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1.
Huan Jing Ke Xue ; 43(6): 2996-3004, 2022 Jun 08.
Article in Chinese | MEDLINE | ID: covidwho-1876194

ABSTRACT

The seasonal variation and spatial distribution of pharmaceuticals in typical drinking water sources in the middle reaches of the Yangtze River were analyzed using the solid-phase extraction and high-performance liquid chromatography-tandem mass spectrometry methods. Combined with the risk entropy method, the corresponding ecological risks for aquatic organisms were evaluated. The results showed that 80% of the target pharmaceuticals were detected in the drinking water sources, with average concentrations of 0.07-13.00 ng·L-1. The concentrations of the target pharmaceuticals were lower than or comparable with those in other drinking water sources reported in China. The spatiotemporal distribution of different pharmaceuticals varied. Generally, the detection level in winter was higher than that in summer, and there was no significant difference between that upstream and that downstream. This might be mainly attributed to seasonal/regional use and emissions of the pharmaceuticals, the impact of flow rate on dilution, and the impact of temperature on biodegradation. Compared with those before the COVID-19 epidemic, the detection concentrations of the target pharmaceuticals were relatively low. The reason for this might be that the prevention and control of the epidemic reduced the use and emission of the pharmaceuticals to a certain extent, and the high rainfall and runoff strengthened the dilution of water flow. The target pharmaceuticals, especially antibiotics, posed medium or low risks to aquatic organisms (especially algae). Considering the ecological risks and genotoxicity of pharmaceuticals and the potential risks of antibiotic-resistant genes, it is suggested to strengthen the investigation, evaluation, treatment, and control of pharmaceuticals in the water environment.


Subject(s)
COVID-19 , Drinking Water , Water Pollutants, Chemical , Anti-Bacterial Agents/analysis , Aquatic Organisms , China , Drinking Water/analysis , Environmental Monitoring/methods , Humans , Pharmaceutical Preparations , Risk Assessment , Water Pollutants, Chemical/analysis
2.
N Engl J Med ; 386(22): 2097-2111, 2022 06 02.
Article in English | MEDLINE | ID: covidwho-1830291

ABSTRACT

BACKGROUND: The ZF2001 vaccine, which contains a dimeric form of the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 and aluminum hydroxide as an adjuvant, was shown to be safe, with an acceptable side-effect profile, and immunogenic in adults in phase 1 and 2 clinical trials. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to investigate the efficacy and confirm the safety of ZF2001. The trial was performed at 31 clinical centers across Uzbekistan, Indonesia, Pakistan, and Ecuador; an additional center in China was included in the safety analysis only. Adult participants (≥18 years of age) were randomly assigned in a 1:1 ratio to receive a total of three 25-µg doses (30 days apart) of ZF2001 or placebo. The primary end point was the occurrence of symptomatic coronavirus disease 2019 (Covid-19), as confirmed on polymerase-chain-reaction assay, at least 7 days after receipt of the third dose. A key secondary efficacy end point was the occurrence of severe-to-critical Covid-19 (including Covid-19-related death) at least 7 days after receipt of the third dose. RESULTS: Between December 12, 2020, and December 15, 2021, a total of 28,873 participants received at least one dose of ZF2001 or placebo and were included in the safety analysis; 25,193 participants who had completed the three-dose regimen, for whom there were approximately 6 months of follow-up data, were included in the updated primary efficacy analysis that was conducted at the second data cutoff date of December 15, 2021. In the updated analysis, primary end-point cases were reported in 158 of 12,625 participants in the ZF2001 group and in 580 of 12,568 participants in the placebo group, for a vaccine efficacy of 75.7% (95% confidence interval [CI], 71.0 to 79.8). Severe-to-critical Covid-19 occurred in 6 participants in the ZF2001 group and in 43 in the placebo group, for a vaccine efficacy of 87.6% (95% CI, 70.6 to 95.7); Covid-19-related death occurred in 2 and 12 participants, respectively, for a vaccine efficacy of 86.5% (95% CI, 38.9 to 98.5). The incidence of adverse events and serious adverse events was balanced in the two groups, and there were no vaccine-related deaths. Most adverse reactions (98.5%) were of grade 1 or 2. CONCLUSIONS: In a large cohort of adults, the ZF2001 vaccine was shown to be safe and effective against symptomatic and severe-to-critical Covid-19 for at least 6 months after full vaccination. (Funded by the National Science and Technology Major Project and others; ClinicalTrials.gov number, NCT04646590.).


Subject(s)
COVID-19 Vaccines , COVID-19 , Vaccines, Subunit , Adolescent , Adult , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/therapeutic use , Double-Blind Method , Humans , SARS-CoV-2 , Vaccination , Vaccines , Vaccines, Subunit/adverse effects , Vaccines, Subunit/therapeutic use , Young Adult
3.
Chin Med J (Engl) ; 134(16): 1967-1976, 2021 07 22.
Article in English | MEDLINE | ID: covidwho-1769434

ABSTRACT

BACKGROUND: Innovative coronavirus disease 2019 (COVID-19) vaccines, with elevated global manufacturing capacity, enhanced safety and efficacy, simplified dosing regimens, and distribution that is less cold chain-dependent, are still global imperatives for tackling the ongoing pandemic. A previous phase I trial indicated that the recombinant COVID-19 vaccine (V-01), which contains a fusion protein (IFN-PADRE-RBD-Fc dimer) as its antigen, is safe and well tolerated, capable of inducing rapid and robust immune responses, and warranted further testing in additional clinical trials. Herein, we aimed to assess the immunogenicity and safety of V-01, providing rationales of appropriate dose regimen for further efficacy study. METHODS: A randomized, double-blind, placebo-controlled phase II clinical trial was initiated at the Gaozhou Municipal Centre for Disease Control and Prevention (Guangdong, China) in March 2021. Both younger (n = 440; 18-59 years of age) and older (n = 440; ≥60 years of age) adult participants in this trial were sequentially recruited into two distinct groups: two-dose regimen group in which participants were randomized either to follow a 10 or 25 µg of V-01 or placebo given intramuscularly 21 days apart (allocation ratio, 3:3:1, n = 120, 120, 40 for each regimen, respectively), or one-dose regimen groups in which participants were randomized either to receive a single injection of 50 µg of V-01 or placebo (allocation ratio, 3:1, n = 120, 40, respectively). The primary immunogenicity endpoints were the geometric mean titers of neutralizing antibodies against live severe acute respiratory syndrome coronavirus 2, and specific binding antibodies to the receptor binding domain (RBD). The primary safety endpoint evaluation was the frequencies and percentages of overall adverse events (AEs) within 30 days after full immunization. RESULTS: V-01 provoked substantial immune responses in the two-dose group, achieving encouragingly high titers of neutralizing antibody and anti-RBD immunoglobulin, which peaked at day 35 (161.9 [95% confidence interval [CI]: 133.3-196.7] and 149.3 [95%CI: 123.9-179.9] in 10 and 25 µg V-01 group of younger adults, respectively; 111.6 [95%CI: 89.6-139.1] and 111.1 [95%CI: 89.2-138.4] in 10 and 25 µg V-01 group of older adults, respectively), and remained high at day 49 after a day-21 second dose; these levels significantly exceed those in convalescent serum from symptomatic COVID-19 patients (53.6, 95%CI: 31.3-91.7). Our preliminary data show that V-01 is safe and well tolerated, with reactogenicity predominantly being absent or mild in severity and only one vaccine-related grade 3 or worse AE being observed within 30 days. The older adult participants demonstrated a more favorable safety profile compared with those in the younger adult group: with AEs percentages of 19.2%, 25.8%, 17.5% in older adults vs. 34.2%, 23.3%, 26.7% in younger adults at the 10, 25 µg V-01 two-dose group, and 50 µg V-01 one-dose group, respectively. CONCLUSIONS: The vaccine candidate V-01 appears to be safe and immunogenic. The preliminary findings support the advancement of the two-dose, 10 µg V-01 regimen to a phase III trial for a large-scale population-based evaluation of safety and efficacy. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx (No. ChiCTR2100045107, http://www.chictr.org.cn/showproj.aspx?proj=124702).


Subject(s)
COVID-19 , Aged , Antibodies, Viral , COVID-19/therapy , COVID-19 Vaccines , Double-Blind Method , Humans , Immunization, Passive , Recombinant Fusion Proteins , SARS-CoV-2
4.
Pharmaceuticals (Basel) ; 15(2)2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1699238

ABSTRACT

With the increased prevalence of new SARS-CoV-2 variants of concern, such as Delta and Omicron, the COVID-19 pandemic has become an ongoing human health disaster, killing millions worldwide. SARS-CoV-2 invades its host through the interaction of its spike (S) protein with a host cell receptor, angiotensin-converting enzyme 2 (ACE2). In addition, heparan sulfate (HS) on the surface of host cells plays an important role as a co-receptor for this viral pathogen-host cell interaction. Our previous studies demonstrated that many sulfated glycans, such as heparin, fucoidans, and rhamnan sulfate have anti-SARS-CoV-2 activities. In the current study, a small library of sulfated glycans and highly negatively charged compounds, including pentosan polysulfate (PPS), mucopolysaccharide polysulfate (MPS), sulfated lactobionic acid, sulodexide, and defibrotide, was assembled and evaluated for binding to the S-proteins and inhibition of viral infectivity in vitro. These compounds inhibited the interaction of the S-protein receptor-binding domain (RBD) (wild type and different variants) with immobilized heparin, a highly sulfated HS, as determined using surface plasmon resonance (SPR). PPS and MPS showed the strongest inhibition of interaction of heparin and S-protein RBD. The competitive binding studies showed that the IC50 of PPS and MPS against the S-protein RBD binding to immobilized heparin was ~35 nM and ~9 nM, respectively, much lower than the IC50 for soluble heparin (IC50 = 56 nM). Both PPS and MPS showed stronger inhibition than heparin on the S-protein RBD or spike pseudotyped lentiviral particles binding to immobilized heparin. Finally, in an in vitro cell-based assay, PPS and MPS exhibited strong antiviral activities against pseudotyped viral particles of SARS-CoV-2 containing wild-type or Delta S-proteins.

5.
Cell Discov ; 8(1): 17, 2022 Feb 15.
Article in English | MEDLINE | ID: covidwho-1692628

ABSTRACT

The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen. When compared with a homo-tri-RBD vaccine candidate in the stage of phase II trial, of which all three RBDs are derived from the SARS-CoV-2 prototype strain, mutI-tri-RBD induced significantly higher neutralizing antibody titers against the Delta and Beta variants, and maintained a similar immune response against the prototype strain. Pseudo-virus neutralization assay demonstrated that mutI-tri-RBD also induced broadly strong neutralizing activities against all tested 23 SARS-CoV-2 variants. The in vivo protective capability of mutI-tri-RBD was further validated in hACE2-transgenic mice challenged by the live virus, and the results showed that mutI-tri-RBD provided potent protection not only against the SARS-CoV-2 prototype strain but also against the Delta and Beta variants.

6.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-312630

ABSTRACT

Background: Since December 2019, COVID-19 has been confirmed in more than18.8 million patients and leads to 0.70 million deaths worldwide. The mortality and disease severity predictors of COVID-19 have been investigated in many studies. However, they are based on early or partial datasets from high epidemic areas. Here, we retrospect benign clinical and epidemiological outcomes-associated factors from a solved epidemic in a low epidemic area. Methods: : All 98 laboratory-confirmed COVID-19 patients in a local epidemic (Zhuhai, China) from January 17, 2020 to March 10, 2020 were enrolled. Data were updated until all patients having final outcomes. Results: : Patients were all hospitalized. The case fatality rate was 1.0%. There were no local secondary infection cases. The median age was 46.3 years. Underlying diseases were found in 33.7% patients. The severe/critical rate was 19.4%. The mean period from disease onset to admission was 4.4 days. Compared with serious/critical cases, mild/common cases on admission were much younger, lacks of comorbidities and normal in functions of vital organs and indicators of secondary bacterial infections. The lymphocyte counts in serious/critical cases began to be significantly lower 3 days before their identification dates. The absence of lymphopenia before the eighth day from disease onset can exclude the possibility of 78.5% to be serious/critical ill. Most patients (88.8%) received antiviral treatments. Early antiviral treatment significantly shortened the viral RNA-negative conversion time. The delayed antiviral treatment was associated with critical patients. Conclusions: : Younger age, lack of aging-related diseases and early hospitalization of all patients to conduct antiviral treatment and prevention of secondary epidemic were the important benign clinical and epidemiological outcomes-associated factors of COVID-19. In combating COVID-19, the active intervention strategies are crucial in low epidemic areas and the continuous monitoring of lymphocytes may be useful to sort patients reasonably in high epidemic areas.

7.
Signal Transduct Target Ther ; 7(1): 18, 2022 01 19.
Article in English | MEDLINE | ID: covidwho-1639142

ABSTRACT

Emerging SARS-CoV-2 variants are the most serious problem for COVID-19 prophylaxis and treatment. To determine whether the SARS-CoV-2 vaccine strain should be updated following variant emergence like seasonal flu vaccine, the changed degree on antigenicity of SARS-CoV-2 variants and H3N2 flu vaccine strains was compared. The neutralization activities of Alpha, Beta and Gamma variants' spike protein-immunized sera were analysed against the eight current epidemic variants and 20 possible variants combining the top 10 prevalent RBD mutations based on the Delta variant, which were constructed using pseudotyped viruses. Meanwhile, the neutralization activities of convalescent sera and current inactivated and recombinant protein vaccine-elicited sera were also examined against all possible Delta variants. Eight HA protein-expressing DNAs elicited-animal sera were also tested against eight pseudotyped viruses of H3N2 flu vaccine strains from 2011-2019. Our results indicate that the antigenicity changes of possible Delta variants were mostly within four folds, whereas the antigenicity changes among different H3N2 vaccine strains were approximately 10-100-fold. Structural analysis of the antigenic characterization of the SARS-CoV-2 and H3N2 mutations supports the neutralization results. This study indicates that the antigenicity changes of the current SARS-CoV-2 may not be sufficient to require replacement of the current vaccine strain.


Subject(s)
Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , COVID-19 Vaccines/metabolism , COVID-19/prevention & control , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Amino Acid Substitution , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/genetics , Antibodies, Viral/chemistry , Antibodies, Viral/genetics , Binding Sites , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/chemistry , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Gene Expression , Humans , Immune Sera/chemistry , Influenza A Virus, H3N2 Subtype/chemistry , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/immunology , Influenza Vaccines/administration & dosage , Influenza Vaccines/chemistry , Influenza Vaccines/metabolism , Influenza, Human/immunology , Influenza, Human/prevention & control , Influenza, Human/virology , Models, Molecular , Mutation , Neutralization Tests , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , SARS-CoV-2/chemistry , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
8.
Mar Drugs ; 19(12)2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1542656

ABSTRACT

The COVID-19 pandemic is a major human health concern. The pathogen responsible for COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), invades its host through the interaction of its spike (S) protein with a host cell receptor, angiotensin-converting enzyme 2 (ACE2). In addition to ACE2, heparan sulfate (HS) on the surface of host cells also plays a significant role as a co-receptor. Our previous studies demonstrated that sulfated glycans, such as heparin and fucoidans, show anti-COVID-19 activities. In the current study, rhamnan sulfate (RS), a polysaccharide with a rhamnose backbone from a green seaweed, Monostroma nitidum, was evaluated for binding to the S-protein from SARS-CoV-2 and inhibition of viral infectivity in vitro. The structural characteristics of RS were investigated by determining its monosaccharide composition and performing two-dimensional nuclear magnetic resonance. RS inhibition of the interaction of heparin, a highly sulfated HS, with the SARS-CoV-2 spike protein (from wild type and different mutant variants) was studied using surface plasmon resonance (SPR). In competitive binding studies, the IC50 of RS against the S-protein receptor binding domain (RBD) binding to immobilized heparin was 1.6 ng/mL, which is much lower than the IC50 for heparin (~750 ng/mL). RS showed stronger inhibition than heparin on the S-protein RBD or pseudoviral particles binding to immobilized heparin. Finally, in an in vitro cell-based assay, RS showed strong antiviral activities against wild type SARS-CoV-2 and the delta variant.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Deoxy Sugars/pharmacology , Mannans/pharmacology , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Seaweed , Antiviral Agents/therapeutic use , Aquatic Organisms , Deoxy Sugars/therapeutic use , Humans , Mannans/therapeutic use , Plant Extracts/therapeutic use , Protein Binding/drug effects , Spike Glycoprotein, Coronavirus/drug effects , Structure-Activity Relationship
9.
Sci Total Environ ; 818: 151711, 2022 Apr 20.
Article in English | MEDLINE | ID: covidwho-1517467

ABSTRACT

The outbreak of COVID-19 has led to the large-scale usage of chlorinated disinfectants in cities. Disinfectants and disinfection by-products (DBPs) enter rivers through urban drainage and surface runoff. We investigated the variations in residual chlorine, DBPs, and different aquatic organisms in the Hanjiang, Fuhe, and Qinglinghe Rivers in Wuhan during the COVID-19 pandemic. The sampling sites were from the wastewater treatment plant outlets to the downstream drinking water treatment plant intakes. Total residual chlorine and DBPs (dichloromethane and trichloromethane) detected in the river water ranged from 0 to 0.84 mg/L and 0 to 0.034 mg/L, respectively. The residual chlorine and DBPs showed a gradual reduction pattern related to water flow, and the concentration at intakes did not exceed the Chinese drinking water source quality standards. Phytoplankton and zooplankton densities were not significantly correlated with residual chlorine and DBPs. The fluctuations in phytoplankton resource use efficiency (RUE) and zooplankton RUE in the Fuhe River, with the highest residual chlorine, and the Qinglinghe River with the highest DBPs, were higher than those in the Hanjiang River. For benthic macroinvertebrates, the number of functional feeding groups in the Hanjiang River was higher than that in the Fuhe and Qinglinghe Rivers. The water and sediment bacterial communities in the Hanjiang River differed significantly from those in the Fuhe and Qingling Rivers. The denitrification function involved in N metabolism was stronger in the Fuhe and Qinglinghe Rivers. Structural equation modelling revealed that residual chlorine and DBPs impacted the diversity of benthos through direct and indirect effects on plankton. Although large-scale chlorine-containing disinfectants use occurred during the investigation, it did not harm the density of the detected aquatic organisms in water sources. With the regular use of chlorinated disinfectants for indoor and outdoor environments in response to the SARS-CoV-2 globally, it is still necessary to study the long-term and accumulated responses of water ecosystems exposed to chlorine-containing disinfectants.


Subject(s)
COVID-19 , Disinfectants , Water Pollutants, Chemical , Water Purification , Aquatic Organisms , Chlorine , Cities , Disinfection , Ecosystem , Halogenation , Humans , Pandemics , SARS-CoV-2 , Water Pollutants, Chemical/analysis
10.
Phys Med Biol ; 66(24)2021 12 06.
Article in English | MEDLINE | ID: covidwho-1493588

ABSTRACT

Coronavirus disease 2019 (COVID-19) has brought huge losses to the world, and it remains a great threat to public health. X-ray computed tomography (CT) plays a central role in the management of COVID-19. Traditional diagnosis with pulmonary CT images is time-consuming and error-prone, which could not meet the need for precise and rapid COVID-19 screening. Nowadays, deep learning (DL) has been successfully applied to CT image analysis, which assists radiologists in workflow scheduling and treatment planning for patients with COVID-19. Traditional methods use cross-entropy as the loss function with a Softmax classifier following a fully-connected layer. Most DL-based classification methods target intraclass relationships in a certain class (early, progressive, severe, or dissipative phases), ignoring the natural order of different phases of the disease progression,i.e.,from an early stage and progress to a late stage. To learn both intraclass and interclass relationships among different stages and improve the accuracy of classification, this paper proposes an ensemble learning method based on ordinal regression, which leverages the ordinal information on COVID-19 phases. The proposed method uses multi-binary, neuron stick-breaking (NSB), and soft labels (SL) techniques, and ensembles the ordinal outputs through a median selection. To evaluate our method, we collected 172 confirmed cases. In a 2-fold cross-validation experiment, the accuracy is increased by 22% compared with traditional methods when we use modified ResNet-18 as the backbone. And precision, recall, andF1-score are also improved. The experimental results show that our proposed method achieves a better classification performance than the traditional methods, which helps establish guidelines for the classification of COVID-19 chest CT images.


Subject(s)
COVID-19 , Deep Learning , COVID-19 Testing , Humans , SARS-CoV-2 , Tomography, X-Ray Computed
11.
Biomed Phys Eng Express ; 7(4)2021 05 20.
Article in English | MEDLINE | ID: covidwho-1225585

ABSTRACT

Segmenting lesion regions of Coronavirus Disease 2019 (COVID-19) from computed tomography (CT) images is a challenge owing to COVID-19 lesions characterized by high variation, low contrast between infection lesions and around normal tissues, and blurred boundaries of infections. Moreover, a shortage of available CT dataset hinders deep learning techniques applying to tackling COVID-19. To address these issues, we propose a deep learning-based approach known as PPM-Unet to segmenting COVID-19 lesions from CT images. Our method improves an Unet by adopting pyramid pooling modules instead of the conventional skip connection and then enhances the representation of the neural network by aiding the global attention mechanism. We first pre-train PPM-Unet on COVID-19 dataset of pseudo labels containing1600 samples producing a coarse model. Then we fine-tune the coarse PPM-Unet on the standard COVID-19 dataset consisting of 100 pairs of samples to achieve a fine PPM-Unet. Qualitative and quantitative results demonstrate that our method can accurately segment COVID-19 infection regions from CT images, and achieve higher performance than other state-of-the-art segmentation models in this study. It offers a promising tool to lay a foundation for quantitatively detecting COVID-19 lesions.


Subject(s)
COVID-19/complications , Deep Learning , Image Processing, Computer-Assisted/methods , Lung Diseases/pathology , Neural Networks, Computer , SARS-CoV-2/isolation & purification , Tomography, X-Ray Computed/methods , Algorithms , COVID-19/virology , Humans , Lung Diseases/diagnostic imaging , Lung Diseases/virology , Specimen Handling
12.
Lancet Infect Dis ; 21(8): 1107-1119, 2021 08.
Article in English | MEDLINE | ID: covidwho-1155669

ABSTRACT

BACKGROUND: Although several COVID-19 vaccines have been developed so far, they will not be sufficient to meet the global demand. Development of a wider range of vaccines, with different mechanisms of action, could help control the spread of SARS-CoV-2 globally. We developed a protein subunit vaccine against COVID-19 using a dimeric form of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein as the antigen. We aimed to assess the safety and immunogenicity of this vaccine, ZF2001, and determine the appropriate dose and schedule for an efficacy study. METHODS: We did two randomised, double-blind, placebo-controlled, phase 1 and phase 2 trials. Phase 1 was done at two university hospitals in Chongqing and Beijing, China, and phase 2 was done at the Hunan Provincial Center for Disease Control and Prevention in Xiangtan, China. Healthy adults aged 18-59 years, without a history of SARS-CoV or SARS-CoV-2 infection, an RT-PCR-positive test result for SARS-CoV-2, a history of contact with confirmed or suspected COVID-19 cases, and severe allergies to any component of the vaccine were eligible for enrolment. In phase 1, participants were randomly assigned (2:2:1) to receive three doses of the vaccine (25 µg or 50 µg) or placebo intramuscularly, 30 days apart. In phase 2, participants were randomly assigned (1:1:1:1:1:1) to receive the vaccine (25 µg or 50 µg) or placebo intramuscularly, 30 days apart, in either a two-dose schedule or a three-dose schedule. Investigators, participants, and the laboratory team were masked to group allocation. For phase 1, the primary outcome was safety, measured by the occurrence of adverse events and serious adverse events. For phase 2, the primary outcome was safety and immunogenicity (the seroconversion rate and the magnitude, in geometric mean titres [GMTs], of SARS-CoV-2-neutralising antibodies). Analyses were done on an intention-to-treat and per-protocol basis. These trials are registered with ClinicalTrials.gov (NCT04445194 and NCT04466085) and participant follow-up is ongoing. FINDINGS: Between June 22 and July 3, 2020, 50 participants were enrolled into the phase 1 trial and randomly assigned to receive three doses of placebo (n=10), the 25 µg vaccine (n=20), or the 50 µg vaccine (n=20). The mean age of participants was 32·6 (SD 9·4) years. Between July 12 and July 17, 2020, 900 participants were enrolled into the phase 2 trial and randomly assigned to receive two doses of placebo (n=150), 25 µg vaccine (n=150), or 50 µg vaccine (n=150), or three doses of placebo (n=150), 25 µg vaccine (n=150), or 50 µg vaccine (n=150). The mean age of participants was 43·5 (SD 9·2) years. In both phase 1 and phase 2, adverse events reported within 30 days after vaccination were mild or moderate (grade 1 or 2) in most cases (phase 1: six [60%] of ten participants in the placebo group, 14 [70%] of 20 in the 25 µg group, and 18 [90%] of 20 in the 50 µg group; phase 2: 37 [25%] of 150 in the two-dose placebo group, 43 [29%] of 150 in the two-dose 25 µg group, 50 [33%] of 150 in the two-dose 50 µg group, 47 [31%] of 150 in the three-dose placebo group, 72 [48%] of 150 in the three-dose 25 µg group, and 65 [43%] of 150 in the three-dose 50 µg group). In phase 1, two (10%) grade 3 or worse adverse events were reported in the 50 µg group. In phase 2, grade 3 or worse adverse events were reported by 18 participants (four [3%] in the two-dose 25 µg vaccine group, two [1%] in the two-dose 50 µg vaccine group, two [1%] in the three-dose placebo group, four [3%] in the three-dose 25 µg vaccine group, and six [4%] in the three-dose 50 µg vaccine group), and 11 were considered vaccine related (two [1%] in the two-dose 25 µg vaccine group, one [1%] in the two-dose 50 µg vaccine group, one [1%] in the three-dose placebo group, two [1%] in the three-dose 25 µg vaccine group, and five [3%] in the three-dose 50 µg vaccine group); seven participants reported serious adverse events (one [1%] in the two-dose 25 µg vaccine group, one [1%] in the two-dose 50 µg vaccine group, two [1%] in the three-dose placebo group, one [1%] in the three-dose 25 µg vaccine group, and two [1%] in the three-dose 50 µg vaccine group), but none was considered vaccine related. In phase 2, on the two-dose schedule, seroconversion rates of neutralising antibodies 14 days after the second dose were 76% (114 of 150 participants) in the 25 µg group and 72% (108 of 150) in the 50 µg group; on the three-dose schedule, seroconversion rates of neutralising antibodies 14 days after the third dose were 97% (143 of 148 participants) in the 25 µg group and 93% (138 of 148) in the 50 µg group. In the two-dose groups in phase 2, the SARS-CoV-2-neutralising GMTs 14 days after the second dose were 17·7 (95% CI 13·6-23·1) in the 25 µg group and 14·1 (10·8-18·3) in the 50 µg group. In the three-dose groups in phase 2, the SARS-CoV-2-neutralising GMTs 14 days after the third dose were 102·5 (95% CI 81·8-128·5) in the 25 µg group and 69·1 (53·0-90·0) in the 50 µg group. INTERPRETATION: The protein subunit vaccine ZF2001 appears to be well tolerated and immunogenic. The safety and immunogenicity data from the phase 1 and 2 trials support the use of the 25 µg dose in a three-dose schedule in an ongoing phase 3 trial for large-scale evaluation of ZF2001's safety and efficacy. FUNDING: National Program on Key Research Project of China, National Science and Technology Major Projects of Drug Discovery, Strategic Priority Research Program of the Chinese Academy of Sciences, and Anhui Zhifei Longcom Biopharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Antibodies, Viral/blood , COVID-19 Vaccines/adverse effects , Double-Blind Method , Female , Humans , Male , Middle Aged , Protein Multimerization , Tandem Repeat Sequences , Vaccination/adverse effects , Vaccines, Subunit/immunology , Vaccines, Synthetic/immunology
14.
Carbohydr Polym ; 260: 117797, 2021 May 15.
Article in English | MEDLINE | ID: covidwho-1084646

ABSTRACT

Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has resulted in a pandemic and continues to spread at an unprecedented rate around the world. Although a vaccine has recently been approved, there are currently few effective therapeutics to fight its associated disease in humans, COVID-19. SARS-CoV-2 and the related severe acute respiratory syndrome (SARS-CoV-1), and Middle East respiratory syndrome (MERS-CoV) result from zoonotic respiratory viruses that have bats as the primary host and an as yet unknown secondary host. While each of these viruses has different protein-based cell-surface receptors, each rely on the glycosaminoglycan, heparan sulfate as a co-receptor. In this study we compare, for the first time, differences and similarities in the structure of heparan sulfate in human and bat lungs. Furthermore, we show that the spike glycoprotein of COVID-19 binds 3.5 times stronger to human lung heparan sulfate than bat lung heparan sulfate.


Subject(s)
Heparitin Sulfate/metabolism , Lung/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Animals , Chiroptera , Female , Heparitin Sulfate/chemistry , Heparitin Sulfate/isolation & purification , Humans , Male , Molecular Structure , Molecular Weight , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/isolation & purification
15.
Biophys J ; 120(6): 1097-1104, 2021 03 16.
Article in English | MEDLINE | ID: covidwho-947143

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Computer simulations of complete viral particles can provide theoretical insights into large-scale viral processes including assembly, budding, egress, entry, and fusion. Detailed atomistic simulations are constrained to shorter timescales and require billion-atom simulations for these processes. Here, we report the current status and ongoing development of a largely "bottom-up" coarse-grained (CG) model of the SARS-CoV-2 virion. Data from a combination of cryo-electron microscopy (cryo-EM), x-ray crystallography, and computational predictions were used to build molecular models of structural SARS-CoV-2 proteins, which were then assembled into a complete virion model. We describe how CG molecular interactions can be derived from all-atom simulations, how viral behavior difficult to capture in atomistic simulations can be incorporated into the CG models, and how the CG models can be iteratively improved as new data become publicly available. Our initial CG model and the detailed methods presented are intended to serve as a resource for researchers working on COVID-19 who are interested in performing multiscale simulations of the SARS-CoV-2 virion.


Subject(s)
Molecular Dynamics Simulation , SARS-CoV-2/chemistry , Virion/chemistry , COVID-19 , Principal Component Analysis , Viral Proteins/chemistry
16.
bioRxiv ; 2020 Oct 02.
Article in English | MEDLINE | ID: covidwho-835255

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Computer simulations of complete viral particles can provide theoretical insights into large-scale viral processes including assembly, budding, egress, entry, and fusion. Detailed atomistic simulations, however, are constrained to shorter timescales and require billion-atom simulations for these processes. Here, we report the current status and on-going development of a largely "bottom-up" coarse-grained (CG) model of the SARS-CoV-2 virion. Structural data from a combination of cryo-electron microscopy (cryo-EM), x-ray crystallography, and computational predictions were used to build molecular models of structural SARS-CoV-2 proteins, which were then assembled into a complete virion model. We describe how CG molecular interactions can be derived from all-atom simulations, how viral behavior difficult to capture in atomistic simulations can be incorporated into the CG models, and how the CG models can be iteratively improved as new data becomes publicly available. Our initial CG model and the detailed methods presented are intended to serve as a resource for researchers working on COVID-19 who are interested in performing multiscale simulations of the SARS-CoV-2 virion. SIGNIFICANCE STATEMENT: This study reports the construction of a molecular model for the SARS-CoV-2 virion and details our multiscale approach towards model refinement. The resulting model and methods can be applied to and enable the simulation of SARS-CoV-2 virions.

17.
chemRxiv; 2020.
Preprint | ChemRxiv | ID: ppcovidwho-470

ABSTRACT

Our studies implied the golden compounds may be more effective against COVID 19 as they synergy inhibit SARS COV 2 replication and down regulation inflammation cytokine level. Our crystal structure studies firstly revealed Au (I) ions, derived from auranofin (AF) or gold cluster (GA), covalently bind sulfur atom of Cys145 and Cys156 of Mpro of SARS COV 2. The auranofin or gold cluster well inhibit Mpro activity in vitro. Auranofin or gold cluster could well suppress inflammation cytokine level of IL 6, IL 1β, TNF α via down regulation NF κactivation in macrophage. The cell viability and rat toxicity studies show gold cluster is more safety when compared FDA approved auranofin. The rat pharmacokinetic studies of gold cluster revealed its good bioavailability.

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