of refractory hypoxemia. Data points collected include demographics, ventilator settings, rates of mortality and progression to ECMO, ventilator-days, and time between symptom onset and intubation, hospital and ICU admission. Endpoints included response in oxygenation (PaO2:FiO2) and mortality. RESULTS: Forty-nine patients were included in the analysis. The average age was 56.9, and 61% of the patients were male. Patients had an average of 19 ventilator-days (2-52), 21 ICU-days (4-54), 26 hospital-days (8-65), an ECMO rate of 27%, and a mortality rate of 55%. Of the 22 survivors, there was an average increase in PaO2:FiO2 by 108, 93.1, and 93 for each of the first three pronations respectively. For the 27 nonsurvivors, there was an average increase in PaO2:FiO2 by 76.1, 84.3, and 50.9 for the first three pronations. The difference in improvement in PaO2:FiO2 was not statistically significant between survivors and non-survivors. There was no inflection point that could be determined that provided a high sensitivity and specificity to predict mortality or need for ECMO based on response to pronation at any of the time points. CONCLUSIONS: Proning improves PaO2:FiO2 in patients with severe hypoxemia related to COVID-19. Survivors in our study had a numerically greater response to proning, but this finding was not statistically significant. The clinical significance remains unclear. Larger studies assessing the efficacy of proning in critically ill patients with COVID-19 are needed.
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INTRODUCTION: Early commentary on SARS-CoV-2 infection proposed a mechanism of cytokine release syndrome (CRS) to explain severe acute respiratory failure associated with COVID-19. Management strategies have included targeted immunomodulation with biologic agents. The role of IL-6 and other cytokines in the pathogenesis of COVID-19 is not well defined. Evidence for use of immunomodulators has been mixed and these agents may expose patients to harm. This study aims to characterize the expression of cytokines and their association with inflammatory biomarkers and outcomes in critically ill patients with COVID-19. METHODS: This was a single-center, retrospective analysis of critically ill patients with COVID-19 confirmed by PCR. Patients were included if they had a partial or full cytokine panel drawn while admitted. Descriptive statistics were used to assess demographics, outcomes, and relationships between cytokine levels and inflammatory markers. The Mann- Whitney U Test was used to compare IL-6 levels between survivors and nonsurvivors. RESULTS: Eighty-nine patients were included with 68 full cytokine panels and 108 IL-6 levels. Patients had a mean (range) of 10 ventilator-days (0-47), 15 ICU-days (1-60), 20 hospital-days (3-69) and a mortality rate of 31%. Cytokine levels were assessed a median of 10 days from symptom onset and 1 day from ICU admission. Levels of IL-1B, IL-2, IL-4, IL-5, IL-8, IL-12, IL-13, IL-17, IFN-G, and TNF-A were undetectable in at least 80% of patients, and expression did not correlate with other inflammatory biomarkers (CRP, ferritin), severity of illness (SOFA), or outcome. IL-2R levels were numerically elevated in most patients (n=68;median 1227, range: 76-30670). IL-6 levels were mildly elevated (n=108;median: 31, range: 2-882, SD: 150), and levels were statistically significantly higher in nonsurvivors (p = 0.002). CONCLUSIONS: Assessment of cytokine levels in critically ill patients with COVID-19 does not support a hypothesis of CRS. While IL-6 levels were numerically higher in nonsurvivors, the clinical significance of this finding is unknown. The role of IL-2R in the pathogenesis of COVID-19 remains unclear. Larger studies exploring the role of inflammatory mediators in pathogenesis and targeted immunomudulators in management of COVID-19 are warranted.