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1.
Vaccines ; 10(5):702, 2022.
Article in English | MDPI | ID: covidwho-1820439

ABSTRACT

With the emergence and rapid spread of new pandemic variants, especially variants of concern (VOCs), the development of next-generation vaccines with broad-spectrum neutralizing activities is of great importance. In this study, SCTV01C, a clinical stage bivalent vaccine based on trimeric spike extracellular domain (S-ECD) of SARS-CoV-2 variants Alpha (B.1.1.7) and Beta (B.1.351) with a squalene-based oil-in-water adjuvant was evaluated in comparison to its two corresponding (Alpha and Beta) monovalent vaccines in mouse immunogenicity studies. The two monovalent vaccines induced potent neutralizing antibody responses against the antigen-matched variants, but drastic reductions in neutralizing antibody titers against antigen-mismatched variants were observed. In comparison, the bivalent vaccine SCTV01C induced relatively higher and broad-spectrum cross-neutralizing activities against various SARS-CoV-2 variants, including the D614G variant, VOCs (B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.1.529), variants of interest (VOIs) (C.37, B.1.621), variants under monitoring (VUMs) (B.1.526, B.1.617.1, B.1.429, C.36.3) and other variants (B.1.618, 20I/484Q). All three vaccines elicited potent Th1-biased T-cell immune responses. These results provide direct evidence that variant-based multivalent vaccines could play important roles in addressing the critical issue of reduced protective efficacy against the existing and emerging SARS-CoV-2 variants.

2.
Acta Pharmacol Sin ; 2022 Mar 16.
Article in English | MEDLINE | ID: covidwho-1747246

ABSTRACT

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25-800 mg. T1/2 was within 4.80-6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

3.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-316017

ABSTRACT

Corona virus disease 2019 (COVID-19) is currently a global pandemic It presents as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to COVID-19 infection. Despite the widespread use of symptomatic, antiviral, , and supportive treatment, the daily death toll from COVID-19 is still rising. The most common lethal complication is acute respiratory distress syndrome (ARDS). Mechanical ventilation is one of the necessary support methods of treating ARDS. Heliox (Helium-oxygen mixture) inhalation can reduce respiratory work of breathing, improve oxygenation, improve lung compliance, and effectively optimize the treatment of ARDS. Heliox also has potential anti-inflammatory, neuroprotective, and cardiac effects, and could reduce the inflammatory storm caused by SARS-CoV-2. This article reviews the properties of heliox, the therapeutic mechanism for ARDS, and the effects of heliox on inflammation, nerves, and the heart. Conclusion: We suggests that heliox is a potential treatment for COVID-19.

4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325434

ABSTRACT

Objective: To compare the epidemiological and clinical characteristics of confirmed and suspected corona virus disease 2019 (COVID-19) cases via the process of “triage-screening-isolation-transfer” in the hospitals of non-epidemic areas. Methods: : The general data, epidemiological history, clinical symptoms, laboratory examination, and chest computed tomography (CT) imaging characteristics of 38 patients with suspected COVID-19, admitted between January 21 and March 5, 2020, were analyzed. Results: : According to the results of the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) ribonucleic acid (RNA) testing, the patients were divided into study group (RNA positive) and control group (RNA negative). Ultimately, 8 cases were RNA-positive and diagnosed as CDVID-19, and 30 cases were negative. Approximately half of the patients in the study group returned to Chongqing from Wuhan;this number was significantly larger than that of the control group (P<0.05). The number of subjects in close contact with the confirmed cases with SARS-CoV-2 RNA-positive and the incidence of aggregation was significantly larger in the study group than in the control group (both P<0.05). The clinical symptom of the study group was mainly low fever (with or without cough). The patients with decreased white blood cells (WBC) in the study group were significantly more than those in the control group (P<0.05). Both group had reduced lymphocytes (Lym) but the number of patients with increased C-reactive protein (CRP) in the study group was significantly more than that in the control group (P<0.05). There were different degrees of chest CT abnormalities in both study and control group (P > 0.05). Conclusion: The epidemiological investigations in screening for infectious diseases is crucial. The risk of infection was high from the primary epidemic area and/or in close contact with the confirmed case. The most common form of clustering occurrence was family aggregation. CDVID-19 was mainly characterized by fever and respiratory symptoms, although asymptomatic infection may also occur. Decreased WBC, decreased Lym, and increased CRP are common characteristics but can also be combined with other respiratory tract virus infections. COVID 19 screening by chest CT alone had certain limitations in non- epidemic areas.

5.
Antimicrob Agents Chemother ; 65(8): e0035021, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1486470

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. This paper describes a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.).


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Antibodies, Neutralizing , Antibodies, Viral , China , Double-Blind Method , Humans
6.
Ann Palliat Med ; 10(8): 8972-8981, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1380166

ABSTRACT

BACKGROUND: The recent emergence of coronavirus disease 2019 (COVID-19) is a major global health threat. Monitoring viral transmission and disease characteristics as the disease spreads globally is vital. This study aimed to describe the clinical characteristics and source of infection in patients with secondary transmission of COVID-19 outside the outbreak area. METHODS: The epidemiological, demographic, clinical, laboratory, radiological, and treatment data of five patients with laboratory-confirmed COVID-19 who were treated in the General Hospital of Ningxia Medical University (Ningxia, China) from 1 January 2020 to 1 March 2020 were presented. The final follow-up evaluation was performed on 12 March 2020. RESULTS: The five participants included two couples and a young woman, none of whom had visited Hubei. It was likely that four of the participants had been infected by exposure to asymptomatic visitors from Wuhan. The other participant lived in a densely-populated community with potential COVID-19 cases. A variety of symptoms were presented by four participants, including cough, fevers, sputum, breathlessness, chest pain, fatigue, sore limbs, sore throats, headaches, and rhinorrhea. A severe infection, with dyspnea and decreased oxygen saturation, was experienced by one participant who had a history of chronic bronchitis. A single participant was asymptomatic, but had ground-glass opacities (GGOs) on chest imaging. Another two participants also displayed GGOs. Lymphopenia was noted in three participants. During the follow-up period, all participants were cured and discharged to their homes. CONCLUSIONS: This study included patients who had acquired infections of COVID-19 through local transmission. These findings will provide a better understanding of secondary transmission of COVID-19.


Subject(s)
COVID-19 , Cough , Disease Outbreaks , Female , Fever , Humans , Retrospective Studies , SARS-CoV-2
7.
EMBO J ; 40(18): e108249, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1323479

ABSTRACT

SARS-CoV-2 is an emerging coronavirus that causes dysfunctions in multiple human cells and tissues. Studies have looked at the entry of SARS-CoV-2 into host cells mediated by the viral spike protein and human receptor ACE2. However, less is known about the cellular immune responses triggered by SARS-CoV-2 viral proteins. Here, we show that the nucleocapsid of SARS-CoV-2 inhibits host pyroptosis by blocking Gasdermin D (GSDMD) cleavage. SARS-CoV-2-infected monocytes show enhanced cellular interleukin-1ß (IL-1ß) expression, but reduced IL-1ß secretion. While SARS-CoV-2 infection promotes activation of the NLRP3 inflammasome and caspase-1, GSDMD cleavage and pyroptosis are inhibited in infected human monocytes. SARS-CoV-2 nucleocapsid protein associates with GSDMD in cells and inhibits GSDMD cleavage in vitro and in vivo. The nucleocapsid binds the GSDMD linker region and hinders GSDMD processing by caspase-1. These insights into how SARS-CoV-2 antagonizes cellular inflammatory responses may open new avenues for treating COVID-19 in the future.


Subject(s)
COVID-19/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Nucleocapsid/metabolism , Phosphate-Binding Proteins/metabolism , Pyroptosis/physiology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Caspase 1/immunology , Caspase 1/metabolism , HEK293 Cells , Host-Pathogen Interactions , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Intracellular Signaling Peptides and Proteins/immunology , Mice , Monocytes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Phosphate-Binding Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , THP-1 Cells
8.
Antimicrob Agents Chemother ; 65(8): e0035021, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1223556

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. This paper describes a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.).


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Antibodies, Neutralizing , Antibodies, Viral , China , Double-Blind Method , Humans
9.
Natl Sci Rev ; 8(3): nwaa297, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-990776

ABSTRACT

Receptor recognition and subsequent membrane fusion are essential for the establishment of successful infection by SARS-CoV-2. Halting these steps can cure COVID-19. Here we have identified and characterized a potent human monoclonal antibody, HB27, that blocks SARS-CoV-2 attachment to its cellular receptor at sub-nM concentrations. Remarkably, HB27 can also prevent SARS-CoV-2 membrane fusion. Consequently, a single dose of HB27 conferred effective protection against SARS-CoV-2 in two established mouse models. Rhesus macaques showed no obvious adverse events when administrated with 10 times the effective dose of HB27. Cryo-EM studies on complex of SARS-CoV-2 trimeric S with HB27 Fab reveal that three Fab fragments work synergistically to occlude SARS-CoV-2 from binding to the ACE2 receptor. Binding of the antibody also restrains any further conformational changes of the receptor binding domain, possibly interfering with progression from the prefusion to the postfusion stage. These results suggest that HB27 is a promising candidate for immuno-therapies against COVID-19.

10.
Nano Today ; 35: 100976, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-779474

ABSTRACT

The recent COVID-19 outbreak has increasingly engaged researchers in the search for effective antiviral drugs as well as therapeutic treatment options. The shortcomings of existing antiviral agents such as narrow spectrum and low bioavailability, can be overcome through the use of engineered nanomaterials, which, therefore, are considered as a significant next-generation therapeutic option. Thus, the development of novel antiviral nanoagents will certainly help address several future challenges and knowledge gaps.

11.
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