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1. Immunogenicity and efficacy of VLA2001 vaccine against SARS-CoV-2 infection in male cynomolgus macaques

Author

Mathilde Galhaut, Urban Lundberg, Romain Marlin, Robert Schlegl, Stefan Seidel, Ursula Bartuschka, Jürgen Heindl-Wruss, Francis Relouzat, Sébastien Langlois, Nathalie Dereuddre-Bosquet, Julie Morin, Maxence Galpin-Lebreau, Anne-Sophie Gallouët, Wesley Gros, Thibaut Naninck, Quentin Pascal, Catherine Chapon, Karine Mouchain, Guillaume Fichet, Julien Lemaitre, Mariangela Cavarelli, Vanessa Contreras, Nicolas Legrand, Andreas Meinke, and Roger Le Grand

Subjects
Medicine
Abstract

Abstract Background The fight against COVID-19 requires mass vaccination strategies, and vaccines inducing durable cross-protective responses are still needed. Inactivated vaccines have proven lasting efficacy against many pathogens and good safety records. They contain multiple protein antigens that may improve response breadth and can be easily adapted every year to maintain preparedness for future seasonally emerging variants. Methods The vaccine dose was determined using ELISA and pseudoviral particle-based neutralization assay in the mice. The immunogenicity was assessed in the non-human primates with multiplex ELISA, neutralization assays, ELISpot and intracellular staining. The efficacy was demonstrated by viral quantification in fluids using RT-qPCR and respiratory tissue lesions evaluation. Results Here we report the immunogenicity and efficacy of VLA2001 in animal models. VLA2001 formulated with alum and the TLR9 agonist CpG 1018™ adjuvant generate a Th1-biased immune response and serum neutralizing antibodies in female BALB/c mice. In male cynomolgus macaques, two injections of VLA2001 are sufficient to induce specific and polyfunctional CD4+ T cell responses, predominantly Th1-biased, and high levels of antibodies neutralizing SARS-CoV-2 infection in cell culture. These antibodies also inhibit the binding of the Spike protein to human ACE2 receptor of several variants of concern most resistant to neutralization. After exposure to a high dose of homologous SARS-CoV-2, vaccinated groups exhibit significant levels of protection from viral replication in the upper and lower respiratory tracts and from lung tissue inflammation. Conclusions We demonstrate that the VLA2001 adjuvanted vaccine is immunogenic both in mouse and NHP models and prevent cynomolgus macaques from the viruses responsible of COVID-19.

Published
2024
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2. Modelling the response to vaccine in non-human primates to define SARS-CoV-2 mechanistic correlates of protection

Author

Marie Alexandre, Romain Marlin, Mélanie Prague, Severin Coleon, Nidhal Kahlaoui, Sylvain Cardinaud, Thibaut Naninck, Benoit Delache, Mathieu Surenaud, Mathilde Galhaut, Nathalie Dereuddre-Bosquet, Mariangela Cavarelli, Pauline Maisonnasse, Mireille Centlivre, Christine Lacabaratz, Aurelie Wiedemann, Sandra Zurawski, Gerard Zurawski, Olivier Schwartz, Rogier W Sanders, Roger Le Grand, Yves Levy, and Rodolphe Thiébaut

Subjects
SARS-CoV-2, correlate of protection, neutralization, vaccines, Medicine, Science, Biology (General), QH301-705.5
Abstract

The definition of correlates of protection is critical for the development of next-generation SARS-CoV-2 vaccine platforms. Here, we propose a model-based approach for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication.

Published
2022
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3. Visualization of HIV-1 reservoir: an imaging perspective

Author

Thibaut Naninck, Celine Mayet, Catherine Chapon, Constantinos Petrovas, and Eirini Moysi

Subjects
CD4-Positive T-Lymphocytes, 0301 basic medicine, Immunology, Simian Acquired Immunodeficiency Syndrome, Human immunodeficiency virus (HIV), HIV Infections, Computational biology, Disease, Biology, Virus Replication, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Virology, medicine, Animals, Humans, 030212 general & internal medicine, Molecular interactions, Oncology (nursing), virus diseases, Virus elimination, Hematology, Viral Load, Simian immunodeficiency virus, Pathogenicity, Macaca mulatta, Antiretroviral therapy, Virus Latency, Visualization, 030104 developmental biology, Infectious Diseases, Oncology, HIV-1, Simian Immunodeficiency Virus
Abstract

Purpose of review The persistence of HIV-1-infected cells, despite the introduction of the combinatorial antiretroviral therapy, is a major obstacle to HIV-1 eradication. Understanding the nature of HIV reservoir will lead to novel therapeutic approaches for the functional cure or eradication of the virus. In this review, we will update the recent development in imaging applications toward HIV-1/simian immunodeficiency virus (SIV) viral reservoirs research and highlight some of their limitations. Recent findings CD4 T cells are the primary target of HIV-1/SIV and the predominant site for productive and latent reservoirs. This viral reservoir preferentially resides in lymphoid compartments that are difficult to access, which renders sampling and measurements problematical and a hurdle for understanding HIV-1 pathogenicity. Novel noninvasive technologies are needed to circumvent this and urgently help to find a cure for HIV-1. Recent technological advancements have had a significant impact on the development of imaging methodologies allowing the visualization of relevant biomarkers with high resolution and analytical capacity. Such methodologies have provided insights into our understanding of cellular and molecular interactions in health and disease. Summary Imaging of the HIV-1 reservoir can provide significant insights for the nature (cell types), spatial distribution, and the role of the tissue microenvironment for its in vivo dynamics and potentially lead to novel targets for the virus elimination.

Published
2021

4. Immunization with synthetic SARS-CoV-2 S glycoprotein virus-like particles protects macaques from infection

Author

Isabelle Bally, Judith A. Burger, Rogier W. Sanders, M. Buisson, Wesley Gros, Pascal Poignard, Axelle Amen, Roger Le Grand, Daphna Fenel, Francis Relouzat, Guy Schoehn, Camille Bouillier, Vanessa Contreras, Nicole M. Thielens, Julien Lemaitre, Franck Fieschi, Guidenn Sulbaran, Sylvie van der Werf, Anne-Sophie Gallouet, Nathalie Dereuddre-Bosquet, Winfried Weissenhorn, Romain Marlin, Michel Thépaut, Thibaut Naninck, Delphine Guilligay, Sebastian Dergan Dylon, Marit J. van Gils, Pauline Maisonnasse, Meliawati Poniman, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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)-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)-Université Grenoble Alpes (UGA), 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, Department of Medical Microbiology and Infection Prevention [Amsterdam], University of Amsterdam [Amsterdam] (UvA), 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), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), This work acknowledges support by the European Union's Horizon 2020 research and innovation program under grant agreement no. 681032, H2020 EHVA (W.W.), the ANR, RA-Covid-19 (W.W. and R.l.G.), and the CNRS (W.W.). W.W. acknowledges access to the platforms of the Grenoble Instruct-ERIC center (IBS and ISBG, UMS 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology (PSB), with support from FRISBI (ANR-10-INBS-05-02) and GRAL, a project of the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003). The IBS acknowledges integration into the Interdisciplinary Research Institute of Grenoble (IRIG, CEA) and financial support from CEA, CNRS, and UGA. The Infectious Disease Models and Innovative Therapies (IDMIT) research infrastructure is supported by the Program Investissements d’Avenir, managed by the National Research Agency (ANR) under reference ANR-11-INBS-0008. The Fondation Bettencourt Schueller and the Region Ile-de-France contributed to the implementation of IDMIT’s facilities and imaging technologies. The NHP study received financial support from REACTing, the Fondation pour la Recherche Médicale (AM-CoV-Path), and the European Infrastructure TRANSVAC2 (730964). We acknowledge support from CoVIC, supported by the Bill and Melinda Gates Foundation. The virus stock was obtained through the EVAg platform (https://www.european-virus-archive.com/), funded by H2020 (653316)., ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), European Project: 681032,H2020,H2020-PHC-2015-single-stage_RTD,EHVA(2016), European Project: 730964, H2020, RIA,H2020-INFRAIA-2016-1,TRANSVAC2(2017), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), Thomas, Frank, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Infrastructures - Infrastructure nationale pour la modélisation des maladies infectieuses humaines - - IDMIT2011 - ANR-11-INBS-0008 - INBS - VALID, European HIV Vaccine Alliance (EHVA): a EU platform for the discovery and evaluation of novel prophylactic and therapeutic vaccine candidates - EHVA - - H20202016-01-01 - 2020-12-31 - 681032 - VALID, European Vaccine Research and Development Infrastructure - TRANSVAC2 - - H2020, RIA2017-05-01 - 2022-04-30 - 730964 - VALID, European Virus Archive goes global - EVAg - - H20202015-04-01 - 2019-03-31 - 653316 - VALID, Medical Microbiology and Infection Prevention, AII - Infectious diseases, Graduate School, Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Epidémiologie et Physiopathologie des Virus Oncogènes / Oncogenic Virus Epidemiology and Pathophysiology (EPVO (UMR_3569 / U-Pasteur_3)), platforms of the Grenoble Instruct-ERIC center (IBS and ISBG, and UMS 3518 CNRS-CEA-UGA-EMBL)

Subjects
Male, [SDV]Life Sciences [q-bio], MESH: Spike Glycoprotein, Coronavirus, Antibodies, Viral, Neutralization, MESH: Antibodies, Neutralizing, MESH: Chlorocebus aethiops, Chlorocebus aethiops, MESH: COVID-19, antibodies, MESH: Animals, MESH: Treatment Outcome, MESH: Immunoglobulin G, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Vaccination, Antibody titer, formaldehyde cross-linking, protection, S glycoprotein, medicine.anatomical_structure, Treatment Outcome, MESH: COVID-19 Vaccines, MESH: HEK293 Cells, Spike Glycoprotein, Coronavirus, Antibody, MESH: Pandemics, COVID-19 Vaccines, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], macaques, T cell, MESH: Vero Cells, Biology, General Biochemistry, Genetics and Molecular Biology, Virus, Article, Immunity, medicine, Animals, Humans, MESH: SARS-CoV-2, Vaccines, Virus-Like Particle, MESH: Immunoglobulin A, MESH: Vaccines, Virus-Like Particle, Pandemics, Vero Cells, B cells, MESH: Humans, SARS-CoV-2, COVID-19, MESH: Vaccination, Th1 Cells, Virology, Antibodies, Neutralizing, immunity, MESH: Male, Immunoglobulin A, Disease Models, Animal, Macaca fascicularis, HEK293 Cells, Immunization, MESH: Macaca fascicularis, MESH: Th1 Cells, Immunoglobulin G, Liposomes, biology.protein, MESH: Liposomes, nanoparticles, MESH: Disease Models, Animal, MESH: Antibodies, Viral
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused an ongoing global health crisis. Here, we present as a vaccine candidate synthetic SARS-CoV-2 spike (S) glycoprotein-coated lipid vesicles that resemble virus-like particles. Soluble S glycoprotein trimer stabilization by formaldehyde cross-linking introduces two major inter-protomer cross-links that keep all receptor-binding domains in the “down” conformation. Immunization of cynomolgus macaques with S coated onto lipid vesicles (S-LVs) induces high antibody titers with potent neutralizing activity against the vaccine strain, Alpha, Beta, and Gamma variants as well as T helper (Th)1 CD4+-biased T cell responses. Although anti-receptor-binding domain (RBD)-specific antibody responses are initially predominant, the third immunization boosts significant non-RBD antibody titers. Challenging vaccinated animals with SARS-CoV-2 shows a complete protection through sterilizing immunity, which correlates with the presence of nasopharyngeal anti-S immunoglobulin G (IgG) and IgA titers. Thus, the S-LV approach is an efficient and safe vaccine candidate based on a proven classical approach for further development and clinical testing., Graphical abstract, Sulbaran et al. find that formaldehyde cross-linked S lipid nanoparticles induce potent neutralizing antibody titers upon cynomolgus macaque vaccination. Notably, vaccinated animals develop sterilizing immunity as highlighted upon virus challenge. Thus, the study provides a path to induce sterilizing immunity correlating with mucosal immune responses, which are desired to prevent virus spreading.

Published
2022

5. Targeting SARS-CoV-2 receptor-binding domain to cells expressing CD40 improves protection to infection in convalescent macaques

Author

Zhiqing Wang, Olivier Schwartz, Mathieu Surenaud, Mireille Centlivre, Gerard Zurawski, Julien Lemaitre, Léa Dupaty, Christine Lacabaratz, Yves Levy, Rodolphe Thiébaut, Sylvie van der Werf, Inga Szurgot, Romain Marlin, Véronique Godot, Severin Coleon, Aurélie Wiedemann, Giuseppe Pantaleo, Pauline Maisonnasse, Delphine Planas, Mélanie Prague, Catherine Chapon, Mario Gomez-Pacheco, Thibaut Naninck, Mathilde Galhaut, Anne-Sophie Gallouet, Jerome Ellis, Mariangela Cavarelli, Sandra Zurawski, Nidhal Kahlaoui, Roger Le Grand, Timothée Bruel, Francis Relouzat, Craig Fenwick, Nathalie Dereuddre-Bosquet, Sylvain Cardinaud, Raphael Ho Tsong Fang, Peter Liljeström, Vanessa Contreras, 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, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Baylor Scott & White Charles A. Sammons Cancer Center [Dallas, TX, USA], Lausanne University Hospital, Université de Lausanne = University of Lausanne (UNIL), Karolinska Institutet [Stockholm], Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), Institut Pasteur [Paris]-Université Paris Cité (UPCité), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Statistics In System biology and Translational Medicine (SISTM), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)- Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Hôpital Henri Mondor, Hôpital Albert Chenevier, The programme was funded by the Vaccine Research Institute via the ANR-10-LABX-77 grant. Studies in hu-mice model have been supported by ARN grant ANR-20-COV6-0004-01. The Infectious Disease Models and Innovative Therapies (IDMIT) research infrastructure is supported by the 'Programme Investissements d’Avenir', managed by the ANR under reference ANR-11-INBS-0008. The Fondation Bettencourt Schueller and the Region Ile-de-France contributed to the implementation of IDMIT’s facilities and imaging technologies. The NHP study received financial support from REACTing, the Fondation pour la Recherche Medicale (FRM, AM-CoV-Path) and the European Infrastructure TRANSVAC2 (730964) for implementation of in vivo imaging technologies an NHP immuno assays. The virus stock used in NHPs was obtained through the EVAg platform (https://www.european-virus-archive.com/), funded by H2020 (653316)., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-20-COV6-0004,DC-CoVaC,Développement de vaccins anti-SARS-CoV-2(2020), ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), European Project: 730964, H2020, RIA,H2020-INFRAIA-2016-1,TRANSVAC2(2017), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), University of Lausanne (UNIL), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris], Vaccine Research Institute [Créteil, France] (VRI), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-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 - laboratoire coordonnateur), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), DARMIGNY, SANDRINE, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Développement de vaccins anti-SARS-CoV-2 - - DC-CoVaC2020 - ANR-20-COV6-0004 - COVID-19 - VALID, Infrastructures - Infrastructure nationale pour la modélisation des maladies infectieuses humaines - - IDMIT2011 - ANR-11-INBS-0008 - INBS - VALID, European Vaccine Research and Development Infrastructure - TRANSVAC2 - - H2020, RIA2017-05-01 - 2022-04-30 - 730964 - VALID, and European Virus Archive goes global - EVAg - - H20202015-04-01 - 2019-03-31 - 653316 - VALID

Subjects
T-Lymphocytes, medicine.medical_treatment, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Mice, 0302 clinical medicine, 030212 general & internal medicine, skin and connective tissue diseases, B-Lymphocytes, 0303 health sciences, Multidisciplinary, biology, Vaccination, 3. Good health, [SDV] Life Sciences [q-bio], Spike Glycoprotein, Coronavirus, Vaccines, Subunit, Antibody, Adjuvant, Protein vaccines, COVID-19 Vaccines, Science, Protein domain, Antigen-Presenting Cells, Virulence, Article, General Biochemistry, Genetics and Molecular Biology, Viral vector, 03 medical and health sciences, Protein Domains, medicine, Animals, Humans, CD40 Antigens, 030304 developmental biology, CD40, SARS-CoV-2, fungi, COVID-19, Convalescence, General Chemistry, Virology, body regions, Viral infection, Preclinical research, Reinfection, Mutation, Humanized mouse, biology.protein, Macaca
Abstract

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

Published
2021

6. SARS-CoV-2 viral dynamics in non-human primates

Author

Andrés Pizzorno, Julien Lemaitre, Nathalie Dereuddre-Bosquet, Flora Donati, Raphael Ho Tsong Fang, Xavier de Lamballerie, Pauline Maisonnasse, Nidhal Kahlaoui, Olivier Terrier, Romain Marlin, Vanessa Contreras, Thibaut Naninck, Caroline Solas, Mélanie Albert, Bruno Hoen, Franck Touret, Antonio Gonçalves, Bruno Lina, Roger Le Grand, Catherine Chapon, Vincent Enouf, Angela Brisebarre, Sylvie van der Werf, Jeremie Guedj, Manuel Rosa Calatrava, Sylvie Behillil, 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, 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, Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), Institut Pasteur [Paris], 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), 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), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Plateforme de Microbiologie Mutualisée (PIBnet) - Mutualized Platform for Microbiology (P2M), 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), Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon] (CNR), Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), This work was funded by the French national research agency (ANR) through the TheraCoV ANR-20-COVI-0018 (JG) and also by the Bill & Melinda Gates Foundation through INV-017335 (JG)., ANR-20-COVI-0018,TheraCoV,Dynamique virale au niveau individuel et populationnel : implications pour l'optimisation des stratégies antivirales(2020), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), 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), Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon] (CNR - laboratoire associé), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Donati, Flora, and Dynamique virale au niveau individuel et populationnel : implications pour l'optimisation des stratégies antivirales - - TheraCoV2020 - ANR-20-COVI-0018 - COVID-19 - VALID

Subjects
Pulmonology, medicine.medical_treatment, Monkeys, Medical Conditions, 0302 clinical medicine, Nasopharynx, Public and Occupational Health, MESH: Animals, Biology (General), Mammals, Innate Immune System, MESH: Cytokines, Eukaryota, 3. Good health, [SDV] Life Sciences [q-bio], Trachea, Computational Theory and Mathematics, Modeling and Simulation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Viral growth, Cytokines, SARS CoV 2, Viral load, Macaque, Primates, QH301-705.5, Immunology, Microbiology, Antiviral Agents, Respiratory Disorders, 03 medical and health sciences, Genetics, MESH: SARS-CoV-2, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Experimental model, Organisms, Biology and Life Sciences, Molecular Development, Virology, MESH: Nasopharynx, Macaca fascicularis, 030104 developmental biology, Viral dynamics, MESH: Macaca fascicularis, Preventive Medicine, MESH: Disease Models, Animal, Digestive System, Basic reproduction number, Developmental Biology, RNA viruses, 0301 basic medicine, Coronaviruses, Physiology, viruses, [SDV]Life Sciences [q-bio], Respiratory System, Basic Reproduction Number, Virus Replication, Immune Physiology, Medicine and Health Sciences, MESH: COVID-19, 030212 general & internal medicine, Pathology and laboratory medicine, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Ecology, Viral Load, Medical microbiology, Vaccination and Immunization, Infectious Diseases, Cytokine, Vertebrates, Viruses, Anatomy, Pathogens, MESH: Viral Load, Research Article, MESH: Antiviral Agents, SARS coronavirus, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Biology, Virus, Cellular and Molecular Neuroscience, Antiviral Therapy, Old World monkeys, medicine, Animals, SARS-CoV-2, MESH: Virus Replication, Viral pathogens, COVID-19, Microbial pathogens, Disease Models, Animal, MESH: Basic Reproduction Number, Immune System, Amniotes, Respiratory Infections, Pharynx, Zoology, Viral Transmission and Infection, MESH: Trachea
Abstract

Non-human primates infected with SARS-CoV-2 exhibit mild clinical signs. Here we used a mathematical model to characterize in detail the viral dynamics in 31 cynomolgus macaques for which nasopharyngeal and tracheal viral load were frequently assessed. We identified that infected cells had a large burst size (>104 virus) and a within-host reproductive basic number of approximately 6 and 4 in nasopharyngeal and tracheal compartment, respectively. After peak viral load, infected cells were rapidly lost with a half-life of 9 hours, with no significant association between cytokine elevation and clearance, leading to a median time to viral clearance of 10 days, consistent with observations in mild human infections. Given these parameter estimates, we predict that a prophylactic treatment blocking 90% of viral production or viral infection could prevent viral growth. In conclusion, our results provide estimates of SARS-CoV-2 viral kinetic parameters in an experimental model of mild infection and they provide means to assess the efficacy of future antiviral treatments., Author summary Non-human primates infected with SARS-CoV-2 develop a mild infection resembling asymptomatic human infection. Here we used viral dynamic modelling to characterize the nasopharyngeal and tracheal viral loads. We found that viral load rapidly declined after peak viral load despite the absence of association between model parameters and immune markers. The within-host reproductive basic reproduction number was approximately equal to 6 and 4 in nasopharynx and trachea suggesting that a prophylactic therapy blocking viral entry or production with 90% efficacy could be sufficient to prevent viral growth and peak viral load.

Published
2021

7. Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection

Author

Anna Z Mykytyn, Max Crispin, Mathieu Claireaux, Karlijn van der Straten, Tom G. Caniels, Rashmi Ravichandran, Raphael Ho Tsong Fang, Kwinten Sliepen, Nisreen M.A. Okba, Mitch Brinkkemper, Nidhal Kahlaoui, Marlon de Gast, Rogier W. Sanders, Ilja Bontjer, Hannah L. Turner, Romain Marlin, Jelle van Schooten, Sylvie van der Werf, Meliawati Poniman, Godelieve J. de Bree, Yoann Aldon, Julien Lemaitre, Thibaut Naninck, Yasunori Watanabe, Roger Le Grand, Eric Ginoux, Ségolène Diry, Pauline Maisonnasse, Julien Villaudy, Edith E. Schermer, Julia M. Giezen, Vanessa Contreras, Bart L. Haagmans, Catherine Chapon, Gius Kerster, Philip J. M. Brouwer, Cynthia A. van der Linden, Yme U. van der Velden, Judith A. Burger, Andrew B. Ward, Virginie Chesnais, Mariëlle J. van Breemen, Marit J. van Gils, Marloes Grobben, Nathalie Dereuddre-Bosquet, Neil P. King, Joel D. Allen, Department of Medical Microbiology and Infection Prevention [Amsterdam], University of Amsterdam [Amsterdam] (UvA), 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, Life and Soft, University of Southampton, University of Oxford, The Scripps Research Institute [La Jolla, San Diego], Imperial College London, Amsterdam UMC - Amsterdam University Medical Center, Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Washington [Seattle], AIMM Therapeutics [Amsterdam, the Netherlands], 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), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), This work was supported by a Netherlands Organisation for Scientific Research (NWO) Vici grant (to R.W.S.), the Bill & Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (CAVD) grants OPP1111923, OPP1132237, and INV-002022 (to R.W.S. and/or N.P.K.), INV-008352/OPP1153692 and OPP1196345/INV-008813 (to M.C.), and OPP1170236 (to A.B.W.), the Fondation Dormeur, Vaduz (R.W.S. and to M.J.v.G.) and Health-Holland PPS-allowance LSHM20040 (to M.J.v.G.), the University of Southampton Coronavirus Response Fund (M.C.), and the Netherlands Organisation for Health Research and Development ZONMW (B.L.H). M.J.v.G. is a recipient of an AMC Fellowship from Amsterdam UMC and a COVID-19 grant from the Amsterdam Institute for Infection and Immunity. R.W.S. and M.J.v.G. are recipients of support from the University of Amsterdam Proof of Concept fund (contract 200421) as managed by Innovation Exchange Amsterdam (IXA). The Infectious Disease Models and Innovative Therapies (IDMIT) research infrastructure is supported by the Programme Investissements d’Avenir, managed by the National Research Agency (ANR) under reference ANR-11-INBS-0008. The Fondation Bettencourt Schueller and the Region Ile-de-France contributed to the implementation of IDMIT’s facilities and imaging technologies. The non-human primate study received financial support from REACTing, the ANR (AM-CoV-Path), and the European Infrastructure TRANSVAC2 (730964)., ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), ANR-20-COVI-0021,AM-Cov-Path,Pathogénèse de l'infection SARS-Cov-2 dans un modèle de primates non humains : un modèle pour les traitements et la prévention(2020), European Project: 730964, H2020, RIA,H2020-INFRAIA-2016-1,TRANSVAC2(2017), Graduate School, AII - Infectious diseases, Medical Microbiology and Infection Prevention, Experimental Immunology, Infectious diseases, APH - Aging & Later Life, APH - Global Health, and Virology

Subjects
T-Lymphocytes, viruses, [SDV]Life Sciences [q-bio], Disease, Public administration, Mice, 0302 clinical medicine, vaccine, Pandemic, antibodies, Spike (database), Neutralizing antibody, 0303 health sciences, B-Lymphocytes, Mice, Inbred BALB C, biology, Transmission (medicine), Viral Load, protection, Models, Animal, Spike Glycoprotein, Coronavirus, Christian ministry, Rabbits, Antibody, Viral load, Healthcare system, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), macaques, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Acquired immunodeficiency syndrome (AIDS), Immunity, Political science, medicine, Animals, 030304 developmental biology, B cells, SARS-CoV-2, Conflict of interest, Spike Protein, COVID-19, medicine.disease, Antibodies, Neutralizing, Virology, immunity, Macaca fascicularis, Immunization, Infectious disease (medical specialty), biology.protein, nanoparticles, 030217 neurology & neurosurgery
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication in the upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic., Graphical Abstract, Brouwer et al. present preclinical evidence in support of a COVID-19 vaccine candidate, designed as a self-assembling two-component protein nanoparticle displaying multiple copies of the SARS-CoV-2 spike protein, which induces strong neutralizing antibody responses and protects from high-dose SARS-CoV-2 challenge.

Published
2021

8. Intranasal inoculation with Bordetella pertussis confers protection without inducing classical whooping cough in baboons

Author

Thibaut Naninck, Loïc Coutte, Aurélie Hébert-Ribon, Vanessa Contreras, Roger Le Grand, Sébastien Langlois, Magali Pelletier, Camille Locht, Nathalie Reveneau, and Catherine Chapon

Subjects
Microbiology (medical), Bordetella pertussis, QH426-470, Microbiology, Pathogenesis, 03 medical and health sciences, Immunology and Microbiology (miscellaneous), Pertussis, Baboons, Immunity, In vivo, Genetics, Medicine, Seroconversion, Whooping cough, 030304 developmental biology, Non-human primates, 0303 health sciences, biology, 030306 microbiology, business.industry, Respiratory infection, respiratory system, biology.organism_classification, medicine.disease, QR1-502, 3. Good health, Infectious Diseases, Immunology, Nasal administration, business
Abstract

Background The resurgence of whooping cough in many countries highlights the crucial need for a better understanding of the pathogenesis of respiratory infection by Bordetella pertussis. Exposure of baboons to B. pertussis by the intranasal and intra-tracheal routes is a recently described preclinical model that reproduces both B. pertussis infection of humans and whooping cough disease. Here, we tested both intranasal and intranasal+intra-tracheal exposure routes and assessed their impact on disease development and immunity. Methods Young baboons were intranasally exposed to the B1917 clinical isolate, representative of circulating strains in Europe, or its green-fluorescent protein expressing derivative. Animals were followed for pertussis symptoms and bacterial colonization and by in vivo probe-based confocal laser endomicroscopy (pCLE) imaging. Sero-conversion and protection against subsequent infection were then evaluated. Results Seroconversion and bacterial colonization of both the nasopharynx and trachea was observed in baboons exposed to B. pertussis by the intranasal route only, and also in those animals challenged by both the intranasal and intra-tracheal routes together. However, baboons exposed solely by the intranasal route developed only mild clinical symptoms, with no paroxysmal cough. These animals were protected against re-infection by B. pertussis. Conclusions Intranasal exposure of baboons to B. pertussis does not induce disease but elicits immune mechanisms that protect them from subsequent exposure to the bacteria. These findings suggest that the intranasal route of inoculation in this non-human primate model could be used in the pre-clinical evaluation of nasal candidate vaccines against pertussis.

Published
2021
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9. Viral dynamic modeling of SARS-CoV-2 in non-human primates

Author

Antonio Gonçalves, Pauline Maisonnasse, Flora Donati, Mélanie Albert, Sylvie Behillil, Vanessa Contreras, Thibaut Naninck, Romain Marlin, Caroline Solas, Andres Pizzorno, Julien Lemaitre, Nidhal Kahlaoui, Olivier Terrier, Raphael Ho Tsong Fang, Vincent Enouf, Nathalie Dereuddre-Bosquet, Angela Brisbarre, Franck Touret, Catherine Chapon, Bruno Hoen, Bruno Lina, Manuel Rosa-Calatrava, Xavier de Lamballerie, France Mentré, Roger Le Grand, Sylvie van der Werf, and Jeremie Guedj

Subjects
business.industry, viruses, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Medicine, business, Virology
Abstract

Non-human primates infected with SARS-CoV-2 exhibit mild clinical signs. Here we used a mathematical model to characterize in detail the viral dynamics in 31 cynomolgus macaques infected with 106 pfu of SARS-CoV-2 for which nasopharyngeal and tracheal viral load were frequently assessed. We identified that infected cells had a large daily viral production (>104 virus) and a within-host reproductive basic number of 6 and 4 in nasopharyngeal and tracheal compartment, respectively. After peak viral load, infected cells were rapidly cleared with a half-life of 9 hours, with no significant association between cytokine elevation and clearance. Translating our model to the context of human-to-human infection, human mild infection may be characterized by a peak occurring 4 days after infection, a viral shedding of ~11 days and a generation time of 4 days. These results improve the understanding of SARS-CoV-2 viral replication and better understand the infection to SARS-CoV-2 in humans.

Published
2020

10. Hydroxychloroquine in the treatment and prophylaxis of SARS-CoV-2 infection in non- human primates

Author

Angela Brisebarre, Jeremie Guedj, Manuel Rosa Calatrava, Bruno Lina, Julien Lemaitre, Romain Marlin, Raphael Ho Tsong Fan, Vanessa Contreras, Catherine Chapon, Roger Le Grand, Antonio Gonçalves, Caroline Solas, Thibaut Naninck, Nathalie Bosquet, Bruno Hoen, Sylvie van der Werf, Sylvie Behillil, Nidhal Kahlaoui, Olivier Terrier, Vincent Enouf, Pauline Maisonnasse, Andrés Pizzorno, Xavier de Lamballerie, and Franck Toure

Subjects
business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Medicine, Hydroxychloroquine, business, Virology, medicine.drug
Abstract

COVID-19 has become a pandemic that has caused over 200,000 deaths worldwide, with no antiviral drug or vaccine yet available. Several clinical studies are ongoing to evaluate the efficacy of repurposed drugs that have demonstrated antiviral efficacy in vitro. Among these candidates, hydroxychloroquine (HCQ) has been given to thousands of individuals worldwide but definitive evidence for HCQ efficacy in treatment of COVID-19 is still missing.We evaluated the antiviral activity of HCQ both in vitro and in SARS-CoV-2-infected macaques. HCQ showed antiviral activity in monkey African green monkey kidney (VeroE6) cells but not in a model of reconstituted human airway epithelium. In macaques, we tested different treatment strategies in comparison to placebo, before and after peak viral load, alone or in combination with azithromycin (AZTH). Neither HCQ nor HCQ+AZTH showed a significant effect on the viral load levels in any of the tested compartments. When the drug was used as a pre-exposure prophylaxis (PrEP), HCQ did not confer protection against acquisition of infection.Our findings do not support the use of HCQ, either alone or in combination with AZTH, as an antiviral treatment for COVID-19 in humans.

Published
2020

12. Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates

Author

Julien Lemaitre, Andrés Pizzorno, Thibaut Naninck, Nathalie Dereuddre-Bosquet, Bruno Hoen, Antonio Gonçalves, Roger Le Grand, Bruno Lina, Jeremie Guedj, Romain Marlin, Xavier de Lamballerie, Olivier Terrier, Catherine Chapon, Nidhal Kahlaoui, Vanessa Contreras, Manuel Rosa Calatrava, Franck Touret, Vincent Enouf, Angela Brisebarre, Sylvie Behillil, Caroline Solas, Sylvie van der Werf, Raphael Ho Tsong Fang, Pauline Maisonnasse, 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, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, 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), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP), 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), Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pasteur International Bioresources network (PIBNet), Plateforme de Microbiologie Mutualisée (PIBnet) - Mutualized Platform for Microbiology (P2M), 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), Hospices Civils de Lyon (HCL), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), This study received financial support from REACTing, the National Research Agency (ANR, AM-CoV-Path) and the European Union’s Horizon 2020 (H2020) research and innovation program Fight-nCov (101003555), European Union IMI2 program CARE (101005077) and the European Infrastructure TRANSVAC2 (730964). The virus stock was obtained through the EVAg platform (https://www.european-virus-archive.com/), funded by H2020 (653316). The Infectious Disease Models and Innovative Therapies (IDMIT) research infrastructure is supported by the ‘Programme Investissements d’Avenir’, managed by the ANR under reference ANR-11-INBS-0008., ANR-21-CO14-0001,FCHG,GWAS francaise pour l'identification des facteurs génétiques de l'hôtes de la COVID19(2021), Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de Référence des virus des infections respiratoires (dont la grippe) [Paris] (CNR), Institut Pasteur [Paris], Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microbiologie mutualisée (Plate-forme) (P2M), Pasteur-Cnam risques infectieux et émergents (PACRI), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris], ANR-20-COVI-0021,AM-CoV-Path,Pathogenesis of SARS-Cov-2 infection in NHP model: insights for treatment and prevention, ANR-11-INBS-0008/11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), European Project: 101003555,H2020, RIA,H2020-SC1-PHE-CORONAVIRUS-2020,Fight-nCoV(2020), European Project: 101005077,H2020, IMI2-RIA,H2020-JTI-IMI2-2020-21-single-stage,CARE(2020), European Project: 730964, H2020, RIA,H2020-INFRAIA-2016-1,TRANSVAC2(2017), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Terrier, Olivier, Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Time Factors, MESH: Treatment Failure, MESH: Coronavirus Infections, MESH: Hydroxychloroquine, Azithromycin, MESH: Chlorocebus aethiops, Chlorocebus aethiops, MESH: Respiratory Mucosa, MESH: Animals, Treatment Failure, media_common, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Cytokines, Multidisciplinary, MESH: Kinetics, Viral Load, 3. Good health, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cytokines, MESH: Betacoronavirus, Female, Coronavirus Infections, MESH: Viral Load, Viral load, Hydroxychloroquine, medicine.drug, Drug, MESH: Pandemics, medicine.drug_class, media_common.quotation_subject, Pneumonia, Viral, 030106 microbiology, MESH: Vero Cells, Respiratory Mucosa, In Vitro Techniques, Virus, Betacoronavirus, 03 medical and health sciences, MESH: Azithromycin, medicine, Animals, Humans, Pandemics, Vero Cells, MESH: In Vitro Techniques, MESH: Humans, SARS-CoV-2, business.industry, MESH: Time Factors, COVID-19, medicine.disease, MESH: Male, COVID-19 Drug Treatment, Disease Models, Animal, Kinetics, Macaca fascicularis, Pneumonia, 030104 developmental biology, MESH: Macaca fascicularis, MESH: Pneumonia, Viral, Immunology, Vero cell, Pre-Exposure Prophylaxis, Antiviral drug, MESH: Disease Models, Animal, business, MESH: Female, MESH: Pre-Exposure Prophylaxis
Abstract

International audience; Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic and no antiviral drug or vaccine is yet available for the treatment of this disease1-3. Several clinical studies are ongoing to evaluate the efficacy of repurposed drugs that have demonstrated antiviral efficacy in vitro. Among these candidates, hydroxychloroquine (HCQ) has been given to thousands of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-the virus that causes COVID-19-worldwide but there is no definitive evidence that HCQ is effective for treating COVID-194-7. Here we evaluated the antiviral activity of HCQ both in vitro and in SARS-CoV-2-infected macaques. HCQ showed antiviral activity in African green monkey kidney cells (Vero E6) but not in a model of reconstituted human airway epithelium. In macaques, we tested different treatment strategies in comparison to a placebo treatment, before and after peak viral load, alone or in combination with azithromycin (AZTH). Neither HCQ nor the combination of HCQ and AZTH showed a significant effect on viral load in any of the analysed tissues. When the drug was used as a pre-exposure prophylaxis treatment, HCQ did not confer protection against infection with SARS-CoV-2. Our findings do not support the use of HCQ, either alone or in combination with AZTH, as an antiviral drug for the treatment of COVID-19 in humans.

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13. Non-human primate models of human respiratory infections

Author

Frédéric Ducancel, Pauline Maisonnasse, Laurent Vecellio, Vanessa Contreras, Marion Holzapfel, Roger Le Grand, Julien Lemaitre, Thibaut Naninck, Camille Bouillier, Frédéric Martinon, Philippe Huber, Nidhal Kahlaoui, Benoit Delache, Sabine Tricot, Justina Creppy, and Quentin Pascal

Subjects
0301 basic medicine, medicine.medical_specialty, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), Immunology, Respiratory tract, Article, 03 medical and health sciences, 0302 clinical medicine, Pandemic, Medicine, Animals, Humans, Potential source, Intensive care medicine, Molecular Biology, Infectious disease, Non human primate, Bacteria, Transmission (medicine), business.industry, SARS-CoV-2, COVID-19, Haplorhini, Non-human primate, Respiratory pathogens, Virus, Disease Models, Animal, 030104 developmental biology, Infectious disease (medical specialty), business, 030215 immunology, Infectious agent
Abstract

Respiratory pathogens represent a great burden for humanity and a potential source of new pandemics, as illustrated by the recent emergence of coronavirus disease 2019 (COVID-19). In recent decades, biotechnological advances have led to the development of numerous innovative therapeutic molecules and vaccine immunogens. However, we still lack effective treatments and vaccines against many respiratory pathogens. More than ever, there is a need for a fast, predictive, preclinical pipeline, to keep pace with emerging diseases. Animal models are key for the preclinical development of disease management strategies. The predictive value of these models depends on their ability to reproduce the features of the human disease, the mode of transmission of the infectious agent and the availability of technologies for monitoring infection. This review focuses on the use of non-human primates as relevant preclinical models for the development of prevention and treatment for human respiratory infections.

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