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1.
Signal Transduct Target Ther ; 7(1): 172, 2022 Jun 06.
Article in English | MEDLINE | ID: covidwho-1878517

ABSTRACT

The increased coronavirus disease 2019 (COVID-19) breakthrough cases pose the need of booster vaccination. We conducted a randomised, double-blinded, controlled, phase 2 trial to assess the immunogenicity and safety of the heterologous prime-boost vaccination with an inactivated COVID-19 vaccine (BBIBP-CorV) followed by a recombinant protein-based vaccine (NVSI-06-07), using homologous boost with BBIBP-CorV as control. Three groups of healthy adults (600 individuals per group) who had completed two-dose BBIBP-CorV vaccinations 1-3 months, 4-6 months and ≥6 months earlier, respectively, were randomly assigned in a 1:1 ratio to receive either NVSI-06-07 or BBIBP-CorV boost. Immunogenicity assays showed that in NVSI-06-07 groups, neutralizing antibody geometric mean titers (GMTs) against the prototype SARS-CoV-2 increased by 21.01-63.85 folds on day 28 after vaccination, whereas only 4.20-16.78 folds of increases were observed in control groups. For Omicron variant, the neutralizing antibody GMT elicited by homologous boost was 37.91 on day 14, however, a significantly higher neutralizing GMT of 292.53 was induced by heterologous booster. Similar results were obtained for other SARS-CoV-2 variants of concerns (VOCs), including Alpha, Beta and Delta. Both heterologous and homologous boosters have a good safety profile. Local and systemic adverse reactions were absent, mild or moderate in most participants, and the overall safety was quite similar between two booster schemes. Our findings indicated that NVSI-06-07 is safe and immunogenic as a heterologous booster in BBIBP-CorV recipients and was immunogenically superior to the homologous booster against not only SARS-CoV-2 prototype strain but also VOCs, including Omicron.


Subject(s)
COVID-19 Vaccines , COVID-19 , Immunization, Secondary , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , SARS-CoV-2
2.
Chaos ; 32(5): 053102, 2022 May.
Article in English | MEDLINE | ID: covidwho-1852629

ABSTRACT

The spreading of novel coronavirus (SARS-CoV-2) has gravely impacted the world in the last year and a half. Understanding the spatial and temporal patterns of how it spreads at the early stage and the effectiveness of a governments' immediate response helps our society prepare for future COVID-19 waves or the next pandemic and contain it before the spreading gets out of control. In this article, a susceptible-exposed-infectious-removed model is used to model the city-to-city spreading patterns of the disease at the early stage of its emergence in China (from December 2019 to February 2020). Publicly available reported case numbers in 312 Chinese cities and between-city mobility data are leveraged to estimate key epidemiological characteristics, such as the transmission rate and the number of infectious people for each city. It is discovered that during any given time period, there are always only a few cities that are responsible for spreading the disease to other cities. We term these few cities as transmission centers. The spatial and temporal changes in transmission centers demonstrate predictable patterns. Moreover, rigorously designed experiments show that in controlling the disease spread in a city, non-pharmaceutical interventions (NPIs) implemented at transmission centers are more effective than the NPI implemented in the city itself. These findings have implications on the control of an infectious disease at the early stage of its spreading: implementing NPIs at transmission centers at early stages is effective in controlling the spread of infectious diseases.


Subject(s)
COVID-19 , Communicable Diseases , COVID-19/epidemiology , Humans , Pandemics/prevention & control , Policy , SARS-CoV-2
3.
Materials (Basel) ; 15(8)2022 Apr 18.
Article in English | MEDLINE | ID: covidwho-1810011

ABSTRACT

In this work, the epitaxial semipolar (11-22) AlN was prepared on nonpolar m-sapphire substrate by combining sputtering and high-temperature annealing. According to our systematic measurements and analysis from XRD, Raman spectra, and AFM, the evolution of crystalline structure and morphology was investigated upon increasing AlN thickness and annealing duration. The annealing operation intensively resets the lattice and improves the crystalline quality. By varying the film thickness, the contribution from the AlN-sapphire interface on crystalline quality and lattice parameters during the annealing process was investigated, and its contribution was found to be not so obvious when the thickness increased from 300 nm to 1000 nm. When the annealing was performed under durations from 1 to 5 h, the crystalline quality was found unchanged; meanwhile, the evolution of morphology was pronounced, and it means the crystalline reorganization happens prior to morphology reset. Finally, the annealing treatment enabled a zig-zag morphology on the AlN template along the sapphire [0001] direction in the plane, which potentially affects the subsequent device epitaxy process. Therefore, our results act as important experience for the semipolar nitride semiconductor laser device preparation, particularly for the epitaxy of microcavity structure through providing the crystalline evolution.

4.
Biochem Biophys Res Commun ; 611: 190-194, 2022 06 30.
Article in English | MEDLINE | ID: covidwho-1800190

ABSTRACT

The 3C-like protease (Mpro, 3CLpro) plays a key role in the replication process in coronaviruses (CoVs). The Mpro is an essential enzyme mediates CoVs replication and is a promising target for development of antiviral drugs. Until now, baicalein has been shown the specific activity for SARS-CoV Mpro in vitro experiments. In this study, we resolved the SARS-CoV Mpro with baicalein by X-ray diffraction at 2.25 Å (PDB code 7XAX), which provided a structural basis for the research and development of baicalein as an anti-CoVs drug.


Subject(s)
SARS Virus , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases , Flavanones , Peptide Hydrolases , Protease Inhibitors/chemistry , SARS-CoV-2
5.
J Virol ; 96(8): e0201321, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1779314

ABSTRACT

The high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One region that appears highly conserved among different genera of coronaviruses is the substrate-binding site of the main protease (Mpro or 3CLpro), making it an attractive target for the development of broad-spectrum drugs for multiple coronaviruses. PF-07321332, developed by Pfizer, is the first orally administered inhibitor targeting the main protease of SARS-CoV-2, which also has shown potency against other coronaviruses. Here, we report three crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome (MERS)-CoV bound to the inhibitor PF-07321332. The structures reveal a ligand-binding site that is conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV, providing insights into the mechanism of inhibition of viral replication. The long and narrow cavity in the cleft between domains I and II of the main protease harbors multiple inhibitor-binding sites, where PF-07321332 occupies subsites S1, S2, and S4 and appears more restricted than other inhibitors. A detailed analysis of these structures illuminated key structural determinants essential for inhibition and elucidated the binding mode of action of the main proteases from different coronaviruses. Given the importance of the main protease for the treatment of SARS-CoV-2 infection, insights derived from this study should accelerate the design of safer and more effective antivirals. IMPORTANCE The current pandemic of multiple variants has created an urgent need for effective inhibitors of SARS-CoV-2 to complement vaccine strategies. PF-07321332, developed by Pfizer, is the first orally administered coronavirus-specific main protease inhibitor approved by the FDA. We solved the crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and MERS-CoV that bound to the PF-07321332, suggesting PF-07321332 is a broad-spectrum inhibitor for coronaviruses. Structures of the main protease inhibitor complexes present an opportunity to discover safer and more effective inhibitors for COVID-19.


Subject(s)
Lactams , Leucine , Nitriles , Peptide Hydrolases , Proline , Antiviral Agents/chemistry , Antiviral Agents/metabolism , COVID-19/drug therapy , Humans , Lactams/chemistry , Lactams/metabolism , Leucine/chemistry , Leucine/metabolism , Middle East Respiratory Syndrome Coronavirus/chemistry , Middle East Respiratory Syndrome Coronavirus/enzymology , Nitriles/chemistry , Nitriles/metabolism , Peptide Hydrolases/chemistry , Peptide Hydrolases/metabolism , Proline/chemistry , Proline/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , SARS Virus/chemistry , SARS Virus/enzymology , SARS-CoV-2/chemistry , SARS-CoV-2/enzymology
6.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331897

ABSTRACT

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the inactivated vaccine BBIBP-CorV. Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

7.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331863

ABSTRACT

The huge disturbance caused by the sudden outbreak of COVID-19 to the short-term passenger flow of railway. The daily passenger flow curves of periodic and seasonal non-stationary time series of Spring Festival travel under the COVID-19 pandemic were analyzed, and the combined model based on SARIMA-LTSM was constructed. SARIMA model was used to predict the linear part and LSTM rolling optimization model was used to predict the nonlinear part. Finally, the two prediction results were put into the weighted sum of attention mechanism module, and the GRU gated loop unit was introduced to assist verification. Through case study and analysis, the results show that the prediction results of SARIMA-LTSM combined model have good control and high accuracy, which can provide theoretical basis for the close representation and prediction of short-term passenger flow data set of epidemic emergencies.

8.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330833

ABSTRACT

Wastewater surveillance serves as a promising approach to elucidate the silent transmission of SARS-CoV-2 in a given community by detecting the virus in wastewater treatment facilities. This study monitored the viral RNA abundance at one WWTP and three communities during the COVID-19 outbreak in the Yanta district of Xi’an city from December 2021 to January 2022. To further understand the decay of the coronavirus in sewage pipes, avian infectious bronchitis virus (IBV) was seeded in two recirculating water systems and operated for 90 days. Based on the viral abundance in the wastewater of Xi’an and the above data regarding the decay of coronavirus in sewage pipes, Monte Carol simulations were performed to estimate the infectious cases in Xi’an. The results suggested that the delta variant was first detected on Dec-10, five days earlier than the reported date of clinical samples. SARS-CoV-2 was detected on Dec 18 in the monitored community two days earlier than the first case and was consecutively detected in the following two sampling times. In pipelines without biofilms, the results showed that high temperature significantly reduced the viral RNA abundance by 3.1 log 10 GC/ml after experiencing 20 km travel distance, while only a 1.6 log 10 GC/L reduction was observed in the pipeline with a low water temperature. After 90 days of operation, the biofilm matured in the pipeline in both systems. Reductions of 2.14 and 4.79 log 10 GC/L were observed in high- and low-temperature systems, respectively. Based on the above results, we adjusted the input parameters for Monte Carol simulation and estimated 23.3, 50.1, 127.3 and 524.2 infected persons in December 14, 18, 22 and 26, respectively, which is largely consistent with the clinical reports. This work highlights the viability of wastewater surveillance for the early warning of COVID-19 at both the community and city levels, which represents a valuable complement to clinical approaches.

9.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329783

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with immune escape ability raises the urgent need for developing cross-neutralizing vaccines against the virus. NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine that integrates the antigens from multiple SARS-CoV-2 strains into a single immunogen. Here, we evaluated the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in adults previously vaccinated with the inactivated vaccine BBIBP-CorV in a randomized, double-blind, controlled, phase 2 trial conducted in the United Arab Emirates ( NCT05069129 ). Three groups of healthy adults over 18 years of age (600 participants per group) who had administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, were vaccinated with either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The primary outcome was immunogenicity and safety of booster vaccinations. The exploratory outcome was cross-reactive immunogenicity against multiple SARS-CoV-2 variants of concerns (VOCs). The incidence of adverse reactions was low in both booster vaccinations, and the overall safety profile of heterologous boost was quite similar to that of homologous boost. Heterologous NVSI-06-08 booster was immunogenically superior to homologous booster of BBIBP-CorV. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster were significantly higher than by the booster of BBIBP-CorV against not only SARS-CoV-2 prototype strain but also multiple VOCs. Especially, the neutralizing activity induced by NVSI-06-08 booster against the immune-evasive Beta variant was no less than that against the prototype strain, and a considerable level of neutralizing antibodies against Omicron (GMT: 367.67;95%CI, 295.50-457.47) was induced by heterologous booster, which was substantially higher than that boosted by BBIBP-CorV (GMT: 45.03;95%CI, 36.37-55.74). Our findings showed that NVSI-06-08 was safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which was immunogenically superior to homologous boost with another dose of BBIBP-CorV. Our study also indicated that the design of hybrid antigen may provide an effective strategy for broad-spectrum vaccine developments.

10.
Frontiers in chemistry ; 10, 2022.
Article in English | EuropePMC | ID: covidwho-1733209

ABSTRACT

Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), the pathogen of the Coronavirus disease-19 (COVID-19), is still devastating the world causing significant chaos to the international community and posing a significant threat to global health. Since the first outbreak in late 2019, several lines of intervention have been developed to prevent the spread of this virus. Nowadays, some vaccines have been approved and extensively administered. However, the fact that SARS-CoV-2 rapidly mutates makes the efficacy and safety of this approach constantly under debate. Therefore, antivirals are still needed to combat the infection of SARS-CoV-2. Papain-like protease (PLpro) of SARS-CoV-2 supports viral reproduction and suppresses the innate immune response of the host, which makes PLpro an attractive pharmaceutical target. Inhibition of PLpro could not only prevent viral replication but also restore the antiviral immunity of the host, resulting in the speedy recovery of the patient. In this review, we describe structural and functional features on PLpro of SARS-CoV-2 and the latest development in searching for PLpro inhibitors. Currently available inhibitors targeting PLpro as well as their structural basis are also summarized.

11.
Journal of Physics: Conference Series ; 2194(1):012010, 2022.
Article in English | ProQuest Central | ID: covidwho-1730587

ABSTRACT

Since the end of 2019, the Corona Virus Disease 2019 (COVID-19) pandemic has led to a surge in the use of all kinds of medical supplies, especially surgical masks. Based on the microstructure and anti-virus mechanism of melt-blown materials used for medical masks, this paper introduces the research status of nonwoven filter materials used for protective masks. At the same time, the surface interface structure of four disposable medical protective masks from different manufacturers was analyzed by scanning electron microscope, and the difference of melt-blown materials of these masks was studied. The results show that the fiber diameter of melt-blown mask with better protective effect is fine and compact, and the aperture formed between fibers is smaller. This reasearch provides new ideas for further research and development of non-woven materials for medical masks.

12.
Mol Med ; 28(1): 27, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1724403

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome, which is a more severe form of ALI, are life-threatening clinical syndromes observed in critically ill patients. Treatment methods to alleviate the pathogenesis of ALI have improved to a great extent at present. Although the efficacy of these therapies is limited, their relevance has increased remarkably with the ongoing pandemic caused by the novel coronavirus disease 2019 (COVID-19), which causes severe respiratory distress syndrome. Several studies have demonstrated the preventive and therapeutic effects of molecular hydrogen in the various diseases. The biological effects of molecular hydrogen mainly involve anti-inflammation, antioxidation, and autophagy and cell death modulation. This review focuses on the potential therapeutic effects of molecular hydrogen on ALI and its underlying mechanisms and aims to provide a theoretical basis for the clinical treatment of ALI and COVID-19.


Subject(s)
Acute Lung Injury/drug therapy , COVID-19/drug therapy , Hydrogen/pharmacology , Protective Agents/pharmacology , Acute Lung Injury/physiopathology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Humans , Sepsis/drug therapy , Sepsis/physiopathology
13.
Anal Chem ; 94(10): 4446-4454, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1713092

ABSTRACT

The enrichment of co-reactants is one of the keys to improving the sensitivity of electrochemiluminescence (ECL) detection. This work developed a novel hydrophobic localized enrichment strategy of co-reactants utilizing the inner hydrophobic cavity of ß-cyclodextrin (ß-CD). Pt nanoparticles (Pt NPs) were grown in situ on the coordination sites for metal ions of ß-CD to prepare the ß-CD-Pt nanocomposite, which could not only enrich co-reactant 3-(dibutylamino) propylamine (TDBA) highly efficiently through its hydrophobic cavity but also immobilize TDBA via the Pt-N bond. Meanwhile, the carboxyl-functionalized poly[2,5-dioctyl-1,4-phenylene] (PDP) polymer nanoparticles (PNPs) were developed as excellent ECL luminophores. With SARS-CoV-2 nucleocapsid protein (ncovNP) as a model protein, the TDBA-ß-CD-Pt nanocomposite combined PDP PNPs to construct a biosensor for ncovNP determination. The PDP PNPs were modified onto the surface of a glassy carbon electrode (GCE) to capture the first antibody (Ab1) and further capture antigen and secondary antibody complexes (TDBA-ß-CD-Pt@Ab2). The resultant biosensor with a sandwich structure achieved a highly sensitive detection of ncovNP with a detection limit of 22 fg/mL. TDBA-ß-CD-Pt shared with an inspiration in hydrophobic localized enrichment of co-reactants for improving the sensitivity of ECL detection. The luminophore PDP PNPs integrated TDBA-ß-CD-Pt to provide a promising and sensitive ECL platform, offering a new method for ncovNP detection.


Subject(s)
Biosensing Techniques , COVID-19 , Metal Nanoparticles , Biosensing Techniques/methods , Electrochemical Techniques/methods , Humans , Limit of Detection , Luminescent Measurements/methods , Metal Nanoparticles/chemistry , Nucleocapsid Proteins , Polymers/chemistry , SARS-CoV-2
14.
J Zhejiang Univ Sci B ; 23(2): 102-122, 2022 Feb 15.
Article in English | MEDLINE | ID: covidwho-1706587

ABSTRACT

Molecular hydrogen exerts biological effects on nearly all organs. It has anti-oxidative, anti-inflammatory, and anti-aging effects and contributes to the regulation of autophagy and cell death. As the primary organ for gas exchange, the lungs are constantly exposed to various harmful environmental irritants. Short- or long-term exposure to these harmful substances often results in lung injury, causing respiratory and lung diseases. Acute and chronic respiratory diseases have high rates of morbidity and mortality and have become a major public health concern worldwide. For example, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. An increasing number of studies have revealed that hydrogen may protect the lungs from diverse diseases, including acute lung injury, chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary arterial hypertension, and pulmonary fibrosis. In this review, we highlight the multiple functions of hydrogen and the mechanisms underlying its protective effects in various lung diseases, with a focus on its roles in disease pathogenesis and clinical significance.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Hydrogen/therapeutic use , Lung Diseases/therapy , Acute Lung Injury , Aging , Animals , Anti-Inflammatory Agents , Antioxidants/chemistry , Asthma/therapy , Autophagy , COVID-19/drug therapy , Humans , Hypertension, Pulmonary/therapy , Inflammation , Lung Neoplasms/therapy , Mice , Oxidative Stress , Pulmonary Disease, Chronic Obstructive/therapy , Pulmonary Fibrosis/therapy , Pyroptosis , Reactive Oxygen Species
15.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-309830

ABSTRACT

Recent emergence of novel coronavirus (SARS-CoV-2) all over the world has resulted more than 33,106 global deaths. To date well-established therapeutics modules for infected patients are unknown. In this present initiative, molecular interactions between FDA-approved antiviral drugs against the Hepatitis-C virus (HCV) have been investigated theoretically against the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. HCV and SARS-CoV-2 are both +ssRNA viruses. At 25o C beclabuvir, a non-nucleoside inhibitor of the RdRpHCV can efficiently bind to RdRp SARS-CoV-2 (ΔGAutoDock = -9.95 kcal mol-1) with an inhibition constant of 51.03 nM. Both the ΔGLondon and ΔGGBVI / WSA values were - 9.06 and - 6.67 kcal mol-1, respectively for binding of beclabuvir to RdRpSARS-CoV-2. In addition, beclabuvir has also shown better binding free energy with RdRpSARS-CoV-2 (ΔGvina = -8.0 kcal mol-1) than that observed with the Thumb 1 domain of RdRpHCV (ΔGvina = -7.1 kcal mol-1). InterProScan has suggested the RNA-directed 5'-3' polymerase activity exists within 549th to 776th amino acid residues of RdRpSARS-CoV, where the major amino acid residues interacting being I591, Y621, C624, D625, A690, N693, L760, D762, D763, and E813-N817. Molecular interaction suggests occupancy of beclabuvir inside the active site environment of the RdRpSARS-CoV-2, the enzyme essential for viral RNA synthesis. In conclusion, results suggest beclabuvir may serve as an anti-SARS-CoV-2 drug.

16.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-326156

ABSTRACT

Ultraviolet-C light-emitting diodes (UVC-LEDs) have great application in pathogen inactivation under various kinds of situations, especially in the fight against the COVID-19. Unfortunately, its epitaxial wafers are so far limited to 2-inch size, which greatly increases the cost of massive production. In this work, we report the 4-inch crack-free high-power UVC-LED wafer. This achievement relies on a proposed strain-tailored strategy, where a three-dimensional to two-dimensional (3D-2D) transition layer is introduced during the homo-epitaxy of AlN on high temperature annealed (HTA)-AlN template, which successfully drives the original compressive strain into tensile one and thus solves the challenge of realizing high quality Al$_{0.6}$Ga$_{0.4}$N layer with a flat surface. This smooth Al$_{0.6}$Ga$_{0.4}$N layer is nearly pseudomorphically grown on the strain-tailored HTA-AlN template, leading to 4-inch UVC-LED wafers with outstanding performances. Our strategy succeeds in compromising the bottlenecked contradictory in producing large-sized UVC-LED wafer on pronounced crystalline AlN template: The compressive strain in HTA-AlN allows for crack-free 4-inch wafer, but at the same time leads to a deterioration of the AlGaN morphology and crystal quality. The launch of 4-inch wafers makes the chip fabrication process of UVC-LEDs matches the mature blue one, and will definitely speed up the universal of UVC-LED in daily life.

17.
Front Immunol ; 12: 764949, 2021.
Article in English | MEDLINE | ID: covidwho-1674330

ABSTRACT

We identified SARS-CoV-2 specific antigen epitopes by HLA-A2 binding affinity analysis and characterized their ability to activate T cells. As the pandemic continues, variations in SARS-CoV-2 virus strains have been found in many countries. In this study, we directly assess the immune response to SARS-CoV-2 epitope variants. We first predicted potential HLA-A*02:01-restricted CD8+ T-cell epitopes of SARS-CoV-2. Using the T2 cell model, HLA-A*02:01-restricted T-cell epitopes were screened for their binding affinity and ability to activate T cells. Subsequently, we examined the identified epitope variations and analyzed their impact on immune response. Here, we identified specific HLA-A2-restricted T-cell epitopes in the spike protein of SARS-CoV-2. Seven epitope peptides were confirmed to bind with HLA-A*02:01 and potentially be presented by antigen-presenting cells to induce host immune responses. Tetramers containing these peptides could interact with specific CD8+ T cells from convalescent COVID-19 patients, and one dominant epitope (n-Sp1) was defined. These epitopes could activate and generate epitope-specific T cells in vitro, and those activated T cells showed cytolytic activity toward target cells. Meanwhile, n-Sp1 epitope variant 5L>F significantly decreased the proportion of specific T-cell activation; n-Sp1 epitope 8L>V variant showed significantly reduced binding to HLA-A*02:01 and decreased proportion of n-Sp1-specific CD8+ T cell, which potentially contributes to the immune escape of SARS-CoV-2. Our data indicate that the variation of a dominant epitope will cause the deficiency of HLA-A*02:01 binding and T-cell activation, which subsequently requires the formation of a new CD8+ T-cell immune response in COVID-19 patients.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , HLA-A2 Antigen/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Amino Acid Sequence , Antigen Presentation , Antigenic Variation , COVID-19/immunology , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/genetics , Female , Humans , Immune Evasion , Lymphocyte Activation , Male , Middle Aged , Molecular Docking Simulation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
18.
J Virol ; 96(1): e0125321, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1639525

ABSTRACT

Over the past 20 years, the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and SARS-CoV-2 emerged, causing severe human respiratory diseases throughout the globe. Developing broad-spectrum drugs would be invaluable in responding to new, emerging coronaviruses and to address unmet urgent clinical needs. Main protease (Mpro; also known as 3CLpro) has a major role in the coronavirus life cycle and is one of the most important targets for anti-coronavirus agents. We show that a natural product, noncovalent inhibitor, shikonin, is a pan-main protease inhibitor of SARS-CoV-2, SARS-CoV, MERS-CoV, human coronavirus (HCoV)-HKU1, HCoV-NL63, and HCoV-229E with micromolar half maximal inhibitory concentration (IC50) values. Structures of the main protease of different coronavirus genus, SARS-CoV from the betacoronavirus genus and HCoV-NL63 from the alphacoronavirus genus, were determined by X-ray crystallography and revealed that the inhibitor interacts with key active site residues in a unique mode. The structure of the main protease inhibitor complex presents an opportunity to discover a novel series of broad-spectrum inhibitors. These data provide substantial evidence that shikonin and its derivatives may be effective against most coronaviruses as well as emerging coronaviruses of the future. Given the importance of the main protease for coronavirus therapeutic indication, insights from these studies should accelerate the development and design of safer and more effective antiviral agents. IMPORTANCE The current pandemic has created an urgent need for broad-spectrum inhibitors of SARS-CoV-2. The main protease is relatively conservative compared to the spike protein and, thus, is one of the most promising targets in developing anti-coronavirus agents. We solved the crystal structures of the main protease of SARS-CoV and HCoV-NL63 that bound to shikonin. The structures provide important insights, have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational design of broad-spectrum anti-coronavirus ligands as new therapeutic agents.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , Catalytic Domain , Coronavirus/classification , Coronavirus/enzymology , Coronavirus 3C Proteases/chemistry , Crystallography, X-Ray , Molecular Docking Simulation , Naphthoquinones/chemistry , Protein Binding
19.
Clin Rev Allergy Immunol ; 2022 Jan 19.
Article in English | MEDLINE | ID: covidwho-1639477

ABSTRACT

The outbreak of the coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become an evolving global health crisis. Currently, a number of risk factors have been identified to have a potential impact on increasing the morbidity of COVID-19 in adults, including old age, male sex, pre-existing comorbidities, and racial/ethnic disparities. In addition to these factors, changes in laboratory indices and pro-inflammatory cytokines, as well as possible complications, could indicate the progression of COVID-19 into a severe and critical stage. Children predominantly suffer from mild illnesses due to COVID-19. Similar to adults, the main risk factors in pediatric patients include age and pre-existing comorbidities. In contrast, supplementation with a healthy diet and sufficient nutrition, COVID-19 vaccination, and atopic conditions may act as protective factors against the infection of SARS-CoV-2. COVID-19 vaccination not only protects vulnerable individuals from SARS-CoV-2 infection, more importantly, it may also reduce the development of severe disease and death due to COVID-19. Currently used therapies for COVID-19 are off-label and empiric, and their impacts on the severity and mortality of COVID-19 are still unclear. The interaction between asthma and COVID-19 may be bidirectional and needs to be clarified in more studies. In this review, we highlight the clinical evidence supporting the rationale for the risk and protective factors for the morbidity, severity, and mortality of COVID-19.

20.
Econ Lett ; 211: 110265, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1611699

ABSTRACT

This paper investigates the pricing of uncertainty associated with the COVID-19 responses for 28 countries/regions in 2020. We find that such uncertainty is priced in the equity options market. Specifically, there is a price premium for options that provide protection to hedge against price risk, variance risk, and tail risk caused by a variety of World Health Organization (WHO) announcements and the lockdown announcements from governments on COVID-19. Moreover, such options tend to be more expensive when the governments place stricter restrictions.

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