A Critical HA1 Neutralizing Domain of H5N1 Influenza in an Optimal Conformation Induces Strong Cross-Protection

A Critical HA1 Neutralizing Domain of H5N1 Influenza in an Optimal Conformation Induces Strong Cross-Protection

The highly pathogenic avian influenza (HPAI) H5N1 viruses, especially the laboratory-generated H5N1 mutants, have demonstrated the potential to cross the species barrier and infect mammals and humans. Consequently, the design of an effective and safe anti-H5N1 vaccine is essential. We previously dem...

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Main Authors: Du, Lanying, Zhao, Guangyu, Sun, Shihui, Zhang, Xiujuan, Zhou, Xiaojun, Guo, Yan, Li, Ye, Zhou, Yusen, Jiang, Shibo
Format: Online
Language:English
Published: Public Library of Science 2013
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539987/
id pubmed-3539987
recordtype oai_dc
spelling pubmed-35399872013-01-14 A Critical HA1 Neutralizing Domain of H5N1 Influenza in an Optimal Conformation Induces Strong Cross-Protection Du, Lanying Zhao, Guangyu Sun, Shihui Zhang, Xiujuan Zhou, Xiaojun Guo, Yan Li, Ye Zhou, Yusen Jiang, Shibo Research Article The highly pathogenic avian influenza (HPAI) H5N1 viruses, especially the laboratory-generated H5N1 mutants, have demonstrated the potential to cross the species barrier and infect mammals and humans. Consequently, the design of an effective and safe anti-H5N1 vaccine is essential. We previously demonstrated that the full-length hemagglutinin 1 (HA1) could induce significant neutralizing antibody response and protection. Here, we intended to identify the critical neutralizing domain (CND) in an optimal conformation that can elicit strong cross-neutralizing antibodies and protection against divergent H5N1 strains. We thus constructed six recombinant proteins covering different regions of HA1 of A/Anhui/1/2005(H5N1), each of which was fused with foldon (Fd) and Fc of human IgG. We found that the critical fragment fused with Fd/Fc (HA-13–263-Fdc, H5 numbering) that could elicit the strongest neutralizing antibody response is located in the N-terminal region of HA1 (residues 13–263), which covers the receptor-binding domain (RBD, residues 112–263). We then constructed three additional recombinants fused with Fd plus His tag (HA-13–263-Fd-His), Fc only (HA-13–263-Fc), and His tag only (HA-13–263-His), respectively. We found that the HA-13–263-Fdc, which formed an oligomeric conformation, induced the strongest neutralizing antibody response and cross-protection against challenges of two tested H5N1 virus strains covering clade 1: A/VietNam/1194/2004 (VN/1194) or clade 2.3.4: A/Shenzhen/406H/06 (SZ/406H), while HA-13–263-Fc dimer and HA-13–263-Fd-His trimer elicited higher neutralizing antibody response and protection than HA-13–263-His monomer. These results suggest that the oligomeric form of the CND containing the RBD can be further developed as an effective and safe vaccine for cross-protection against divergent strains of H5N1 viruses. Public Library of Science 2013-01-08 /pmc/articles/PMC3539987/ /pubmed/23320093 http://dx.doi.org/10.1371/journal.pone.0053568 Text en © 2013 Du et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Du, Lanying
Zhao, Guangyu
Sun, Shihui
Zhang, Xiujuan
Zhou, Xiaojun
Guo, Yan
Li, Ye
Zhou, Yusen
Jiang, Shibo
spellingShingle Du, Lanying
Zhao, Guangyu
Sun, Shihui
Zhang, Xiujuan
Zhou, Xiaojun
Guo, Yan
Li, Ye
Zhou, Yusen
Jiang, Shibo
A Critical HA1 Neutralizing Domain of H5N1 Influenza in an Optimal Conformation Induces Strong Cross-Protection
author_facet Du, Lanying
Zhao, Guangyu
Sun, Shihui
Zhang, Xiujuan
Zhou, Xiaojun
Guo, Yan
Li, Ye
Zhou, Yusen
Jiang, Shibo
author_sort Du, Lanying
title A Critical HA1 Neutralizing Domain of H5N1 Influenza in an Optimal Conformation Induces Strong Cross-Protection
title_short A Critical HA1 Neutralizing Domain of H5N1 Influenza in an Optimal Conformation Induces Strong Cross-Protection
title_full A Critical HA1 Neutralizing Domain of H5N1 Influenza in an Optimal Conformation Induces Strong Cross-Protection
title_fullStr A Critical HA1 Neutralizing Domain of H5N1 Influenza in an Optimal Conformation Induces Strong Cross-Protection
title_full_unstemmed A Critical HA1 Neutralizing Domain of H5N1 Influenza in an Optimal Conformation Induces Strong Cross-Protection
title_sort critical ha1 neutralizing domain of h5n1 influenza in an optimal conformation induces strong cross-protection
description The highly pathogenic avian influenza (HPAI) H5N1 viruses, especially the laboratory-generated H5N1 mutants, have demonstrated the potential to cross the species barrier and infect mammals and humans. Consequently, the design of an effective and safe anti-H5N1 vaccine is essential. We previously demonstrated that the full-length hemagglutinin 1 (HA1) could induce significant neutralizing antibody response and protection. Here, we intended to identify the critical neutralizing domain (CND) in an optimal conformation that can elicit strong cross-neutralizing antibodies and protection against divergent H5N1 strains. We thus constructed six recombinant proteins covering different regions of HA1 of A/Anhui/1/2005(H5N1), each of which was fused with foldon (Fd) and Fc of human IgG. We found that the critical fragment fused with Fd/Fc (HA-13–263-Fdc, H5 numbering) that could elicit the strongest neutralizing antibody response is located in the N-terminal region of HA1 (residues 13–263), which covers the receptor-binding domain (RBD, residues 112–263). We then constructed three additional recombinants fused with Fd plus His tag (HA-13–263-Fd-His), Fc only (HA-13–263-Fc), and His tag only (HA-13–263-His), respectively. We found that the HA-13–263-Fdc, which formed an oligomeric conformation, induced the strongest neutralizing antibody response and cross-protection against challenges of two tested H5N1 virus strains covering clade 1: A/VietNam/1194/2004 (VN/1194) or clade 2.3.4: A/Shenzhen/406H/06 (SZ/406H), while HA-13–263-Fc dimer and HA-13–263-Fd-His trimer elicited higher neutralizing antibody response and protection than HA-13–263-His monomer. These results suggest that the oligomeric form of the CND containing the RBD can be further developed as an effective and safe vaccine for cross-protection against divergent strains of H5N1 viruses.
publisher Public Library of Science
publishDate 2013
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539987/
_version_ 1611945399358062592

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