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1.
Comput Econ ; 59(3): 1113-1134, 2022.
Article in English | MEDLINE | ID: covidwho-1782851

ABSTRACT

The stochastic elasticity of variance model introduced by Kim et al. (Appl Stoch Models Bus Ind 30(6):753-765, 2014) is a useful model for forecasting extraordinary volatility behavior which would take place in a financial crisis and high volatility of a market could be linked to default risk of option contracts. So, it is natural to study the pricing of options with default risk under the stochastic elasticity of variance. Based on a framework with two separate scales that could minimize the number of necessary parameters for calibration but reflect the essential characteristics of the underlying asset and the firm value of the option writer, we obtain a closed form approximation formula for the option price via double Mellin transform with singular perturbation. Our formula is explicitly expressed as the Black-Scholes formula plus correction terms. The correction terms are given by the simple derivatives of the Black-Scholes solution so that the model calibration can be done very fast and effectively.

2.
Front Cell Infect Microbiol ; 12: 824578, 2022.
Article in English | MEDLINE | ID: covidwho-1775646

ABSTRACT

Coronavirus disease 2019 (COVID-19) remains a serious emerging global health problem, and little is known about the role of oropharynx commensal microbes in infection susceptibility and severity. Here, we present the oropharyngeal microbiota characteristics identified by full-length 16S rRNA gene sequencing through the NANOPORE platform of oropharynx swab specimens from 10 mild COVID-19 patients and 10 healthy controls. Our results revealed a distinct oropharyngeal microbiota composition in mild COVID-19 patients, characterized by enrichment of opportunistic pathogens such as Peptostreptococcus anaerobius and Pseudomonas stutzeri and depletion of Sphingomonas yabuuchiae, Agrobacterium sullae, and Pseudomonas veronii. Based on the relative abundance of the oropharyngeal microbiota at the species level, we built a microbial classifier to distinguish COVID-19 patients from healthy controls, in which P. veronii, Pseudomonas fragi, and S. yabuuchiae were identified as the most prominent signatures for their depletion in the COVID-19 group. Several members of the genus Campylobacter, especially Campylobacter fetus and Campylobacter rectus, which were highly enriched in COVID-19 patients with higher severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and showed a significant correlation with disease status and several routine clinical blood indicators, indicate that several bacteria may transform into opportunistic pathogen in COVID-19 patients when facing the challenges of viral infection. We also found the diver taxa Streptococcus anginosus and Streptococcus alactolyticus in the network of disease patients, suggesting that these oropharynx microbiota alterations may impact COVID-19 severity by influencing the microbial association patterns. In conclusion, the low sample size of SARS-CoV-2 infection patients (n = 10) here makes these results tentative; however, we have provided the overall characterization that oropharyngeal microbiota alterations and microbial correlation patterns were associated with COVID-19 severity in Anhui Province.


Subject(s)
COVID-19 , Microbiota , Humans , Oropharynx/microbiology , RNA, Ribosomal, 16S/genetics , SARS-CoV-2
3.
Protein Cell ; 2022 Apr 04.
Article in English | MEDLINE | ID: covidwho-1773029

ABSTRACT

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Based on our findings, neuropilin 1 (NRP1), a receptor of SARS-CoV-2, was significantly elevated in cerebral cortex post infection, accompanied by active immune response releasing inflammatory factors and signal transmission among tissues, which enhanced infection of the central nervous system (CNS) in a positive feedback way, leading to viral encephalitis. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.

4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330164

ABSTRACT

Objectives: Since the outbreak of coronavirus disease 2019 (COVID-19), it has caused serious casualties worldwide. In recent months, the virus has mutated into an increasingly infectious form (Delta variant) and spread rapidly. Methods In the current study, we analyzed the clinical, epidemiological and viral genetic characteristics of the first four imported Delta cases in Anhui Province, China. Results The four imported Delta cases developed chest inflammation, tissue damage and recovered after admission, the serum high-sensitivity C-reactive protein (hs-CRP) and CRP levels showed a first increasing and then decreasing trend. The changes of hs-CRP /CRP and serum neutralizing antibodies (Nab) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) levels were associated with the regression of chest lesions. The combination of genetic sequencing and epidemiological analysis suggested that the SARS-CoV-2 delta variant infection of these four patients may originate from Russia. Conclusions Our study found the certain correlations of serum hs-CRP/CRP and Nab levels with the occurrence, development and outcome of COVID-19 delta variant, suggesting that monitoring hs-CRP/CRP and Nab levels of COVID-19 delta variant patients at hospital admission may be useful for understanding the severity of patients’ current conditions.

5.
Front Med (Lausanne) ; 9: 829273, 2022.
Article in English | MEDLINE | ID: covidwho-1715010

ABSTRACT

Detection of serum-specific SARS-CoV-2 antibody has become a complementary means for the identification of coronavirus disease 2019 (COVID-19). As we already know, the neutralizing antibody titers in patients with COVID-19 decrease during the course of time after convalescence, whereas the duration of antibody responses in the convalescent patients has not been defined clearly. In the current study, we collected 148 serum samples from 37 confirmed COVID-19 cases with different disease severities. The neutralizing antibodies (Nabs), IgM and IgG against COVID-19 were determined by CLIA Microparticle and microneutralization assay, respectively. The time duration of serum titers of SARS-CoV-2 antibodies were recorded. Our results indicate that IgG (94.44%) and Nabs (89.19%) can be detected at low levels within 190-266 days of disease onset. The findings can advance knowledge regarding the antibody detection results for COVID-19 patients and provide a method for evaluating the immune response after vaccination.

6.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324820

ABSTRACT

Background: COVID-19 is a newly emerging disease caused by a novel coronavirus (SARS-CoV-2), which spread globally in early 2020. Asymptomatic carriers of the virus contribute to the propagation of this disease, and the existence of asymptomatic infection has caused widespread fear and concern in the control of this pandemic. Methods: : In this study, we investigated the origin and transmission route of SARS-CoV-2 in Anhui’s two clusters, analyzed the role and infectiousness of asymptomatic patients in disease transmission, and characterized the complete spike gene sequences in the Anhui strains. Results: : We conducted an epidemiological investigation of two clusters caused by asymptomatic infections sequenced the spike gene of viruses isolated from 12 patients. All cases of the two clusters we investigated had clear contact histories, both from Wuhan, Hubei province. The viruses isolated from two outbreaks in Anhui were found to show a genetically close link to the virus from Wuhan. In addition, new single nucleotide variations were discovered in the spike gene. Conclusions: : Both clusters may have resulted from close contact and droplet-spreading and asymptomatic infections were identified as the initial cause. We also analyzed the infectiousness of asymptomatic cases and the challenges to the current epidemic to provided information for the development of control strategies.

7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-324533

ABSTRACT

SARS-CoV-2 infection causes complicated clinic manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various tissues/organs examined, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Neuronal receptor NRP1 expression showed a significant induction by SARS-CoV-2 in cerebral cortex, which might be responsible for a higher infectivity and consequent inflammatory response. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.

8.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324286

ABSTRACT

OBJECTIVE: The purpose of this article was to perform a systematic review and meta- analysis regarding the diagnostic test accuracy of chest CT for detecting Coronavirus Disease 2019 (COVID-19). METHODS: PubMed, EMBASE, Web of Science and CNKI were searched up to March 12, 2020. We included studies providing information regarding diagnostic test accuracy of chest CT for COVID-19 detection. The methodologic quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies–2 tool. Sensitivity and specificity were pooled. RESULTS: Ten studies ( n = 2657 patients) were included. The risks of bias in all studies were moderate in general. Pooled sensitivity was 93% (95% CI: 85 - 97%), and only one study reported specificity (25%, 95% CI:22-30%). There was substantial heterogeneity according to the Cochran Q test ( p < 0.01) and Higgins I 2 heterogeneity index (96% for sensitivity). After dividing the studies into two groups based on the study site, we found that the sensitivity of chest CT was great in Wuhan (the most affected city by the epidemic) and the sensitivity values were very close to each other (97%, 96% and 99%, respectively). In the regions other than Wuhan, the sensitivity varied from 69% to 98%. CONCLUSION: Chest CT offers the great sensitivity for detecting COVID-19, especially in region with severe epidemic situation. However, the specificity is low. In the context of emergency disease control, chest CT provide a fast, convenient and effective method to early recognize suspicious cases and might contribute to confine epidemic.

9.
Economic Analysis and Policy ; 2021.
Article in English | ScienceDirect | ID: covidwho-1561897

ABSTRACT

In this study, we investigate the dynamic connectedness between the volatility of Northeast Asia, namely South Korea, Japan, China, and the United States (US). Specifically, we employ Diebold and Yilmaz’s (2012) spillover index to measure connectedness in stock market volatility. Furthermore, we analyze the dynamic connectedness during the global financial crisis (GFC) and COVID-19 pandemic periods to identify the changes in their relationship following the two crises. Our findings can be summarized as follows. First, the connectedness between the volatility of the four stock markets varies over time. However, the US has played a role as a net transmitter of volatility shocks during the entire period. Second, interdependence increased during the two crisis periods. Based on the total volatility spillover index, interdependence is stronger during the GFC than during the COVID-19 pandemic period. Third, the magnitude of volatility shock transmission to other countries is time-varying. In particular, for the South Korean stock market, the volatility shock transmitted from the Chinese stock market has been larger than that of the US market since 2015. These empirical findings have several important implications for portfolio managers, policymakers, and investors.

10.
Biosens Bioelectron ; 197: 113771, 2022 Feb 01.
Article in English | MEDLINE | ID: covidwho-1536447

ABSTRACT

Due to the similar clinical symptoms of influenza (Flu) and coronavirus disease 2019 (COVID-19), there is a looming infection threat of concurrent Flu viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this work, we introduce a customized isothermal amplification integrated lateral flow strip (LFS) that is capable performing duplex reverse transcription-recombinase polymerase amplification (RT-RPA) and colorimetric LFS in a sequential manner. With customized amplification primer sets targeted to SARS-CoV-2 (opening reading frame 1a/b and nucleoprotein genes) and Flu viruses (Flu A and Flu B), the platform allows the rapid and simultaneous visual screening of SARS-CoV-2 and Flu viruses (Flu A and Flu B) without cross reactivity, false positives, and false negatives. Moreover, it maximally eases the detection, reduces the detection time (1 h), and improves the assay performance to detect as low as 10 copies of the viral RNA. Its clinical application is powerfully demonstrated with 100% accuracy for evaluating 15 SARS-CoV-2-positive clinical samples, 10 Flu viruses-positive clinical samples, and 5 negative clinical samples, which were pre-confirmed by standard qRT-PCR. We envision this portable device can meet the increasing need of online monitoring the serious infectious diseases that substantially affects health care systems worldwide.


Subject(s)
Biosensing Techniques , COVID-19 , Influenza, Human , Humans , Influenza, Human/diagnosis , Nucleic Acid Amplification Techniques , SARS-CoV-2 , Sensitivity and Specificity
11.
Mol Biomed ; 1(1): 14, 2020 Nov 30.
Article in English | MEDLINE | ID: covidwho-1515460

ABSTRACT

The global pandemic of COVID-19 has attracted extensive drug searching interets for the new coronavirus SARS-CoV-2. Although currently several of clinically used "old" drugs have been repurposed to this new disease for the urgent clinical investigation, there is still great demand for more effective therapies for the anti-infections. Here we report the discovery that an "old" drug Emetine could potently inhibit SARS-CoV-2 virus replication and displayed virus entry blocking effect in Vero cells at low dose. In addition, Emetine could significantly reduce the lipopolysaccharide (LPS) induced interleukin-6 (IL-6) protein level and moderately reduce the tumor necrosis factor (TNF-α) protein level in the M1 polarized THP-1 macrophages. In vivo animal pharmacokinetics (PK) study revealed that Emetine was enriched in the lung tissue and had a long retention time (over 12 h). With 1 mg/kg single oral dose, the effective concentration of Emetine in lung was up to 1.8 µM (mice) and 1.6 µM (rats) at 12 h, which is over 200-fold higher than the EC50 of the drug. The potent in vitro antiviral replication efficacy and the high enrichment in target tissue, combining with the well documented safety profiles in human indicate that low dose of Emetine might be a potentially effective anti-SARS-CoV-2 infection therapy.

12.
J Med Virol ; 93(10): 5998-6007, 2021 10.
Article in English | MEDLINE | ID: covidwho-1432442

ABSTRACT

In the context of the coronavirus disease 2019 pandemic, we investigated the epidemiological and clinical characteristics of a young patient infected by avian influenza A (H5N6) virus in Anhui Province, East China, and analyzed genomic features of the pathogen in 2020. Through the cross-sectional investigation of external environment monitoring (December 29-31, 2020), 1909 samples were collected from Fuyang City. It was found that the positive rate of H5N6 was higher than other areas obviously in Tianma poultry market, where the case appeared. In addition, dual coinfections were detected with a 0.057% polymerase chain reaction positive rate the surveillance years. The virus was the clade 2.3.4.4, which was most likely formed by genetic reassortment between H5N6 and H9N2 viruses. This study found that the evolution rates of the hemagglutinin and neuraminidase genes of the virus were higher than those of common seasonal influenza viruses. The virus was still highly pathogenic to poultry and had a preference for avian receptor binding.


Subject(s)
COVID-19/epidemiology , Influenza A virus/isolation & purification , Influenza in Birds/virology , Influenza, Human/virology , Animals , Child, Preschool , China , Female , Genome, Viral/genetics , Humans , Influenza A virus/classification , Influenza A virus/genetics , Influenza, Human/diagnosis , Mutation , Phylogeny , Poultry/virology , Reassortant Viruses/classification , Reassortant Viruses/genetics , Reassortant Viruses/isolation & purification , SARS-CoV-2 , Viral Proteins/genetics
13.
Front Immunol ; 12: 693775, 2021.
Article in English | MEDLINE | ID: covidwho-1394758

ABSTRACT

Small number of SARS-CoV-2 epidemic lineages did not efficiently exhibit a neutralization profile, while single amino acid mutation in the spike protein has not been confirmed in altering viral antigenicity resulting in immune escape. To identify crucial mutations in spike protein that escape humoral immune response, we evaluated the cross-neutralization of convalescent plasmas and RBD-specific monoclonal antibodies (mAbs) against various spike protein-based pseudoviruses. Three of 24 SARS-CoV-2 pseudoviruses containing different mutations in spike protein, including D614G, A475V, and E484Q, consistently showed an altered sensitivity to neutralization by convalescent plasmas. A475V and E484Q mutants are highly resistant to neutralization by mAb B38 and 2-4, suggesting that some crucial mutations in spike protein might evolve SARS-CoV-2 variants capable of escaping humoral immune response.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/immunology , Mutation , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Amino Acid Substitution/genetics , Amino Acid Substitution/immunology , Antibodies, Neutralizing/immunology , Convalescence , Humans , Immune Evasion , Immunity, Humoral , Neutralization Tests , Protein Binding
14.
Food Chem Toxicol ; 153: 112286, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1385569

ABSTRACT

Higher selenium status has been shown to improve the clinical outcome of infections caused by a range of evolutionally diverse viruses, including SARS-CoV-2. However, the impact of SARS-CoV-2 on host-cell selenoproteins remains elusive. The present study investigated the influence of SARS-CoV-2 on expression of selenoprotein mRNAs in Vero cells. SARS-CoV-2 triggered an inflammatory response as evidenced by increased IL-6 expression. Of the 25 selenoproteins, SARS-CoV-2 significantly suppressed mRNA expression of ferroptosis-associated GPX4, DNA synthesis-related TXNRD3 and endoplasmic reticulum-resident SELENOF, SELENOK, SELENOM and SELENOS. Computational analysis has predicted an antisense interaction between SARS-CoV-2 and TXNRD3 mRNA, which is translated with high efficiency in the lung. Here, we confirmed the predicted SARS-CoV-2/TXNRD3 antisense interaction in vitro using DNA oligonucleotides, providing a plausible mechanism for the observed mRNA knockdown. Inhibition of TXNRD decreases DNA synthesis which is thereby likely to increase the ribonucleotide pool for RNA synthesis and, accordingly, RNA virus production. The present findings provide evidence for a direct inhibitory effect of SARS-CoV-2 replication on the expression of a specific set of selenoprotein mRNAs, which merits further investigation in the light of established evidence for correlations between dietary selenium status and the outcome of SARS-CoV-2 infection.


Subject(s)
DNA/biosynthesis , Endoplasmic Reticulum Stress/physiology , Ferroptosis/physiology , RNA, Messenger/metabolism , SARS-CoV-2/physiology , Selenoproteins/metabolism , Animals , Chlorocebus aethiops , Gene Expression Regulation/physiology , RNA, Messenger/genetics , Selenoproteins/genetics , Vero Cells
16.
J Med Virol ; 93(10): 5998-6007, 2021 10.
Article in English | MEDLINE | ID: covidwho-1298504

ABSTRACT

In the context of the coronavirus disease 2019 pandemic, we investigated the epidemiological and clinical characteristics of a young patient infected by avian influenza A (H5N6) virus in Anhui Province, East China, and analyzed genomic features of the pathogen in 2020. Through the cross-sectional investigation of external environment monitoring (December 29-31, 2020), 1909 samples were collected from Fuyang City. It was found that the positive rate of H5N6 was higher than other areas obviously in Tianma poultry market, where the case appeared. In addition, dual coinfections were detected with a 0.057% polymerase chain reaction positive rate the surveillance years. The virus was the clade 2.3.4.4, which was most likely formed by genetic reassortment between H5N6 and H9N2 viruses. This study found that the evolution rates of the hemagglutinin and neuraminidase genes of the virus were higher than those of common seasonal influenza viruses. The virus was still highly pathogenic to poultry and had a preference for avian receptor binding.


Subject(s)
COVID-19/epidemiology , Influenza A virus/isolation & purification , Influenza in Birds/virology , Influenza, Human/virology , Animals , Child, Preschool , China , Female , Genome, Viral/genetics , Humans , Influenza A virus/classification , Influenza A virus/genetics , Influenza, Human/diagnosis , Mutation , Phylogeny , Poultry/virology , Reassortant Viruses/classification , Reassortant Viruses/genetics , Reassortant Viruses/isolation & purification , SARS-CoV-2 , Viral Proteins/genetics
17.
J Virol Methods ; 295: 114185, 2021 09.
Article in English | MEDLINE | ID: covidwho-1243068

ABSTRACT

OBJECTIVE: Viral nucleic acid detection by real-time reverse transcription polymerase chain reaction (qPCR) is the current standard method for diagnosis of SARS-CoV-2 infection. However, due to low viral load in some COVID-19 patients, false negative results from this method have been repeatedly reported. METHOD: In this study, we compared the sensitivity and specificity of digital PCR (dPCR) in simulated samples and clinical samples with qPCR assay through a series of vigorous tests. RESULTS: The results showed that dPCR was more sensitive than qPCR especially for samples with low viral load (≤3 copies). In addition, dPCR had similar specificity as qPCR and could effectively distinguish other human coronaviruses and influenza virus from SARS-CoV-2. More importantly, dPCR was more sensitive than qPCR in detecting the virus in the "negative" samples from recurrent COVID-19 patients. CONCLUSIONS: In summary, dPCR could serve as a powerful complement to the current qPCR method for SARS-CoV-2 detection, especially for the samples with extremely low viral load, such as recurrent COVID-19 patients.


Subject(s)
COVID-19 Nucleic Acid Testing/methods , COVID-19/diagnosis , Real-Time Polymerase Chain Reaction/methods , SARS-CoV-2/isolation & purification , Viral Load , COVID-19/virology , Humans , RNA, Viral/genetics , Recurrence , SARS-CoV-2/genetics , Sensitivity and Specificity
18.
Physica A: Statistical Mechanics and its Applications ; : 125988, 2021.
Article in English | ScienceDirect | ID: covidwho-1164322

ABSTRACT

In this study, we test the efficient market hypothesis for a number of sectors in the US stock market during the COVID-19 pandemic to identify its effects on individual sectors. To test this hypothesis, we define the average price for 11 sectors within the S&P 500 and apply multifractal detrended fluctuation analysis to the average return series. Furthermore, we also investigate these sectors’ efficiency and multifractality during the global financial crisis (GFC) to analyze the features of the COVID-19 pandemic. Our findings can be summarized as follows. First, the average return series show non-persistent and persistent features during the GFC and the COVID-19 pandemic, respectively. Second, during each of these crisis periods, the consumer discretionary and utilities sectors had the highest and lowest levels of efficiency, respectively. Third, while both long-range correlations and fat-tailed distribution contributed to the multifractal properties, the latter of these was the chief contributor. Furthermore, the lower the efficiency ranking, the greater the impact of the fat-tailed distribution on multifractalilty. Finally, we classify sectors with low market efficiency for the two crisis periods. These findings have several important implications for asset allocations by investors in US stock markets.

19.
Biomed Res Int ; 2021: 5909612, 2021.
Article in English | MEDLINE | ID: covidwho-1138456

ABSTRACT

BACKGROUND: The outbreak of coronavirus disease (COVID-19) has become a global public health emergency. OBJECTIVE: To evaluate the characteristics and outcomes of patients with COVID-19 in Anhui and to identify predictors of viral clearance. METHODS: We retrospectively analyzed the data collected from discharged patients with laboratory-confirmed SARS-CoV-2 infections. We compared clinical features between viral clearance and viral persistence, and evaluated factors associated with SARS-CoV-2 shedding using multiple linear regression. RESULTS: Among the 83 patients involved in the study, the median age was 43 years, while 60.2% were male, 35.4% had comorbidities, and the mortality was zero. The median time from illness onset to admission was 5 days (interquartile range (IQR), 2-7 days), and the median time from the illness onset to SARS-CoV-2 RNA detection was 16 days (IQR, 13-18 days). The factors influencing viral clearance were as follows: (1) delayed admission (beta 1.057, 95% CI 0.810-1.304; p ≤ 0.001) and (2) underlying comorbidities (beta 1.907, 95% CI 0.198-3.616; p = 0.029). No significant differences were observed in the length of stay (p = 0.246) and pneumonia between asymptomatic and symptomatic patients based on computed tomography (CT) (p = 0.124). CONCLUSIONS: Delayed admission and underlying comorbidities may effectively predict SARS-CoV-2 RNA clearance. For those infected with SARS-CoV-2, even asymptomatic patients without any clinical symptoms should be traced and isolated. This practice may reduce the spread of SARS-CoV-2 and slow the COVID-19 pandemic caused by the virus. Clinical Trial Registration Number: This trial is registered with 2020-051.


Subject(s)
Asymptomatic Infections/epidemiology , COVID-19/epidemiology , COVID-19/virology , SARS-CoV-2/genetics , Adolescent , Adult , Comorbidity , Disease Outbreaks , Female , Humans , Male , RNA, Viral/genetics , Retrospective Studies , Virus Shedding/genetics , Young Adult
20.
J Virol ; 2021 Mar 03.
Article in English | MEDLINE | ID: covidwho-1117219

ABSTRACT

Cell entry by SARS-CoV-2 requires the binding between the receptor-binding domain (RBD) of the viral Spike protein and the cellular angiotensin-converting enzyme 2 (ACE2). As such, RBD has become the major target for vaccine development, while RBD-specific antibodies are pursued as therapeutics. Here, we report the development and characterization of SARS-CoV-2 RBD-specific VHH/nanobody (Nb) from immunized alpacas. Seven RBD-specific Nbs with high stability were identified using phage display. They bind to SARS-CoV-2 RBD with affinity KD ranging from 2.6 to 113 nM, and six of them can block RBD-ACE2 interaction. The fusion of the Nbs with IgG1 Fc resulted in homodimers with greatly improved RBD-binding affinities (KD ranging from 72.7 pM to 4.5 nM) and nanomolar RBD-ACE2 blocking abilities. Furthermore, the fusion of two Nbs with non-overlapping epitopes resulted in hetero-bivalent Nbs, namely aRBD-2-5 and aRBD-2-7, with significantly higher RBD binding affinities (KD of 59.2 pM and 0.25 nM) and greatly enhanced SARS-CoV-2 neutralizing potency. The 50% neutralization dose (ND50) of aRBD-2-5 and aRBD-2-7 was 1.22 ng/mL (∼0.043 nM) and 3.18 ng/mL (∼0.111 nM), respectively. These high-affinity SARS-CoV-2 blocking Nbs could be further developed into therapeutics as well as diagnostic reagents for COVID-19.ImportanceTo date, SARS-CoV-2 has caused tremendous loss of human life and economic output worldwide. Although a few COVID-19 vaccines have been approved in several countries, the development of effective therapeutics, including SARS-CoV-2 targeting antibodies, remains critical. Due to their small size (13-15 kDa), high solubility, and stability, Nbs are particularly well suited for pulmonary delivery and more amenable to engineer into multivalent formats than the conventional antibody. Here, we report a series of new anti-SARS-CoV-2 Nbs isolated from immunized alpaca and two engineered hetero-bivalent Nbs. These potent neutralizing Nbs showed promise as potential therapeutics against COVID-19.

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