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1. Resistance of Omicron subvariants BA.2.75.2, BA.4.6, and BQ.1.1 to neutralizing antibodies

Author: Delphine Planas, Timothée Bruel, Isabelle Staropoli, Florence Guivel-Benhassine, Françoise Porrot, Piet Maes, Ludivine Grzelak, Matthieu Prot, Said Mougari, Cyril Planchais, Julien Puech, Madelina Saliba, Riwan Sahraoui, Florent Fémy, Nathalie Morel, Jérémy Dufloo, Rafael Sanjuán, Hugo Mouquet, Emmanuel André, Laurent Hocqueloux, Etienne Simon-Loriere, David Veyer, Thierry Prazuck, Hélène Péré, and Olivier Schwartz
Subjects: Science
Abstract: In this work, Planas et al. report that Omicron subvariants BA.2.75.2, BA.4.6, and BQ.1.1 escape neutralization from monoclonal antibodies, and sera from vaccinated individuals with or without Omicron BA.1/2 or BA.5 breakthrough infection.
Published: 2023
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2. Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients

Author: Thi H. O. Nguyen, Marios Koutsakos, Carolien E. van de Sandt, Jeremy Chase Crawford, Liyen Loh, Sneha Sant, Ludivine Grzelak, Emma K. Allen, Tim Brahm, E. Bridie Clemens, Maria Auladell, Luca Hensen, Zhongfang Wang, Simone Nüssing, Xiaoxiao Jia, Patrick Günther, Adam K. Wheatley, Stephen J. Kent, Malet Aban, Yi-Mo Deng, Karen L. Laurie, Aeron C. Hurt, Stephanie Gras, Jamie Rossjohn, Jane Crowe, Jianqing Xu, David Jackson, Lorena E. Brown, Nicole La Gruta, Weisan Chen, Peter C. Doherty, Stephen J. Turner, Tom C. Kotsimbos, Paul G. Thomas, Allen C. Cheng, and Katherine Kedzierska
Subjects: Science
Abstract: The immunological parameters that define severe influenza disease are not clear within human real time infections. Here the authors compare a severe influenza infection cohort with an influenza vaccinated cohort to understand correlates of severe influenza disease.
Published: 2021
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3. Release of infectious virus and cytokines in nasopharyngeal swabs from individuals infected with non-alpha or alpha SARS-CoV-2 variants: an observational retrospective study

Author: Blandine Monel, Delphine Planas, Ludivine Grzelak, Nikaïa Smith, Nicolas Robillard, Isabelle Staropoli, Pedro Goncalves, Françoise Porrot, Florence Guivel-Benhassine, Nathalie Demory Guinet, Julien Rodary, Julien Puech, Victor Euzen, Laurent Bélec, Galdric Orvoen, Léa Nunes, Véronique Moulin, Jacques Fourgeaud, Maxime Wack, Sandrine Imbeaud, Pascal Campagne, Darragh Duffy, James P. Di Santo, Timothée Bruel, Hélène Péré, David Veyer, and Olivier Schwartz
Subjects: COVID-19, SARS-CoV-2, Nasal swabs, variants, infectious particles, Medicine, Medicine (General), R5-920
Abstract: Background: The dynamics of SARS-CoV-2 alpha variant shedding and immune responses at the nasal mucosa remain poorly characterised. Methods: We measured infectious viral release, antibodies and cytokines in 426 PCR+ nasopharyngeal swabs from individuals harboring non-alpha or alpha variants. Findings: With both lineages, viral titers were variable, ranging from 0 to >106 infectious units. Rapid antigenic diagnostic tests were positive in 94% of samples with infectious virus. 68 % of individuals carried infectious virus within two days after onset of symptoms. This proportion decreased overtime. Viable virus was detected up to 14 days. Samples containing anti-spike IgG or IgA did not generally harbor infectious virus. Ct values were slightly but not significantly lower with alpha. This variant was characterized by a fast decrease of infectivity overtime and a marked release of 13 cytokines (including IFN-b, IP-10 and IL-10). Interpretation: The alpha variant displays modified viral decay and cytokine profiles at the nasopharyngeal mucosae during symptomatic infection. Funding: This retrospective study has been funded by Institut Pasteur, ANRS, Vaccine Research Institute, Labex IBEID, ANR/FRM and IDISCOVR, Fondation pour la Recherche Médicale.
Published: 2021
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4. Asymptomatic and symptomatic SARS-CoV-2 infections elicit polyfunctional antibodies

Author: Jérémy Dufloo, Ludivine Grzelak, Isabelle Staropoli, Yoann Madec, Laura Tondeur, François Anna, Stéphane Pelleau, Aurélie Wiedemann, Cyril Planchais, Julian Buchrieser, Rémy Robinot, Marie-Noelle Ungeheuer, Hugo Mouquet, Pierre Charneau, Michael White, Yves Lévy, Bruno Hoen, Arnaud Fontanet, Olivier Schwartz, and Timothée Bruel
Subjects: SARS-CoV-2, ADCC, complement, asymptomatic, antibody, Medicine (General), R5-920
Abstract: Summary: Many SARS-CoV-2-infected individuals remain asymptomatic. Little is known about the extent and quality of their antiviral humoral response. Here, we analyze antibody functions in 52 asymptomatic infected individuals, 119 mildly symptomatic, and 21 hospitalized patients with COVID-19. We measure anti-spike immunoglobulin G (IgG), IgA, and IgM levels with the S-Flow assay and map IgG-targeted epitopes with a Luminex assay. We also evaluate neutralization, complement deposition, and antibody-dependent cellular cytotoxicity (ADCC) using replication-competent SARS-CoV-2 or reporter cell systems. We show that COVID-19 sera mediate complement deposition and kill infected cells by ADCC. Sera from asymptomatic individuals neutralize the virus, activate ADCC, and trigger complement deposition. Antibody levels and functions are lower in asymptomatic individuals than they are in symptomatic cases. Antibody functions are correlated, regardless of disease severity. Longitudinal samplings show that antibody functions follow similar kinetics of induction and contraction. Overall, asymptomatic SARS-CoV-2 infection elicits polyfunctional antibodies neutralizing the virus and targeting infected cells.
Published: 2021
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5. Single-Cell Approach to Influenza-Specific CD8+ T Cell Receptor Repertoires Across Different Age Groups, Tissues, and Following Influenza Virus Infection

Author: Sneha Sant, Ludivine Grzelak, Zhongfang Wang, Angela Pizzolla, Marios Koutsakos, Jane Crowe, Thomas Loudovaris, Stuart I. Mannering, Glen P. Westall, Linda M. Wakim, Jamie Rossjohn, Stephanie Gras, Michael Richards, Jianqing Xu, Paul G. Thomas, Liyen Loh, Thi H. O. Nguyen, and Katherine Kedzierska
Subjects: T cell receptor repertoire, influenza A virus, human T lymphocytes, CD8+ T cells, aging, tissues, Immunologic diseases. Allergy, RC581-607
Abstract: CD8+ T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory CD8+ T cells change throughout the human lifetime and across tissue compartments, we investigated how T cell receptor (TCR) composition and diversity relate to memory CD8+ T cells across anatomical sites and immunological phases of human life. We used ex vivo peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both the TCR-alpha (TCRα) and TCR-beta (TCRβ) chains, and new TCRdist and grouping of lymphocyte interactions by paratope hotspots (GLIPH) algorithms to compare TCRs directed against the most prominent human influenza epitope, HLA-A*02:01-M158–66 (A2+M158). We dissected memory TCR repertoires directed toward A2+M158 CD8+ T cells within human tissues and compared them to human peripheral blood of young and elderly adults. Furthermore, we compared these memory CD8+ T cell repertoires to A2+M158 CD8+ TCRs during acute influenza disease in patients hospitalized with avian A/H7N9 virus. Our study provides the first ex vivo comparative analysis of paired antigen-specific TCR-α/β clonotypes across different tissues and peripheral blood across different age groups. We show that human A2+M158 CD8+ T cells can be readily detected in human lungs, spleens, and lymph nodes, and that tissue A2+M158 TCRαβ repertoires reflect A2+M158 TCRαβ clonotypes derived from peripheral blood in healthy adults and influenza-infected patients. A2+M158 TCRαβ repertoires displayed distinct features only in elderly adults, with large private TCRαβ clonotypes replacing the prominent and public TRBV19/TRAV27 TCRs. Our study provides novel findings on influenza-specific TCRαβ repertoires within human tissues, raises the question of how we can prevent the loss of optimal TCRαβ signatures with aging, and provides important insights into the rational design of T cell-mediated vaccines and immunotherapies.
Published: 2018
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6. Resistance of Omicron subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies

Author: Delphine Planas, Timothée Bruel, Isabelle Staropoli, Florence Guivel-Benhassine, Françoise Porrot, Piet Maes, Ludivine Grzelak, Matthieu Prot, Said Mougari, Cyril Planchais, Julien Puech, Madelina Saliba, Riwan Sahraoui, Florent Fémy, Nathalie Morel, Jérémy Dufloo, Rafael Sanjuán, Hugo Mouquet, Emmanuel André, Laurent Hocqueloux, Etienne Simon-Loriere, David Veyer, Thierry Prazuck, Hélène Péré, Olivier Schwartz, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), I2SysBio (CSIC-UV), Universitat de València (UV), University Hospitals Leuven [Leuven], Centre Hospitalier Régional d'Orléans (CHRO), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Bruel, Timothee, Grzelak, Ludivine, Sanjuán, Rafael, Simon-Loriere, Etienne, Schwartz, Olivier, Institute for Integrative Systems Biology [Valencia] (i2sysbio), Spanish National Research Council (CSIC)-Universitat de València (UV), Work in OS lab is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale (FRM) EQU202003010172, ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR / FRM Flash Covid PROTEO-SARS-CoV-2, ANR Coronamito, HERA European funding, Sanofi and IDISCOVR. DP is supported by the Vaccine Research Institute. The E.S.-L. laboratory is funded by Institut Pasteur, the INCEPTION program (Investissements d’Avenir grant ANR-16-CONV-0005) and the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant no. ANR-10-LABX-62-IBEID). HERA European funding and the NIH PICREID (grant no U01AI151758). The Opera system was co-funded by Institut Pasteur and the Région ile de France (DIM1Health). Work in UPBI is funded by grant ANR-10-INSB-04-01 and Région Ile-de-France program DIM1-Health. P.M. acknowledges the support of a COVID-19 research grant from ‘Fonds Wetenschappelijk Onderzoek’/Research Foundation Flanders (grant G0H4420N) and ‘Internal Funds KU Leuven’ (grant 3M170314)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), ANR-21-CO14-0007,CoronaMito,Conséquences de l'infection par le SRAS-CoV-2 sur la fonction mitochondriale(2021), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)
Subjects: Multidisciplinary, Breakthrough Infections, SARS-CoV-2, [SDV]Life Sciences [q-bio], General Physics and Astronomy, COVID-19, General Chemistry, Antibodies, Viral, Antibodies, Neutralizing, Antiviral Agents, General Biochemistry, Genetics and Molecular Biology, Spike Glycoprotein, Coronavirus, Humans, BNT162 Vaccine
Abstract: Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 lineages has led to the emergence of several new subvariants, including BA.2.75.2, BA.4.6. and BQ.1.1. The subvariants BA.2.75.2 and BQ.1.1 are expected to become predominant in many countries in November 2022. They carry an additional and often redundant set of mutations in the spike, likely responsible for increased transmissibility and immune evasion. Here, we established a viral amplification procedure to easily isolate Omicron strains. We examined their sensitivity to 6 therapeutic monoclonal antibodies (mAbs) and to 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 or BA.5 breakthrough infection. Ronapreve (Casirivimab and Imdevimab) and Evusheld (Cilgavimab and Tixagevimab) lost any antiviral efficacy against BA.2.75.2 and BQ.1.1, whereas Xevudy (Sotrovimab) remained weakly active. BQ.1.1 was also resistant to Bebtelovimab. Neutralizing titers in triply vaccinated individuals were low to undetectable against BQ.1.1 and BA.2.75.2, 4 months after boosting. A BA.1/BA.2 breakthrough infection increased these titers, which remained about 18-fold lower against BA.2.75.2 and BQ.1.1, than against BA.1. Reciprocally, a BA.5 breakthrough infection increased more efficiently neutralization against BA.5 and BQ.1.1 than against BA.2.75.2. Thus, the evolution trajectory of novel Omicron subvariants facilitated their spread in immunized populations and raises concerns about the efficacy of most currently available mAbs.
Published: 2022
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7. Type I interferon response and vascular alteration in chilblain‐like lesions during the COVID‐19 outbreak*

Author: Jérôme Hadjadj, Bruno Charbit, Djaouida Bengoufa, A. Philippe, Laura Barnabei, Olivier Schwartz, Coralie L. Guerin, Léa Jaume, Hervé Bachelez, Darragh Duffy, David M. Smadja, Jean-David Bouaziz, Nicolas Gendron, A. Calugareanu, B. Joly, Sonia Meynier, Martine Bagot, Saint-Louis Core, Frédéric Rieux-Laucat, Jérôme LeGoff, H. Le Buanec, Marisa Battistella, S. Maylin, Nader Yatim, C. Delaugerre, V. Siguret, Richard Chocron, Charles Cassius, L. Frumholtz, Ludivine Grzelak, Nikaïa Smith, Université de Paris, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut Curie [Paris], Hôpital Lariboisière-Fernand-Widal [APHP], Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), Genetic skin diseases : from disease mechanism to therapies (Equipe Inserm U1163), Fondation Alain Carpentier - (Centre Médical International) [Paris] (FAC - CMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), The study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and by a government grant managed by the Agence National de la Recherche as part of the ‘Investment for the Future’ programme (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010), grants from the Agence National de la Recherche (ANR-flash Covid19 ‘AIROCovid’ to F.R.L.) and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). J.H. was a recipient of an INSERM ‘poste d’acceuil’ programme, and an Institut Imagine MD-PhD fellowship programme supported by the Fondation Bettencourt Schueller. L.B. was a recipient of an Imagine Institute PhD international programme supported by the Fondation Bettencourt Schueller. S. Meynier was a recipient of an INSERM and Institut Imagine postdoctoral programme supported by the Fondation pour la Recherche Médicale (FRM no. SPF20170938825)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), and ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018)
Subjects: 0303 health sciences, business.industry, Angiogenesis, [SDV]Life Sciences [q-bio], Dermatology, Gene signature, medicine.disease, Endothelial progenitor cell, Pathophysiology, 3. Good health, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Immune system, immune system diseases, hemic and lymphatic diseases, Immunology, Medicine, Endothelial dysfunction, business, Chilblains, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Anti-neutrophil cytoplasmic antibody
Abstract: International audience; BackgroundThe outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear.ObjectivesTo study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus.MethodsThis observational study was conducted during 9–16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included.ResultsHistological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic–natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL.ConclusionsOur findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.
Published: 2021
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8. Sex Differences in the Evolution of Neutralizing Antibodies to Severe Acute Respiratory Syndrome Coronavirus 2

Author: Cyril Planchais, David Rey, Aurélie Velay, Ludivine Grzelak, Yoann Madec, Yves Hansmann, Isabelle Staropoli, Marie-Josée Wendling, Samira Fafi-Kremer, Arnaud Fontanet, Catherine Schmidt-Mutter, Timothée Bruel, Hugo Mouquet, Nathalie Reix, Ludovic Glady, Floriane Gallais, Olivier Schwartz, María González, Nicolas Meyer, Jérôme De Seze, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPCité), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Strasbourg, Groupe Méthodes en Recherche Clinique [Strasbourg] (GMRC), Nouvel Hôpital Civil [Strasbourg], CHU Strasbourg-CHU Strasbourg, Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), S. F. K.’s laboratory is funded by Strasbourg University Hospitals (Hôpitaux Universitaires de Strasbourg, PRI 7782), Agence Nationale de la Recherche (ANR-18-CE17-0028), Laboratoire d’Excellence TRANSPLANTEX (ANR-11-LABX-0070_TRANSPLANTEX), and Institut National de la Santé et de la Recherche Médicale (UMR_S 1109). O. S.’s laboratory is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Agence Nationale de recherches sur le sida, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), 'TIMTAMDEN' Agence Nationale de la Recherche ANR-14-CE14-0029, 'CHIKV-Viro-Immuno' ANR-14-CE14-0015-01, the Gilead HIV cure program, and ANR/Fondation Pour la Recherche Médicale Flash COVID. L. Gr., is supported by the French Ministry of Higher Education, Research and Innovation., ANR-18-CE17-0028,HuMABK,Les anticorps monoclonaux humains : une Nouvelle approche thérapeutique contre l'infection par le virus BK et les maladies associées(2018), ANR-11-LABX-0070,TRANSPLANTEX,Nouveaux loci d'histocompatibilité/biomarqueurs en transplantation humaine: de la découverte à l'app(2011), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute [Créteil, France] (VRI), univOAK, Archive ouverte, APPEL À PROJETS GÉNÉRIQUE 2018 - Les anticorps monoclonaux humains : une Nouvelle approche thérapeutique contre l'infection par le virus BK et les maladies associées - - HuMABK2018 - ANR-18-CE17-0028 - AAPG2018 - VALID, Nouveaux loci d'histocompatibilité/biomarqueurs en transplantation humaine: de la découverte à l'app - - TRANSPLANTEX2011 - ANR-11-LABX-0070 - LABX - VALID, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Appel à projets générique - Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue - - TIMTAMDEN2014 - ANR-14-CE14-0029 - Appel à projets générique - VALID, and Appel à projets générique - Multiplication et Relation avec l'hôte du virus Chikungunya - - CHIKV-Viro-Immuno2014 - ANR-14-CE14-0015 - Appel à projets générique - VALID
Subjects: 0301 basic medicine, sex-related differences, MESH: Spike Glycoprotein, Coronavirus, medicine.disease_cause, Immunoglobulin G, MESH: Antibodies, Neutralizing, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, antibodies, MESH: COVID-19, Immunology and Allergy, Medicine, MESH: SARS-CoV-2, 030212 general & internal medicine, Polymerase chain reaction, Coronavirus, MESH: Immunoglobulin G, 2. Zero hunger, MESH: Humans, MESH: Middle Aged, biology, SARS-CoV-2, business.industry, COVID-19, MESH: Adult, MESH: Immunoglobulin M, MESH: Male, 3. Good health, 030104 developmental biology, Infectious Diseases, Real-time polymerase chain reaction, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], Immunoglobulin M, MESH: HEK293 Cells, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Immunology, biology.protein, MESH: Health Personnel, Antibody, business, MESH: Female, Body mass index, MESH: Antibodies, Viral, MESH: Sex Characteristics, Sex characteristics
Abstract: We measured anti-spike (S), nucleoprotein (N), and neutralizing antibodies in sera from 308 healthcare workers with a positive reverse-transcription quantitative polymerase chain reaction result for severe acute respiratory syndrome coronavirus 2 and with mild disease, collected at 2 timepoints up to 6 months after symptom onset. At month 1, anti-S and -N antibody levels were higher in male participants aged >50 years and participants with a body mass index (BMI) >25 kg/m2. At months 3–6, anti-S and anti-N antibodies were detected in 99% and 59% of individuals, respectively. Anti-S antibodies and neutralizing antibodies declined faster in men than in women, independent of age and BMI, suggesting an association of sex with evolution of the humoral response.
Published: 2021
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9. IRF8 regulates efficacy of therapeutic anti-CD20 monoclonal antibodies

Author: Ludivine Grzelak, Ferdinand Roesch, Amaury Vaysse, Anne Biton, Rachel Legendre, Françoise Porrot, Pierre‐Henri Commère, Cyril Planchais, Hugo Mouquet, Marco Vignuzzi, Timothée Bruel, Olivier Schwartz, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris] (IP), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale (FRM, IDISCOVR European Health Emergency Preparedness and Response Authority (HERA), French Ministry of Higher Education, Research and Innovation, ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), and ANR-21-CO14-0007,CoronaMito,Conséquences de l'infection par le SRAS-CoV-2 sur la fonction mitochondriale(2021)
Subjects: Immunology, Antineoplastic Agents, anti-CD20 monoclonal antibodies, Antigens, CD20, IRF8, DLBCL, Interferon Regulatory Factors, Immunology and Allergy, [SDV.IMM]Life Sciences [q-bio]/Immunology, Humans, RNA, CD20 protein, Rituximab, CRISPR/Cas9
Abstract: International audience; Anti-CD20 monoclonal antibodies such as Rituximab, Ofatumumab, and Obinutuzumab are widely used to treat lymphomas and autoimmune diseases. They act by depleting B cells, mainly through Fc-dependent effectors functions. Some patients develop resistance to treatment but the underlying mechanisms are poorly understood. Here, we performed a genome-wide CRISPR/Cas9 screen to identify genes regulating the efficacy of anti-CD20 antibodies. We used as a model the killing of RAJI B cells by Rituximab through complement-dependent-cytotoxicity (CDC). As expected, the screen identified MS4A1, encoding CD20, the target of Rituximab. Among other identified genes, the role of Interferon Regulatory Factor 8 (IRF8) was validated in two B-cell lines. IRF8 KO also decreased the efficacy of antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) induced by anti-CD20 antibodies. We further show that IRF8 is necessary for efficient CD20 transcription. Levels of IRF8 and CD20 RNA or proteins correlated in normal B cells and in hundreds of malignant B cells. Therefore, IRF8 regulates CD20 expression and controls the depleting capacity of anti-CD20 antibodies. Our results bring novel insights into the pathways underlying resistance to CD20-targeting immunotherapies.
Published: 2022
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10. Poor sensitivity of iPSC-derived neural progenitors and glutamatergic neurons to SARS-CoV-2

Author: Marija Zivaljic, Mathieu Hubert, Ludivine Grzelak, Giulia Sansone, Uwe Maskos, and Olivier Schwartz
Abstract: COVID-19 is a respiratory disease affecting multiple organs including the central nervous system (CNS), with a characteristic loss of smell and taste. Although frequently reported, the neurological symptoms remain enigmatic. There is no consensus on the extent of CNS infection. Here, we derived human induced pluripotent stem cells (hiPSC) into neural progenitor cells (NPCs) and cortical excitatory neurons to study their permissiveness to SARS-CoV-2 infection. Flow cytometry and western blot analysis indicated that NPCs and neurons do not express detectable levels of the SARS-CoV-2 receptor ACE2. We thus generated cells expressing ACE2 by lentiviral transduction to analyze in a controlled manner the properties of SARS-CoV-2 infection relative to ACE2 expression. Sensitivity of parental and ACE2 expressing cells was assessed with GFP- or luciferase-carrying pseudoviruses and with authentic SARS-CoV-2 Wuhan, D614G, Alpha or Delta variants. SARS-CoV-2 replication was assessed by microscopy, RT-qPCR and infectivity assays. Pseudoviruses infected only cells overexpressing ACE2. Neurons and NPCs were unable to efficiently replicate SARS-CoV-2, whereas ACE2 overexpressing neurons were highly sensitive to productive infection. Altogether, our results indicate that primary NPCs and cortical neurons remain poorly permissive to SARS-CoV-2 across the variants’ spectrum, in the absence of ACE2 expression.
Published: 2022
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11. Human Mucosal-Associated Invariant T Cells in Older Individuals Display Expanded TCRαβ Clonotypes with Potent Antimicrobial Responses

Author: Katherine Kedzierska, Dale I. Godfrey, Liyen Loh, James McCluskey, Carolien E. van de Sandt, Nicholas A Gherardin, E. Kaitlynn Allen, Paul G. Thomas, Sidonia B G Eckle, Martha Lappas, Thomas Loudovaris, Ludivine Grzelak, Jane Crowe, Kylie M. Quinn, Jeremy Chase Crawford, Hui-Fern Koay, Sneha Sant, Katie L. Flanagan, Nicola L. Bird, Marcela de Lima Moreira, Jamie Rossjohn, and Landsteiner Laboratory
Subjects: Adult, Male, Chemokine, Receptors, Antigen, T-Cell, alpha-beta, medicine.medical_treatment, T cell, Immunology, Mucosal associated invariant T cell, CD8-Positive T-Lymphocytes, Biology, CD8-Positive T-Lymphocytes/immunology, Granzymes, Mucosal-Associated Invariant T Cells, GZMB, Interferon-gamma, 03 medical and health sciences, alpha-beta/immunology, 0302 clinical medicine, Immune system, Granzymes/immunology, Antigen, Lysosomal-Associated Membrane Protein 1, Receptors, Escherichia coli, medicine, Humans, Immunology and Allergy, Lysosomal-Associated Membrane Protein 1/immunology, Aged, Escherichia coli/immunology, Tumor Necrosis Factor-alpha, Middle Aged, T-Cell, Tumor Necrosis Factor-alpha/immunology, Viruses/immunology, Cytokine, medicine.anatomical_structure, Receptors, Antigen, T-Cell, alpha-beta/immunology, Interferon-gamma/immunology, Viruses, biology.protein, Female, Mucosal-Associated Invariant T Cells/immunology, CD8, 030215 immunology
Abstract: Mucosal-associated invariant T (MAIT) cells are important for immune responses against microbial infections. Although known to undergo marked numerical changes with age in humans, our understanding of how MAIT cells are altered during different phases across the human life span is largely unknown. Although also abundant in the tissues, our study focuses on MAIT cell analyses in blood. Across the human life span, we show that naive-like MAIT cells in umbilical cord blood switch to a central/effector memory-like profile that is sustained into older age. Whereas low-grade levels of plasma cytokine/chemokine were apparent in older donors (>65 y old), surprisingly, they did not correlate with the ex vivo MAIT hyperinflammatory cytokine profile observed in older adults. Removal of MAIT cells from older individuals and an aged environment resulted in the reversal of the baseline effector molecule profile comparable with MAIT cells from younger adults. An upregulated basal inflammatory profile accounted for reducedEscherichia coli–specific responses in aged MAIT cells compared with their young adult counterparts when fold change in expression levels of GzmB, CD107a, IFN-γ, and TNF was examined. However, the magnitude of antimicrobial MR1-dependent activation remained as potent and polyfunctional as with younger adults. Paired TCRαβ analyses of MAIT cells revealed large clonal expansions in older adults and tissues that rivalled, remarkably, the TCRαβ repertoire diversity of virus-specific CD8+T cells. These data suggest that MAIT cells in older individuals, although associated with large clonal TCRαβ expansions and increased baseline inflammatory potential, demonstrate plasticity and provide potent antimicrobial immunity.
Published: 2020
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12. SARS-CoV-2 Alpha, Beta, and Delta variants display enhanced Spike-mediated syncytia formation

Author: Mathieu Hubert, Jérémy Dufloo, Rémy Robinot, Hugo Mouquet, Olivier Schwartz, Ludivine Grzelak, Nell Saunders, Elodie Bishop, Françoise Porrot, Delphine Planas, Maaran Michael Rajah, Julian Buchrieser, Lisa A. Chakrabarti, Marija Zivaljic, Alice Bongers, Stacy Gellenoncourt, Florence Guivel-Benhassine, Cyril Planchais, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPCité), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Sorbonne Université (SU), Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Institut Pasteur [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ecole doctorale Cerveau Cognition et Comportement [Paris] (ED 158 - 3C), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Work in OS lab is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Fondation Pour la Recherche Médicale (FRM), Labex IBEID (ANR-10-LABX62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, ANR CoronaMito AAP RA-COVID-19 V14, and IDISCOVR. Work in UPBI is funded by grant ANR-10-INSB-04-01 and Région Ile-de-France program DIM1-Health. MMR and MZ are supported by the Pasteur-Paris University (PPU) International Doctoral Program. MMR is also supported by Institut Pasteur Department of Virology 'Bourse de Soudure' fellowship. DP is supported by the Vaccine Research Institute. LG is supported by the French Ministry of Higher Education, Research and Innovation. EB is supported by the Medecine-Sciences ENS-PSL Program. HM laboratory is funded by the Institut Pasteur, the Milieu Intérieur Program (ANR-10-LABX-69- 01), the INSERM, REACTing, EU (RECOVER), and Fondation de France (#00106077) grants., We thank members of the Virus and Immunity Unit for helpful discussions, Dr. Nicoletta Casartelli for her critical reading of the manuscript, and Nathalie Aulner and the UtechS Photonic BioImaging (UPBI) core facility (Institut Pasteur), a member of the France BioImaging network, for image acquisition and analysis support., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), ANR-21-CO14-0007,CoronaMito,Conséquences de l'infection par le SRAS-CoV-2 sur la fonction mitochondriale(2021), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ziani, Isma, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Protéomique du SARS-CoV-2 - - PROTEO-SARS-CoV-22020 - ANR-20-COVI-0059 - COVID-19 - VALID, Conséquences de l'infection par le SRAS-CoV-2 sur la fonction mitochondriale - - CoronaMito2021 - ANR-21-CO14-0007 - COVID-19 - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, and Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID
Subjects: fusion, coronavirus, MESH: Spike Glycoprotein, Coronavirus, MESH: Angiotensin-Converting Enzyme 2, medicine.disease_cause, Virus Replication, Giant Cells, SARS‐CoV‐2, MESH: Antibodies, Monoclonal, MESH: Giant Cells, MESH: Chlorocebus aethiops, Chlorocebus aethiops, MESH: Animals, Receptor, Coronavirus, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Syncytium, Strain (chemistry), General Neuroscience, Antibodies, Monoclonal, Articles, Transmembrane protein, Microbiology, Virology & Host Pathogen Interaction, Cell biology, MESH: HEK293 Cells, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Spike Glycoprotein, Coronavirus, MESH: Caco-2 Cells, Angiotensin-Converting Enzyme 2, MESH: Mutation, medicine.drug_class, Immunology, Alpha (ethology), MESH: Vero Cells, Biology, Monoclonal antibody, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, medicine, Animals, Humans, MESH: SARS-CoV-2, Beta (finance), syncytia, Molecular Biology, Vero Cells, MESH: Humans, General Immunology and Microbiology, SARS-CoV-2, MESH: Virus Replication, spike, MESH: Cell Line, HEK293 Cells, Mutation, Caco-2 Cells
Abstract: Severe COVID‐19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when SARS‐CoV‐2 spike protein expressed on the surface of infected cells interacts with the ACE2 receptor on neighboring cells. The syncytia forming potential of spike variant proteins remain poorly characterized. Here, we first assessed Alpha (B.1.1.7) and Beta (B.1.351) spread and fusion in cell cultures, compared with the ancestral D614G strain. Alpha and Beta replicated similarly to D614G strain in Vero, Caco‐2, Calu‐3, and primary airway cells. However, Alpha and Beta formed larger and more numerous syncytia. Variant spike proteins displayed higher ACE2 affinity compared with D614G. Alpha, Beta, and D614G fusion was similarly inhibited by interferon‐induced transmembrane proteins (IFITMs). Individual mutations present in Alpha and Beta spikes modified fusogenicity, binding to ACE2 or recognition by monoclonal antibodies. We further show that Delta spike also triggers faster fusion relative to D614G. Thus, SARS‐CoV‐2 emerging variants display enhanced syncytia formation., Spike protein mutations expressed by emerging SARS‐CoV‐2 variants‐of‐concern differentially affect host cell‐to‐cell fusion, ACE2 receptor binding, and antibody escape.
Published: 2021
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13. Characteristics Associated with Olfactory and Taste Disorders in COVID-19

Author: Ludivine Grzelak, Charlotte Renaudat, Arnaud Fontanet, Timothée Bruel, Bruno Hoen, Marie-Noëlle Ungeheuer, Olivier Schwartz, Yoann Madec, Laura Tondeur, Simon Galmiche, Isabelle Cailleau, Isabelle Staropoli, Sandrine Fernandes Pellerin, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Université Paris Cité (UPCité)-Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Direction de la recherche médicale de l'Institut Pasteur, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pasteur-Cnam Risques infectieux et émergents (PACRI), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Cité (UPCité), This work was supported by Institut Pasteur, and several laboratories participating in the study received funding from the Labex IBEID (ANR-10-LABX-62-IBEID), REACTing, and the INCEPTION project (PIA/ANR-16-CONV-0005) for studies focusing on emerging viruses. OS lab is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro-Immuno' ANR-14-CE14-0015-01, and the Gilead HIV cure program. L.G. is supported by the French Ministry of Higher Education, Research, and Innovation., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-08-BLAN-0046,REACTING,Reactivity of inorganic radicals in aqueous solution(2008), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris]-Université Paris Cité (UPCité), and Vaccine Research Institute (VRI)
Subjects: Adult, medicine.medical_specialty, Adolescent, Coronavirus disease 2019 (COVID-19), Epidemiology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Anosmia, Antibodies, Viral, Olfaction Disorders, Taste Disorders, Young Adult, Risk Factors, Internal medicine, Humans, Medicine, In patient, Child, Retrospective Studies, Original Paper, business.industry, Headache, Outbreak, COVID-19, Retrospective cohort study, Ageusia, Severe acute respiratory syndrome coronavirus-2, Taste disorder, Neurology (clinical), medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Introduction: Olfactory and taste disorders (OTDs) have been reported in COVID-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the mechanisms of which remain unclear. We conducted a detailed analysis of OTDs as part of 2 seroepidemiological investigations of COVID-19 outbreaks. Methods: Two retrospective cohort studies were conducted in a high school and primary schools of Northern France following a COVID-19 epidemic in February-March 2020. Students, their relatives, and school staff were included. Anti-SARS-CoV-2 antibodies were identified using a flow-cytometry-based assay detecting anti-S IgG. Results: Among 2,004 participants (median [IQR] age: 31 [11–43] years), 303 (15.2%) tested positive for SARS-CoV-2 antibodies. OTDs were present in 91 (30.0%) and 92 (30.3%) of them, respectively, and had 85.1 and 78.0% positive predictive values for SARS-CoV-2 infection, respectively. In seropositive participants, OTDs were independently associated with an age above 18 years, female gender, fatigue, and headache. Conclusion: This study confirms the higher frequency of OTDs in females than males and adults than children. Their high predictive value for the diagnosis of COVID-19 suggests that they should be systematically searched for in patients with respiratory symptoms, fever, or headache. The association of OTDs with headache, not previously reported, suggests that they share a common mechanism, which deserves further investigation.
Published: 2021
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14. A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inflammatory syndrome in children with severe myocarditis

Author: Cécile Masson, Aurélien Corneau, Florence Moulin, Ghaith Abdessalem, Pedro Gonçalves, Marianne Leruez, James P. Di Santo, Mathie Lorrot, Julie Toubiana, Julien Haroche, Camille Bruneau, Isabelle Melki, Bruno Charbit, Zahra Belhadjer, Loïc de Pontual, Camille de Cevins, Brigitte Bader Meunier, Alain Fischer, Victor Garcia-Paredes, Brieuc P. Perot, Marine Luka, Damien Bonnet, Quentin Riller, Nikaïa Smith, Slimane Allali, Sonia Meynier, Aude Magérus, Christele Gras Leguen, Shen-Ying Zhang, Olivier Schwartz, Jean-Laurent Casanova, Frédéric Rieux-Laucat, Nicolas Cagnard, Francesco Carbone, Tinhinane Fali, Mélanie Parisot, Mickaël M. Ménager, Maxime Beretta, Mohammed Zarhrate, Christine Bole-Feysot, Vithura Pirabarakan, Ludivine Grzelak, Mehdi Oualha, Darragh Duffy, Laura Barnabei, Hugo Mouquet, Maxime Batignes, Alexandre Boullé, Boris Sorin, Marie-Claude Stolzenberg, Inflammatory Responses and Transcriptomic Networks in diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Sanofi Aventis R&D [Chilly-Mazarin], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunité Innée - Innate Immunity, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital universitaire Robert-Debré [Paris], Université Paris Cité (UPCité), CHU Trousseau [APHP], Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Jean Verdier [AP-HP], Université Paris 13 (UP13), Collège de France (CdF (institution)), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017), ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), and Université Paris Cité (UPC)
Subjects: Adult, Vascular Endothelial Growth Factor A, Chemokine, Myocarditis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MIS-C, Monocytes, chemistry.chemical_compound, Viewpoint, scRNA-seq, medicine, otorhinolaryngologic diseases, Humans, Kawasaki Disease, Child, Connective Tissue Diseases, biology, business.industry, SARS-CoV-2, Monocyte, NF-kappa B, COVID-19, General Medicine, Dendritic Cells, Gene signature, medicine.disease, Pathophysiology, Systemic Inflammatory Response Syndrome, Vascular endothelial growth factor, medicine.anatomical_structure, Cytokine, chemistry, TNF-α and NF-κB signaling, Immunology, biology.protein, Cytokines, Tumor necrosis factor alpha, lack of responses to type I and type II IFN secretion, Clinical and Translational Article, Chemokines, myocarditis, business, PIMS-TS
Abstract: Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally milder than in adults, but a proportion of cases result in hyperinflammatory conditions often including myocarditis. Methods To better understand these cases, we applied a multiparametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. Plasma cytokine and chemokine levels and blood cellular composition were measured, alongside gene expression at the bulk and single-cell levels. Findings The most severe forms of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 that resulted in myocarditis were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomics analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis characterized by sustained nuclear factor κB (NF-κB) activity and tumor necrosis factor alpha (TNF-α) signaling and associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type I and type II interferons, hyperinflammation, and response to oxidative stress related to increased HIF-1α and Vascular endothelial growth factor (VEGF) signaling. Conclusions These results provide potential for a better understanding of disease pathophysiology. Funding Agence National de la Recherche (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01; Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010; Laboratoire d’Excellence ‘‘Milieu Intérieur,” grant ANR-10-LABX-69-01; ANR-flash Covid19 “AIROCovid” and “CoVarImm”), Institut National de la Santé et de la Recherche Médicale (INSERM), and the “URGENCE COVID-19” fundraising campaign of Institut Pasteur., Graphical abstract, Context and significance Children with SARS-CoV-2 infection were initially thought to have only mild COVID-19 symptoms. However, several weeks into the first wave of SARS-CoV-2 infections, there was a surge of a postacute pathology called multisystem inflammatory syndrome in children (MIS-C). The authors recruited a cohort of children with suspicion of SARS-CoV-2 infection and uncovered hyperinflammation, hypoxic conditions, exacerbation of TNF-α signaling via NF-κB, and absence of responses to type I and type II IFN secretion in the most severe forms of MIS-C with severe myocarditis. This work led the authors to identify in monocytes and validate in peripheral blood mononuclear cells a molecular signature of 25 genes that allows discrimination of the most severe forms of MIS-C with myocarditis., Multiparametric analysis identifies, in monocytes and dendritic cells, a molecular signature of the most severe forms of multisystem inflammatory syndrome in children caused by SARS-CoV-2 infection. Severe myocarditis is characterized by an excess of TNF-α signaling via NF-κB, hypoxic conditions, and hyperinflammation in the absence of type I and type II interferon responses.
Published: 2021
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15. Immune checkpoint inhibitors increase T cell immunity during SARS-CoV-2 infection

Author: Jeremy Boussier, Olivier Peyrony, Majdi Jebali, Bruno Charbit, Benjamin Terrier, Nora Kramkimel, Céleste Lebbé, Aurélien Corneau, Magnus Fontes, Jérôme LeGoff, Selim Aractingi, Laetitia Da Meda, Frédéric Rieux-Laucat, Vincent Calmettes, P. Tetu, Olivier Schwartz, Laura Barnabei, Darragh Duffy, Nikaïa Smith, Clara Allayous, Jérôme Hadjadj, Timothée Bruel, Charles Cassius, Nader Yatim, Isabelle Staropoli, F. Herms, Catherine Blanc, Ludivine Grzelak, Barouyr Baroudjian, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris]-Université Paris Cité (UPCité), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Laboratoire Roche [Boulogne-Billancourt], Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), N.Y. and C.L. acknowledge grant from the ARC Flash Covid-19 and Cancer call (ONCOVID). N.Y. and D.D. acknowledge grants from the Institut Pasteur for Covid-19 research and the ANR Flash Covid-19 call (CoVarImm). N.S. was supported by an Institut Pasteur Roux Cantarini fellowship. B.T. was supported by the Fonds IMMUNOV, for Innovation in Immunopathology. F.R.-L. acknowledges grants from the ANR Flash Covid-19 (AIROCOVID) and the FAST foundation. The study was also supported by the Institut National de la Santé et de la Recherche Médicale (Inserm) and by government grants managed by the Agence Nationale de la Recherche as part of the 'Investment for the future' program (ANR-10 IAHU-01 and ANR-18-RHUS-0010). L.B. was also supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) and is part of the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its 'Investments for the future' program., ANR-20-COVI-0053,CoVarImm,Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence(2020), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018), ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vougny, Marie-Christine, Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence - - CoVarImm2020 - ANR-20-COVI-0053 - COVID-19 - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation - - ATRACTION2018 - ANR-18-RHUS-0010 - RHUS - VALID, Génétique et Epigénétique Nouvelle Ecole - - GENE2017 - ANR-17-EURE-0013 - EURE - VALID, Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Paris (UP)
Subjects: Male, animal diseases, T-Lymphocytes, Adaptive Immunity, CD8-Positive T-Lymphocytes, Antibodies, Viral, Lymphocyte Activation, 0302 clinical medicine, Interferon, Prospective Studies, Immune Checkpoint Inhibitors, Melanoma, Research Articles, 0303 health sciences, Multidisciplinary, Effector, SciAdv r-articles, Middle Aged, Acquired immune system, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Spike Glycoprotein, Coronavirus, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, medicine.drug, Research Article, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immunology, Inflammation, chemical and pharmacologic phenomena, 03 medical and health sciences, Immune system, medicine, Humans, Health and Medicine, 030304 developmental biology, Aged, business.industry, SARS-CoV-2, COVID-19, biochemical phenomena, metabolism, and nutrition, medicine.disease, Coronavirus, bacteria, business, Immunologic Memory, CD8
Abstract: Immune checkpoint inhibitors for melanoma improve adaptive T cell immunity during COVID-19 without exacerbating inflammation., The COVID-19 pandemic has spread worldwide, yet the role of antiviral T cell immunity during infection and the contribution of immune checkpoints remain unclear. By prospectively following a cohort of 292 patients with melanoma, half of which treated with immune checkpoint inhibitors (ICIs), we identified 15 patients with acute or convalescent COVID-19 and investigated their transcriptomic, proteomic, and cellular profiles. We found that ICI treatment was not associated with severe COVID-19 and did not alter the induction of inflammatory and type I interferon responses. In-depth phenotyping demonstrated expansion of CD8 effector memory T cells, enhanced T cell activation, and impaired plasmablast induction in ICI-treated COVID-19 patients. The evaluation of specific adaptive immunity in convalescent patients showed higher spike (S), nucleoprotein (N), and membrane (M) antigen-specific T cell responses and similar induction of spike-specific antibody responses. Our findings provide evidence that ICI during COVID-19 enhanced T cell immunity without exacerbating inflammation.
Published: 2021
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16. Analysis of T‐cell responses directed against the spike and/or membrane and/or nucleocapsid proteins in patients with chilblain‐like lesions during the COVID‐19 pandemic

Author: Assia Samri, Jean-David Bouaziz, P. Moghadam, Olivier Schwartz, Nader Yatim, D. Bergerat, C. Delaugerre, Martine Bagot, Jérôme LeGoff, C. Grolleau, Laure Frumholtz, Charles Cassius, L. Jaume, H. Le Buanec, Ludivine Grzelak, M. Merandet, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunologie Translationnelle - Translational Immunology lab, Saint-Louis CORE (COvid REsearch), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut Pasteur [Paris], Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Le Buanec, Hélène
Subjects: 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), T-Lymphocytes, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), T cell, [SDV]Life Sciences [q-bio], Dermatology, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Pandemic, Research Letter, medicine, Humans, Pandemics, Nucleocapsid Proteins, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, COVID-19, Virology, 3. Good health, Chilblains, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Spike Glycoprotein, Coronavirus, Spike (software development), business
Abstract: International audience; No abstract available
Published: 2021
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17. SARS-CoV-2 Alpha, Beta and Delta variants display enhanced Spike-mediated Syncytia Formation

Author: Florence Guivel-Benhassine, Lisa A. Chakrabarti, Mathieu Hubert, Julian Buchrieser, Nell Saunders, Maaran Michael Rajah, Ludivine Grzelak, Françoise Porrot, Hugo Mouquet, Cyril Planchais, Marija Zivaljic, Alice Bongers, Stacy Gellenoncourt, Rémy Robinot, Jérémy Dufloo, Elodie Bishop, Olivier Schwartz, and Delphine Planas
Subjects: Syncytium, Mutation, biology, Chemistry, medicine.drug_class, Alpha (ethology), medicine.disease_cause, Monoclonal antibody, Transmembrane protein, Cell biology, Interferon, medicine, biology.protein, Antibody, Beta (finance), medicine.drug
Abstract: Severe COVID-19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when SARS-CoV-2 spike protein expressed on the surface of infected cells interacts with the ACE2 receptor on neighbouring cells. The syncytia forming potential of spike variant proteins remain poorly characterized. Here, we first assessed Alpha and Beta spread and fusion in cell cultures. Alpha and Beta replicated similarly to D614G reference strain in Vero, Caco-2, Calu-3 and primary airway cells. However, Alpha and Beta formed larger and more numerous syncytia. Alpha, Beta and D614G fusion was similarly inhibited by interferon induced transmembrane proteins (IFITMs). Individual mutations present in Alpha and Beta spikes differentially modified fusogenicity, binding to ACE2 and recognition by monoclonal antibodies. We further show that Delta spike also triggers faster fusion relative to D614G. Thus, SARS-CoV-2 emerging variants display enhanced syncytia formation.SynopsisThe Spike protein of the novel SARS-CoV-2 variants are comparative more fusogenic than the earlier strains. The mutations in the variant spike protein differential modulate syncytia formation, ACE2 binding, and antibody escape.The spike protein of Alpha, Beta and Delta, in the absence of other viral proteins, induce more syncytia than D614GThe ACE2 affinity of the variant spike proteins correlates to their fusogenicityVariant associated mutations P681H, D1118H, and D215G augment cell-cell fusion, while antibody escape mutation E484K, K417N and Δ242-244 hamper it.Variant spike-mediated syncytia formation is effectively restricted by IFITMs
Published: 2021
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18. A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis

Author: Ludivine Grzelak, Maxime Beretta, Slimane Allali, Aude Magérus, Hugo Mouquet, Maxime Batignes, Isabelle Melki, Olivier Schwartz, Quentin Riller, Mehdi Oualha, Nicolas Cagnard, Christine Bole-Feysot, Camille de Cevins, James P. Di Santo, Christele Gras Leguen, Florence Moulin, Jean-Laurent Casanova, Cécile Masson, Aurélien Corneau, Damien Bonnet, Vithura Pirabarakan, Mickaël M. Ménager, Camille Bruneau, Brieuc P. Perot, Francesco Carbone, Darragh Duffy, Mohammed Zarhrate, Marie-Claude Stolzenberg, Alexandre Boullé, Mélanie Parisot, Boris Sorin, Ghaith Abdessalem, Alain Fischer, Marianne Leruez, Julie Toubiana, Victor Garcia-Paredes, Mathie Lorrot, Loïc de Pontual, Zahra Belhadjer, Bruno Charbit, Tinhinane Fali, Marine Luka, Nikaïa Smith, Brigitte Bader Meunier, Shen-Ying Zhang, Sonia Meynier, Fredéric Rieux Laucat, Julien Haroche, Pedro Gonçalves, Laura Barnabei, Inflammatory Responses and Transcriptomic Networks in diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sanofi Aventis R&D [Chilly-Mazarin], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Rockefeller University [New York], Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital universitaire Robert-Debré [Paris], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département des urgences pédiatriques [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Virologie [CHU Necker], Département de Pédiatrie et maladies infectieuses [CHU Necker], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Collège de France (CdF (institution)), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, The study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), by the 'URGENCE COVID-19' fundraising campaign of Institut Pasteur, by the Atip-Avenir, Emergence ville de Paris program and fond de dotation Janssen Horizon and by government grants managed by the Agence National de la Recherche as part of the 'Investment for the Future' program (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010, Laboratoire d’Excellence ‘‘Milieu Intérieur', grant ANR-10-LABX-69-01), the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), the Agence National de la Recherche (ANR-flash Covid19 'AIROCovid' to FRL and 'CoVarImm' to DD and JDS), and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). The LabTech Single Cell@Imagine is supported by the Paris Region and the 'Investissements d’avenir' program through the 2019 ATF funding – Sésame Filières PIA (Grant N°3877871). CdC is the recipient of a CIFRE-PhD (Sanofi). L.B. was a recipient of an Imagine institute PhD international program supported by the Fondation Bettencourt Schueller. L.B. was also supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) and is part of the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its 'Investments for the Future' program. S.M. was a recipient of an INSERM and Institut Imagine post-doctorat program supported by the Fondation pour la Recherche Médicale (FRM N°SPF20170938825). NS was a recipient of the Pasteur-Roux-Cantarini Fellowship. VGP obtained an Imagine international PhD fellowship program supported by the Fondation Bettencourt Schueller. BPP is the recipient of an ANRS post-doctoral fellowship., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-20-COVI-0022,AIROCovid19,Analyse Omics de la réponse immune aigue au cours de l'infection à Covid19: rationnel moléculaire pour un traitement ciblé(2020), ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0303 health sciences, Chemokine, Myocarditis, biology, business.industry, Monocyte, Dendritic cell, Gene signature, medicine.disease_cause, medicine.disease, Pathophysiology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, biology.protein, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, business, Oxidative stress, 030304 developmental biology
Abstract: SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κB activity, TNF-α signaling, associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology.
Published: 2021

19. Distinct systemic and mucosal immune responses to SARS-CoV-2

Author: Ludivine Grzelak, Bruno Charbit, Vincent Bondet, Hélène Péré, Hugo Mouquet, Cyril Planchais, Darragh Duffy, Benjamin Terrier, Vincent Rouilly, Sarah H. Merkling, Nader Yatim, Pedro Gonçalves, Maxime Beretta, Timothée Bruel, Frederic Rieux-Leucat, Nikaïa Smith, Solen Kernéis, Jérôme Hadjadj, James P. Di Santo, Olivier Schwartz, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Immunité Innée - Innate Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Immunologie humorale - Humoral Immunology, Datactix, Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), Université de Paris, Paris, France, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Epidémiologie et modélisation de la résistance aux antimicrobiens - Epidemiology and modelling of bacterial escape to antimicrobials (EMAE), This study was supported by an Institut Pasteur Covid-19 research grant and by a grant (CoVarImm) from the Agence National de la Recherche (ANR-flash Covid19) awarded to DD and JPD, and by the Laboratoire d’Excellence ‘‘Milieu Intérieur' (grant no. ANR-10-LABX-69-01) and the Fonds IMMUNOV, for Innovation in Immunopathology. NS is a recipient of the Pasteur-Roux-Cantarini Fellowship. We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting Luminex and Simoa analysis. We thank Laurence Motreff and Laurence Ma, Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09), IBISA and the Illumina COVID-19 Projects’ offer for microbial sequencing., ANR-20-COVI-0053,CoVarImm,Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence(2020), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord
Subjects: systemic immunity, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Immune system, Interferon, medicine, Microbiome, 030304 developmental biology, 0303 health sciences, biology, business.industry, Compartmentalization (psychology), cytokines, 3. Good health, Immunology, biology.protein, mucosal immunity, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, business, Covid-19, Viral load, 030217 neurology & neurosurgery, medicine.drug
Abstract: SummaryCoordinated local mucosal and systemic immune responses following SARS-CoV-2 infection protect against COVID-19 pathologies or fail leading to severe clinical outcomes. To understand this process, we performed an integrated analysis of SARS-CoV-2 spike-specific antibodies, cytokines, viral load and 16S bacterial communities in paired nasopharyngeal swabs and plasma samples from a cohort of clinically distinct COVID-19 patients during acute infection. Plasma viral load was associated with systemic inflammatory cytokines that were elevated in severe COVID-19, and also with spike-specific neutralizing antibodies. In contrast, nasopharyngeal viral load correlated with SARS-CoV-2 humoral responses but inversely with interferon responses, the latter associating with protective microbial communities. Potential pathogenic microrganisms, often implicated in secondary respiratory infections, were associated with mucosal inflammation and elevated in severe COVID-19. Our results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes.
Published: 2021

20. Release of infectious virus and cytokines in nasopharyngeal swabs from individuals infected with non-B.1.1.7 or B.1.1.7 SARS-CoV-2 variants

Author: Nathalie Demory, Pascal Campagne, David Veyer, Jacques Fourgeaud, Julien Puech, Laurent Bélec, Isabelle Staropoli, Galdric Orvoen, Florence Guivel-Benhassine, Julien Rodary, Veronique Moulin, Darragh Duffy, Blandine Monel, Ludivine Grzelak, Victor Euzen, Hélène Péré, Nikaïa Smith, Maxime Wack, Timothée Bruel, Lea Nunes, Delphine Planas, Pedro Gonçalves, Sandrine Imbeaud, Françoise Porrot, Olivier Schwartz, James P. Di Santo, and Nicolas Robillard
Subjects: Infectivity, Titer, Cytokine, Antigen, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, medicine, biology.protein, Biology, Antibody, Virology, Virus, Infectious virus
Abstract: The mechanisms that allowed for the SARS-CoV-2 B.1.1.7 variant to rapidly outcompete pre-existing variants in many countries remain poorly characterized. Here, we analyzed viral release, anti-SARS-CoV-2 antibodies and cytokine production in a retrospective series of 427 RT–qPCR+ nasopharyngeal swabs collected in COVID-19 patients harbouring either non-B.1.1.7 or B.1.17 variants. We utilized a novel rapid assay, based on S-Fuse-T reporter cells, to quantify infectious SARS-CoV-2. With both non-B.1.1.7 and B.1.1.7 variants, viral titers were highly variable, ranging from 0 to >106 infectious units, and correlated with viral RNA levels. Lateral flow antigenic rapid diagnostic tests (RDTs) were positive in 96% of the samples harbouring infectious virus. About 67 % of individuals carried detectable infectious virus within the first two days after onset of symptoms. This proportion decreased overtime, and viable virus was detected up to 14 days. Samples containing anti-SARS-CoV-2 IgG or IgA did not generally harbour infectious virus. The proportion of individuals displaying viable virus or being RDT-positive was not higher with B.1.1.7 than with non-B.1.1.7 variants. Ct values were slightly but not significantly lower with B.1.1.7. The variant was characterized by a fast decrease of infectivity overtime and a marked release of 17 cytokines (including IFN-β, IP-10, IL-10 and TRAIL). Our results highlight differences between non-B.1.1.7 and B.1.1.7 variants. B.1.1.7 is associated with modified viral decays and cytokine profiles at the nasopharyngeal mucosae during symptomatic infection.
Published: 2021
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21. Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients

Author: Adam K. Wheatley, Karen L. Laurie, Carolien E. van de Sandt, Stephen J. Kent, Patrick Günther, Lorena E. Brown, Simone Nüssing, Jamie Rossjohn, Weisan Chen, Stephanie Gras, David C. Jackson, E. Bridie Clemens, Jane Crowe, Jianqing Xu, Paul G. Thomas, Yi-Mo Deng, E.K. Allen, Liyen Loh, Xiaoxiao Jia, Ludivine Grzelak, Thi H. O. Nguyen, Malet Aban, Marios Koutsakos, Stephen J. Turner, Peter C. Doherty, Allen C. Cheng, Tim Brahm, Tom Kotsimbos, Jeremy Chase Crawford, Aeron C. Hurt, Sneha Sant, Luca Hensen, Nicole L. La Gruta, Katherine Kedzierska, Maria Auladell, Zhongfang Wang, and Landsteiner Laboratory
Subjects: CD4-Positive T-Lymphocytes, 0301 basic medicine, Cellular immunity, Antibody Formation/immunology, T-Lymphocytes, General Physics and Astronomy, Disease, CD8-Positive T-Lymphocytes, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Influenza, Human/immunology, Influenza A virus, Medicine, Phylogeny, B-Lymphocytes, Multidisciplinary, Helper-Inducer/immunology, musculoskeletal, neural, and ocular physiology, Vaccination, Human/immunology, virus diseases, B-Lymphocytes/immunology, T-Lymphocytes, Helper-Inducer, Middle Aged, Influenza Vaccines/immunology, Phenotype, 3. Good health, Hospitalization, Influenza Vaccines, 030220 oncology & carcinogenesis, CD4-Positive T-Lymphocytes/immunology, Cytokines, Influenza A virus/classification, Science, macromolecular substances, CD8-Positive T-Lymphocytes/immunology, General Biochemistry, Genetics and Molecular Biology, Virus, 03 medical and health sciences, Immune system, Cytokines/immunology, T-Lymphocytes, Helper-Inducer/immunology, Influenza, Human, Humans, Vaccination/methods, Hospitalization/statistics & numerical data, business.industry, General Chemistry, Influenza, 030104 developmental biology, nervous system, Antibody Formation, Immunology, business, CD8
Abstract: How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8+ or CD4+ T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.
Published: 2021

22. Impact des inhibiteurs de checkpoints immunitaires au cours de la COVID-19 chez les patients atteints de mélanome

Author: Aurélien Corneau, Selim Aractingi, Ludivine Grzelak, Timothée Bruel, P. Tetu, Jérôme Hadjadj, Catherine Blanc, Nikaïa Smith, L. Da Meda, C. Lebbé, Benjamin Terrier, J. Le Goff, Olivier Schwartz, Clara Allayous, J. Boussier, Nader Yatim, Isabelle Staropoli, Frédéric Rieux-Laucat, Darragh Duffy, and Nora Kramkimel
Subjects: Gynecology, 2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Co018, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Gastroenterology, Internal Medicine, medicine, business
Abstract: Introduction La restauration immunitaire induite par les inhibiteurs de checkpoints immunitaires ont révolutionné le pronostic des cancers métastatiques [1]. La contribution de cette stratégie thérapeutique pour la prise en charge des infections reste toutefois controversée, malgré quelques études en faveur de leur utilisation, notamment dans le contexte de paralysie immunitaire au décours d’un sepsis sévère [2], [3], ou dans les situations d’épuisement immunitaire au cours des infections virales chroniques [4], [5]. Au cours de la COVID-19, des études suggèrent qu’un état d’épuisement immunitaire en lien avec une anergie et/ou une déplétion des lymphocytes T serait partiellement responsable de la virulence du SARS-CoV-2 [6], [7], [8], [9], [10]. Certains proposent donc l’utilisation des anti-PD1 comme stratégie thérapeutique tandis que d’autres suggèrent qu’au contraire, elle pourrait aggraver l’hyperinflammation [11], [12]. Patients et méthodes Nous avons suivi de façon prospective 292 patients atteints de mélanome lors de la première vague de COVID-19 (de mars à juin 2020) dont la moitié était traitée par immunothérapie (anti-PD1 ± anti-CTLA4). Les patients présentant des symptômes de COVID-19 étaient dépistés par PCR. Une sérologie SARS-CoV-2 était recherchée de façon systématique. Les patients présentant une infection symptomatique active ( 21 jours du début des symptômes, PCR négative, sérologie positive) ont été inclus pour une étude approfondie de la réponse immunitaire par une analyse transcriptionnelle (Nanostring), protéomique (SIMOA, Luminex) et cellulaire (cytométrie de masse). Résultats Quinze patients atteints de COVID-19 ont été identifiés (infection active ou convalescente) avec une estimation de la séroprévalence à 8,6 % de la cohorte. Quatre patients sur 15 ont nécessité une hospitalisation (26,7 %). Les données cliniques ne retrouvaient pas d’éléments en faveur d’une forme plus sévère de COVID-19 lors d’un traitement par anti-PD1, seul un patient ayant également une leucémie lymphoïde chronique, a développé une forme sévère de la COVID-19 et est décédé de défaillance respiratoire. L’analyse de la réponse immunitaire, en comparaison avec une cohorte de patients non traités par immunothérapie, retrouvait une réponse immunitaire innée semblable dans les deux cohortes. De même, le taux d’anticorps anti-Spike (IgG et IgA), la capacité neutralisante ainsi que la longévité des anticorps (suivi du taux sur une période d’1 an) étaient similaires en présence ou non d’un traitement par immunothérapie. En revanche, l’analyse de la réponse cellulaire mettait en évidence, chez les patients traités par immunothérapie, une expansion de la population de lymphocytes T CD8+ effecteurs mémoires, une augmentation de l’activation des lymphocytes T CD4+ et CD8+, et une augmentation la production d’IFN-gamma lors d’une stimulation ex-vivo par des peptides issus du SARS-CoV-2. Conclusion Nos résultats sont en faveur d’une augmentation de la réponse cellulaire T anti-SARS-CoV-2 lors d’un traitement par anti-PD1 chez les patients suivis pour mélanome, et de l’absence d’une exacerbation de la réponse inflammatoire. Il est nécessaire de confirmer ces résultats avec un plus grand nombre de patients, dans d’autres types de cancers et dans d’autres centres.
Published: 2021

23. SARS-CoV-2 infection in schools in a northern French city: a retrospective serological cohort study in an area of high transmission, France, January to April 2020

Author: Ludivine Grzelak, Charlotte Renaudat, Yoann Madec, Lucie Kuhmel, Laurence Arowas, Caroline Demeret, Kuang-Yu Chen, Christèle Huon, Marie Noelle Ungeheuer, Marc Eloit, Olivier Schwartz, Thomas Bigot, Bernadette Crescenzo-Chaigne, Sandrine Fernandes Pellerin, Arnaud Fontanet, Isabelle Staropoli, Bruno Hoen, Nathalie Jolly, Camille Besombes, Sandie Munier, Isabelle Cailleau, Timothée Bruel, Pierre Charneau, Laura Tondeur, Sarah Temmam, Blanca Liliana Perlaza, Rebecca Grant, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity, Université de Paris (UP), Direction de la recherche médicale de l'Institut Pasteur, Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Centre Médical de l'Institut Pasteur, Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biologie des ARN et virus influenza - RNA Biology of Influenza Virus, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, École nationale vétérinaire d'Alfort (ENVA), The study was funded by Institut Pasteur, and several laboratories participating in the study receive funding from the Labex IBEID (ANR-10-LABX-62-IBEID), REACTing and the INCEPTION project (PIA/ANR-16-CONV-0005) for studies focusing on emerging viruses. OS lab is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro- Immuno' ANR-14-CE14-0015-01 and the Gilead HIV cure program. LG is supported by the French Ministry of Higher Education, Research and Innovation. ME lab is funded by Institut Pasteur, Labex IBEID (ANR-10-LABX-62-IBEID), REACTing (Research & Action Emerging Infectious Diseases), EU Grant 101003589 RECoVER., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Université Paris Cité (UPCité), Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École nationale vétérinaire - Alfort (ENVA), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-TheraVectys
Subjects: 0301 basic medicine, Emerging infectious diseases, medicine.medical_specialty, MESH: Schools, Epidemiology, [SDV]Life Sciences [q-bio], Context (language use), Asymptomatic, Serology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Virology, MESH: Child, Humans, Medicine, MESH: COVID-19, MESH: SARS-CoV-2, 030212 general & internal medicine, Child, MESH: Cohort Studies, Retrospective Studies, Schools, MESH: Humans, Transmission (medicine), business.industry, SARS-CoV-2, Research, 4. Education, Public Health, Environmental and Occupational Health, COVID-19, Outbreak, Retrospective cohort study, MESH: Retrospective Studies, 3. Good health, Coronavirus disease 2019 (COVID-19), MESH: France, 030104 developmental biology, France, medicine.symptom, business, Demography, Cohort study
Abstract: Background Children’s role in SARS-CoV-2 epidemiology remains unclear. We investigated an initially unnoticed SARS-CoV-2 outbreak linked to schools in northern France, beginning as early as mid-January 2020. Aims This retrospective observational study documents the extent of SARS-CoV-2 transmission, linked to an affected high school (n = 664 participants) and primary schools (n = 1,340 study participants), in the context of unsuspected SARS-CoV-2 circulation and limited control measures. Methods Between 30 March and 30 April 2020, all school staff, as well as pupils and their parents and relatives were invited for SARS-CoV-2 antibody testing and to complete a questionnaire covering symptom history since 13 January 2020. Results In the high school, infection attack rates were 38.1% (91/239), 43.4% (23/53), and 59.3% (16/27), in pupils, teachers, and non-teaching staff respectively vs 10.1% (23/228) and 12.0% (14/117) in the pupils’ parents and relatives (p Conclusions Viral circulation can occur in high and primary schools so keeping them open requires consideration of appropriate control measures and enhanced surveillance.
Published: 2021
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24. Dual TCR-alpha expression on MAIT cells as a potential confounder of TCR interpretation

Author: Segundo R León, Liyen Loh, Lars Kjer-Nielsen, James McCluskey, Ludivine Grzelak, Sarah K. Iwany, Tonatiuh A. Ocampo, Kattya Lopez Tamara, Jamie Rossjohn, Katherine Kedzierska, Leonid Lecca Garcia, Roger Calderon, Alexandra J. Corbett, Ildiko Van Rhijn, Megan Murray, Sara Suliman, and D. Branch Moody
Subjects: medicine.anatomical_structure, Antigen, Tetramer, Chemistry, T cell, T-cell receptor, Cell, medicine, Alpha (ethology), Endogeny, Transfection, Cell biology
Abstract: Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are highly abundant in human blood and tissues. Most MAIT cells have an invariant T cell receptor (TCR) α chain that uses TRAV1-2 joined to TRAJ33/20/12 and recognize metabolites from bacterial riboflavin synthesis bound to the antigen-presenting molecule, MR1. Recently, our attempts to identify alternative MR1-presented antigens led to the discovery of rare MR1-restricted T cells with non-TRAV1-2 TCRs. Because altered antigen specificity is likely to lead to altered affinity for the most potent known antigen, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), we performed bulk TCRα and β chain sequencing, and single cell-based paired TCR sequencing, on T cells that bound the MR1-5-OP-RU tetramer, but with differing intensities. Bulk sequencing showed that use of V genes other than TRAV1-2 was enriched among MR1-5-OP-RU tetramerlow cells. Whereas we initially interpreted these as diverse MR1-restricted TCRs, single cell TCR sequencing revealed that cells expressing atypical TCRα chains also co-expressed an invariant MAIT TCRα chain. Transfection of each non-TRAV1-2 TCRα chain with the TCRβ chain from the same cell demonstrated that the non-TRAV1-2 TCR did not bind the MR1-5-OP-RU tetramer. Thus, dual TCRα chain expression in human T cells and competition for the endogenous β chain explains the existence of some MR1-5-OP-RU tetramerlow T cells. The discovery of simultaneous expression of canonical and non-canonical TCRs on the same T cell means that claims of roles for non-TRAV1-2 TCR in MR1 response must be validated by TCR transfer-based confirmation of antigen specificity.
Published: 2021
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25. Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies

Author: Samira Fafi-Kremer, Maaran Michael Rajah, Julian Buchrieser, Flora Donati, Thierry Prazuck, Mélanie Albert, Hugo Mouquet, Florence Guivel-Benhassine, Sylvie van der Werf, Aymeric Sève, Etienne Simon-Loriere, Laurent Hocqueloux, Françoise Porrot, Emmanuelle Varon, Hélène Péré, Karl Stefic, Vincent Enouf, Frédérique Schortgen, Layla Yahyaoui, Olivier Schwartz, Sylvie Behillil, Marianne Maquart, David Veyer, María González, Delphine Planas, Jérôme De Seze, Isabelle Staropoli, Elodie Bishop, Timothée Bruel, Matthieu Prot, Mounira Smati-Lafarge, Ludivine Grzelak, Cyril Planchais, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Cité (UPCité), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), Institut Pasteur [Paris], Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Intercommunal de Créteil (CHIC), CHU Strasbourg, CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Régional d'Orléans (CHRO), Université de Strasbourg (UNISTRA), Centre National de Référence du VIH [Tours] (CNR VIH), Work in the laboratory of O.S. is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash COVID PROTEO-SARS-CoV-2 and IDISCOVR. Work in UPBI is funded by grant ANR-10-INSB-04-01 and Région Ile-de-France program DIM1-Health. D.P. is supported by the Vaccine Research Institute. L.G. is supported by the French Ministry of Higher Education, Research and Innovation. The laboratory of H.M. is funded by the Institut Pasteur, the Milieu Intérieur Program (ANR-10-LABX-69-01), the INSERM, REACTing and EU (RECOVER) grants. The laboratory of S.v.d.W. is funded by Institut Pasteur, CNRS, Université de Paris, Santé publique France, Labex IBEID (ANR-10-LABX-62-IBEID), REACTing, EU grant RECOVER. The laboratory of S.F.-K. is funded by Strasbourg University Hospital (SeroCoV-HUS, PRI 7782), Programme Hospitalier de Recherche Clinique (PHRC N 2017-HUS no. 6997), the Agence Nationale de la Recherche (ANR-18-CE17-0028), Laboratoire d’Excellence TRANSPLANTEX (ANR-11-LABX-0070_TRANSPLANTEX) and Institut National de la Santé et de la Recherche Médicale (UMR_S 1109). Work in CHR Orléans is funded by COREVIH Centre Val de Loire., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-18-CE17-0028,HuMABK,Les anticorps monoclonaux humains : une Nouvelle approche thérapeutique contre l'infection par le virus BK et les maladies associées(2018), ANR-11-LABX-0070,TRANSPLANTEX,Nouveaux loci d'histocompatibilité/biomarqueurs en transplantation humaine: de la découverte à l'app(2011), Université de Paris (UP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Donati, Flora, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Les anticorps monoclonaux humains : une Nouvelle approche thérapeutique contre l'infection par le virus BK et les maladies associées - - HuMABK2018 - ANR-18-CE17-0028 - AAPG2018 - VALID, Nouveaux loci d'histocompatibilité/biomarqueurs en transplantation humaine: de la découverte à l'app - - TRANSPLANTEX2011 - ANR-11-LABX-0070 - LABX - VALID, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Vaccine Research Institute [Créteil, France] (VRI), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), and Centre National de Référence du VIH [Tours] - laboratoire associé (CNR VIH)
Subjects: 0301 basic medicine, COVID-19 Vaccines, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Cross Reactions, Antibodies, Viral, Sensitivity and Specificity, General Biochemistry, Genetics and Molecular Biology, Neutralization, Virus, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Immune system, Neutralization Tests, Humans, Medicine, media_common, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology, medicine.diagnostic_test, SARS-CoV-2, business.industry, Convalescence, Vaccination, COVID-19, General Medicine, Antibodies, Neutralizing, Virology, 3. Good health, [SDV] Life Sciences [q-bio], Titer, 030104 developmental biology, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, Antibody, business
Abstract: International audience; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.7 and B.1.351 variants were first identified in the United Kingdom and South Africa, respectively, and have since spread to many countries. These variants harboring diverse mutations in the gene encoding the spike protein raise important concerns about their immune evasion potential. Here, we isolated infectious B.1.1.7 and B.1.351 strains from acutely infected individuals. We examined sensitivity of the two variants to SARS-CoV-2 antibodies present in sera and nasal swabs from individuals infected with previously circulating strains or who were recently vaccinated, in comparison with a D614G reference virus. We utilized a new rapid neutralization assay, based on reporter cells that become positive for GFP after overnight infection. Sera from 58 convalescent individuals collected up to 9 months after symptoms, similarly neutralized B.1.1.7 and D614G. In contrast, after 9 months, convalescent sera had a mean sixfold reduction in neutralizing titers, and 40% of the samples lacked any activity against B.1.351. Sera from 19 individuals vaccinated twice with Pfizer Cominarty, longitudinally tested up to 6 weeks after vaccination, were similarly potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Neutralizing titers increased after the second vaccine dose, but remained 14-fold lower against B.1.351. In contrast, sera from convalescent or vaccinated individuals similarly bound the three spike proteins in a flow cytometry-based serological assay. Neutralizing antibodies were rarely detected in nasal swabs from vaccinees. Thus, faster-spreading SARS-CoV-2 variants acquired a partial resistance to neutralizing antibodies generated by natural infection or vaccination, which was most frequently detected in individuals with low antibody levels. Our results indicate that B1.351, but not B.1.1.7, may increase the risk of infection in immunized individuals.
Published: 2021
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26. Cluster of COVID-19 in northern France: A retrospective closed cohort study

Author: Nathalie Jolly, Christèle Huon, Laura Tondeur, Bernadette Crescenzo, Sarah Temmam, Sandie Munier, Camille Besombes, Isabelle Staropoli, Timothée Bruel, Isabelle Cailleau, Rebecca Grant, Pierre Gallian, Simon Cauchemez, Marie-Noëlle Ungeheuer, Yoann Madec, Sylvie van der Werf, Bruno Hoen, Ludivine Grzelak, Marc Eloit, Sandrine Fernandes Pellerin, Olivier Schwartz, Caroline Demeret, Kuang-Yu Chen, Arnaud Fontanet, Lucie Kuhmel, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Sorbonne Université (SU), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Direction de la recherche médicale de l'Institut Pasteur, Centre Médical de l'Institut Pasteur (CMIP), Découverte de pathogènes – Pathogen discovery, Biologie des ARN et virus influenza - RNA Biology of Influenza Virus, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Université Paris Cité (UPCité), Etablissement Français du Sang [La Plaine Saint-Denis] (EFS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modélisation mathématique des maladies infectieuses - Mathematical modelling of Infectious Diseases, École nationale vétérinaire - Alfort (ENVA), Funding: Institut Pasteur, CNRS, Université de Paris, Santé publique France, Labex IBEID (ANR-10-LABX-62-IBEID), REACTing, EU grant Recover, INCEPTION project (PIA/ANR-16-CONV-0005)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Virus et Immunité - Virus and immunity, Université de Paris (UP), École nationale vétérinaire d'Alfort (ENVA), demeret, caroline, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID, Rapid European COVID-19 Emergency Response research - RECOVER - - H2020-SC1-PHE-CORONAVIRUS-20202020-02-14 - 2022-02-13 - 101003589 - VALID, Centre Médical de l'Institut Pasteur, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0303 health sciences, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, [SDV]Life Sciences [q-bio], Attack rate, Ageusia, Disease cluster, Confidence interval, 3. Good health, Herd immunity, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Internal medicine, Case fatality rate, medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030212 general & internal medicine, medicine.symptom, business, 030304 developmental biology, Cohort study
Abstract: SummaryBackgroundThe Oise department in France has been heavily affected by COVID-19 in early 2020.MethodsBetween 30 March and 4 April 2020, we conducted a retrospective closed cohort study among pupils, their parents and siblings, as well as teachers and non-teaching staff of a high-school located in Oise. Participants completed a questionnaire that covered history of fever and/or respiratory symptoms since 13 January 2020 and had blood tested for the presence of anti-SARS-CoV-2 antibodies. The infection attack rate (IAR) was defined as the proportion of participants with confirmed SARS-CoV-2 infection based on antibody detection. Blood samples from two blood donor centres collected between 23 and 27 March 2020 in the Oise department were also tested for presence of anti-SARS-CoV-2 antibodies.FindingsOf the 661 participants (median age: 37 years), 171 participants had anti-SARS-CoV-2 antibodies. The overall IAR was 25.9% (95% confidence interval (CI) = 22.6-29.4), and the infection fatality rate was 0% (one-sided 97.5% CI = 0 - 2.1). Nine of the ten participants hospitalised since mid-January were in the infected group, giving a hospitalisation rate of 5.3% (95% CI = 2.4 –9.8). Anosmia and ageusia had high positive predictive values for SARS-CoV-2 infection (84.7% and 88.1%, respectively). Smokers had a lower IAR compared to non-smokers (7.2% versus 28.0%, P InterpretationThe relatively low IAR observed in an area where SARS-CoV-2 actively circulated weeks before confinement measures indicates that establishing herd immunity will take time, and that lifting these measures in France will be long and complex.FundingInstitut Pasteur, CNRS, Université de Paris, Santé publique France, Labex IBEID (ANR-10-LABX-62-IBEID), REACTing, EU grant Recover, INCEPTION project (PIA/ANR-16-CONV-0005).Research in contextEvidence before the studyThe first COVID-19 cases in France were reported on 24 January 2020. Substantial transmission has occurred since then, with the Oise department, north of Paris, one of the heaviest affected areas in the early stages of the epidemic in France. As of 13 April 2020, 98,076 cases had been diagnosed in France, including 5,379 deaths.Epidemiological and clinical characteristics of patients with COVID-19 have been widely reported, but this has largely been centred on cases requiring medical care. What remains unclear at this stage is the extent to which SARS-CoV-2 infections may be asymptomatic or present as subclinical, non-specific symptoms. While extensive contact tracing has identified asymptomatic infections using RT-PCR testing, serologic detection of anti-SARS-CoV-2 antibodies is needed to determine the real infection attack rate and the proportion of all infections that are asymptomatic or subclinical.Added value of this studyUsing a combination of serologic assays with high sensitivity and specificity for anti-SARS-CoV-2 antibodies, we conducted a retrospective closed cohort study. In a high school linked to a cluster of COVID-19 in the Oise department, we showed an overall infection attack rate (IAR) of 40.9% in the high school group, and 10.9% in parents and siblings of the pupils. The proportion of infected individuals who had no symptoms during the study period was 17.0%.Implications of all of the available evidenceThe relatively low IAR in this area where SARS-CoV-2 actively circulated before confinement measures were introduced indicates that establishing herd immunity will take time, and that the lifting of these measures in France will be long and complex.
Published: 2021

27. Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies

Author: Ludivine Grzelak, Mélanie Albert, María González, Vincent Enouf, Françoise Porrot, Hélène Péré, Marianne Maquart, Flora Donati, Timothée Bruel, Maaran Michael Rajah, Olivier Schwartz, Jérôme De Seze, Isabelle Staropoli, Julian Buchrieser, Sylvie van der Werf, Aymeric Sève, Florence Guivel-Benhassine, Laurent Hocqueloux, Samira Fafi-Kremer, Karl Stefic, David Veyer, Cyril Planchais, Etienne Simon-Loriere, Delphine Planas, Elodie Bishop, Thierry Prazuck, Hugo Mouquet, and Sylvie Behillil
Subjects: biology, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Virology, Virus, Neutralization, Vaccination, Titer, Nasal Swab, Humoral immunity, biology.protein, Medicine, Antibody, business
Abstract: SARS-CoV-2 B.1.1.7 and B.1.351 variants emerged respectively in United Kingdom and South Africa and spread in many countries. Here, we isolated infectious B.1.1.7 and B.1.351 strains and examined their sensitivity to anti-SARS-CoV-2 antibodies present in sera and nasal swabs, in comparison with a D614G reference virus. We established a novel rapid neutralization assay, based on reporter cells that become GFP+ after overnight infection. B.1.1.7 was neutralized by 79/83 sera from convalescent patients collected up to 9 months post symptoms, almost similar to D614G. There was a mean 6-fold reduction in titers and even loss of activity against B.1.351 in 40% of convalescent sera after 9 months. Early sera from 19 vaccinated individuals were almost as potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Nasal swabs from vaccine recipients were not neutralizing, except in individuals who were diagnosed COVID-19+ before vaccination. Thus, faster-spreading variants acquired a partial resistance to humoral immunity generated by natural infection or vaccination, mostly visible in individuals with low antibody levels.
Published: 2021
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28. A Monocyte/Dendritic Cell Molecular Signature of SARS-CoV-2 Related Multisystem Inflammatory Syndrome in Children (MIS-C) with Severe Myocarditis

Author: Camille de Cevins, Marine Luka, Nikaia Smith, Sonia Meynier, Aude Magérus, Francesco Carbone, Victor Garcia-Paredes, Laura Barnabei, Maxime Batignes, Alexandre Boullé, Marie-Claude Stolzenberg, Brieuc P. Pérot, Bruno Charbit, Tinhinane Fali, Vithura Pirabarakan, Boris Sorin, Quentin Riller, Ghaith Abdessalem, Maxime Beretta, Ludivine Grzelak, Pedro Goncalves, James Di Santo, Hugo Mouquet, Olivier Schwartz, Mohammed Zarhrate, Mélanie Parisot, Christine Bole-Feysot, Cécile Masson, Nicolas Cagnard, Aurelien Corneau, Camille Bruneau, Shen-Ying Zhang, Jean-Laurent Casanova, Brigitte Bader Meunier, Julien Haroche, Isabelle Melki, Mathie Lorrot, Mehdi Oualha, Florence Moulin, Damien Bonnet, Zahra Belhadjer, Mariane Leruez, Slimane Allali, Christele Gras Leguen, Loic de Pontual, Pediatric-Biocovid Study Group, Alain Fischer, Darragh Duffy, Frederic Rieux-Laucat, Julie Toubiana, and Mickaël Mathieu Ménager
Subjects: Gynecology, medicine.medical_specialty, Myocarditis, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Monocyte, education, Ethics committee, medicine.disease, medicine.anatomical_structure, Medicine, VEGF signaling, business
Abstract: SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κ B activity, TNF-α signaling, associated with decreased gene expression of NF-κ B inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology. Funding: The study was supported by the Institut National de la Sante et de la Recherche Medicale (INSERM), by the “URGENCE COVID-19” fundraising campaign of Institut Pasteur, by the Atip-Avenir, Emergence ville de Paris program and fond de dotation Janssen Horizon and by government grants managed by the Agence National de la Recherche as part of the “Investment for the Future” program (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010, Laboratoire d’Excellence ‘‘Milieu Interieur”, grant ANR-10-LABX-69-01), the Centre de Reference Deficits Immunitaires Hereditaires (CEREDIH), the Agence National de la Recherche (ANR-flash Covid19 “AIROCovid” to FRL and “CoVarImm” to DD and JDS), and by the FASTFoundation (French Friends of Sheba Tel Hashomer Hospital). The LabTech Single-Cell@Imagine is supported by the Paris Region and the “Investissements d’avenir” program through the 2019 ATF funding – Sesame Filieres PIA (Grant N°3877871).CdC is the recipient of a CIFRE-PhD (Sanofi). L.B. was a recipient of an Imagine institute PhD international program supported by the Fondation Bettencourt Schueller. L.B. was also supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) and is part of the Universite de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its“Investments for the Future” program. S.M. was a recipient of an INSERM and Institut Imagine post-doctorat program supported by the Fondation pour la Recherche Medicale (FRMN°SPF20170938825). NS was a recipient of the Pasteur-Roux-Cantarini Fellowship. VGP obtained an Imagine international PhD fellowship program supported by the Fondation Bettencourt Schueller. BPP is the recipient of an ANRS post-doctoral fellowship. Conflict of Interest: DD, FRL, JT and MMM are listed as inventors on a patent application related to this technology (European Patent Application no. EP21305197, entitled “Methods of predicting multisystem inflammatory syndrome (MIS-C) with severe myocarditis in subjects suffering from a SARS-CoV-2 infection”). Ethical Approval: The study was approved by the Ethics Committee (Comite de Protection des Personnes Ouest IV, n° DC-2017-2987).
Published: 2021
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29. Sex differences in the decline of neutralizing antibodies to SARS-CoV-2

Author: Yoann Madec, Aurélie Velay, Isabelle Staropoli, Hugo Mouquet, Olivier Schwartz, Floriane Gallais, Ludivine Grzelak, Marie-Josée Wendling, Samira Fafi-Kremer, Cyril Planchais, Yves Hansmann, Nicolas Meyer, Catherine Schmidt-Mutter, David Rey, María González, Arnaud Fontanet, Timothée Bruel, Ludovic Glady, and Jérôme De Seze
Subjects: Longitudinal study, biology, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Physiology, Antibody level, Serology, Vaccination, biology.protein, Medicine, Antibody, business, Mild disease, Body mass index
Abstract: The evolution of SARS-CoV-2 humoral response in infected individuals remains poorly characterized. Here, we performed a longitudinal study of sera from 308 RT-qPCR+ individuals with mild disease, collected at two time-points, up to 6 months post-onset of symptoms (POS). We performed two anti-S and one anti-N serology assays and quantified neutralizing antibodies (NAbs). At month 1 (M1), males, individuals > 50 years of age or with a body mass index (BMI) > 25 exhibited higher levels of antibodies. Antibody levels decreased over time. At M3-6, anti-S antibodies persisted in 99% of individuals while anti-N IgG were measurable in only 59% of individuals. The decline in anti-S and NAbs was faster in males than in females, independently of age and BMI. Our results show that some serology tests are less reliable overtime and suggest that the duration of protection after SARS-CoV-2 infection or vaccination will be different in women and men.
Published: 2020
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30. Asymptomatic and symptomatic SARS-CoV-2 infections elicit polyfunctional antibodies

Author: Stéphane Pelleau, François Anna, Michael T. White, Pierre Charneau, Arnaud Fontanet, Timothée Bruel, Hugo Mouquet, Bruno Hoen, Yoann Madec, Jérémy Dufloo, Yves Levy, Ludivine Grzelak, Isabelle Staropoli, Marie-Noëlle Ungeheuer, Laura Tondeur, Rémy Robinot, Julian Buchrieser, Aurélie Wiedemann, Cyril Planchais, Olivier Schwartz, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Malaria : parasites et hôtes - Malaria : parasites and hosts, Institut Pasteur [Paris], Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Direction de la recherche médicale de l'Institut Pasteur, Conservatoire National des Arts et Métiers [CNAM] (CNAM), This work was supported by the Urgence COVID-19 Fundraising Campaign of Institut Pasteur. O.S. is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), the 'TIMTAMDEN' project (a collaboration of Inserm, Institut Pasteur, and IRD, ANR-14-CE14-0029), the ANR 'CHIKV-Viro-Immuno' project (ANR-14-CE14-0015-01), and the Gilead HIV cure program. J.D. and L.G. are supported by the French Ministry of Higher Education, Research and Innovation. H.M. is funded by the Institut Pasteur, the Milieu Intérieur Program (ANR-10-LABX-69-01), Inserm, and REACTing and EU RECOVER grants. C.P. is supported by a fellowship from the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS)., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Institut Pasteur [Paris] (IP)-TheraVectys, Institut Pasteur [Paris] (IP), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)
Subjects: Male, Medicine (General), [SDV]Life Sciences [q-bio], Cell, Antibodies, Viral, Severity of Illness Index, Epitope, Immunoglobulin G, Neutralization, Antigen-Antibody Reactions, Epitopes, 0302 clinical medicine, antibody, Medicine, complement, Antibody-dependent cell-mediated cytotoxicity, 0303 health sciences, biology, Middle Aged, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, Spike Glycoprotein, Coronavirus, Female, medicine.symptom, Antibody, ADCC, Adult, Adolescent, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Asymptomatic, General Biochemistry, Genetics and Molecular Biology, Article, Virus, Young Adult, 03 medical and health sciences, R5-920, Neutralization Tests, Humans, asymptomatic, 030304 developmental biology, SARS-CoV-2, business.industry, Antibody-Dependent Cell Cytotoxicity, COVID-19, Complement System Proteins, Asymptomatic Diseases, Immunology, biology.protein, business, 030217 neurology & neurosurgery
Abstract: A large proportion of SARS-CoV-2 infected individuals remains asymptomatic. Little is known about the extent and quality of their antiviral humoral response. Here, we analyze antibody functions in 52 asymptomatic infected individuals, 119 mild and 21 hospitalized COVID-19 patients. We measured anti-Spike IgG, IgA and IgM levels with the S-Flow assay and map IgG-targeted epitopes by Luminex. We also evaluated neutralization, complement deposition and Antibody-Dependent Cellular Cytotoxicity (ADCC) using replication-competent SARS-CoV-2 or reporter cell systems. We show that COVID-19 sera mediate complement deposition and kill infected cells by ADCC. Sera from asymptomatic individuals neutralize the virus, activate ADCC and trigger complement deposition. Antibody levels and functions are lower in asymptomatic individuals than in symptomatic cases. Antibody functions are correlated, regardless of disease severity. Longitudinal samplings show that antibody functions follow similar kinetics of induction and contraction. Overall, asymptomatic SARS-CoV-2 infection elicits polyfunctional antibodies neutralizing the virus and targeting infected cells., Graphical Abstract, Dufloo et al. show that SARS-CoV-2 infection elicits antibodies that neutralize the virus, activate the complement system and kill infected cells by ADCC. These polyfunctional antibodies are slightly more abundant in symptomatic COVID-19 patients than in asymptomatic individuals and correlate with disease severity.
Published: 2020
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31. Serologic responses to SARS-CoV-2 infection among hospital staff with mild disease in eastern France

Author: Yoann Madec, François Anna, Sandrine Fernandes-Pellerin, Marie Mielcarek, Olivier Schwartz, Rebecca Grant, Nicolas Collongues, Isabelle Staropoli, David Rey, Alexandre Bolle, Nathalie Jolly, Laura Tondeur, Charlotte Renaudat, Ludivine Grzelak, Nicolas Lefebvre, Marie-Noëlle Ungeheuer, Arnaud Fontanet, Bruno Hoen, Jérôme De Seze, Timothée Bruel, Catherine Schmidt-Mutter, Samira Fafi-Kremer, Aurélie Velay, Pierre Charneau, Philippe Souque, Nicolas Meyer, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), CHU Strasbourg, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Université Paris Cité (UPCité), Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys, Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Institut Pasteur [Paris] (IP), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Groupe Méthodes en Recherche Clinique [Strasbourg] (GMRC), Nouvel Hôpital Civil [Strasbourg], CHU Strasbourg-CHU Strasbourg, École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Direction de la recherche médicale de l'Institut Pasteur, Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), OS lab is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR- 10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro- Immuno' ANR-14-CE14-0015-01 and the Gilead HIV cure program. LG is supported by the French Ministry of Higher Education, Research and Innovation. SFK lab receives funding from Strasbourg University Hospitals (COVID-HUS, CE-2020-34)., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), univOAK, Archive ouverte, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Appel à projets générique - Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue - - TIMTAMDEN2014 - ANR-14-CE14-0029 - Appel à projets générique - VALID, Appel à projets générique - Multiplication et Relation avec l'hôte du virus Chikungunya - - CHIKV-Viro-Immuno2014 - ANR-14-CE14-0015 - Appel à projets générique - VALID, Vaccine Research Institute [Créteil, France] (VRI), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-TheraVectys, Institut Pasteur [Paris], and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE)
Subjects: Male, 0301 basic medicine, Future studies, MESH: Coronavirus Infections, [SDV]Life Sciences [q-bio], Antibodies, Viral, Severity of Illness Index, Neutralization, Serology, MESH: Antibodies, Neutralizing, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: COVID-19, 030212 general & internal medicine, Mild disease, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Middle Aged, biology, Reverse Transcriptase Polymerase Chain Reaction, General Medicine, Middle Aged, MESH: Hospitals, Hospitals, 3. Good health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, MESH: RNA, Viral, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, RNA, Viral, MESH: Betacoronavirus, Female, France, Sample collection, Antibody, Coronavirus Infections, Research Paper, Adult, medicine.medical_specialty, MESH: Pandemics, Coronavirus disease 2019 (COVID-19), Health Personnel, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, Article, General Biochemistry, Genetics and Molecular Biology, Antibodies, Betacoronavirus, 03 medical and health sciences, Internal medicine, MESH: Severity of Illness Index, medicine, Humans, Serologic Tests, MESH: SARS-CoV-2, Symptom onset, Pandemics, 030304 developmental biology, MESH: Humans, business.industry, Mild covid-19, SARS-CoV-2, MESH: Serologic Tests, COVID-19, MESH: Adult, Antibodies, Neutralizing, MESH: Male, Personnel, Hospital, MESH: France, 030104 developmental biology, MESH: Pneumonia, Viral, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Antibody Formation, biology.protein, MESH: Health Personnel, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, MESH: Antibodies, Viral
Abstract: PMCID: PMC7502660; International audience; BACKGROUND: The serologic response of individuals with mild forms of SARS-CoV-2 infection is poorly characterized.METHODS: Hospital staff who had recovered from mild forms of PCR-confirmed SARS-CoV-2 infection were tested for anti-SARS-CoV-2 antibodies using two assays: a rapid immunodiagnostic test (99.4% specificity) and the S-Flow assay (~99% specificity). The neutralizing activity of the sera was tested with a pseudovirus-based assay.FINDINGS: Of 162 hospital staff who participated in the investigation, 160 reported SARS-CoV-2 infection that had not required hospital admission and were included in these analyses. The median time from symptom onset to blood sample collection was 24 days (IQR: 21-28, range 13-39). The rapid immunodiagnostic test detected antibodies in 153 (95.6%) of the samples and the S-Flow assay in 159 (99.4%), failing to detect antibodies in one sample collected 18 days after symptom onset (the rapid test did not detect antibodies in that patient). Neutralizing antibodies (NAbs) were detected in 79%, 92% and 98% of samples collected 13-20, 21-27 and 28-41 days after symptom onset, respectively (P = 0.02). INTERPRETATION: Antibodies against SARS-CoV-2 were detected in virtually all hospital staff sampled from 13 days after the onset of COVID-19 symptoms. This finding supports the use of serologic testing for the diagnosis of individuals who have recovered from SARS-CoV-2 infection. The neutralizing activity of the antibodies increased overtime. Future studies will help assess the persistence of the humoral response and its associated neutralization capacity in recovered patients.FUNDINGS: The funders had no role in study design, data collection, interpretation, or the decision to submit the work for publication.
Published: 2020
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32. In-concert immune dynamics during natural influenza virus infection and recovery in acute hospitalized patients

Author: Aeron C. Hurt, Sneha Sant, Stephen J. Turner, Xiaoxiao Jia, Yi-Mo Deng, Zhongfang Wang, Ludivine Grzelak, Carolien E. van de Sandt, Weisan Chen, Jane Crowe, Maria Auladell, E. Bridie Clemens, Stephanie Gras, Malet Aban, E.K. Allen, Marios Koutsakos, Thi H. O. Nguyen, Stephen J. Kent, Tim Brahm, Liyen Loh, Luca Hensen, David C. Jackson, Jeremy Chase Crawford, Adam K. Wheatley, Paul G. Thomas, Patrick Günther, Simone Nüssing, Nicole L. La Gruta, Jamie Rossjohn, Peter C. Doherty, Allen C. Cheng, Katherine Kedzierska, Tom Kotsimbos, Jianqing Xu, Karen L. Laurie, and Lorena E. Brown
Subjects: Immune system, Antibody response, business.industry, Hospitalized patients, Follicular phase, Immunology, Medicine, In patient, Disease, business, CD8, Virus
Abstract: We report in-concert dynamics of 18 key immune parameters, related to clinical, genetic and virological factors, in patients hospitalized with influenza across different severity levels. Influenza disease was associated with correlated increases in IL6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells (cTfhs) correlated with peak antibody-secreting cells (ASC) and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differed from vaccination-induced B-cell responses. Influenza-specific CD8+/CD4+ T-cells increased early in disease and remained activated during patient recovery. Here, we describe the broadest to-date immune cellular networks underlying recovery from influenza infection, highly relevant to other infectious diseases.
Published: 2020
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33. SARS-CoV-2 infection in primary schools in northern France: A retrospective cohort study in an area of high transmission

Author: Yoann Madec, Pierre Charneau, Bruno Hoen, François Anna, Isabelle Cailleau, Marie-Noëlle Ungeheuer, Caroline Demeret, Lucie Kuhmel, Ludivine Grzelak, Laura Tondeur, Arnaud Fontanet, Olivier Schwartz, Rebecca Grant, Timothée Bruel, Isabelle Staropoli, Charlotte Renaudat, Sandrine Fernandes Pellerin, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Direction de la recherche médicale de l'Institut Pasteur, Institut Pasteur [Paris], Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Centre Médical de l'Institut Pasteur (CMIP), Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), The study was funded by Institut Pasteur, and several laboratories participating in the study receive funding from the Labex IBEID (ANR-10-LABX-62-IBEID), REACTing and the INCEPTION project (PIA/ANR-16-CONV-0005) for studies focusing on emerging viruses. OS lab is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro- Immuno' ANR-14-CE14-0015-01 and the Gilead HIV cure program. LG is supported by the French Ministry of Higher Education, Research and Innovation., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Centre Médical de l'Institut Pasteur, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-TheraVectys, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: business.industry, Transmission (medicine), [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), education, Attack rate, School setting, Retrospective cohort study, Familial clustering, Asymptomatic, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, High transmission, Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030212 general & internal medicine, medicine.symptom, business, Demography
Abstract: BackgroundThe extent of SARS-CoV-2 transmission among pupils in primary schools and their families is unknown.MethodsBetween 28-30 April 2020, a retrospective cohort study was conducted among pupils, their parents and relatives, and staff of primary schools exposed to SARS-CoV-2 in February and March 2020 in a city north of Paris, France. Participants completed a questionnaire that covered sociodemographic information and history of recent symptoms. A blood sample was tested for the presence of anti-SARS-CoV-2 antibodies using a flow-cytometry-based assay.ResultsThe infection attack rate (IAR) was 45/510 (8.8%), 3/42 (7.1%), 1/28 (3.6%), 76/641 (11.9%) and 14/119 (11.8%) among primary school pupils, teachers, non-teaching staff, parents, and relatives, respectively (P = 0.29). Prior to school closure on February 14, three SARS-CoV-2 infected pupils attended three separate schools with no secondary cases in the following 14 days among pupils, teachers and non-teaching staff of the same schools. Familial clustering of cases was documented by the high proportion of antibodies among parents and relatives of infected pupils (36/59 = 61.0% and 4/9 = 44.4%, respectively). In children, disease manifestations were mild, and 24/58 (41.4%) of infected children were asymptomatic.InterpretationIn young children, SARS-CoV-2 infection was largely mild or asymptomatic and there was no evidence of onwards transmission from children in the school setting.
Published: 2020
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34. SARS-CoV-2 serological analysis of COVID-19 hospitalized patients, pauci-symptomatic individuals and blood donors

Author: Lucie Le Fevre, Diane Descamps, Sylvie van der Werf, Nicolas Escriou, Delphine Planas, Olivier Schwartz, Flora Donati, Cyril Planchais, Rémy Robinot, Isabelle Staropoli, Bernadette Crescenzo, Bruno Hoen, Mireille Nowakowski, Marion Gransagne, Mélanie Albert, Jérémy Dufloo, Marc Eloit, Stéphane Petres, Camille Besombes, Ludivine Grzelak, Yazdan Yazdanpanah, Hugo Mouquet, Sarah Temmam, Arnaud Fontanet, Pierre Charneau, Marija Backovic, Vincent Enouf, Pascal Morel, Françoise Porrot, Quentin Le Hingrat, Audrey Lemaitre, Timothée Bruel, Philippe Souque, Maxime Chazal, Guillaume Mellon, Laura Tondeur, Anabelle Pourbaix, Simon Rolland, Félix A. Rey, Christèle Huon, Julian Buchrieser, Sylvie Behillil, Marie-Noëlle Ungeheuer, François Anna, Maaran Michael Rajah, Lila Bouadma, Florence Guivel, Jacques Bellalou, Marie-Aude Creach, Caroline Demeret, and Kuang-Yu Chen
Subjects: 0303 health sciences, education.field_of_study, biology, 030306 microbiology, business.industry, Population, Antibody titer, Virology, Asymptomatic, 3. Good health, Serology, 03 medical and health sciences, Antigen, biology.protein, Medicine, Seroprevalence, Antibody, Seroconversion, medicine.symptom, education, business, 030304 developmental biology
Abstract: It is of paramount importance to evaluate the prevalence of both asymptomatic and symptomatic cases of SARS-CoV-2 infection and their antibody response profile. Here, we performed a pilot study to assess the levels of anti-SARS-CoV-2 antibodies in samples taken from 491 pre-epidemic individuals, 51 patients from Hôpital Bichat (Paris), 209 pauci-symptomatic individuals in the French Oise region and 200 contemporary Oise blood donors. Two in-house ELISA assays, that recognize the full-length nucleoprotein (N) or trimeric Spike (S) ectodomain were implemented. We also developed two novel assays: the S-Flow assay, which is based on the recognition of S at the cell surface by flow-cytometry, and the LIPS assay that recognizes diverse antigens (including S1 or N C-terminal domain) by immunoprecipitation. Overall, the results obtained with the four assays were similar, with differences in sensitivity that can be attributed to the technique and the antigen in use. High antibody titers were associated with neutralisation activity, assessed using infectious SARS-CoV-2 or lentiviral-S pseudotypes. In hospitalized patients, seroconversion and neutralisation occurred on 5-14 days post symptom onset, confirming previous studies. Seropositivity was detected in 29% of pauci-symptomatic individuals within 15 days post-symptoms and 3 % of blood of healthy donors collected in the area of a cluster of COVID cases. Altogether, our assays allow for a broad evaluation of SARS-CoV2 seroprevalence and antibody profiling in different population subsets.
Published: 2020
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35. Cluster of COVID-19 in Northern France: A Retrospective Closed Cohort Study

Author: Olivier Schwartz, Yoann Madec, Timothée Bruel, Camille Besombes, Nathalie Jolly, Christèle Huon, Laura Tondeur, Rebecca Grant, Marie-Noëlle Ungeheuer, Sandie Munier, Bruno Hoen, Sylvie van der Werf, Sandrine Fernandes Pellerin, Sarah Temmam, Ludivine Grzelak, Pierre Gallian, Marc Eloit, Isabelle Cailleau, Caroline Demeret, Simon Cauchemez, Kuang-Yu Chen, Arnaud Fontanet, Lucie Kuhmel, Bernadette Crescenzo, and Isabelle Staropoli
Subjects: medicine.medical_specialty, biology, Coronavirus disease 2019 (COVID-19), business.industry, Attack rate, Disease cluster, biology.organism_classification, Herd immunity, Informed consent, Family medicine, Case fatality rate, medicine, business, Sida, Cohort study
Abstract: Background: The Oise department in France has been heavily affected by COVID-19 in early 2020. Methods: Between 30 March and 4 April 2020, we conducted a retrospective closed cohort study among pupils, their parents and siblings, as well as teachers and non-teaching staff of a high-school located in Oise. Participants completed a questionnaire that covered history of fever and/or respiratory symptoms since 13 January 2020 and had blood tested for the presence of anti-SARS-CoV-2 antibodies. The infection attack rate (IAR) was defined as the proportion of participants with confirmed SARS-CoV-2 infection based on antibody detection. Blood samples from two blood donor centres collected between 23 and 27 March 2020 in the Oise department were also tested for presence of anti-SARS-CoV-2 antibodies. Findings: Of the 661 participants (median age: 37 years), 171 participants had anti-SARS-CoV-2 antibodies. The overall IAR was 25.9% (95% confidence interval (CI) = 22.6-29.4), and the infection fatality rate was 0% (one-sided 97.5% CI = 0 - 2.1). Nine of the ten participants hospitalised since mid-January were in the infected group, giving a hospitalisation rate of 5.3% (95% CI = 2.4 –9.8). Anosmia and ageusia had high positive predictive values for SARS-CoV-2 infection (84.7% and 88.1%, respectively). Smokers had a lower IAR compared to non-smokers (7.2% versus 28.0%, P
Published: 2020
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36. Anti‐ HIV ‐1 antibodies trigger non‐lytic complement deposition on infected cells

Author: Ludivine Grzelak, Valérie Lorin, Julian Buchrieser, Guillaume Mestrallet, Katia Bourdic, Jérémy Dufloo, Timothée Bruel, Emilie Dupouy, Olivier Schwartz, Olivier Lambotte, Florence Guivel-Benhassine, Hugo Mouquet, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de Médecine Interne - Immunologie Clinique [AP-HP Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Work in OS laboratory is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), the Labex IBEID (ANR-10-IHUB-0002), the 'TIMTAMDEN' ANR-14-CE14-0029, the 'CHIKV-Viro-Immuno' ANR-14-CE14-0015-01, L'Oréal Sponsorship, and the Gilead HIV cure program. HM is supported by the European Research Council (ERC)—Seventh Framework Program (ERC-2013-StG 337146), the G5 Institut Pasteur Program, the Milieu Intérieur Program (ANR-10-LABX-69-01), the INSERM, and the ANRS. JD is supported by a grant from the French Ministry of Higher Education, Research and Innovation., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), European Project: 337146,EC:FP7:ERC,ERC-2013-StG,HUMANTIVIRUSES(2014), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute [Créteil, France] (VRI), Virus et Immunité, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Work in OS laboratory is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR‐10‐LABX‐77), the Labex IBEID (ANR‐10‐IHUB‐0002), the 'TIMTAMDEN' ANR‐14‐CE14‐0029, the 'CHIKV‐Viro‐Immuno' ANR‐14‐CE14‐0015‐01, L'Oréal Sponsorship, and the Gilead HIV cure program. HM is supported by the European Research Council (ERC)—Seventh Framework Program (ERC‐2013‐StG 337146), the G5 Institut Pasteur Program, the Milieu Intérieur Program (ANR‐10‐LABX‐69‐01), the INSERM, and the ANRS. JD is supported by a grant from the French Ministry of Higher Education, Research and Innovation., We thank members of the Virus and Immunity Unit for discussion and help. We thank patients who participated in the study and Cécile Goujard for supervision of the patients’ enrollment. We thank the NIH AIDS Reagent Program for providing reagents. We thank Michel C. Nussenzweig (The Rockefeller University) for providing the pMX‐YU2 ENVΔCT‐GFP‐PuroR expression vector. We thank Frank Kirchhoff and Daniel Sauter (Ulm University) for providing CH058, CH058∆Nef, CH058∆Vpu, and CH058∆Nef∆Vpu plasmids., and ANR-10-LABX-0077/10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010)
Subjects: [SDV]Life Sciences [q-bio], MESH: Complement System Proteins, HIV Infections, CD59, V3 loop, HIV Antibodies, Biochemistry, MESH: HIV-1, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, complement, Cytotoxicity, Molecular Biology, 030304 developmental biology, 0303 health sciences, MESH: Humans, biology, MESH: HIV Antibodies, broadly neutralizing antibodies, virus diseases, Complement System Proteins, MESH: HIV Infections, Virology, 3. Good health, Raji cell, Complement system, Lytic cycle, Polyclonal antibodies, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, HIV-1, Antibody, 030217 neurology & neurosurgery
Abstract: International audience; The effect of anti-HIV-1 antibodies on complement activation at the surface of infected cells remains partly understood. Here, we show that a subset of anti-Envelope (Env) broadly neutralizing antibodies (bNAbs), targeting the CD4 binding site and the V3 loop, triggers C3 deposition and complement-dependent cytotoxicity (CDC) on Raji cells engineered to express high surface levels of HIV-1 Env. Primary CD4 T cells infected with laboratory-adapted or primary HIV-1 strains and treated with bNAbs are susceptible to C3 deposition but not to rapid CDC. The cellular protein CD59 and viral proteins Vpu and Nef protect infected cells from CDC mediated by bNAbs or by polyclonal IgGs from HIV-positive individuals. However, complement deposition accelerates the disappearance of infected cells within a few days of culture. Altogether, our results uncover the contribution of complement to the antiviral activity of anti-HIV-1 bNAbs.
Published: 2019
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37. Human CD8+ T cell cross-reactivity across influenza A, B and C viruses

Author: Glen P. Westall, Auda A. Eltahla, Steve Rockman, Pradyot Dash, Aeron C. Hurt, Brendon Y. Chua, Sneha Sant, Nicole A. Mifsud, Marios Koutsakos, Jamie Rossjohn, E. Kaitlynn Allen, Linda M. Wakim, Anthony W. Purcell, Michael J Richards, Chinn Yi Wong, Ludivine Grzelak, Fabio Luciani, Katherine Kedzierska, Stuart I. Mannering, Thi H. O. Nguyen, Patricia T. Illing, David C. Jackson, Thomas Loudovaris, Stuart G. Tangye, Simone Rizzetto, Paul G. Thomas, Allen C. Cheng, Stephanie Gras, David F. Boyd, Weiguang Zeng, Tom Kotsimbos, E. Bridie Clemens, Michael Elliott, Don Teng, Dhanasekaran Vijaykrishna, Jeremy Chase Crawford, and Ian G. Barr
Subjects: 0301 basic medicine, animal structures, T cell, Immunology, T lymphocyte, Biology, CD38, medicine.disease_cause, Cross-reactivity, Virology, Epitope, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, embryonic structures, Influenza A virus, medicine, Immunology and Allergy, Cytotoxic T cell, CD8, 030215 immunology
Abstract: Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8+ T cells confer cross-protection against IAV strains, however the responses of CD8+ T cells to IBV and ICV are understudied. We investigated the breadth of CD8+ T cell cross-recognition and provide evidence of CD8+ T cell cross-reactivity across IAV, IBV and ICV. We identified immunodominant CD8+ T cell epitopes from IBVs that were protective in mice and found memory CD8+ T cells directed against universal and influenza-virus-type-specific epitopes in the blood and lungs of healthy humans. Lung-derived CD8+ T cells displayed tissue-resident memory phenotypes. Notably, CD38+Ki67+CD8+ effector T cells directed against novel epitopes were readily detected in IAV- or IBV-infected pediatric and adult subjects. Our study introduces a new paradigm whereby CD8+ T cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for the design of universal vaccines.
Published: 2019

38. Human CD8

Author: Marios, Koutsakos, Patricia T, Illing, Thi H O, Nguyen, Nicole A, Mifsud, Jeremy Chase, Crawford, Simone, Rizzetto, Auda A, Eltahla, E Bridie, Clemens, Sneha, Sant, Brendon Y, Chua, Chinn Yi, Wong, E Kaitlynn, Allen, Don, Teng, Pradyot, Dash, David F, Boyd, Ludivine, Grzelak, Weiguang, Zeng, Aeron C, Hurt, Ian, Barr, Steve, Rockman, David C, Jackson, Tom C, Kotsimbos, Allen C, Cheng, Michael, Richards, Glen P, Westall, Thomas, Loudovaris, Stuart I, Mannering, Michael, Elliott, Stuart G, Tangye, Linda M, Wakim, Jamie, Rossjohn, Dhanasekaran, Vijaykrishna, Fabio, Luciani, Paul G, Thomas, Stephanie, Gras, Anthony W, Purcell, and Katherine, Kedzierska
Subjects: Adult, Male, Influenzavirus C, Adolescent, Epitopes, T-Lymphocyte, CD8-Positive T-Lymphocytes, Cross Reactions, Middle Aged, Influenza B virus, Mice, Young Adult, Influenza A virus, Influenza Vaccines, Influenza, Human, Animals, Humans, Female, Child, Aged
Abstract: Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8
Published: 2018

39. Longitudinal analysis of serum neutralization of SARS-CoV-2 Omicron BA.2, BA.4, and BA.5 in patients receiving monoclonal antibodies

Author: Timothée Bruel, Karl Stéfic, Yann Nguyen, Donatella Toniutti, Isabelle Staropoli, Françoise Porrot, Florence Guivel-Benhassine, William-Henry Bolland, Delphine Planas, Jérôme Hadjadj, Lynda Handala, Cyril Planchais, Matthieu Prot, Etienne Simon-Lorière, Emmanuel André, Guy Baele, Lize Cuypers, Luc Mouthon, Hugo Mouquet, Julian Buchrieser, Aymeric Sève, Thierry Prazuck, Piet Maes, Benjamin Terrier, Laurent Hocqueloux, Olivier Schwartz, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Référence du VIH [Tours] - laboratoire associé (CNR VIH), Centre de référence des maladies auto-immunes systémiques rares d'Île-de-France / National Reference Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre Hospitalier Régional d'Orléans (CHRO), Work in the O.S. lab is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale (FRM), ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, and ANR Coronamito and IDISCOVR. Work in the UPBI facility is funded by grant ANR-10-INSB-04-01 and the Région Ȋle-de-France program DIM1Health. D.P. is supported by the Vaccine Research Institute. P.M. acknowledges the support of a COVID-19 research grant from 'Fonds Wetenschappelijk Onderzoek' /Research Foundation Flanders (grant G0H4420N) and 'Internal Funds KU Leuven' (grant 3M170314). E.S.-L. acknowledges funding from the INCEPTION program (Investissements d’Avenir grant ANR-16-CONV-0005)., We thank the European Health Emergency Preparedness and Response Authority (HERA) for supporting the work being done at Institut Pasteur and UK Leuven. We thank the patients who participated in this study. We thank members of the Virus and Immunity Unit for discussions and help. We thank Ludivine Grzelak for her help in creating an illustration of SARS-CoV-2 variant mutations. We thank N. Aulner and the UtechS Photonic BioImaging (UPBI) core facility (Institut Pasteur), a member of the France BioImaging network, for image acquisition and analysis. The Opera system was co-funded by Institut Pasteur and the Région Ȋle-de-France (DIM1Health). We thank F. Peira, V. Legros, and L. Courtellemont for their help with the cohorts. UZ Leuven, as a national reference center for respiratory pathogens, is supported by Sciensano, which is gratefully acknowledged. We thank Hélène Péré and David Veyer for their help in sequencing viral strains and helpful discussions., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), ANR-21-CO14-0007,CoronaMito,Conséquences de l'infection par le SRAS-CoV-2 sur la fonction mitochondriale(2021), and ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016)
Subjects: Omicron, SARS-CoV-2, Antibody-Dependent Cell Cytotoxicity, antibodies, Humans, COVID-19, Antibodies, Monoclonal, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, neutralization, ADCC, Antiviral Agents, General Biochemistry, Genetics and Molecular Biology
Abstract: The emergence of novel Omicron lineages, such as BA.5, may impact the therapeutic efficacy of anti-SARS-CoV-2 neutralizing monoclonal antibodies (mAbs). Here, we evaluated the neutralization and ADCC activity of 6 therapeutic mAbs against Delta, BA.2, BA.4 and BA.5 isolates. The Omicron sub-variants escaped most of the antibodies but remained sensitive to Bebtelovimab and Cilgavimab. Consistent with their shared spike sequence, BA.4 and BA.5 displayed identical neutralization profiles. Sotrovimab was the most efficient at eliciting ADCC. We also analyzed 121 sera from 40 immunocompromised individuals up to 6 months after infusion of 1200 mg of Ronapreve (Imdevimab + Casirivimab), and 300 or 600 mg of Evusheld (Cilgavimab + Tixagevimab). Sera from Ronapreve-treated individuals did not neutralize Omicron subvariants. Evusheld-treated individuals neutralized BA.2 and BA.5, but titers were reduced by 41- and 130-fold, respectively, compared to Delta. A longitudinal evaluation of sera from Evusheld-treated patients revealed a slow decay of mAb levels and neutralization. The decline was more rapid against BA.5. Our data shed light on the antiviral activities of therapeutic mAbs and the duration of effectiveness of Evusheld pre-exposure prophylaxis.
Published: 2022
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40. Viral evolution sustains a dengue outbreak of enhanced severity

Author: Anavaj Sakuntabhai, Myrielle Dupont-Rouzeyrol, Etienne Simon-Loriere, Marie-Amélie Goujart, Sylvie Laumond, Antoine Biron, Ingrid Marois, Arnaud Tarantola, Ann-Claire Gourinat, Elodie Descloux, Catherine Inizan, Marine Minier, Carole Forfait, Matthieu Prot, Olivia O’Connor, Dengue et Arbovirose (URE-DA), Institut Pasteur de Nouvelle-Calédonie, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris], Direction des affaires sanitaires et sociales de Nouvelle-Calédonie, Centre hospitalier territorial Gaston-Bourret [Dumbea] (CHT), Centre hospitalier territorial Gaston-Bourret [Nouméa], Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Génomique évolutive, modélisation et santé (CNRS-UMR2000), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Epidemiology - Epidémiologie [Nouméa, Nouvelle-Calédonie], The current work was supported by an internal seed-funding from the Institut Pasteur in New Caledonia as well as the Arbo-VIRTUESS project funded by the Actions Concertées Interpasteuriennes (project number ACIP 2014-053). ESL acknowledges funding from the French Agence Nationale de la Recherche (INCEPTION program, Investissements d'Avenir grant ANR-16-CONV-0005). This study has received funding from the French Agence Nationale de la Recherche, Investissement d'Avenir program for the Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant n°ANR-10-LABX-62-IBEID)., We warmly thank the Clinical Research Department of the Centre for Translational Research at Institut Pasteur in Paris for their support in ethic procedures. We thank Fabiana Gámbaro and Deborah Delaune for their contribution to whole-genome sequencing. We thank Ludivine Grzelak for her support in the implementation of in vitro replication kinetics., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Génomique évolutive, modélisation et santé (GEMS)
Subjects: 0301 basic medicine, Epidemiology, viruses, Virus Replication, Severity of Illness Index, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Disease Outbreaks, Dengue fever, Dengue, Drug Discovery, hepatitis, Phylogeny, Severe dengue, General Medicine, 3. Good health, Infectious Diseases, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, whole-genome sequencing, Viral evolution, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Viral, Research Article, Genotype, 030106 microbiology, Immunology, viral fitness, Genome, Viral, Biology, Microbiology, Cell Line, Evolution, Molecular, 03 medical and health sciences, New Caledonia, Virology, medicine, Animals, Humans, Hepatitis, Whole Genome Sequencing, Sequence Analysis, RNA, Genetic Variation, Outbreak, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Dengue Virus, medicine.disease, Dengue outbreak, 030104 developmental biology, Amino Acid Substitution, Mutation, Viral fitness, Parasitology
Abstract: Compared to the previous 2013–2014 outbreak, dengue 2016–2017 outbreak in New Caledonia was characterized by an increased number of severe forms associated with hepatic presentations. In this study, we assessed the virological factors associated with this enhanced severity. Whole-genome sequences were retrieved from dengue virus (DENV)-1 strains collected in 2013–2014 and from severe and non-severe patients in 2016–2017. Fitness, hepatic tropism and cytopathogenicity of DENV 2016–2017 strains were compared to those of 2013–2014 strains using replication kinetics in the human hepatic cell line HuH7. Whole-genome sequencing identified four amino acid substitutions specific to 2016–2017 strains and absent from 2013–2014 strains. Three of these mutations occurred in predicted T cell epitopes, among which one was also a B cell epitope. Strains retrieved from severe forms did not exhibit specific genetic features. DENV strains from 2016–2017 exhibited a trend towards reduced replicative fitness and cytopathogenicity in vitro compared to strains from 2013–2014. Overall, the 2016–2017 dengue outbreak in New Caledonia was associated with a viral genetic evolution which had limited impact on DENV hepatic tropism and cytopathogenicity. These mutations, however, may have modified DENV strains antigenicity, altering the anti-DENV immune response in some patients, in turn favoring the development of severe forms. Trial registration: ClinicalTrials.gov identifier: NCT04615364.
Published: 2021
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