ABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is undergoing continuous evolution and convergent mutation, which has led to the rapid emergence of several new variants. These new subvariants carry different mutations in theirreceptor-binding domain (RBD), raising concerns that they may evade neutralizing monoclonal antibodies (mAbs). In this study, we investigated the serum neutralization efficacy of Evusheld (cilgavimab and tixagevimab) antibody cocktails against SARS-CoV-2 Omicron sublineages BA.2, BA.2.75, BA.2.76, BA.5, BF.7, BQ.1.1 and XBB.1.5. Our results show that Evusheld retained neutralizing activity against BA.2, BA.2.75 and BA.5, albeit with somewhat reduced titers. However, the neutralizing activity of Evusheld against BA.2.76, BF.7, BQ.1.1 and XBB.1.5 significantly decreased, with XBB.1.5 showing the greatest escape activity among the subvariants, followed by BQ.1.1, BA.2.76 and BF.7. We also observed that recipients of Evusheld displayed elevated antibody levels in their serum, which efficiently neutralized the original variant, and exhibited different characteristics of infection than those who did not receive Evusheld. These findings provide important guidance for the application of Evusheld in treating SARS-CoV-2 subvariant infections.
Subject(s)
Coronavirus Infections , Severe Acute Respiratory SyndromeABSTRACT
Background: An in-silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (Mpro), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods: A 2-center, randomized, double-blind, placebo-controlled trial was performed among patients hospitalized with COVID-19 infection. Enrolled patients were randomized 2:1 to atovaquone 1500 mg BID versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Saliva was collected at baseline and twice per day for up to 10 days for RNA extraction for SARS-CoV-2 viral load measurement by quantitative reverse-transcriptase PCR. The primary outcome was the between group difference in log-transformed viral load (copies/mL) using a generalized linear mixed-effect models of repeated measures from all samples. Results: Of the 61 patients enrolled; 41 received atovaquone and 19 received placebo. Overall, the population was predominately male (63%) and Hispanic (70%), with a mean age of 51 years, enrolled a mean of 5 days from symptom onset. The log10 viral load was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Change in viral load did not differ over time between the atovaquone plus standard of care arm versus the placebo plus standard of care arm. Pharmacokinetic (PK) studies of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, with an inverse correlation between BMI and atovaquone levels, (Rho -0.45, p=0.02). In post hoc analysis, an inverse correlation was observed between atovaquone levels and viral load (Rho -0.54, p= 0.005). Conclusion: In this prospective, randomized, placebo-controlled trial, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo. However, based on the observed inverse correlation between atovaquone levels and viral load, additional PK-guided studies may be warranted to examine the antiviral effect of atovaquone in COVID-19 patients. clincialtrials.gov (NCT04456153).
Subject(s)
COVID-19ABSTRACT
Background Pulmonary fibrosis (PF) is a common interstitial pneumonia disease, also occurred in post-COVID-19 survivors. The mechanism underlying the anti-PF effect of Qing Fei Hua Xian Decotion (QFHXD), a traditional Chinese medicine formula applied for treating PF in COVID-19 survivors, is unclear. This study aimed to uncover the mechanisms related to the anti-PF effect of QFHXD through analysis of network pharmacology and experimental verification.Methods The candidate chemical compounds of QFHXD and its putative targets for treating PF were achieved from public databases, thereby we established the corresponding “herb- compound -target” network of QFHXD. Moreover, The protein–protein interaction (PPI) network of potential targets was also constructed to screen the core targets. Furthermore, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to predict targets, and pathways, then validated by in vivo experiments.Results A total of 188 active compounds in QFHXD and 50 target genes were identified from databases. The key therapeutic targets of QFHXD, such as PI3K/Akt, IL-6, TNF, IL-1β, STAT3, MMP-9, and TGF-β1 were identified by KEGG and GO analysis. Anti-PF effects of QFHXD (in a dose-dependent manner) and prednisone were confirmed by HE, Masson staining, and Sirius red staining as well as in vivo Micro-CT and immunohistochemical analysis in a rat model of bleomycin-induced PF. Besides, QFXHD remarkably inhibits the activity of PI3K/Akt/NF-κB and TGF‑β1/Smad2/3.Conclusion QFXHD significantly attenuated bleomycin-induced PF via inhibiting inflammation and EMT. PI3K/Akt/NF-κB and TGF‑β1/Smad2/3 pathways might be the potential therapeutic effects of QFHXD for treating PF.
Subject(s)
COVID-19ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the COVID-19 pandemic, is rapidly evolving. Due to the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOC), including the currently most prevalent Delta variant, orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously we showed that adenosine analogue 69-0 (also known as GS-441524), possesses potent anti-SARS-CoV-2 activity. Herein, we report that esterification of the 5-hydroxyl moieties of 69-0 markedly improved the antiviral potency. The 5-hydroxyl -isobutyryl prodrug, ATV006, showed excellent oral bioavailability in rats and cynomolgus monkeys and potent antiviral efficacy against different VOCs of SARS-CoV-2 in cell culture and three mouse models. Oral administration of ATV006 significantly reduced viral loads, alleviated lung damage and rescued mice from death in the K18-hACE2 mouse model challenged with the Delta variant. Moreover, ATV006 showed broad antiviral efficacy against different mammal-infecting coronaviruses. These indicate that ATV006 represents a promising oral drug candidate against SARS-CoV-2 VOCs and other coronaviruses.
Subject(s)
COVID-19 , Adenomatous Polyposis Coli , Lung Diseases , Coronavirus Infections , Severe Acute Respiratory Syndrome , DeathABSTRACT
With the ongoing global pandemic of coronavirus disease 2019 (COVID-19), there is an increasing quest for more accessible, easy-to-use, rapid, inexpensive, and high accuracy diagnostic tools. Traditional disease diagnostic methods such as qRT-PCR (quantitative reverse transcription-PCR) and ELISA (enzyme-linked immunosorbent assay) require multiple steps, trained technicians, and long turnaround time that may worsen the disease surveillance and pandemic control. In sight of this situation, a rapid, one-step, easy-to-use, and high accuracy diagnostic platform will be valuable for future epidemic control especially for regions with scarce medical resources. Herein, we report a magnetic particle spectroscopy (MPS) platform for detection of SARS-CoV-2 biomarkers: spike and nucleocapsid proteins.
Subject(s)
COVID-19ABSTRACT
Background: Nationwide nonpharmaceutical interventions (NPI) were used to combat the novel coronavirus disease (COVID-19) during 2020 in the mainland of China. These NPIs have proven effective on mitigating the spread of COVID-19, but their broad impact on other diseases remains under-investigated. In this study, we aim to assess whether such broad impact exists on notifiable diseases in China.Methods: Weekly incidence and mortality data for 31 major notifiable infectious diseases at the province level were extracted from the China Information System for Disease Control and Prevention from 2014 to 2020. We assessed the impact of NPIs by contrasting the incidences of each infectious disease in predefined COVID-19 phases during 2020 to the average incidences in the corresponding time intervals during 2014-2019.Findings: We observed decreased incidences of most diseases during the phases after the lockdown of Wuhan. In general, respiratory diseases and gastrointestinal or enteroviral diseases were more affected than sexually transmitted or bloodborne diseases and vector-borne or zoonotic diseases. Seasonal flu and rubella were the most sensitive to the NPIs, with reductions of 67-99% in incidence rates throughout the NPI-implemented phases in China (Jan 27-Dec 31, 2020). Among gastrointestinal or enteroviral diseases, the hand, foot and mouth disease (HFMD) was subject to the largest declines during Jan 27-Aug 31, 2020, with >90% reduction in incidence rate. Phases with more stringent NPIs were associated with more reductions. Non-respiratory diseases, particularly HFMD, gonorrhea and brucellosis, rebounded towards the end of the year as the NPIs were relaxed.Interpretation: NPIs are broadly effective in containing infectious diseases. Less disruptive NPIs such as wearing face masks are still effective in mitigating respiratory diseases but are not adequate for containing non-respiratory diseases.Funding Statement: This work was supported by grants from the National Natural Science Funds [91846302, 81825019], the China Mega-Project on Infectious Disease Prevention [2018ZX10713001, 2018ZX10713002, 2018ZX10201001 and 2017ZX10103004], and the US National Institutes of Health [R56 AI148284].Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: Missing.
Subject(s)
COVID-19 , Gastrointestinal Diseases , Hand, Foot and Mouth Disease , Gonorrhea , Communicable DiseasesABSTRACT
Background Little is known about the dynamics of SARS-CoV-2 antigen burden in respiratory samples in different patient populations at different stages of infection. Current rapid antigen tests cannot quantitate and track antigen dynamics with high sensitivity and specificity in respiratory samples. Methods We developed and validated an ultra-sensitive SARS-CoV-2 antigen assay with smartphone readout using the Microbubbling Digital Assay previously developed by our group, which is a platform that enables highly sensitive detection and quantitation of protein biomarkers. A computer vision-based algorithm was developed for microbubble smartphone image recognition and quantitation. A machine learning-based classifier was developed to classify the smartphone images based on detected microbubbles. Using this assay, we tracked antigen dynamics in serial swab samples from COVID patients hospitalized in ICU and immunocompromised COVID patients. Results The limit of detection (LOD) of the Microbubbling SARS-CoV-2 Antigen Assay was 0.5 pg/mL (10.6 fM) recombinant nucleocapsid (N) antigen or 4000 copies/mL inactivated SARS-CoV-2 virus in nasopharyngeal (NP) swabs, comparable to many rRT-PCR methods. The assay had high analytical specificity towards SARS-CoV-2. Compared to EUA-approved rRT-PCR methods, the Microbubbling Antigen Assay demonstrated a positive percent agreement (PPA) of 97% (95% confidence interval (CI), 92-99%) in symptomatic individuals within 7 days of symptom onset and positive SARS-CoV-2 nucleic acid results, and a negative percent agreement (NPA) of 97% (95% CI, 94-100%) in symptomatic and asymptomatic individuals with negative nucleic acid results. Antigen positivity rate in NP swabs gradually decreased as days-after-symptom-onset increased, despite persistent nucleic acid positivity of the same samples. The computer vision and machine learning-based automatic microbubble image classifier could accurately identify positives and negatives, based on microbubble counts and sizes. Total microbubble volume, a potential marker of antigen burden, correlated inversely with Ct values and days-after-symptom-onset. Antigen was detected for longer periods of time in immunocompromised patients with hematologic malignancies, compared to immunocompetent individuals. Simultaneous detectable antigens and nucleic acids may indicate the presence of replicating viruses in patients with persistent infections. Conclusions The Microbubbling SARS-CoV-2 Antigen Assay enables sensitive and specific detection of acute infections, and quantitation and tracking of antigen dynamics in different patient populations at various stages of infection. With smartphone compatibility and automated image processing, the assay is well-positioned to be adapted for point-of-care diagnosis and to explore the clinical implications of antigen dynamics in future studies.
Subject(s)
Nasopharyngitis , Hematologic NeoplasmsABSTRACT
Objective: We tested a model of individual health literacy information sharing with family members, personal preventive behaviours and family well-being during the Coronavirus Disease 2019 (COVID-19) pandemic in Hong Kong. Methods: We analysed data of 1501 randomly selected Chinese adults from a cross-sectional survey in Hong Kong from 9 to 23 April, 2020. Individual health literacy about COVID-19 with the items extracted from the questionnaire in World Health Organization Risk Communication and Community Engagement (RCCE) Action Plan Guidance for COVID-19 preparedness and response, COVID-19 information sharing with family members, preventive behaviours against COVID-19 and family well-being were measured. Structural equation modelling analysis tested the proposed model. Findings: COVID-19 information sharing with family members partially mediated the association between individual health literacy and personal preventive behaviours. The direct effect of 0.24 was shown, and the indirect effect through COVID-19 information sharing with family members was small at 0.03 (Z = 3.66, p < 0.001). Family well-being was associated with personal preventive behaviours against COVID-19. The model was adjusted for sex, age, and socioeconomic status factors and had good fit with RMSEA = 0.04, CFI = 0.98, TLI = 0.96, and SRMR = 0.02. Conclusion: COVID-19 information sharing with family members was a partial mediator between individual health literacy and personal preventive behaviours against COVID-19. Strategies for enhancing health literacy and preventive measures against COVID-19 are needed to promote family well-being in the pandemic.
Subject(s)
COVID-19ABSTRACT
Nowadays, there is an increasing demand for more accessible routine diagnostics for patients with respect to high accuracy, ease of use, and low cost. However, the quantitative and high accuracy bioassays in large hospitals and laboratories usually require trained technicians and equipment that is both bulky and expensive. In addition, the multi-step bioassays and long turnaround time could severely affect the disease surveillance and control especially in pandemics such as influenza and COVID-19. In view of this, a portable, quantitative bioassay device will be valuable in regions with scarce medical resources and help relieve burden on local healthcare systems. Herein, we introduce the MagiCoil diagnostic device, an inexpensive, portable, quantitative and rapid bioassay platform based on magnetic particle spectrometer (MPS) technique. MPS detects the dynamic magnetic responses of magnetic nanoparticles (MNPs) and uses the harmonics from oscillating MNPs as metrics for sensitive and quantitative bioassays. This device does not require trained technicians to operate and employs a fully automatic, one-step, wash-free assay with user friendly smartphone interface. Using a streptavidin-biotin binding system as a model, we show that the detection limit of the current portable device for streptavidin is 64 nM (equal to 5.12 pmole). In addition, this MPS technique is very versatile and allows for the detection of different diseases just by changing the surface modifications on MNPs.
Subject(s)
COVID-19ABSTRACT
Background:The asymptomatic of COVID-2019 are getting more and more attention from all walks of life. Now, America has become the epicenter of the pandemic, with more reported cases and deaths than other regions of the world. Studying the development asymptomatic populations may play a key role in managing the outbreak effectively. Methods:We propose a new model to predict the course of the epidemic and simulate the transmission of the asymptomatic. The model considers seven stages of infection: susceptible (S), exposed (E), infected (I), asymptomatic (A), confirmed (C), recovered (R), dead (D), we named it as SEIACRD. We used a model to study the interaction between asymptomatic patients and viral transmission.Result:Our model confirms that about 12 million people will be infected with the virus. Changes in mortality rates will be volatile, first falling, then rising. Not only the number of patients, but also the spread of the epidemic will be affected by the ability to detect asymptomatic persons. Contact with asymptomatic infected patients also significantly promoted the spread of the virus. But these methods had no significant effect on changes in patient mortality.Conclusion:American Asymptomatic patients have a strong interaction with epidemic transmission. They are no less at risk of transmission than symptomatic patients. In terms of controlling the number of infections, efforts to improve detection capacity are more effective than simply suppressing the spread of the virus. Extensive testing and effective social distancing measures should be taken to protect more people from the virus.
Subject(s)
COVID-19 , InfectionsABSTRACT
The outbreak of coronavirus disease 2019 (COVID-19) rapidly spreads across worldwide and becomes a global pandemic. Remdesivir is the only COVID-19 treatment approved by U.S. Food and Drug Administration (FDA); however, its effectiveness is still under questioning as raised by the results of a large WHO Solidarity Trial. Herein, we report that the parent nucleotide of remdesivir, GS-441524, potently inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero E6 and other cells. It exhibits good plasma distribution and longer half-life (t1/2=4.8h) in rat PK study. GS-441524 is highly efficacious against SARS-CoV-2 in AAV-hACE2 transduced mice and murine hepatitis virus (MHV) in mice, reducing the viral titers in CoV-attacked organs, without noticeable toxicity. Given that GS-441524 was the predominant metabolite of remdesivir in the plasma, the anti-COVID-19 effect of remdesivir may partly come from the effect of GS-441524. Our results also supported that GS-441524 as a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases.
Subject(s)
COVID-19 , Adenomatous Polyposis Coli , Drug-Related Side Effects and Adverse Reactions , Hepatitis, Viral, Human , EmergenciesABSTRACT
Background: To explore the kinetic changes in virology, specific antibody response and imaging during the clinical course of COVID-19. Methods: : This observational study enrolled 20 patients with COVID-19, who were hospitalized between January 20-April 6, 2020, in the two COVID-19 designated hospitals of Zhoushan, Zhejiang and Rushan, Shandong, China, The laboratory findings, imaging, serum response to viral infection, and viral RNA level in the throat and stool samples were assessed from onset to recovery phase in patients with COVID-19. Results: : SARS-COV-2 RNA was positive as early as day four. It remained positive until day 55 post-onset in the sputum-throat swabs and became negative in most cases (55%) within 14 days after onset. Lymphocytopenia occurred in 40% (8/20) of patients during the peak infection period and returned to normal at week five. The most severe inflammation in the lungs appeared in week 2 or 3 after onset, and this was completely absorbed between week 6 and 8 in 85.7% of patients. All patients had detectable antibodies to the receptor binding domain (RBD), and 95% of these patients had IgG to viral N proteins. The antibody titer peaked at week four. Anti-S IgM was positive in 7 of 20 patients after week three. Conclusions: : All COVID-19 patients in this study were self-limiting and recovered well though it may take as long as 6-8 weeks. Our findings on the kinetic changes in imaging, serum response to viral infection and viral RNA level may help understand pathogenesis and define clinical course of COVID-19.
Subject(s)
COVID-19ABSTRACT
With an increasing number of SARS-CoV-2 sequences available day by day, new genomic information is getting revealed to us. As SARS-CoV-2 sequences highlight wide changes across the samples, we aim to explore whether these changes reveal the geographical origin of the corresponding samples. The k-mer distributions, denoting normalized frequency counts of all possible combinations of nucleotide of size upto k, are often helpful to explore sequence level patterns. Given the SARS-CoV-2 sequences are highly imbalanced by its geographical origin (relatively with a higher number samples collected from the USA), we observe that with proper under-sampling k-mer distributions in the SARS-CoV-2 sequences predict its geographical origin with more than 90% accuracy. The experiments are performed on the samples collected from six countries with maximum number of sequences available till July 07, 2020. This comprises SARS-CoV-2 sequences from Australia, USA, China, India, Greece and France. Moreover, we demonstrate that the changes of genomic sequences characterize the continents as a whole. We also highlight that the network motifs present in the sequence similarity networks have a significant difference across the said countries. This, as a whole, is capable of predicting the geographical shift of SARS-CoV-2.
ABSTRACT
Objective: To evaluate if the number of admitted extremely preterm (EP) infants (born before 28weeks of gestational age) has changed in the neonatal intensive care units (NICUs) of the SafeBoosC-III consortium during the global lockdown when compared to the corresponding time period in 2019. Design: This is a retrospective, observational study. Forty-six out of 79 NICUs (58%) from 17 countries participated. Principal investigators were asked to report the following information: 1) Total number of EP infant admissions to their NICU in the three months where the lockdown restrictions were most rigorous during the first phase of the COVID-19 pandemic, 2) Similar EP infant admissions in the corresponding three months of 2019, 3) the level of local restrictions during the lockdown period and 4) the local impact of the COVID-19 lockdown on the everyday life of a pregnant woman. Results: There was no significant difference between the number of EP infant admissions during the three most rigorous lockdown months of the COVID-19 pandemic compared to the corresponding three months in 2019 (n=428 versus n=457 respectively, p=0.33). There were no significant changes within individual geographic regions and no significant association between the level of lockdown restrictions and change in the number of EP infant admissions (p=0.334). Conclusion: This larger ad hoc study did not confirm previous studies report of a major reduction in the number of extremely preterm births during the first phase of the COVID-19 pandemic.
Subject(s)
COVID-19ABSTRACT
Objective: We tested a model of individual health literacy, information sharing with family members, personal preventive behaviours and family well-being during COVID-19 pandemic in Hong Kong. Methods: We analysed data of 1501 randomly selected Chinese adults from a cross-sectional survey in Hong Kong from 9 to 23 April 2020. Individual health literacy, COVID-19 information sharing with family members, preventive behaviours against COVID-19 and family well-being were measured. Structural equation modelling analysis tested the proposed model. Findings: COVID-19 information sharing with family members partially mediated the association between individual health literacy and personal preventive behaviours. The direct effect of .24 was shown and indirect effect through COVID-19 information sharing with family members was small with .03 (Z = 3.66, p < .001). Family well-being was associated with personal preventive behaviours against COVID-19. The model was adjusted for sex, age, and socioeconomic status factors and had good fit with RMSEA = .04, CFI = .98, TLI = .96, and SRMR = .02. Conclusion: COVID-19 information sharing with family members was a partial mediator between individual health literacy and personal preventive behaviours against COVID-19. Strategies for enhancing health literacy and preventive measures against COVID-19 are needed to promote family well-being in the pandemic.
Subject(s)
COVID-19ABSTRACT
A severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) has recently caused a pandemic COVID-19 disease that infected more than 25.6 million and killed 852,000 people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its envelope spike protein for binding the host angiotensin-converting enzyme 2 (ACE2) to gain viral entry. Currently, extensive efforts are being made to produce vaccines against a surface fragment of a SARS-CoV-2, such as the spike protein, in order to boost protective antibody responses. It was previously unknown how spike protein-targeting antibodies would affect innate inflammatory responses to SARS-CoV-2 infections. Here we generated a highly purified recombinant protein corresponding to the RBM of SARS-CoV-2, and used it to screen for cross-reactive monoclonal antibodies (mAbs). We found two RBM-binding mAbs that competitively inhibited its interaction with human ACE2, and specifically blocked the RBM-induced GM-CSF secretion in both human monocyte and murine macrophage cultures. Our findings have suggested a possible strategy to prevent SARS-CoV-2-elicited "cytokine storm", and provided a potentially useful criteria for future assessment of innate immune-modulating properties of various SARS-CoV-2 vaccines. One Sentence SummaryRBM-binding Antibodies Inhibit GM-CSF Induction.
Subject(s)
COVID-19ABSTRACT
Sharp increases in COVID-19 cases occurred after reopening in the United States. We show that the post-intervention effective reproduction number is a strong predictor of the surge in late June. Lax interventions in the early stages coupled with elevated virus spread are primarily responsible for surges in most affected states.