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1. Qualitative monitoring of SARS-CoV-2 mRNA vaccination in humans using droplet microfluidics

Author

Matteo Broketa, Aurélien Sokal, Michael Mor, Pablo Canales-Herrerias, Angga Perima, Annalisa Meola, Ignacio Fernández, Bruno Iannascoli, Guilhem Chenon, Alexis Vandenberghe, Laetitia Languille, Marc Michel, Bertrand Godeau, Sébastien Gallien, Giovanna Melica, Marija Backovic, Felix A. Rey, Jean Baudry, Natalia T. Freund, Matthieu Mahévas, and Pierre Bruhns

Subjects
Immunology, Vaccines, Medicine
Abstract

SARS-CoV-2 mRNA vaccination generates protective B cell responses targeting the SARS-CoV-2 spike glycoprotein. Whereas anti-spike memory B cell responses are long lasting, the anti-spike humoral antibody response progressively wanes, making booster vaccinations necessary for maintaining protective immunity. Here, we qualitatively investigated the plasmablast responses by measuring from single cells within hours of sampling the affinity of their secreted antibody for the SARS-CoV-2 spike receptor binding domain (RBD) in cohorts of BNT162b2-vaccinated naive and COVID-19–recovered individuals. Using a droplet microfluidic and imaging approach, we analyzed more than 4,000 single IgG-secreting cells, revealing high interindividual variability in affinity for RBD, with variations over 4 logs. High-affinity plasmablasts were induced by BNT162b2 vaccination against Hu-1 and Omicron RBD but disappeared quickly thereafter, whereas low-affinity plasmablasts represented more than 65% of the plasmablast response at all time points. Our droplet-based method thus proves efficient at fast and qualitative immune monitoring and should be helpful for optimization of vaccination protocols.

Published
2023
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2. Fusogenicity and neutralization sensitivity of the SARS-CoV-2 Delta sublineage AY.4.2

Author

Nell Saunders, Delphine Planas, William H. Bolland, Christophe Rodriguez, Slim Fourati, Julian Buchrieser, Cyril Planchais, Matthieu Prot, Isabelle Staropoli, Florence Guivel-Benhassine, Françoise Porrot, David Veyer, Hélène Péré, Nicolas Robillard, Madelina Saliba, Artem Baidaliuk, Aymeric Seve, Laurent Hocqueloux, Thierry Prazuck, Felix A. Rey, Hugo Mouquet, Etienne Simon-Lorière, Timothée Bruel, Jean-Michel Pawlotsky, and Olivier Schwartz

Subjects
SARS-CoV-2, Delta, AY.4.2, Vaccines, Fusogenicity, Neutralization, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: SARS-CoV-2 lineages are continuously evolving. As of December 2021, the AY.4.2 Delta sub-lineage represented 20 % of sequenced strains in the UK and had been detected in dozens of countries. It has since then been supplanted by Omicron. The AY.4.2 spike displays three additional mutations (T95I, Y145H and A222V) in the N-terminal domain when compared to the original Delta variant (B.1.617.2) and remains poorly characterized. Methods: We compared the Delta and the AY.4.2 spikes, by assessing their binding to antibodies and ACE2 and their fusogenicity. We studied the sensitivity of an authentic AY.4.2 viral isolate to neutralizing antibodies. Findings: The AY.4.2 spike exhibited similar binding to all the antibodies and sera tested, and similar fusogenicity and binding to ACE2 than the ancestral Delta spike. The AY.4.2 virus was slightly less sensitive than Delta to neutralization by a panel of monoclonal antibodies; noticeably, the anti-RBD Imdevimab showed incomplete neutralization. Sensitivity of AY.4.2 to sera from vaccinated individuals was reduced by 1.3 to 3-fold, when compared to Delta. Interpretation: Our results suggest that mutations in the NTD remotely impair the efficacy of anti-RBD antibodies. The spread of AY.4.2 was not due to major changes in spike fusogenicity or ACE2 binding, but more likely to a partially reduced neutralization sensitivity. Funding: The work was funded by Institut Pasteur, Fondation pour la Recherche Médicale, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute, Labex IBEID, ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR.

Published
2022
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3. SARS‐CoV‐2 Omicron emergence urges for reinforced One‐Health surveillance

Author

Xavier Montagutelli, Sylvie van der Werf, Felix A Rey, and Etienne Simon‐Loriere

Subjects
Medicine (General), R5-920, Genetics, QH426-470
Abstract

Graphical Abstract SARS‐CoV‐2 Omicron harbors substitutions in the receptor binding domain of the spike which strongly suggest its capacity to infect rodents. Wild animal reservoirs could favor the emergence of new variants with risks of spillback to humans and should be closely monitored.

Published
2022
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4. Immunization with GP1 but Not Core-like Particles Displaying Isolated Receptor-Binding Epitopes Elicits Virus-Neutralizing Antibodies against Junín Virus

Author

Gleyder Roman-Sosa, Anne Leske, Xenia Ficht, Tung Huy Dau, Julia Holzerland, Thomas Hoenen, Martin Beer, Robert Kammerer, Reinhold Schirmbeck, Felix A. Rey, Sandra M. Cordo, and Allison Groseth

Subjects
arenavirus, Junín virus, immune response, neutralizing antibodies, glycoprotein, GP1, Medicine
Abstract

New World arenaviruses are rodent-transmitted viruses and include a number of pathogens that are responsible for causing severe human disease. This includes Junín virus (JUNV), which is the causative agent of Argentine hemorrhagic fever. The wild nature and mobility of the rodent reservoir host makes it difficult to control the disease, and currently passive immunization with high-titer neutralizing antibody-containing plasma from convalescent patients is the only specific therapy. However, dwindling supplies of naturally available convalescent plasma, and challenges in developing similar resources for other closely related viruses, have made the development of alternative antibody-based therapeutic approaches of critical importance. In this study, we sought to induce a neutralizing antibody response in rabbits against the receptor-binding subunit of the viral glycoprotein, GP1, and the specific peptide sequences in GP1 involved in cellular receptor contacts. While these specific receptor-interacting peptides did not efficiently induce the production of neutralizing antibodies when delivered as a particulate antigen (as part of hepatitis B virus core-like particles), we showed that recombinant JUNV GP1 purified from transfected mammalian cells induced virus-neutralizing antibodies at high titers in rabbits. Further, neutralization was observed across a range of unrelated JUNV strains, a feature that is critical for effectiveness in the field. These results underscore the potential of GP1 alone to induce a potent neutralizing antibody response and highlight the importance of epitope presentation. In addition, effective virus neutralization by rabbit antibodies supports the potential applicability of this species for the future development of immunotherapeutics (e.g., based on humanized monoclonal antibodies). Such information can be applied in the design of vaccines and immunogens for both prevention and specific therapies against this and likely also other closely related pathogenic New World arenaviruses.

Published
2022
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5. SARS‐CoV‐2‐related bat virus behavior in human‐relevant models sheds light on the origin of COVID‐19

Author

Sarah Temmam, Xavier Montagutelli, Cécile Herate, Flora Donati, Béatrice Regnault, Mikael Attia, Eduard Baquero Salazar, Delphine Chretien, Laurine Conquet, Grégory Jouvion, Juliana Pipoli Da Fonseca, Thomas Cokelaer, Faustine Amara, Francis Relouzat, Thibaut Naninck, Julien Lemaitre, Nathalie Derreudre‐Bosquet, Quentin Pascal, Massimiliano Bonomi, Thomas Bigot, Sandie Munier, Felix A Rey, Roger Le Grand, Sylvie van der Werf, Marc Eloit, Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre Collaborateur de l'OIE de Détection et identification chez l’homme des pathogènes animaux émergents et développement d’outils pour leur diagnostic / Collaborating Center for the Detection and identification in humans of emerging animal pathogens and development of tools for their diagnoses (CCOIE-OIECC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé Animale / World Organisation Animal Health [Paris] (OIE)-Université Paris Cité (UPCité), Génétique de la souris - Mouse Genetics, 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, 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), Virologie Structurale - Structural Virology, École nationale vétérinaire - Alfort (ENVA), Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biomics (plateforme technologique), Bioinformatique structurale - Structural Bioinformatics, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Next-generation sequencing was performed with the help of Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09), IBISA, and the Illumina COVID-19 Projects' offer. The work was funded by an Institut Pasteur 'Covid Taskforce' and in part by the H2020 project 101003589 (RECOVER) and Labex IBEID (ANR-10-LABX62-IBEID) grants. 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 model of SARS-CoV-2 infection have been developed thanks to the support from REACTing, the Fondation pour la Recherche Medicale (FRM, AM-CoV-Path)., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), and European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020)

Subjects
animal model, pathogenesis, [SDE]Environmental Sciences, Genetics, adaptive mutations, serology, bat coronavirus, Molecular Biology, Biochemistry
Abstract

International audience; Bat sarbecovirus BANAL-236 is highly related to SARS-CoV-2 and infects human cells, albeit lacking the furin cleavage site in its spike protein. BANAL-236 replicates efficiently and pauci-symptomatically in humanized mice and in macaques, where its tropism is enteric, strongly differing from that of SARS-CoV-2. BANAL-236 infection leads to protection against superinfection by a virulent strain. We find no evidence of antibodies recognizing bat sarbecoviruses in populations in close contact with bats in which the virus was identified, indicating that such spillover infections, if they occur, are rare. Six passages in humanized mice or in human intestinal cells, mimicking putative early spillover events, select adaptive mutations without appearance of a furin cleavage site and no change in virulence. Therefore, acquisition of a furin site in the spike protein is likely a pre-spillover event that did not occur upon replication of a SARS-CoV-2-like bat virus in humans or other animals. Other hypotheses regarding the origin of the SARS-CoV-2 should therefore be evaluated, including the presence of sarbecoviruses carrying a spike with a furin cleavage site in bats.

Published
2023

6. The crystal structure of a simian Foamy Virus receptor binding domain provides clues about entry into host cells

Author

Ignacio Fernández, Lasse Toftdal Dynesen, Youna Coquin, Riccardo Pederzoli, Delphine Brun, Ahmed Haouz, Antoine Gessain, Felix A. Rey, Florence Buseyne, Marija Backovic, Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Epidémiologie et Physiopathologie des Virus Oncogènes / Oncogenic Virus Epidemiology and Pathophysiology (EPVO (UMR_3569 / U-Pasteur_3)), Cristallographie (Plateforme) - Crystallography (Platform), This work was funded by the ‘Agence Nationale de la Recherche’ (ANR-10-LABX62-IBEID, Intra-Labex Grant, M.B.), the ‘Programme de recherche transversal from Institut Pasteur’ (PTR2020-353 ZOOFOAMENV, F.B.), and recurrent funding from Institut Pasteur (F.A.R, A.G.), We thank the staff from the Utechs Cytometry & Biomarkers and Crystallography platform at the Institut Pasteur, the synchrotron source SOLEIL (Saint-Aubin, France) for granting access to the facility, and to the staff of Proxima 1 and Proxima 2A beamlines for their kindness and assistance during X-ray data collections. We are grateful to Jan Hellert, Pablo Guardado-Calvo and Philippe Afonso for the discussions and advice, with special thanks to Max Baker for reading the manuscript and English language corrections., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV]Life Sciences [q-bio], General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract

The surface envelope glycoprotein (Env) of all retroviruses mediates virus binding to cells and fusion of the viral and cellular membranes. A structure-function relationship for the HIV Env that belongs to the Orthoretrovirus subfamily has been well established. Structural information is however largely missing for the Env of Foamy viruses (FVs), the second retroviral subfamily. FV Envs lack sequence similarity with their HIV counterpart. We present the X-ray structure of the receptor binding domain (RBD) of a simian FV Env at 2.6 Å resolution, revealing two subdomains and an unprecedented fold. We have generated a model for the organization of the RBDs within the trimeric Env which indicates that the upper subdomain is important for stabilization of the full-length Env, and have demonstrated that residues K342, R343, R359 and R369 in the lower subdomain play key roles in the interaction of the RBD and viral particles with heparan sulfate.

Published
2023

7. Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination

Author

Aurélien Sokal, Paul Bastard, Pascal Chappert, Giovanna Barba-Spaeth, Slim Fourati, Alexis Vanderberghe, Pauline Lagouge-Roussey, Isabelle Meyts, Adrian Gervais, Magali Bouvier-Alias, Imane Azzaoui, Ignacio Fernández, Andréa de la Selle, Qian Zhang, Lucy Bizien, Isabelle Pellier, Agnès Linglart, Anya Rothenbuhler, Estelle Marcoux, Raphael Anxionnat, Nathalie Cheikh, Juliane Léger, Blanca Amador-Borrero, Fanny Fouyssac, Vanessa Menut, Jean-Christophe Goffard, Caroline Storey, Caroline Demily, Coralie Mallebranche, Jesus Troya, Aurora Pujol, Marie Zins, Pierre Tiberghien, Paul E. Gray, Peter McNaughton, Anna Sullivan, Jane Peake, Romain Levy, Laetitia Languille, Carlos Rodiguez-Gallego, Bertrand Boisson, Sébastien Gallien, Bénédicte Neven, Marc Michel, Bertrand Godeau, Laurent Abel, Felix A. Rey, Jean-Claude Weill, Claude-Agnès Reynaud, Stuart G. Tangye, Jean-Laurent Casanova, Matthieu Mahévas, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Rockefeller University [New York], 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), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Henri Mondor [Créteil], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Saclay, Hôpital Nord Franche-Comté [Hôpital de Trévenans] (HNFC), Service de pédiatrie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), AP-HP. Nord - Université Paris Cité, Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nancy (CHU Nancy), Hôpital Mère-Enfant [Hôpital Hôtel Dieu, Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Université libre de Bruxelles (ULB), Hôpital Robert Debré, Centre Hospitalier le Vinatier [Bron], Hospital Universitario Infanta Leonor [Madrid], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Etablissement Français du Sang [La Plaine Saint-Denis] (EFS), Sydney Children's hospital, University of New South Wales [Sydney] (UNSW), Children’s Health Queensland [Brisbane] (CHQ), CHU Necker - Enfants Malades [AP-HP], Universidad Fernando Pessoa Canarias [Las Palmas de Gran Canaria, Spain], Garvan Institute of medical research, Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), Funder(s): Agence Nationale de la Recherche Award Id(s): ANR-21-RHUS-0008, ANR-10-IAHU-01, ANR-10-LABX-62-IBEID , ANR-20-CE93-003Funder(s): Fondation pour la Recherche MédicaleAward Id(s): MEMO-COV-2-FRMFunder(s): Institut PasteurFunder(s): Agence Nationale de Recherches sur le Sida et les Hépatites ViralesFunder(s): Howard Hughes Medical InstituteFunder(s): Rockefeller UniversityFunder(s): St. Giles FoundationFunder(s): National Institutes of Health Award Id(s): R01AI088364, R01AI163029, UL1TR001866Funder(s): National Center for Advancing Translational SciencesFunder(s): Fisher Center for Alzheimer’s Research FoundationFunder(s): Meyer FoundationFunder(s): JPB FoundationFunder(s): French Foundation for Medical Research Award Id(s): EQU201903007798, EA20170638020Funder(s): European Union’s Horizon 2020 Award Id(s): 824110Funder(s): Square FoundationFunder(s): Fondation du SouffleFunder(s): French Ministry of Higher Education, Research, and Innovation Award Id(s): MESRI-COVID-19Funder(s): Institut National de la Santé et de la Recherche MédicaleFunder(s): Fondation Bettencourt SchuellerFunder(s): CSL BehringFunder(s): KU Leuven Award Id(s): C16/18/007Funder(s): http://dx.doi.org/10.13039/501100003130 Award Id(s): G0C8517N, G0B5120N, G0E8420NFunder(s): Jeffrey Modell FoundationFunder(s): National Health and Medical Research Council Award Id(s): 1176665Funder(s): Allergy and Immunology Foundation of AustraliaFunder(s): John Brown Cook FoundationFunder(s): Fondation Princesse GraceFunder(s): Comité ad-hoc de pilotage national des essais thérapeutiques et autres recherchesFunder(s): Assistance Publique—Hôpitaux de Paris Award Id(s): MEMO-COV-2Funder(s): Société Nationale de Médecine InterneFunder(s): ANRS Nord-Sud Award Id(s): ANRS-COV05Funder(s): ANR-RHU Award Id(s): ANR-21-RHUS-08 (COVIFERON)Funder(s): HORIZON-HLTH-2021-DISEASE-04 Award Id(s): 01057100Funder(s): Grandir - Fonds de solidarité pour l’enfanceFunder(s): SCOR Corporate Foundation for ScienceFunder(s): REACTing-INSERMFunder(s): University of Paris CitéFunder(s): Imagine InstituteFunder(s): VIB GC PIDFunder(s): European Research Council Award Id(s): ERC-StG MORE2ADA2, ANR-21-RHUS-0008,COVIFERON,Covid-19 and interferons: from discovery to therapy(2021), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), European Project: 948959,ERC-2020-STG,MORE2ADA2(2021), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and CHU Henri Mondor

Subjects
EXPRESSION, COVID-19 Vaccines, Immunology, VECTOR, Research & Experimental Medicine, Antibodies, Viral, DISEASE, Immunology and Allergy, Humans, PSEUDOURIDINE, Autoantibodies, B-Lymphocytes, Science & Technology, SARS-CoV-2, Vaccination, COVID-19, Antibodies, Neutralizing, Medicine, Research & Experimental, Toll-Like Receptor 7, ANTIBODIES, Spike Glycoprotein, Coronavirus, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, mRNA Vaccines, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Life Sciences & Biomedicine
Abstract

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines. ispartof: JOURNAL OF EXPERIMENTAL MEDICINE vol:220 issue:1 ispartof: location:United States status: published

Published
2023

8. Neutralization of zoonotic retroviruses by human antibodies: Genotype-specific epitopes within the receptor-binding domain from simian foamy virus

Author

Lasse Toftdal Dynesen, Ignacio Fernandez, Youna Coquin, Manon Delaplace, Thomas Montange, Richard Njouom, Chanceline Bilonga-Ndongo, Felix A. Rey, Antoine Gessain, Marija Backovic, Florence Buseyne, Epidémiologie et Physiopathologie des Virus Oncogènes / Oncogenic Virus Epidemiology and Pathophysiology (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Virologie Structurale - Structural Virology, Centre Pasteur du Cameroun, Réseau International des Instituts Pasteur (RIIP), Ministère de la Santé Publique [Yaoundé, Cameroun], This work was supported by the Agence Nationale de la Recherche (ANR-10-LABX62-IBEID, Intra-Labex Grant (MB)), and the Programme de Recherche Transversal from the Institut Pasteur (PTR2020-353 ZOOFOAMENV, FB). SFV protein production was supported by the European Virus Archive-GLOBAL project, which has received funding from the EU Horizon 2020 Research and Innovation Programme (grant agreement number 871029). LTD was supported by the Pasteur-Paris-University (PPU) International Doctoral Program and the Fondation pour la Recherche Médicale, including additional supportive funding from the Danish Pasteur Society, Augustinus Fonden, Knud-Højgaards Fond, and Viet-Jacobsen Fonden., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and European Project: 871029,H2020,H2020-INFRAIA-2019-1,EVA-GLOBAL(2020)

Subjects
[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Virology, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Genetics, Parasitology, Molecular Biology, Microbiology
Abstract

Infection with viruses of animal origin pose a significant threat to human populations. Simian foamy viruses (SFVs) are frequently transmitted to humans, in which they establish a life-long infection, with the persistence of replication-competent virus. However, zoonotic SFVs do not induce severe disease nor are they transmitted between humans. Thus, SFVs represent a model of zoonotic retroviruses that lead to a chronic infection successfully controlled by the human immune system. We previously showed that infected humans develop potent neutralizing antibodies (nAbs). Within the viral envelope (Env), the surface protein (SU) carries a variable region that defines two genotypes, overlaps with the receptor binding domain (RBD), and is the exclusive target of nAbs. However, its antigenic determinants are not understood. Here, we characterized nAbs present in plasma samples from SFV-infected individuals living in Central Africa. Neutralization assays were carried out in the presence of recombinant SU that compete with SU at the surface of viral vector particles. We defined the regions targeted by the nAbs using mutant SU proteins modified at the glycosylation sites, RBD functional subregions, and genotype-specific sequences that present properties of B-cell epitopes. We observed that nAbs target conformational epitopes. We identified three major epitopic regions: the loops at the apex of the RBD, which likely mediate interactions between Env protomers to form Env trimers, a loop located in the vicinity of the heparan binding site, and a region proximal to the highly conserved glycosylation site N8. We provide information on how nAbs specific for each of the two viral genotypes target different epitopes. Two common immune escape mechanisms, sequence variation and glycan shielding, were not observed. We propose a model according to which the neutralization mechanisms rely on the nAbs to block the Env conformational change and/or interfere with binding to susceptible cells. As the SFV RBD is structurally different from known retroviral RBDs, our data provide fundamental knowledge on the structural basis for the inhibition of viruses by nAbs. Trial registration: The study was registered at www.clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT03225794/.

Published
2023

9. Antigenic mapping and functional characterization of human New World hantavirus neutralizing antibodies

Author

Taylor B. Engdahl, Elad Binshtein, Rebecca L. Brocato, Natalia A. Kuzmina, Lucia M Principe, Steven A. Kwilas, Robert K. Kim, Nathaniel S. Chapman, Monique S. Porter, Pablo Guardado-Calvo, Felix A. Rey, Laura S. Handal, Summer M. Diaz, Irene A. Zagol-Ikapitte, Joseph X. Reidy, Andrew Trivette, Alexander Bukreyev, Jay W. Hooper, and James. E. Crowe

Abstract

Hantaviruses are high-priority emerging pathogens carried by rodents and transmitted to humans by aerosolized excreta or, in rare cases, person-to-person contact. While sporadic in North and South America, many infections occur in Europe and Asia, with mortality ranging from 1 to 40% depending on the hantavirus species. There are currently no FDA-approved vaccines or therapeutics for hantaviruses, and the only treatment for infection is supportive care for respiratory or kidney failure. Additionally, the humoral immune response to hantavirus infection is incompletely understood, especially the location of major antigenic sites on the viral glycoproteins and conserved neutralizing epitopes. Here, we report antigenic mapping and functional characterization for four neutralizing hantavirus antibodies. The broadly neutralizing antibody SNV-53 targets an interface between Gn/Gc, neutralizes through fusion inhibition and cross-protects against the Old World hantavirus species Hantaan virus when administered pre- or post-exposure. Another broad antibody, SNV-24, also neutralizes through fusion inhibition but targets domain I of Gc and demonstrates weak neutralizing activity across hantavirus species. ANDV-specific, neutralizing antibodies (ANDV-5 and ANDV-34) neutralize through attachment blocking and protect against hantavirus cardiopulmonary syndrome (HCPS) in animals but target two different antigenic faces on the head domain of Gn. Determining the antigenic sites for neutralizing antibodies will contribute to further therapeutic development for hantavirus-related diseases and inform the design of new broadly protective hantavirus vaccines.

Published
2022

10. Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses

Author

Eva Mittler, Anna Z. Wec, Janne Tynell, Pablo Guardado-Calvo, Julia Wigren-Byström, Laura C. Polanco, Cecilia M. O’Brien, Megan M. Slough, Dafna M. Abelson, Alexandra Serris, Mrunal Sakharkar, Gerard Pehau-Arnaudet, Russell R. Bakken, James C. Geoghegan, Rohit K. Jangra, Markus Keller, Larry Zeitlin, Olli Vapalahti, Rainer G. Ulrich, Zachary A. Bornholdt, Clas Ahlm, Felix A. Rey, John M. Dye, Steven B. Bradfute, Tomas Strandin, Andrew S. Herbert, Mattias N. E. Forsell, Laura M. Walker, Kartik Chandran, Albert Einstein College of Medicine [New York], Adimab [Lebanon], Umeå University, Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Mapp Biopharmaceutical Inc., Institute of Novel and Emerging Infectious Diseases (INNT), Friedrich-Loeffler-Institut (FLI), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The University of New Mexico [Albuquerque], This research was supported by NIAID of the NIH under award number U19AI142777 (Centers of Excellence in Translational Research) to K.C., L.M.W., J.M.D., Z.A.B., A.S.H., S.B.B., M.N.E.F., and L.Z. M.N.E.F. was supported by a Consolidator grant from the Swedish Science Council (#2020-06235). C.A. was supported by a Cutting Edge Research Grant from Region Västerbotten (VLL-579011). T.S. was supported by the Academy of Finland (#321809). P.G.-C. was supported by a grant of the National French Research Agency (ANR-18-CE11-0011). A.S. was supported by a fellowship of the French Foundation pour la Recherche Médicale (FRM, fellowship FDM20170638040). F.A.R. and P.G.-C. were supported by Labex IBEID (ANR-10-LABX-62-IBEID). R.G.U. was supported by the Bundesministerium für Bildung und Forschung (BMBF) within the Research Network Zoonotic Infectious Diseases (01KI1721A and 01KI2004A)., ANR-18-CE11-0011,LISEFU,Base structurale de la détection des lipides dans la fusion virale(2018), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Orthohantavirus, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Hantavirus Infections, virus diseases, General Medicine, Antibodies, Viral, Antibodies, Neutralizing, Puumala virus, Article, Epitopes, Cricetinae, Hemorrhagic Fever with Renal Syndrome, Animals, Humans, Glycoproteins
Abstract

International audience; The rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have substantial case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the “capping loop” of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines.

Published
2022

11. Structural basis of synergistic neutralization of Crimean-Congo hemorrhagic fever virus by human antibodies

Author

Akaash K. Mishra, Jan Hellert, Natalia Freitas, Pablo Guardado-Calvo, Ahmed Haouz, J. Maximilian Fels, Daniel P. Maurer, Dafna M. Abelson, Zachary A. Bornholdt, Laura M. Walker, Kartik Chandran, François-Loïc Cosset, Jason S. McLellan, Felix A. Rey, University of Texas at Austin [Austin], Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), Cristallographie (Plateforme) - Crystallography (Platform), Albert Einstein College of Medicine [New York], Adimab LLC, Mapp Biopharmaceutical Inc., This work was supported by National Institutes of Health award U19 AI142777 to J.S.M., Z.A.B., K.C., and L.M.W., as well as by Institut Pasteur, CNRS and grant ANR-10-LABX-62-10 IBEID to F.A.R. and by the LabEx Ecofect (ANR-11-LABX-0048) of the 'Université de Lyon,' within the program 'Investissements d’Avenir' (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR), to F.-L.C. Research was funded in part by Welch Foundation grant F-0003-19620604 awarded to J.S.M. The Pasteur-Cantarini 24-month fellowship was granted to J.H., who was further supported by the Région Ile de France (Domaine d’intérêt majeur - innovative technologies for life sciences, DIM 1HEALTH)., ANR-11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-11-IDEX-0007,Avenir L.S.E.,PROJET AVENIR LYON SAINT-ETIENNE(2011), 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), Ribierre, Hélène, Dynamiques eco-évolutives des maladies infectieuses - - ECOFECT2011 - ANR-11-LABX-0048 - LABX - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, and PROJET AVENIR LYON SAINT-ETIENNE - - Avenir L.S.E.2011 - ANR-11-IDEX-0007 - IDEX - VALID

Subjects
Models, Molecular, Protein Folding, Multidisciplinary, Protein Conformation, [SDV]Life Sciences [q-bio], Virus Internalization, Antibodies, Viral, Crystallography, X-Ray, Antibodies, Neutralizing, Article, [SDV] Life Sciences [q-bio], Epitopes, Immunoglobulin Fab Fragments, Protein Domains, Neutralization Tests, Hemorrhagic Fever Virus, Crimean-Congo, Humans, Protein Multimerization, Viral Fusion Proteins, Protein Binding
Abstract

International audience; Crimean-Congo hemorrhagic fever virus (CCHFV) is the most widespread tick-borne zoonotic virus, with a 30% case fatality rate in humans. Structural information is lacking in regard to the CCHFV membrane fusion glycoprotein Gc-the main target of the host neutralizing antibody response-as well as antibody-mediated neutralization mechanisms. We describe the structure of prefusion Gc bound to the antigen-binding fragments (Fabs) of two neutralizing antibodies that display synergy when combined, as well as the structure of trimeric, postfusion Gc. The structures show the two Fabs acting in concert to block membrane fusion, with one targeting the fusion loops and the other blocking Gc trimer formation. The structures also revealed the neutralization mechanism of previously reported antibodies against CCHFV, providing the molecular underpinnings essential for developing CCHFVspecific medical countermeasures for epidemic preparedness.

Published
2022

13. Immunization with GP1 but Not Core-like Particles Displaying Isolated Receptor-Binding Epitopes Elicits Virus-Neutralizing Antibodies against Junín Virus

Author

Gleyder Roman-Sosa, Anne Leske, Xenia Ficht, Tung Huy Dau, Julia Holzerland, Thomas Hoenen, Martin Beer, Robert Kammerer, Reinhold Schirmbeck, Felix A. Rey, Sandra M. Cordo, and Allison Groseth

Subjects
Pharmacology, Infectious Diseases, Drug Discovery, Immunology, Pharmacology (medical), arenavirus, Junín virus, immune response, neutralizing antibodies, glycoprotein, GP1
Abstract

New World arenaviruses are rodent-transmitted viruses and include a number of pathogens that are responsible for causing severe human disease. This includes Junín virus (JUNV), which is the causative agent of Argentine hemorrhagic fever. The wild nature and mobility of the rodent reservoir host makes it difficult to control the disease, and currently passive immunization with high-titer neutralizing antibody-containing plasma from convalescent patients is the only specific therapy. However, dwindling supplies of naturally available convalescent plasma, and challenges in developing similar resources for other closely related viruses, have made the development of alternative antibody-based therapeutic approaches of critical importance. In this study, we sought to induce a neutralizing antibody response in rabbits against the receptor-binding subunit of the viral glycoprotein, GP1, and the specific peptide sequences in GP1 involved in cellular receptor contacts. While these specific receptor-interacting peptides did not efficiently induce the production of neutralizing antibodies when delivered as a particulate antigen (as part of hepatitis B virus core-like particles), we showed that recombinant JUNV GP1 purified from transfected mammalian cells induced virus-neutralizing antibodies at high titers in rabbits. Further, neutralization was observed across a range of unrelated JUNV strains, a feature that is critical for effectiveness in the field. These results underscore the potential of GP1 alone to induce a potent neutralizing antibody response and highlight the importance of epitope presentation. In addition, effective virus neutralization by rabbit antibodies supports the potential applicability of this species for the future development of immunotherapeutics (e.g., based on humanized monoclonal antibodies). Such information can be applied in the design of vaccines and immunogens for both prevention and specific therapies against this and likely also other closely related pathogenic New World arenaviruses.

Published
2021

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