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1.
EBioMedicine ; 75: 103811, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1638699

ABSTRACT

BACKGROUND: We report on the safety and immunogenicity of V591, a measles vector-based SARS-CoV-2 vaccine candidate. METHODS: In this multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial, healthy adults with no history of COVID-19 disease were assigned to intramuscular injection of V591 or placebo (4:1 ratio). In part 1, younger adults (18-55 years) received V591 median tissue culture infectious dose (TCID50)-levels of 1×105 or 1×106 or placebo, 56 days apart. In part 2, younger and older (>55 years) adults received a single dose of one of four (104/105/106/107) or one of two (105/106) V591 TCID50 levels, respectively, or placebo. PRIMARY OUTCOME: safety/tolerability. Secondary outcome: humoral immunogenicity. ClinicalTrials.gov: NCT04498247. FINDINGS: From August-December 2020, 444 participants were screened and 263 randomised (210 V591; 53 placebo); 262 received at least one and 10 received two doses of V591 or placebo. Adverse events were experienced by 140/209 (67.0%) V591 dose-group participants and 37/53 (69.8%) placebo-group participants following injection 1; most frequent were fatigue (57 [27.3%] vs 20 [37.7%]), headache (57 [27.3%] vs 19 [35.8%]), myalgia (35 [16.7%] vs 10 [18.9%]), and injection-site pain (35 [16.7%] vs 4 [7.5%]). No deaths nor vaccine-related serious adverse events occurred. At Day 29, no anti-SARS-CoV-2 spike serum neutralising antibody and IgG-responses were identified in placebo or the three lower V591 dose-groups; responses were detected with V591 1×107 TCID50, although titres were lower than convalescent serum. INTERPRETATION: V591 was generally well tolerated, but immunogenicity was insufficient to warrant continued development. FUNDING: Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/immunology , Genetic Vectors , Immunogenicity, Vaccine , Measles virus , SARS-CoV-2/immunology , Adolescent , Adult , COVID-19/genetics , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Double-Blind Method , Female , Humans , Male , Middle Aged , SARS-CoV-2/genetics
2.
Biophys J ; 120(14): 2848-2858, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1607443

ABSTRACT

Large-scale conformational transitions in the spike protein S2 domain are required during host-cell infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Although conventional molecular dynamics simulations have been extensively used to study therapeutic targets of SARS-CoV-2, it is still challenging to gain molecular insight into the key conformational changes because of the size of the spike protein and the long timescale required to capture these transitions. In this work, we have developed an efficient simulation protocol that leverages many short simulations, a dynamic selection algorithm, and Markov state models to interrogate the structural changes of the S2 domain. We discovered that the conformational flexibility of the dynamic region upstream of the fusion peptide in S2 is coupled to the proteolytic cleavage state of the spike protein. These results suggest that opening of the fusion peptide likely occurs on a submicrosecond timescale after cleavage at the S2' site. Building on the structural and dynamical information gained to date about S2 domain dynamics, we provide proof of principle that a small molecule bound to a seam neighboring the fusion peptide can slow the opening of the fusion peptide, leading to a new inhibition strategy for experiments to confirm. In aggregate, these results will aid the development of drug cocktails to inhibit infections caused by SARS-CoV-2 and other coronaviruses.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Peptides , SARS-CoV-2 , Virus Internalization
3.
Sci Rep ; 11(1): 16307, 2021 08 11.
Article in English | MEDLINE | ID: covidwho-1354117

ABSTRACT

Structure-based drug design targeting the SARS-CoV-2 virus has been greatly facilitated by available virus-related protein structures. However, there is an urgent need for effective, safe small-molecule drugs to control the spread of the virus and variants. While many efforts are devoted to searching for compounds that selectively target individual proteins, we investigated the potential interactions between eight proteins related to SARS-CoV-2 and more than 600 compounds from a traditional Chinese medicine which has proven effective at treating the viral infection. Our original ensemble docking and cooperative docking approaches, followed by a total of over 16-micorsecond molecular simulations, have identified at least 9 compounds that may generally bind to key SARS-CoV-2 proteins. Further, we found evidence that some of these compounds can simultaneously bind to the same target, potentially leading to cooperative inhibition to SARS-CoV-2 proteins like the Spike protein and the RNA-dependent RNA polymerase. These results not only present a useful computational methodology to systematically assess the anti-viral potential of small molecules, but also point out a new avenue to seek cooperative compounds toward cocktail therapeutics to target more SARS-CoV-2-related proteins.


Subject(s)
Antiviral Agents/pharmacology , Drug Evaluation, Preclinical , Drugs, Chinese Herbal/pharmacology , Medicine, Chinese Traditional , SARS-CoV-2/drug effects , Viral Proteins/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Cats , Computational Biology , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/metabolism , Flavonoids/metabolism , Humans , Molecular Dynamics Simulation , Protein Binding , RNA-Dependent RNA Polymerase/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship
4.
Med Sci Monit ; 27: e929708, 2021 Apr 11.
Article in English | MEDLINE | ID: covidwho-1148368

ABSTRACT

BACKGROUND Since the outbreak of COVID-19 in December 2019, there have been 96 623 laboratory-confirmed cases and 4784 deaths by December 29 in China. We aimed to analyze the risk factors and the incidence of thrombosis from patients with confirmed COVID-19 pneumonia. MATERIAL AND METHODS Eighty-eight inpatients with confirmed COVID-19 pneumonia were reported (31 critical cases, 33 severe cases, and 24 common cases). The thrombosis risk factor assessment, laboratory results, ultrasonographic findings, and prognoses of these patients were analyzed, and compared among groups with different severity. RESULTS Nineteen of the 88 cases developed DVT (12 critical cases, 7 severe cases, and no common cases). In addition, among the 18 patients who died, 5 were diagnosed with DVT. Positive correlations were observed between the increase in D-dimer level (≥5 µg/mL) and the severity of COVID-19 pneumonia (r=0.679, P<0.01), and between the high Padua score (≥4) and the severity (r=0.799, P<0.01). In addition, the CRP and LDH levels on admission had positive correlations with the severity of illness (CRP: r=0.522, P<0.01; LDH: r=0.600, P<0.01). A negative correlation was observed between the lymphocyte count on admission and the severity of illness (r=-0.523, P<0.01). There was also a negative correlation between the lymphocyte count on admission and mortality in critical patients (r=-0.499, P<0.01). Univariable logistic regression analysis showed that the occurrence of DVT was positively correlated with disease severity (crude odds ratio: 3.643, 95% CI: 1.218-10.896, P<0.05). CONCLUSIONS Our report illustrates that critically or severely ill patients have an associated high D-dimer value and high Padua score, and illustrates that a low threshold to screen for DVT may help improve detection of thromboembolism in these groups of patients, especially in asymptomatic patients. Our results suggest that early administration of prophylactic anticoagulant would benefit the prognosis of critical patients with COVID-19 pneumonia and would likely reduce thromboembolic rates.


Subject(s)
COVID-19/complications , Fibrin Fibrinogen Degradation Products/analysis , Venous Thrombosis/epidemiology , Adult , Aged , Asymptomatic Diseases , COVID-19/blood , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Testing , China/epidemiology , Female , Hospital Mortality , Humans , Incidence , Lower Extremity/blood supply , Lower Extremity/diagnostic imaging , Male , Middle Aged , Patient Admission , Prognosis , Retrospective Studies , Risk Assessment/methods , Risk Assessment/statistics & numerical data , Risk Factors , SARS-CoV-2/isolation & purification , Severity of Illness Index , Ultrasonography , Venous Thrombosis/blood , Venous Thrombosis/diagnosis , Venous Thrombosis/etiology
5.
Jpn J Infect Dis ; 73(6): 404-410, 2020 Nov 24.
Article in English | MEDLINE | ID: covidwho-976564

ABSTRACT

This study aims to investigate blood and biochemical laboratory findings in patients with severe coronavirus disease 2019 (COVID-19) and to develop a joint predictor for predicting the likelihood of severe COVID-19 and its adverse clinical outcomes and to provide more information for treatment. We collected the data of 88 patients with laboratory-confirmed COVID-19. Further, the patients were divided into a non-severe group and a critical group (including critically ill cases). Univariate analysis showed that the absolute lymphocyte count, albumin level, albumin/globulin ratio, lactate dehydrogenase level, interleukin-6 (IL-6) level, erythrocyte count, globulin level, blood glucose level, and age were significantly correlated with the severity of COVID-19. The multivariate binary logistic regression model revealed that age, absolute lymphocyte count, and IL-6 level were independent risk factors in patients with COVID-19. The receiver operating characteristic curve revealed that the combination of IL-6 level, absolute lymphocyte count, and age is superior to a single factor as predictors for severe COVID-19, regardless of whether it is in terms of the area under the curve or the prediction sensitivity and specificity. Early application is beneficial to early identification of critically ill patients and timing individual treatments to reduce mortality.


Subject(s)
COVID-19 Testing , COVID-19/diagnosis , COVID-19/pathology , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19 Testing/statistics & numerical data , Female , Humans , Interleukin-6/blood , Logistic Models , Lymphocyte Count , Male , Middle Aged , ROC Curve , Retrospective Studies , Risk Assessment , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Young Adult
6.
J Clin Lab Anal ; 35(1): e23598, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-808714

ABSTRACT

OBJECTIVE: This study aims to investigate blood and biochemical laboratory findings in patients with coronavirus disease (COVID-19) and analyze the potential predictors of poor outcome in patients with COVID-19. METHODS: The clinical, laboratory, and outcome data of 87 patients with COVID-19 were collected and retrospectively analyzed. Only data collected at the time of admission were used in the analysis for predictors of poor outcome. These patients were divided into two groups: the adverse prognosis group (36 patients) and the non-adverse prognosis group (51 patients). The adverse prognosis of COVID-19 patients was defined as admission to the intensive care unit or death. RESULTS: On the univariate analysis, age, white blood cell (WBC) count, neutrophil counts, lymphocytes count, neutrophils-to-lymphocytes ratio (NLR), interleukin-6, albumin-to-globulin ratio (AGR), albumin, lactate dehydrogenase, glutamyl transpeptidase, and blood glucose were found to be the significant predictors. On the multivariate analysis, the predictors of poor outcome of patients with COVID-19 were NLR (OR = 2.741, [95% CI = 1.02 ~ 7.35], P = .045) and IL-6 (OR = 1.405, [95% CI = 1.04 ~ 1.89, P = .025]). The receiver operating characteristic (ROC) curve revealed that the AUC of NLR, interleukin-6, pneumonia severity index (PSI) score, and Confusion-Urea-Respiratory Rate-Blood pressure-65 (CURB-65) score were 0.883, 0.852, 0.824, and 0.782, respectively. CONCLUSION: High interleukin-6 (6 pg/mL, cuff value) and NLR (4.48, cuff value) can be used to predict poor outcomes in patients with COVID-19 on admission, thus can serve as a beneficial tool for timely identifying COVID-19 patients prone to poor outcome and reduce patient mortality through early intervention.


Subject(s)
COVID-19/blood , COVID-19/mortality , Adult , Aged , Aged, 80 and over , Blood Chemical Analysis , COVID-19/etiology , COVID-19/therapy , Female , Humans , Intensive Care Units , Interleukin-6/blood , Leukocyte Count , Lymphocyte Count , Male , Middle Aged , Multivariate Analysis , Neutrophils , Prognosis , ROC Curve , Retrospective Studies , Young Adult
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