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1.
Stem Cell Reports ; 17(4): 789-803, 2022 04 12.
Article in English | MEDLINE | ID: covidwho-1815188

ABSTRACT

Several studies have pointed to retinal involvement in COVID-19, yet many questions remain regarding the ability of SARS-CoV-2 to infect and replicate in retinal cells and its effects on the retina. Here, we have used human pluripotent stem cell-derived retinal organoids to study retinal infection by SARS-CoV-2. Indeed, SARS-CoV-2 can infect and replicate in retinal organoids, as it is shown to infect different retinal lineages, such as retinal ganglion cells and photoreceptors. SARS-CoV-2 infection of retinal organoids also induces the expression of several inflammatory genes, such as interleukin 33, a gene associated with acute COVID-19 and retinal degeneration. Finally, we show that the use of antibodies to block ACE2 significantly reduces SARS-CoV-2 infection of retinal organoids, indicating that SARS-CoV-2 infects retinal cells in an ACE2-dependent manner. These results suggest a retinal involvement in COVID-19 and emphasize the need to monitor retinal pathologies as potential sequelae of "long COVID."


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , COVID-19/complications , Humans , Organoids/metabolism , Retina , Retinal Ganglion Cells , SARS-CoV-2
2.
Pharmaceuticals (Basel) ; 15(5)2022 Apr 25.
Article in English | MEDLINE | ID: covidwho-1810076

ABSTRACT

For almost two years, the COVID-19 pandemic has constituted a major challenge to human health, particularly due to the lack of efficient antivirals to be used against the virus during routine treatment interventions. Multiple treatment options have been investigated for their potential inhibitory effect on SARS-CoV-2. Natural products, such as plant extracts, may be a promising option, as they have shown an antiviral activity against other viruses in the past. Here, a quantified extract of Hypericum perforatum was tested and found to possess a potent antiviral activity against SARS-CoV-2. The antiviral potency of the extract could be attributed to the naphtodianthrones hypericin and pseudohypericin, in contrast to other tested ingredients of the plant material, which did not show any antiviral activity. Hypericum perforatum and its main active ingredient hypericin were also effective against different SARS-CoV-2 variants (Alpha, Beta, Delta, and Omicron). Concerning its mechanism of action, evidence was obtained that Hypericum perforatum and hypericin may hold a direct virus-blocking effect against SARS-CoV-2 virus particles. Taken together, the presented data clearly emphasize the promising antiviral activity of Hypericum perforatum and its active ingredients against SARS-CoV-2 infections.

3.
J Virol ; 96(5): e0218621, 2022 03 09.
Article in English | MEDLINE | ID: covidwho-1736028

ABSTRACT

Recent emergence of SARS-CoV-1 variants demonstrates the potential of this virus for targeted evolution, despite its overall genomic stability. Here we show the dynamics and the mechanisms behind the rapid adaptation of SARS-CoV-2 to growth in Vero E6 cells. The selective advantage for growth in Vero E6 cells is due to increased cleavage efficiency by cathepsins at the mutated S1/S2 site. S1/S2 site also constitutes a heparan sulfate (HS) binding motif that influenced virus growth in Vero E6 cells, but HS antagonist did not inhibit virus adaptation in these cells. The entry of Vero E6-adapted virus into human cells is defective because the mutated spike variants are poorly processed by furin or TMPRSS2. Minor subpopulation that lack the furin cleavage motif in the spike protein rapidly become dominant upon passaging through Vero E6 cells, but wild type sequences are maintained at low percentage in the virus swarm and mediate a rapid reverse adaptation if the virus is passaged again on TMPRSS2+ human cells. Our data show that the spike protein of SARS-CoV-2 can rapidly adapt itself to available proteases and argue for deep sequence surveillance to identify the emergence of novel variants. IMPORTANCE Recently emerging SARS-CoV-2 variants B.1.1.7 (alpha variant), B.1.617.2 (delta variant), and B.1.1.529 (omicron variant) harbor spike mutations and have been linked to increased virus pathogenesis. The emergence of these novel variants highlights coronavirus adaptation and evolution potential, despite the stable consensus genotype of clinical isolates. We show that subdominant variants maintained in the virus population enable the virus to rapidly adapt to selection pressure. Although these adaptations lead to genotype change, the change is not absolute and genomes with original genotype are maintained in the virus swarm. Thus, our results imply that the relative stability of SARS-CoV-2 in numerous independent clinical isolates belies its potential for rapid adaptation to new conditions.


Subject(s)
COVID-19/metabolism , Furin/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Adaptation, Physiological , Animals , COVID-19/genetics , COVID-19/virology , Chlorocebus aethiops , Cytopathogenic Effect, Viral , Furin/genetics , HEK293 Cells , High-Throughput Nucleotide Sequencing , Humans , Mutation , SARS-CoV-2/genetics , Serine Endopeptidases/genetics , Spike Glycoprotein, Coronavirus/genetics , Vero Cells , Virus Replication
4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329328

ABSTRACT

Coronaviruses, in particular the current pandemic strains of SARS-CoV-2, represent an ever-evolving threat to human life. Currently available antiviral drugs are not suitable for severely infected patients in later hyperinflammatory stages of the disease. New therapeutics that inhibit virus propagation and target inflammation would be ideal. We demonstrate that the host targeted MEK inhibitor zapnometinib displays such a dual effect. The drug efficiently reduced virus titers of different SARS-CoV-2 variants and other highly pathogenic human coronaviruses such as SARS-CoV-1 and MERS-CoV in vitro. In a Syrian hamster infection model, zapnometinib reduced SARS-CoV-2 viral load and alleviated lung pathology. Drug safety biomarkers, body weight change and clinical observations, indicated that zapnometinib was well tolerated and showed no toxicity. Moreover, the immune dampening effect could be confirmed in an acute lung injury mouse model and in vitro experiments in primary human blood cells that demonstrated the reduction of disease related cytokines and chemokines. Thus, in contrast to direct-acting antivirals, zapnometinib displays a dual therapeutic effect highlighting its potential in the treatment of severe COVID-19 and other acute viral infections leading to hyperinflammation.

5.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-312513

ABSTRACT

SARS-CoV-2 utilizes the ACE2 transmembrane peptidase as essential cellular entry receptor. Several studies have suggested abundant ACE2 expression in the human lung, inferring strong permissiveness to SARS-CoV-2 infection with resultant alveolar damage and lung injury. Against this expectation, we provide evidence that ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation in the human alveolus. Instead, spectral imaging of ex vivo infected human lungs and COVID-19 autopsy samples depicted that alveolar macrophages were frequently positive for SARS-CoV-2, indicating viral phagocytosis. Single-cell transcriptomics of SARS-CoV-2 infected human lung tissue further revealed strong inflammatory and anti-viral activation responses in macrophages and monocytes, comparable to those induced by MERS-CoV, but with virus-specific gene expression profiles. Collectively, our findings indicate that severe lung injury in COVID-19 likely results from an overwhelming immune activation rather than direct viral damage of the alveolar compartment.Funding: ACH, LES, SH were supported by Berlin University Alliance GC2 Global Health (Corona Virus Pre-Exploration Project). ACH, SH, TW and CD were supported by BMBF (RAPID) and ACH, SH by BMBF (alvBarriereCOVID-19). KH, LB, SL, SH, CD, TW, ACH were funded by BMBF (NFN-COVID 19, Organo-Strat). KH, NS, LES, MW, SH, ADG, CD, TW and ACH were supported by DFG (SFB-TR 84). ACH was supported by BIH, Charite 3R, and Charité-Zeiss MultiDim. KH was supported by BMBF (Camo-COVID-19). MW, NS and SH was supported by BMBF (PROVID). MW and NS was supported by BIH and BMBF (SYMPATH, CAPSyS, NAPKON). BO and DB were funded through the BIH Clinical Single Cell Bioinformatics Pipeline. LB was supported by the BMBF (CoIMMUNE), the DFG (KFO 342) and the IZKF of the Medical Faculty of the WWU. Conflict of Interest: The authors declare no competing interests.Ethical Approval: The study was approved by the ethics committee at the Charité clinic (projects EA2/079/13) and Ärztekammer Westfalen-Lippe and of the Westfälischen Wilhelms-Universität (AZ: 2016-265-f-S). Written informed consent was obtained from all patients.

6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-308569

ABSTRACT

Global pandemics by influenza or coronaviruses cause severe disruptions to the public health and lead to severe morbidity and mortality. Vaccines against these pathogens remain a medical need. CMV (cytomegalovirus) is a β-herpesvirus that induces uniquely robust immune responses, where outstandingly large populations of antigen-specific CD8+ T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing the hemagglutinin (HA) of influenza A virus (MCMVHA) or the spike protein of the severe acute respiratory syndrome coronavirus 2 (MCMVS). A single shot of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMVHA vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to effects of memory T cells. Conclusively, we show here that MCMV vectors do not only induce long-term cellular immunity, but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.

7.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Article in English | MEDLINE | ID: covidwho-1671749

ABSTRACT

Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies, and have been successfully employed for the treatment of viral diseases. Humans express 12 IFN-alpha (α) subtypes, which activate downstream signaling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in IFN-I immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19; therefore, early administration of IFN-I may be protective against life-threatening disease. Here we comprehensively analyzed the antiviral activity of all IFNα subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate, and low antiviral IFNs. In particular, IFNα5 showed superior antiviral activity against SARS-CoV-2 infection in vitro and in SARS-CoV-2-infected mice in vivo. Dose dependency studies further displayed additive effects upon coadministration with the broad antiviral drug remdesivir in cell culture. Transcriptomic analysis of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting, and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in IFN-I signaling pathways, negative regulation of viral processes, and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multimodular definition of antiviral host responses mediated by defined IFN-I. This knowledge will support the development of novel therapeutic approaches against SARS-CoV-2.


Subject(s)
COVID-19/drug therapy , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Transcriptome , Virus Replication/drug effects , Animals , COVID-19/immunology , COVID-19/virology , Chlorocebus aethiops , Cloning, Molecular , Disease Models, Animal , Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression Profiling , Gene Expression Regulation , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Humans , Interferon-alpha/genetics , Interferon-alpha/immunology , Mice , Protein Isoforms/classification , Protein Isoforms/genetics , Protein Isoforms/immunology , Protein Isoforms/pharmacology , Recombinant Proteins/classification , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Recombinant Proteins/pharmacology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Signal Transduction , Vero Cells
8.
Cell Mol Life Sci ; 79(1): 65, 2022 Jan 10.
Article in English | MEDLINE | ID: covidwho-1616112

ABSTRACT

Coronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections. We find that SARS-CoV-2 transiently activates Raf/MEK/ERK signaling in the very early infection phase and that ERK1/2 knockdown limits virus replication in cell culture models. We demonstrate that ATR-002, a specific inhibitor of the upstream MEK1/2 kinases which is currently evaluated in clinical trials as an anti-influenza drug, displays strong anti-SARS-CoV-2 activity in cell lines as well as in primary air-liquid-interphase epithelial cell (ALI) cultures, with a safe and selective treatment window. We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Fenamates/pharmacology , MAP Kinase Signaling System/drug effects , Protein Kinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , A549 Cells , Adult , Animals , COVID-19/metabolism , Cell Line , Cells, Cultured , Chlorocebus aethiops , Cytokines/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Kinase 2/metabolism , SARS-CoV-2/physiology , Vero Cells , Virus Replication/drug effects
9.
Cell Mol Immunol ; 19(2): 234-244, 2022 02.
Article in English | MEDLINE | ID: covidwho-1612184

ABSTRACT

Global pandemics caused by influenza or coronaviruses cause severe disruptions to public health and lead to high morbidity and mortality. There remains a medical need for vaccines against these pathogens. CMV (cytomegalovirus) is a ß-herpesvirus that induces uniquely robust immune responses in which remarkably large populations of antigen-specific CD8+ T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector for expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing hemagglutinin (HA) of influenza A virus (MCMVHA) or the spike protein of severe acute respiratory syndrome coronavirus 2 (MCMVS). A single injection of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMVHA-vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to the effects of memory T cells. Conclusively, we show here that MCMV vectors induce not only long-term cellular immunity but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Immunity, Humoral , Influenza A virus/immunology , Influenza Vaccines/immunology , Orthomyxoviridae Infections/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/virology , Chlorocebus aethiops , Cytomegalovirus/immunology , Dogs , Female , HEK293 Cells , Humans , Immunity, Cellular , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Orthomyxoviridae Infections/virology , Vero Cells
10.
Sci Rep ; 11(1): 24416, 2021 12 24.
Article in English | MEDLINE | ID: covidwho-1585784

ABSTRACT

Since the beginning of the COVID -19 pandemic, many contact sport teams are facing major challenges to safely continue training and competition. We present the design and implementation of a structured monitoring concept for the Austrian national football league. 146 professional players from five clubs of the professional Austrian football league were monitored for a period of 12 weeks. Subjective health parameters, PCR- test results and data obtained from a geo-tracking app were collected. Simulations modelling the consequences of a COVID-19 case with increasing reproduction number were computed. No COVID -19 infection occurred during the observation period in the players. Infections in the nearer surroundings lead to increased perceived risk of infection. Geo tracking was particularly hindered due to technical problems and reluctance of users. Simulation models suggested a hypothetical shut-down of all training and competition activities. A structured monitoring concept can help to continue contact sports safely in times of a pandemic. Cooperation of all involved is essential. Trial registration: ID: DRKS00022166 15/6/2020 https://www.who.int/ictrp/search/en/ .


Subject(s)
COVID-19/diagnosis , Computer Simulation , Algorithms , Austria , COVID-19/virology , Humans , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Soccer
11.
[Unspecified Source]; 2020.
Preprint in English | [Unspecified Source] | ID: ppcovidwho-292768

ABSTRACT

Antiviral therapy is urgently needed to combat the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The protease inhibitor camostat mesylate inhibits SARS-CoV-2 infection of lung cells by blocking the virus-activating host cell protease TMPRSS2. Camostat mesylate has been approved for treatment of pancreatitis in Japan and is currently being repurposed for COVID-19 treatment. However, potential mechanisms of viral resistance as well as camostat mesylate metabolization and antiviral activity of metabolites are unclear. Here, we show that SARS-CoV-2 can employ TMPRSS2-related host cell proteases for activation and that several of them are expressed in viral target cells. However, entry mediated by these proteases was blocked by camostat mesylate. The camostat metabolite GBPA inhibited the activity of recombinant TMPRSS2 with reduced efficiency as compared to camostat mesylate and was rapidly generated in the presence of serum. Importantly, the infection experiments in which camostat mesylate was identified as a SARS-CoV-2 inhibitor involved preincubation of target cells with camostat mesylate in the presence of serum for 2 h and thus allowed conversion of camostat mesylate into GBPA. Indeed, when the antiviral activities of GBPA and camostat mesylate were compared in this setting, no major differences were identified. Our results indicate that use of TMPRSS2-related proteases for entry into target cells will not render SARS-CoV-2 camostat mesylate resistant. Moreover, the present and previous findings suggest that the peak concentrations of GBPA established after the clinically approved camostat mesylate dose (600 mg/day) will result in antiviral activity.

12.
Front Immunol ; 12: 752227, 2021.
Article in English | MEDLINE | ID: covidwho-1477830

ABSTRACT

Since November 2019 the SARS-CoV-2 pandemic has caused nearly 200 million infection and more than 4 million deaths globally (Updated information from the World Health Organization, as on 2nd Aug 2021). Within only one year into the pandemic, several vaccines were designed and reached approval for the immunization of the world population. The remarkable protective effects of the manufactured vaccines are demonstrated in countries with high vaccination rates, such as Israel and UK. However, limited production capacities, poor distribution infrastructures and political hesitations still hamper the availability of vaccines in many countries. In addition, due to the emergency of SARS-CoV-2 variants with immune escape properties towards the vaccines the global numbers of new infections as well as patients developing severe COVID-19, remains high. New studies reported that about 8% of infected individuals develop long term symptoms with strong personal restrictions on private as well as professional level, which contributes to the long socioeconomic problems caused by this pandemic. Until today, emergency use-approved treatment options for COVID-19 are limited to the antiviral Remdesivir, a nucleoside analogue targeting the viral polymerase, the glucocorticosteroide Dexamethasone as well as neutralizing antibodies. The therapeutic benefits of these treatments are under ongoing debate and clinical studies assessing the efficiency of these treatments are still underway. To identify new therapeutic treatments for COVID-19, now and by the post-pandemic era, diverse experimental approaches are under scientific evaluation in companies and scientific research teams all over the world. To accelerate clinical translation of promising candidates, repurposing approaches of known approved drugs are specifically fostered but also novel technologies are being developed and are under investigation. This review summarizes the recent developments from the lab bench as well as the clinical status of emerging therapeutic candidates and discusses possible therapeutic entry points for the treatment strategies with regard to the biology of SARS-CoV-2 and the clinical course of COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 Vaccines/immunology , COVID-19/drug therapy , SARS-CoV-2/drug effects , Antibodies, Monoclonal/therapeutic use , COVID-19/pathology , COVID-19/prevention & control , Humans , SARS-CoV-2/immunology , Vaccination
13.
Viruses ; 13(10)2021 10 14.
Article in English | MEDLINE | ID: covidwho-1469382

ABSTRACT

Respiratory viruses are known to be the most frequent causative mediators of lung infections in humans, bearing significant impact on the host cell signaling machinery due to their host-dependency for efficient replication. Certain cellular functions are actively induced by respiratory viruses for their own benefit. This includes metabolic pathways such as glycolysis, fatty acid synthesis (FAS) and the tricarboxylic acid (TCA) cycle, among others, which are modified during viral infections. Here, we summarize the current knowledge of metabolic pathway modifications mediated by the acute respiratory viruses respiratory syncytial virus (RSV), rhinovirus (RV), influenza virus (IV), parainfluenza virus (PIV), coronavirus (CoV) and adenovirus (AdV), and highlight potential targets and compounds for therapeutic approaches.


Subject(s)
Citric Acid Cycle/physiology , Energy Metabolism/physiology , Fatty Acids/biosynthesis , Glycolysis/physiology , Respiratory Tract Infections/pathology , Respiratory Tract Infections/virology , Adenoviridae/metabolism , Coronavirus/metabolism , Humans , Orthomyxoviridae/metabolism , Parainfluenza Virus 1, Human/metabolism , Respiratory Syncytial Viruses/metabolism , Rhinovirus/metabolism
14.
Vaccines (Basel) ; 9(10)2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1438754

ABSTRACT

Since late 2019 the newly emerged pandemic SARS-CoV-2, the causative agent of COVID-19, has hit the world with recurring waves of infections necessitating the global implementation of non-pharmaceutical interventions, including strict social distancing rules, the wearing of masks and the isolation of infected individuals in order to restrict virus transmissions and prevent the breakdown of our healthcare systems. These measures are not only challenging on an economic level but also have a strong impact on social lifestyles. Using traditional and novel technologies, highly efficient vaccines against SARS-CoV-2 were developed and underwent rapid clinical evaluation and approval to accelerate the immunization of the world population, aiming to end the pandemic and return to normality. However, the emergence of virus variants with improved transmission, enhanced fitness and partial immune escape from the first generation of vaccines poses new challenges, which are currently being addressed by scientists and pharmaceutical companies all over the world. In this ongoing pandemic, the evaluation of SARS-CoV-2 vaccines underlies diverse unpredictable dynamics, posed by the first broad application of the mRNA vaccine technology and their compliance, the occurrence of unexpected side effects and the rapid emergence of variations in the viral antigen. However, despite these hurdles, we conclude that the available SARS-CoV-2 vaccines are very safe and efficiently protect from severe COVID-19 and are thereby the most powerful tools to prevent further harm to our healthcare systems, economics and individual lives. This review summarizes the unprecedented pathways of vaccine development and approval during the ongoing SARS-CoV-2 pandemic. We focus on the real-world effectiveness and unexpected positive and negative side effects of the available vaccines and summarize the timeline of the applied adaptations to the recommended vaccination strategies in the light of emerging virus variants. Finally, we highlight upcoming strategies to improve the next generations of SARS-CoV-2 vaccines.

15.
Am J Infect Control ; 50(4): 420-426, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1432733

ABSTRACT

BACKGROUND: During shortages of filtering face pieces (FFP) in a pandemic, it is necessary to implement a method for safe reuse or extended use. Our aim was to develop a simple, inexpensive and ecological method for decontamination of disposable FFPs that preserves filtration efficiency and material integrity. MATERIAL AND METHODS: Contamination of FFPs (3M Aura 9320+) with SARS-CoV-2 (1.15 × 104 PFUs), Enterococcus faecium (>106 CFUs), and physiological nasopharyngeal flora was performed prior to decontamination by submersion in a solution of 6 % acetic acid and 6 % hydrogen peroxide (6%AA/6%HP solution) over 30 minutes. Material integrity was assessed by testing the filtering efficiency, loss of fit and employing electron microscopy. RESULTS AND DISCUSSION: Decontamination with the 6%AA/6%HP solution resulted in the complete elimination of SARS-CoV-2, E. faecium and physiological nasopharyngeal flora. Material characterization post-treatment showed neither critical material degradation, loss of fit or reduction of filtration efficiency. Electron microscopy revealed no damage to the fibers, and the rubber bands' elasticity was not affected by the decontamination procedure. No concerning residuals of the decontamination procedure were found. CONCLUSION: The simple application and widespread availability of 6%AA/6%HP solution for decontaminating disposable FFPs make this solution globally viable, including developing and third world countries.


Subject(s)
COVID-19 , Pandemics , COVID-19/prevention & control , Decontamination/methods , Equipment Reuse , Humans , Pandemics/prevention & control , Peracetic Acid/pharmacology , SARS-CoV-2 , Ventilators, Mechanical
16.
Pharmaceutics ; 13(9)2021 Sep 03.
Article in English | MEDLINE | ID: covidwho-1390724

ABSTRACT

The ongoing SARS-CoV-2 pandemic requires efficient and safe antiviral treatment strategies. Drug repurposing represents a fast and low-cost approach to the development of new medical treatment options. The direct antiviral agent remdesivir has been reported to exert antiviral activity against SARS-CoV-2. Whereas remdesivir only has a very short half-life time and a bioactivation, which relies on pro-drug activating enzymes, its plasma metabolite GS-441524 can be activated through various kinases including the adenosine kinase (ADK) that is moderately expressed in all tissues. The pharmacokinetics of GS-441524 argue for a suitable antiviral drug that can be given to patients with COVID-19. Here, we analyzed the antiviral property of a combined treatment with the remdesivir metabolite GS-441524 and the antidepressant fluoxetine in a polarized Calu-3 cell culture model against SARS-CoV-2. The combined treatment with GS-441524 and fluoxetine were well-tolerated and displayed synergistic antiviral effects against three circulating SARS-CoV-2 variants in vitro in the commonly used reference models for drug interaction. Thus, combinatory treatment with the virus-targeting GS-441524 and the host-directed drug fluoxetine might offer a suitable therapeutic treatment option for SARS-CoV-2 infections.

17.
Arch Public Health ; 79(1): 144, 2021 Aug 16.
Article in English | MEDLINE | ID: covidwho-1360627

ABSTRACT

BACKGROUND: This study aimed to explore which measures and risk factors for a COVID - 19 infection are considered most important in the general population, health experts and policymakers and to assess the level of agreement across the groups from Austria and Germany. METHODS: A two-phased survey was conducted, participants were matched according to age and gender. Three different groups were asked which measures they considered most relevant in reducing a COVID-19 transmission, to determine which factors contribute most to the risk of disease, and to evaluate the level of agreement in the assessment of risk factor relevance for (a) the transmission of the disease and (b) the risk of a severe course of COVID-19. RESULTS: Risk factors for an infection that were selected from all three groups were immunosuppression/deficiency, cancer, chronic lung disease, smoking, age and working as a health care professional. Interrater agreement per population was only poor to slight and results were highly heterogeneous. CONCLUSIONS: Our survey shows a broad spectrum of opinions and the associated general uncertainty about the risk factors for infection and a severe course of disease across the groups. Profound knowledge of politicians and experts is of high relevance to provide the public with valid information to ensure cooperation fighting the pandemic. TRIAL REGISTRATION: https://apps.who.int/trialsearch/ (ID: DRKS00022166). Registered 15 June 2020.

18.
Br J Pharmacol ; 178(11): 2339-2350, 2021 06.
Article in English | MEDLINE | ID: covidwho-1171214

ABSTRACT

BACKGROUND AND PURPOSE: The SARS-COV-2 pandemic and the global spread of coronavirus disease 2019 (COVID-19) urgently call for efficient and safe antiviral treatment strategies. A straightforward approach to speed up drug development at lower costs is drug repurposing. Here, we investigated the therapeutic potential of targeting the interface of SARS CoV-2 with the host via repurposing of clinically licensed drugs and evaluated their use in combinatory treatments with virus- and host-directed drugs in vitro. EXPERIMENTAL APPROACH: We tested the antiviral potential of the antifungal itraconazole and the antidepressant fluoxetine on the production of infectious SARS-CoV-2 particles in the polarized Calu-3 cell culture model and evaluated the added benefit of a combinatory use of these host-directed drugs with the direct acting antiviral remdesivir, an inhibitor of viral RNA polymerase. KEY RESULTS: Drug treatments were well-tolerated and potently impaired viral replication. Importantly, both itraconazole-remdesivir and fluoxetine-remdesivir combinations inhibited the production of infectious SARS-CoV-2 particles > 90% and displayed synergistic effects, as determined in commonly used reference models for drug interaction. CONCLUSION AND IMPLICATIONS: Itraconazole-remdesivir and fluoxetine-remdesivir combinations are promising starting points for therapeutic options to control SARS-CoV-2 infection and severe progression of COVID-19.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Pharmaceutical Preparations , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Fluoxetine/pharmacology , Hepatitis C, Chronic/drug therapy , Humans , Itraconazole/pharmacology , SARS-CoV-2
19.
Nat Commun ; 12(1): 1577, 2021 03 11.
Article in English | MEDLINE | ID: covidwho-1132068

ABSTRACT

COVID-19 is a severe acute respiratory disease caused by SARS-CoV-2, a new recently emerged sarbecovirus. This virus uses the human ACE2 enzyme as receptor for cell entry, recognizing it with the receptor binding domain (RBD) of the S1 subunit of the viral spike protein. We present the use of phage display to select anti-SARS-CoV-2 spike antibodies from the human naïve antibody gene libraries HAL9/10 and subsequent identification of 309 unique fully human antibodies against S1. 17 antibodies are binding to the RBD, showing inhibition of spike binding to cells expressing ACE2 as scFv-Fc and neutralize active SARS-CoV-2 virus infection of VeroE6 cells. The antibody STE73-2E9 is showing neutralization of active SARS-CoV-2 as IgG and is binding to the ACE2-RBD interface. Thus, universal libraries from healthy human donors offer the advantage that antibodies can be generated quickly and independent from the availability of material from recovering patients in a pandemic situation.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Antibodies, Neutralizing/genetics , Antibodies, Viral/genetics , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/chemistry , Animals , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/isolation & purification , Antibody Affinity , COVID-19/epidemiology , Cell Line , Chlorocebus aethiops , Gene Library , Healthy Volunteers , Host Microbial Interactions/immunology , Humans , Immunoglobulin G/genetics , Immunoglobulin G/isolation & purification , Models, Molecular , Mutation , Neutralization Tests , Pandemics , Peptide Library , Protein Interaction Domains and Motifs , Recombinant Proteins/genetics , Recombinant Proteins/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells
20.
EBioMedicine ; 65: 103255, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1116567

ABSTRACT

BACKGROUND: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. METHODS: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. FINDINGS: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. INTERPRETATION: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. FUNDING: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Esters/pharmacology , Guanidines/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/metabolism , Animals , Cell Line , Chlorocebus aethiops , Cricetinae , HEK293 Cells , Humans , Lung/pathology , Lung/virology , Membrane Proteins/biosynthesis , Molecular Dynamics Simulation , Serine Endopeptidases/biosynthesis , Serine Proteases/biosynthesis , Vero Cells , Virus Activation/drug effects , Virus Internalization/drug effects
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