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Intranasal vaccination of recombinant H5N1 HA1 proteins fused with foldon and Fc induces strong mucosal immune responses with neutralizing activity: Implication for developing novel mucosal influenza vaccines.

ABSTRACT: The highly pathogenic avian influenza (HPAI) H5N1 virus remains a threat to public health because of its continued spread in poultry in some countries and its ability to infect humans with high mortality rate, calling for the development of effective and safe vaccines against H5N1 infection. Here, we constructed 4 candidate vaccines by fusing H5N1 hemagglutinin 1 (HA1) with foldon (HA1-Fd), human IgG Fc (HA1-Fc), foldon and Fc (HA1-FdFc) or His-tag (HA1-His). We then compared their ability to induce mucosal immune responses and neutralizing antibodies in the presence or absence of Poly(I:C) and CpG adjuvants via the intranasal route. Without an adjuvant, HA1-FdFc could elicit appreciable humoral immune responses and local mucosal IgA antibodies in immunized mice, while other vaccine candidates only induced background immune responses. In the presence of Poly(I:C) and CpG, both HA1-Fd and HA1-Fc elicited much higher levels of serum IgG and local mucosal IgA antibodies than HA1-His. Poly(I:C) and CpG could also augment the neutralizing antibody responses induced by these 4 vaccine candidates in the order of HA1-FdFc > HA1-Fc > HA1-Fd > HA1-His. These results suggest that both Fd and Fc potentiate the immunogenicity of the recombinant HA1 protein and that Poly(I:C) and CpG serve as efficient mucosal adjuvants in promoting efficacy of these vaccine candidates to induce strong systemic and local antibody responses and potent neutralizing antibodies, providing a useful strategy to develop effective and safe mucosal H5N1 vaccines.

SUBMITTER: Yu F

PROVIDER: S-EPMC5054784 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Intranasal vaccination of recombinant H5N1 HA1 proteins fused with foldon and Fc induces strong mucosal immune responses with neutralizing activity: Implication for developing novel mucosal influenza vaccines.

Yu Fei F Li Ye Y Guo Yan Y Wang Lili L Yang Jie J Zhao Guangyu G Zhou Yusen Y Du Lanying L Jiang Shibo S

Human vaccines & immunotherapeutics 20150101 12

The highly pathogenic avian influenza (HPAI) H5N1 virus remains a threat to public health because of its continued spread in poultry in some countries and its ability to infect humans with high mortality rate, calling for the development of effective and safe vaccines against H5N1 infection. Here, we constructed 4 candidate vaccines by fusing H5N1 hemagglutinin 1 (HA1) with foldon (HA1-Fd), human IgG Fc (HA1-Fc), foldon and Fc (HA1-FdFc) or His-tag (HA1-His). We then compared their ability to in ...[more]

PMID: 26260706

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Project description:Sudden increases in the number of human A (H7N9) cases reported during December and January have been observed in previous years. Most reported infection cases are due to prior exposure to live poultry or potentially contaminated environments. Low pathogenicity of influenza A (H7N9) virus in avian species complicates timely discovery of infected birds. Therefore, there is a pressing need to develop safe and effective anti-H7N9 vaccines for poultry to reduce the risk of human infection and prevent the emergence of novel mutated strains. In addition to a good antigen, an effective vaccine also requires an appropriate adjuvant to enhance its immunogenicity. Previously, we generated an H7N9 influenza recombinant subunit vaccine (HA1-2-fliC), in which haemagglutinin globular head domain (HA1-2) was fused with flagellin (fliC), a potent TLR5 ligand, and demonstrated that HA1-2-fliC elicited effective HA1-2-specific immune responses in mice.In this study, we determined flagellin-induced expression profiles of cytokines and chemokines in different types of avian immune cells in vitro and ex vivo. We found that flagellin significantly increased the expression levels of CXCL inflammatory chemokines (CXCLi1 and CXCLi2) and CCL chemokines (MIP-1? and MCP-3) in avian macrophage HD11 cells. In addition, HA1-2-fliC induced significant upregulation of cytokines (IL-1?, IL-6, IL-18 and IFN-?) and chemokines (CXCLi1, CXCLi2 and MIP-1?) in ex vivo splenic lymphocytes and peripheral blood mononuclear cells (PBMCs), suggesting that flagellin promoted immune responses of avian cells in vitro. We also evaluated specific humoural and cellular immune responses induced by HA1-2-fliC and found that chickens immunised intramuscularly with HA1-2-fliC showed significantly higher HA1-2-specific immunoglobulin (Ig)G titers in serum. Furthermore, HA1-2-fliC potentiated cellular immune responses, as reflected by an increase in CD4+ and CD8+ T cells and proliferation of PBMCs. Significantly higher levels of IFN-? and IL-4 in PBMCs from chickens vaccinated with HA1-2-fliC further indicated that HA1-2-fliC promoted a balanced Th1/Th2 immune response.We demonstrated that the use of the flagellin as an adjuvant potentiated immunogenicity of influenza subunit vaccine HA1-2 in vitro and in vivo. These findings provide a basis for the development of H7N9 influenza HA1-2 subunit vaccines for chickens.

Project description:We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI) intratracheal and intranasal challenge in a ferret model. Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments) or intranasally (CSN adjuvanted and placebo treatments only) with clade 1 HPAI A/Vietnam/1194/2004 (H5N1) virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings. In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratracheal challenge; serologically, protective titres were demonstrable after one vaccination. The 2-dose schedule with TM-CSN vaccine also induced cross-reactive antibodies to clade 2.1 and 2.2 H5N1 viruses. Furthermore ferrets immunised with TM-CSN had no detectable virus in the respiratory tract or brain, whereas there were signs of virus in the throat and lungs, albeit at significantly reduced levels, in CSN vaccinated animals. This study demonstrated for the first time that CSN and in particular TM-CSN adjuvanted intranasal vaccines have the potential to protect against significant mortality and morbidity arising from infection with HPAI H5N1 virus.

Dataset Information

Intranasal vaccination of recombinant H5N1 HA1 proteins fused with foldon and Fc induces strong mucosal immune responses with neutralizing activity: Implication for developing novel mucosal influenza vaccines.

Publications

Intranasal vaccination of recombinant H5N1 HA1 proteins fused with foldon and Fc induces strong mucosal immune responses with neutralizing activity: Implication for developing novel mucosal influenza vaccines.

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