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A critical HA1 neutralizing domain of H5N1 influenza in an optimal conformation induces strong cross-protection.

Du L, Zhao G, Sun S, Zhang X, Zhou X, Guo Y, Li Y, Zhou Y, Jiang S - PLoS ONE (2013)

Bottom Line: Consequently, the design of an effective and safe anti-H5N1 vaccine is essential.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.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.

View Article: PubMed Central - PubMed

Affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.

ABSTRACT
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.

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Comparison of viral titers in virus-challenged lung tissues of mice vaccinated with HA-13–263 proteins.Viral titers of VN/1194 (clade 1) and SZ/406H (clade 2.3.4) H5N1 viruses were determined in the lung tissues of the mice vaccinated with HA-13–263 proteins, respectively, collected on 5 day post-challenge. Mice injected with PBS were used as the negative control. * indicates significant difference (P<0.05), respectively, between HA-13–263-Fdc, HA-13–263-Fc, or HA-13–263-Fd-His vaccination groups and HA-13–263-His or PBS control group. The data are expressed as mean ± SD of viral titers 50% tissue culture infective dose (Log10TCID50/g) of lung tissues from five mice per group. The limit of detection is 1.5 Log10TCID50/g of tissues.
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pone-0053568-g009: Comparison of viral titers in virus-challenged lung tissues of mice vaccinated with HA-13–263 proteins.Viral titers of VN/1194 (clade 1) and SZ/406H (clade 2.3.4) H5N1 viruses were determined in the lung tissues of the mice vaccinated with HA-13–263 proteins, respectively, collected on 5 day post-challenge. Mice injected with PBS were used as the negative control. * indicates significant difference (P<0.05), respectively, between HA-13–263-Fdc, HA-13–263-Fc, or HA-13–263-Fd-His vaccination groups and HA-13–263-His or PBS control group. The data are expressed as mean ± SD of viral titers 50% tissue culture infective dose (Log10TCID50/g) of lung tissues from five mice per group. The limit of detection is 1.5 Log10TCID50/g of tissues.

Mentions: The cross-protective effect induced by HA-13–263 proteins fused with or without Fd and/or Fc was further evaluated by detection of viral titers in the lung tissues of vaccinated mice challenged with H5N1 virus. As shown in Fig. 9, a significantly lower level of virus titers was detected in the mice vaccinated with HA-13–263-Fdc, HA-13–263-Fc and HA-13–263-Fd-His proteins than those vaccinated with HA-13–263-His protein after challenge with both VN/1194 and SZ/406H viruses (P<0.05). However, virus titer in the PBS control group was still significantly higher than that of the HA-13–263-His vaccination group. These results suggested that the HA-13–263 proteins with suitable polymeric conformation after the addition of Fd and/or Fc can induce strong cross-protection against divergent H5N1 virus challenge.


A critical HA1 neutralizing domain of H5N1 influenza in an optimal conformation induces strong cross-protection.

Du L, Zhao G, Sun S, Zhang X, Zhou X, Guo Y, Li Y, Zhou Y, Jiang S - PLoS ONE (2013)

Comparison of viral titers in virus-challenged lung tissues of mice vaccinated with HA-13–263 proteins.Viral titers of VN/1194 (clade 1) and SZ/406H (clade 2.3.4) H5N1 viruses were determined in the lung tissues of the mice vaccinated with HA-13–263 proteins, respectively, collected on 5 day post-challenge. Mice injected with PBS were used as the negative control. * indicates significant difference (P<0.05), respectively, between HA-13–263-Fdc, HA-13–263-Fc, or HA-13–263-Fd-His vaccination groups and HA-13–263-His or PBS control group. The data are expressed as mean ± SD of viral titers 50% tissue culture infective dose (Log10TCID50/g) of lung tissues from five mice per group. The limit of detection is 1.5 Log10TCID50/g of tissues.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3539987&req=5

pone-0053568-g009: Comparison of viral titers in virus-challenged lung tissues of mice vaccinated with HA-13–263 proteins.Viral titers of VN/1194 (clade 1) and SZ/406H (clade 2.3.4) H5N1 viruses were determined in the lung tissues of the mice vaccinated with HA-13–263 proteins, respectively, collected on 5 day post-challenge. Mice injected with PBS were used as the negative control. * indicates significant difference (P<0.05), respectively, between HA-13–263-Fdc, HA-13–263-Fc, or HA-13–263-Fd-His vaccination groups and HA-13–263-His or PBS control group. The data are expressed as mean ± SD of viral titers 50% tissue culture infective dose (Log10TCID50/g) of lung tissues from five mice per group. The limit of detection is 1.5 Log10TCID50/g of tissues.
Mentions: The cross-protective effect induced by HA-13–263 proteins fused with or without Fd and/or Fc was further evaluated by detection of viral titers in the lung tissues of vaccinated mice challenged with H5N1 virus. As shown in Fig. 9, a significantly lower level of virus titers was detected in the mice vaccinated with HA-13–263-Fdc, HA-13–263-Fc and HA-13–263-Fd-His proteins than those vaccinated with HA-13–263-His protein after challenge with both VN/1194 and SZ/406H viruses (P<0.05). However, virus titer in the PBS control group was still significantly higher than that of the HA-13–263-His vaccination group. These results suggested that the HA-13–263 proteins with suitable polymeric conformation after the addition of Fd and/or Fc can induce strong cross-protection against divergent H5N1 virus challenge.

Bottom Line: Consequently, the design of an effective and safe anti-H5N1 vaccine is essential.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.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.

View Article: PubMed Central - PubMed

Affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus