Potent human broadly neutralizing antibodies to hepatitis B virus from natural controllers

Rare individuals can naturally clear chronic hepatitis B virus (HBV) infection and acquire protection from reinfection as conferred by vaccination. To examine the protective humoral response against HBV, we cloned and characterized human antibodies specific to the viral surface glycoproteins (HBsAg) from memory B cells of HBV vaccinees and controllers. We found that human HBV antibodies are encoded by a diverse set of immunoglobulin genes and recognize various conformational HBsAg epitopes. Strikingly, HBsAg-specific memory B cells from natural controllers mainly produced neutralizing antibodies able to cross-react with several viral genotypes. Furthermore, monotherapy with the potent broadly neutralizing antibody Bc1.187 suppressed viremia in vivo in HBV mouse models and led to post-therapy control of the infection in a fraction of animals. Thus, human neutralizing HBsAg antibodies appear to play a key role in the spontaneous control of HBV and represent promising immunotherapeutic tools for achieving HBV functional cure in chronically infected humans.

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Immunotherapy Vaccinology

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Submission Type	File
Deposit type	Journal articles
Title	en Potent human broadly neutralizing antibodies to hepatitis B virus from natural controllers
Abstract	en Rare individuals can naturally clear chronic hepatitis B virus (HBV) infection and acquire protection from reinfection as conferred by vaccination. To examine the protective humoral response against HBV, we cloned and characterized human antibodies specific to the viral surface glycoproteins (HBsAg) from memory B cells of HBV vaccinees and controllers. We found that human HBV antibodies are encoded by a diverse set of immunoglobulin genes and recognize various conformational HBsAg epitopes. Strikingly, HBsAg-specific memory B cells from natural controllers mainly produced neutralizing antibodies able to cross-react with several viral genotypes. Furthermore, monotherapy with the potent broadly neutralizing antibody Bc1.187 suppressed viremia in vivo in HBV mouse models and led to post-therapy control of the infection in a fraction of animals. Thus, human neutralizing HBsAg antibodies appear to play a key role in the spontaneous control of HBV and represent promising immunotherapeutic tools for achieving HBV functional cure in chronically infected humans.
Authors	Verena Hehle ¹ , Maxime Beretta ¹ , M Bourgine ² , Malika Ait-Goughoulte ³ , Cyril Planchais ¹ , Solen Morisse ² , Benjamin Vesin ² , Valérie Lorin ¹ , Thierry Hieu ¹ , Andrea Stauffer ³ , Oriane Fiquet ⁴ , Jordan D. Dimitrov ⁵ , Marie-Louise Michel ⁶ , Marie-Noëlle Ungeheuer ⁷ , Camille Sureau ⁸ , Stanislas Pol ⁹ , James P. Di Santo ⁴ , Hélène Strick-Marchand ⁴ , Nadège Pelletier ³ , Hugo Mouquet ¹ 1 Immunologie humorale - Humoral Immunology ( 565896 ) - Département d'Immunologie 25-28, rue du Docteur Roux 75724 Paris cedex 15 - France Institut Pasteur [Paris] ( 300027 ) ; Institut National de la Santé et de la Recherche Médicale U1222 ( 303623 ) 2 Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology ( 1055613 ) - Département de Virologie 25-28, rue du Docteur Roux 75724 Paris Cedex 15 - France Institut Pasteur [Paris] ( 300027 ) 3 F. Hoffmann-La Roche [Basel] ( 322997 ) - F. Hoffmann-La Roche Ltd. Headquarter Grenzacherstrasse 124 CH-4070 Basel - Switzerland 4 Immunité Innée - Innate Immunity ( 130822 ) - Département d'Immunologie, 25-28 rue du Docteur Roux, 75724 Paris Cedex 15 - France Institut Pasteur [Paris] ( 300027 ) ; Institut National de la Santé et de la Recherche Médicale U1223 ( 303623 ) 5 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers ( 1004777 ) - 15 rue de l'Ecole de Médecine - Bâtiment B - 75270 Paris Cedex 06 - France École Pratique des Hautes Études ( 110691 ) ; Université Paris Sciences et Lettres ( 564132 ) ; Institut National de la Santé et de la Recherche Médicale U1138 ( 303623 ) ; Sorbonne Université ( 413221 ) ; Université Paris Cité UMR_S_1138 ( 557826 ) 6 IP - Institut Pasteur [Paris] ( 300027 ) - 25-28, rue du docteur Roux, 75724 Paris cedex 15 - France 7 ICAReB - Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources ( 411827 ) - Centre de Recherche Translationnelle - 25-28, rue du Docteur Roux - 75724 Paris Cedex 15 - France Institut Pasteur [Paris] ( 300027 ) 8 BIGR (UMR_S_1134 / U1134) - Biologie Intégrée du Globule Rouge ( 1005032 ) - 6 rue Alexandre Cabanel - 75739 Paris cedex 15 - France Institut National de la Transfusion Sanguine [Paris] ( 266750 ) ; Université de La Réunion ( 300316 ) ; Institut National de la Santé et de la Recherche Médicale U1134 ( 303623 ) ; CHU Pointe-à-Pitre/Abymes [Guadeloupe] ( 328176 ) ; Université des Antilles ( 524399 ) ; Université Paris Cité UMR_S_1134 ( 557826 ) 9 CRT - Centre de Recherche Translationnelle - Center for Translational Science ( 463040 ) - 25-28 rue du docteur Roux, 75724 Paris cedex 15 - France Institut Pasteur [Paris] ( 300027 )
Fulltext language	English
Journal	J Exp Med - Journal of Experimental Medicine (ISSN : 0022-1007, Electronic ISSN : 1540-9538) Published by Rockefeller University Press
Science popularization	No
Peer-reviewed	Yes
Audience	International
Volume	217
Number	10
Licence	Attribution - NonCommercial - ShareAlike
Publication date	2020-06-24
Page number	e20200840
Domain	Life Sciences [q-bio]/Immunology/Immunotherapy Life Sciences [q-bio]/Immunology/Vaccinology
Project/Collaboration	We are grateful to members of the Center for Translational Sciences (Institut Pasteur), Cassandre Von Platen (Clinical core) for the preparation of the RAPIVIB protocol, and Gloria Morizot (Investigation Clinique et Accès aux Ressources Biologiques) for collecting biological samples and associated personal data. We also thank Sandrine Schmutz, Sophie Novault (UTechS CB, Center for Translational Sciences, Institut Pasteur), and Ayrin Kök for their technical help with single cell sorting, and Dr. J. Aguilar (Center for Genetic Engineering and Biotechnology, Havana, Cuba) for providing us with the purified adw HBsAg particles.
ANR project(s)	GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE [For more information] MILIEU INTERIEUR - ANR-10-LABX-0069 LABX - 2010
European project(s)	HUMANTIVIRUSES - Human Antibody Responses to Viruses CORDIS number : 337146
Contract, financing	H. Mouquet received core grants from the G5 Institut Pasteur Program, the Milieu Intérieur Program (ANR-10-LABX-69-01) and INSERM. This work was funded by Institut Roche. V. Hehle and M. Beretta were supported by postdoctoral fellowships from Roche. V. Hehle and T. Hieu were also supported by the European Research Council–Seventh Framework Program (ERC-2013-StG 337146). H. Strick-Marchand was supported by the Institut Pasteur and Agence Nationale de Recherches sur le Sida et les Hépatites Virales (2016-16365, 2019-19241).
Mesh thesaurus	Animals Antibodies, Neutralizing Enzyme-Linked Immunosorbent Assay Epitopes Flow Cytometry Hepatitis B Hepatitis B Surface Antigens Hepatitis B Vaccines Hepatitis B virus Hepatitis B, Chronic Humans Immunologic Memory Mice Neutralization Tests B-Lymphocytes Cross Reactions
DOI	10.1084/jem.20200840
PubMed	32579155
PubMed Central	PMC7537403

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Submitted on: Monday, May 31, 2021 at 11:43:06 AM

Last modification on: Friday, April 19, 2024 at 4:18:59 PM

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pasteur-03242779, version 1 (31-05-2021)

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Attribution - NonCommercial - ShareAlike - CC BY 4.0

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HAL Id : pasteur-03242779 , version 1
DOI : 10.1084/jem.20200840
PUBMED : 32579155
PUBMEDCENTRAL : PMC7537403

Cite

Verena Hehle, Maxime Beretta, M Bourgine, Malika Ait-Goughoulte, Cyril Planchais, et al.. Potent human broadly neutralizing antibodies to hepatitis B virus from natural controllers. Journal of Experimental Medicine, 2020, 217 (10), pp.e20200840. ⟨10.1084/jem.20200840⟩. ⟨pasteur-03242779⟩

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