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260 Research products, page 1 of 26

  • COVID-19
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  • Open Access English
    Authors: 
    Romain Marlin; Delphine Desjardins; Vanessa Contreras; Guillaume Lingas; Caroline Solas; Pierre Roques; Thibaut Naninck; Quentin Pascal; Sylvie Behillil; Pauline Maisonnasse; +17 more
    Publisher: HAL CCSD
    Country: France
    Project: EC | TRANSVAC2 (730964), EC | EVAg (653316), EC | ZIKAlliance (734548)

    AbstractThe COVID-19 pandemic has exemplified that rigorous evaluation in large animal models is key for translation from promising in vitro results to successful clinical implementation. Among the drugs that have been largely tested in clinical trials but failed so far to bring clear evidence of clinical efficacy is favipiravir, a nucleoside analogue with large spectrum activity against several RNA viruses in vitro and in small animal models. Here, we evaluate the antiviral activity of favipiravir against Zika or SARS-CoV-2 virus in cynomolgus macaques. In both models, high doses of favipiravir are initiated before infection and viral kinetics are evaluated during 7 to 15 days after infection. Favipiravir leads to a statistically significant reduction in plasma Zika viral load compared to untreated animals. However, favipiravir has no effects on SARS-CoV-2 viral kinetics, and 4 treated animals have to be euthanized due to rapid clinical deterioration, suggesting a potential role of favipiravir in disease worsening in SARS-CoV-2 infected animals. To summarize, favipiravir has an antiviral activity against Zika virus but not against SARS-CoV-2 infection in the cynomolgus macaque model. Our results support the clinical evaluation of favipiravir against Zika virus but they advocate against its use against SARS-CoV-2 infection.

  • Open Access English
    Authors: 
    Mehdi Stiti; Guillaume Castanet; Andrew Corber; Marcus Aldén; Edouard Berrocal;
    Publisher: HAL CCSD
    Country: France
    Project: EC | Spray-Imaging (638546)

    To control the evolution of a pandemic such as COVID-19, knowing the conditions under which the pathogen is being transmitted represents a critical issue, especially when implementing protection strategies like social distancing and face masks wearing. For viruses and bacteria that spread via airborne and/or droplet pathways, this requires understanding how saliva droplets evolve over time after their expulsion by speaking or coughing. Within this context, the transition from saliva droplets to solid residues, due to water evaporation, is studied here both experimentally, considering the saliva from 5 men and 5 women, and via numerical modeling to accurately predict the dynamics of this process. The model assumes saliva to be a binary water/salt mixture and is validated against experimental results using saliva droplets that are suspended in an ultrasound levitator. We demonstrate that droplets with an initial diameter smaller than 21 μm will produce a solid residue that would be considered an aerosol of <5 μm diameter within less than 2 second (for any relative humidity less than 80% and/or any temperature greater than 20 °C). Finally, the model developed here accounts for the influence of the saliva composition, relative humidity and ambient temperature on droplet drying. Thus, the travel distance prior to becoming a solid residue can be deduced. We found that saliva droplets of initial size below 80 μm, which corresponds to the vast majority of speech and cough droplets, will become solid residues prior to touching the ground when expelled from a height of 160 cm.

  • Open Access English
    Authors: 
    Tom H Karlsen; Nick Sheron; Shira Zelber-Sagi; Patrizia Carrieri; Geoffrey Dusheiko; Elisabetta Bugianesi; Rachel Pryke; Sharon J Hutchinson; Bruno Sangro; Natasha K Martin; +47 more
    Countries: Netherlands, France, France, United Kingdom, Italy, France
    Project: EC | SHARE-DEV3 (676536)

    Liver diseases have become a major health threat across Europe, and the face of European hepatology is changing due to the cure of viral hepatitis C and the control of chronic viral hepatitis B, the increasingly widespread unhealthy use of alcohol, the epidemic of obesity, and undiagnosed or untreated liver disease in migrant populations. Consequently, Europe is facing a looming syndemic, in which socioeconomic and health inequities combine to adversely affect liver disease prevalence, outcomes, and opportunities to receive care. In addition, the COVID-19 pandemic has magnified pre-existing challenges to uniform implementation of policies and equity of access to care in Europe, arising from national borders and the cultural and historical heterogeneity of European societies. In following up on work from the Lancet Commission on liver disease in the UK and epidemiological studies led by the European Association for the Study of the Liver (EASL), our multidisciplinary Commission, comprising a wide range of public health, medical, and nursing specialty groups, along with patient representatives, set out to provide a snapshot of the European landscape on liver diseases and to propose a framework for the principal actions required to improve liver health in Europe. We believe that a joint European process of thinking, and construction of uniform policies and action, implementation, and evaluation can serve as a powerful mechanism to improve liver care in Europe and set the way for similar changes globally.

  • Open Access English
    Authors: 
    Laura Di Domenico; Giulia Pullano; Chiara E. Sabbatini; Pierre-Yves Boëlle; Vittoria Colizza;
    Publisher: HAL CCSD
    Country: France
    Project: EC | MOOD (874850), ANR | DataRedux (ANR-19-CE46-0008), ANR | SPHINx (ANR-17-CE36-0008)

    As countries in Europe implement strategies to control the COVID-19 pandemic, different options are chosen regarding schools. Through a stochastic age-structured transmission model calibrated to the observed epidemic in Île-de-France in the first wave, we explored scenarios of partial, progressive, or full school reopening. Given the uncertainty on children’s role, we found that reopening schools after lockdown may increase COVID-19 cases, yet protocols exist to keep the epidemic controlled. Under a scenario with stable epidemic activity if schools were closed, reopening pre-schools and primary schools would lead to up to 76% [67, 84]% occupation of ICU beds if no other school level reopened, or if middle and high schools reopened later. Immediately reopening all school levels may overwhelm the ICU system. Priority should be given to pre- and primary schools allowing younger children to resume learning and development, whereas full attendance in middle and high schools is not recommended for stable or increasing epidemic activity. Large-scale test and trace is required to keep the epidemic under control. Ex-post assessment shows that progressive reopening of schools, limited attendance, and strong adoption of preventive measures contributed to a decreasing epidemic after lifting the first lockdown. The role of children in the spread of COVID-19 is not fully understood, and the circumstances under which schools should be opened are therefore debated. Here, the authors demonstrate protocols by which schools in France can be safely opened without overwhelming the healthcare system.

  • Open Access English
    Authors: 
    Romain Marlin; Véronique Godot; Sylvain Cardinaud; Mathilde Galhaut; Severin Coleon; Sandra Zurawski; Nathalie Dereuddre-Bosquet; Mariangela Cavarelli; Anne-Sophie Gallouet; Pauline Maisonnasse; +28 more
    Publisher: HAL CCSD
    Country: France
    Project: ANR | IDMIT (ANR-11-INBS-0008), EC | TRANSVAC2 (730964), EC | EVAg (653316)

    Achieving sufficient worldwide vaccination coverage against SARS-CoV-2 will require additional approaches to currently approved viral vector and mRNA vaccines. Subunit vaccines may have distinct advantages when immunizing vulnerable individuals, children and pregnant women. Here, we present a new generation of subunit vaccines targeting viral antigens to CD40-expressing antigen-presenting cells. We demonstrate that targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to CD40 (αCD40.RBD) induces significant levels of specific T and B cells, with long-term memory phenotypes, in a humanized mouse model. Additionally, we demonstrate that a single dose of the αCD40.RBD vaccine, injected without adjuvant, is sufficient to boost a rapid increase in neutralizing antibodies in convalescent non-human primates (NHPs) exposed six months previously to SARS-CoV-2. Vaccine-elicited antibodies cross-neutralize different SARS-CoV-2 variants, including D614G, B1.1.7 and to a lesser extent B1.351. Such vaccination significantly improves protection against a new high-dose virulent challenge versus that in non-vaccinated convalescent animals. In this study, Marlin et al. provide insights into the potential use of subunit vaccines that induce a high level of protection against SARS-CoV-2 in animal models.

  • Open Access English
    Authors: 
    Andronico, Alessio; Tran Kiem, Cécile; Paireau, Juliette; Succo, Tiphanie; Bosetti, Paolo; Lefrancq, Noémie; Nacher, Mathieu; Djossou, Félix; Sanna, Alice; Flamand, Claude; +3 more
    Countries: France, United Kingdom
    Project: ANR | INCEPTION (ANR-16-CONV-0005), EC | RECoVER (101003589)

    Abstract: While general lockdowns have proven effective to control SARS-CoV-2 epidemics, they come with enormous costs for society. It is therefore essential to identify control strategies with lower social and economic impact. Here, we report and evaluate the control strategy implemented during a large SARS-CoV-2 epidemic in June–July 2020 in French Guiana that relied on curfews, targeted lockdowns, and other measures. We find that the combination of these interventions coincided with a reduction in the basic reproduction number of SARS-CoV-2 from 1.7 to 1.1, which was sufficient to avoid hospital saturation. We estimate that thanks to the young demographics, the risk of hospitalisation following infection was 0.3 times that of metropolitan France and that about 20% of the population was infected by July. Our model projections are consistent with a recent seroprevalence study. The study showcases how mathematical modelling can be used to support healthcare planning in a context of high uncertainty. Funder: We acknowledge financial support from the Investissement d'Avenir program, the Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases program (Grant ANR-10-LABX-62-IBEID), Sante Publique France, the INCEPTION project (PIA/ANR-16-CONV-0005) and European Union V.E.O and RECOVER projects.

  • Open Access English
    Authors: 
    Samuele Bovo; Giuseppina Schiavo; Anisa Ribani; Valerio Joe Utzeri; Valeria Taurisano; Mohamad Ballan; María Muñoz; Estefania Alves; José Pedro Araújo; Riccardo Bozzi; +22 more
    Countries: France, France, Italy, France, France, Serbia, Spain, Croatia, Croatia, Serbia ...
    Project: EC | TREASURE (634476), EC | TREASURE (634476)

    AbstractCoronaviruses silently circulate in human and animal populations, causing mild to severe diseases. Therefore, livestock are important components of a “One Health” perspective aimed to control these viral infections. However, at present there is no example that considers pig genetic resources in this context. In this study, we investigated the variability of four genes (ACE2, ANPEP and DPP4 encoding for host receptors of the viral spike proteins and TMPRSS2 encoding for a host proteinase) in 23 European (19 autochthonous and three commercial breeds and one wild boar population) and two Asian Sus scrofa populations. A total of 2229 variants were identified in the four candidate genes: 26% of them were not previously described; 29 variants affected the protein sequence and might potentially interact with the infection mechanisms. The results coming from this work are a first step towards a “One Health” perspective that should consider conservation programs of pig genetic resources with twofold objectives: (i) genetic resources could be reservoirs of host gene variability useful to design selection programs to increase resistance to coronaviruses; (ii) the described variability in genes involved in coronavirus infections across many different pig populations might be part of a risk assessment including pig genetic resources.

  • Open Access English
    Authors: 
    Benjamin Gaborit; Bernard Vanhove; Marie-Anne Vibet; Aurélie Le Thuaut; Karine Lacombe; Vincent Dubee; Florence Ader; Virginie Ferre; Eric Vicaut; Jéremie Orain; +14 more
    Publisher: BMC
    Country: France
    Project: EC | BRIGHT (962036)

    Abstract Background Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions. By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations. New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2. Methods Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population. Discussion This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used. Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis. Trial registration ClinicalTrials.gov NCT04453384, registered on 1 July 2020, and EUDRACT 2020-002574-27, registered 6 June 2020.

  • Publication . Preprint . Article . 2021
    Open Access English
    Authors: 
    Evangelos Kontos; Aria Samimi; Renate W. Hakze-van der Honing; J. Priem; Aurore Avarguès-Weber; Alexander Haverkamp; Marcel Dicke; Jose L. Gonzales; Wim H.M. van der Poel;
    Publisher: HAL CCSD
    Countries: Netherlands, France
    Project: EC | One Health EJP (773830)

    AbstractThe COVID-19 pandemic has illustrated the need for the development of fast and reliable testing methods for novel, zoonotic, viral diseases in both humans and animals. Pathologies lead to detectable changes in the Volatile Organic Compound (VOC) profile of animals, which can be monitored, thus allowing the development of a rapid VOC-based test. In the current study, we successfully trained honeybees (Apis mellifera) to identify SARS-CoV-2 infected minks (Neovison vison) thanks to Pavlovian conditioning protocols. The bees can be quickly conditioned to respond specifically to infected mink’s odours and could therefore be part of a wider SARS-CoV-2 diagnostic system. We tested two different training protocols to evaluate their performance in terms of learning rate, accuracy and memory retention. We designed a non-invasive rapid test in which multiple bees are tested in parallel on the same samples. This provided reliable results regarding a subject’s health status. Using the data from the training experiments, we simulated a diagnostic evaluation trial to predict the potential efficacy of our diagnostic test, which yielded a diagnostic sensitivity of 92% and specificity of 86%. We suggest that a honeybee-based diagnostics can offer a reliable and rapid test that provides a readily available, low-input addition to the currently available testing methods. A honeybee-based diagnostic test might be particularly relevant for remote and developing communities that lack the resources and infrastructure required for mainstream testing methods.

  • Open Access English
    Authors: 
    Natacha S. Ogando; Priscila El Kazzi; Jessika C. Zevenhoven-Dobbe; Brenda w. Bontes; Alice Decombe; Clara C. Posthuma; Volker Thiel; Bruno Canard; François Ferron; Etienne Decroly; +1 more
    Countries: France, Switzerland, Netherlands
    Project: EC | ANTIVIRALS (642434)

    As coronaviruses (CoVs) replicate in the host cell cytoplasm, they rely on their own capping machinery to ensure the efficient translation of their messenger RNAs (mRNAs), protect them from degradation by cellular 5′ exoribonucleases (ExoNs), and escape innate immune sensing. The CoV nonstructural protein 14 (nsp14) is a bifunctional replicase subunit harboring an N-terminal 3′-to-5′ ExoN domain and a C-terminal (N7-guanine)–methyltransferase (N7-MTase) domain that is presumably involved in viral mRNA capping. Here, we aimed to integrate structural, biochemical, and virological data to assess the importance of conserved N7-MTase residues for nsp14’s enzymatic activities and virus viability. We revisited the crystal structure of severe acute respiratory syndrome (SARS)–CoV nsp14 to perform an in silico comparative analysis between betacoronaviruses. We identified several residues likely involved in the formation of the N7-MTase catalytic pocket, which presents a fold distinct from the Rossmann fold observed in most known MTases. Next, for SARS-CoV and Middle East respiratory syndrome CoV, site-directed mutagenesis of selected residues was used to assess their importance for in vitro enzymatic activity. Most of the engineered mutations abolished N7-MTase activity, while not affecting nsp14-ExoN activity. Upon reverse engineering of these mutations into different betacoronavirus genomes, we identified two substitutions (R310A and F426A in SARS-CoV nsp14) abrogating virus viability and one mutation (H424A) yielding a crippled phenotype across all viruses tested. Our results identify the N7-MTase as a critical enzyme for betacoronavirus replication and define key residues of its catalytic pocket that can be targeted to design inhibitors with a potential pan-coronaviral activity spectrum. Significance The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emphasizes the urgent need to develop efficient broad-spectrum anti-CoV drugs. The structure–function characterization of conserved CoV replicative enzymes is key to identifying the most suitable drug targets. Using a multidisciplinary comparative approach and different betacoronaviruses, we characterized the key conserved residues of the nsp14 (N7-guanine)–methyltransferase, a poorly defined subunit of the CoV messenger RNA–synthesizing machinery. Our study highlights the unique structural features of this enzyme and establishes its essential role in betacoronavirus replication, while identifying two residues that are critical for the replication of the four betacoronaviruses tested, including SARS-CoV-2.