A Combination of Human Broadly Neutralizing Antibodies against Hepatitis B Virus HBsAg with Distinct Epitopes Suppresses Escape Mutations.
Animals
Antibodies, Monoclonal
/ immunology
Broadly Neutralizing Antibodies
/ immunology
Cell Line, Tumor
Child, Preschool
Disease Models, Animal
Epitopes
/ immunology
Female
HEK293 Cells
Hep G2 Cells
Hepatitis B Antibodies
/ immunology
Hepatitis B Surface Antigens
/ immunology
Hepatitis B virus
/ immunology
Hepatitis B, Chronic
/ drug therapy
Humans
Infant
Mice
Mice, Knockout
Protein Conformation
Hepatitis B infection
broadly neutralizing antibodies
crystal structure
elite neutralizing activity
escape mutations
humanized mice
passive immunotherapy
prophylaxis
Journal
Cell host & microbe
ISSN: 1934-6069
Titre abrégé: Cell Host Microbe
Pays: United States
ID NLM: 101302316
Informations de publication
Date de publication:
12 08 2020
12 08 2020
Historique:
received:
26
01
2020
revised:
09
03
2020
accepted:
08
05
2020
pubmed:
7
6
2020
medline:
13
5
2021
entrez:
7
6
2020
Statut:
ppublish
Résumé
Although there is no effective cure for chronic hepatitis B virus (HBV) infection, antibodies are protective and correlate with recovery from infection. To examine the human antibody response to HBV, we screened 124 vaccinated and 20 infected, spontaneously recovered individuals. The selected individuals produced shared clones of broadly neutralizing antibodies (bNAbs) that targeted 3 non-overlapping epitopes on the HBV S antigen (HBsAg). Single bNAbs protected humanized mice against infection but selected for resistance mutations in mice with prior established infection. In contrast, infection was controlled by a combination of bNAbs targeting non-overlapping epitopes with complementary sensitivity to mutations that commonly emerge during human infection. The co-crystal structure of one of the bNAbs with an HBsAg peptide epitope revealed a stabilized hairpin loop. This structure, which contains residues frequently mutated in clinical immune escape variants, provides a molecular explanation for why immunotherapy for HBV infection may require combinations of complementary bNAbs.
Identifiants
pubmed: 32504577
pii: S1931-3128(20)30292-4
doi: 10.1016/j.chom.2020.05.010
pmc: PMC8182833
mid: NIHMS1693407
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Broadly Neutralizing Antibodies
0
Epitopes
0
Hepatitis B Antibodies
0
Hepatitis B Surface Antigens
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
335-349.e6Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001866
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK085713
Pays : United States
Organisme : NIH HHS
ID : S10 OD021527
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027037
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK107164
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI111825
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK090576
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI143295
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests Q.W. and M.C.N. have a provisional patent application with the U.S. Patent and Trademark Office (62898735). Other authors have no conflicts of interest to declare.
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