Incorporation of Membrane-Anchored Flagellin into Influenza Virus-Like Particles Enhances the Breadth of Immune Responses

Wang, Bao‐Zhong; Quan, Fu‐Shi; Kang, Sang-Moo; Bozja, Jadranka; Skountzou, Ioanna; Compans, Richard W.

doi:10.1128/jvi.01076-08

Cited by 122 publications

(189 citation statements)

References 66 publications

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“…Flagellar polymers thus activate TLR5 but to a lesser extent than flagellin monomers (59). A variety of heterologous prokaryotic, viral, and eukaryotic protein antigens have shown increased immunogenicity in mice following genetic fusion or chemical conjugation with flagellin (6,43,69).…”

mentioning

confidence: 99%

Salmonella enterica Serovar Enteritidis Core O Polysaccharide Conjugated to H:g,m Flagellin as a Candidate Vaccine for Protection against Invasive Infection withS.Enteritidis

et al. 2011

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mentioning

confidence: 99%

Salmonella enterica Serovar Enteritidis Core O Polysaccharide Conjugated to H:g,m Flagellin as a Candidate Vaccine for Protection against Invasive Infection withS.Enteritidis

et al. 2011

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“…Spodoptera frugiperda Sf9, Madin-Darby canine kidney (MDCK; ATCC PTA-6500), and RAW264.7 (ATCC TIB-71) cells were maintained as described previously (40). Mouse-adapted influenza A/PR/8/34 (A/PR8; H1N1) and A/Philippines/2/82 (A/Philippines; H3N2) viruses were prepared as described previously (28).…”

Section: Methodsmentioning

confidence: 99%

“…Both FliC and FljB share conserved N and C termini which form the flagellar filament backbone (22) and contain motifs recognized by TLR5. Previously, we have found that a membrane-anchored form of the Salmonella enterica serovar Typhimurium phase I flagellin (FliC) can be coincorporated into influenza VLPs as an adjuvant molecule (40). The variable central region of FliC has been found to be hyperimmunogenic and unnecessary for its TLR5 binding activity (35).…”

mentioning

confidence: 99%

Enhanced Influenza Virus-Like Particle Vaccines Containing the Extracellular Domain of Matrix Protein 2 and a Toll-Like Receptor Ligand

Wang

Gill

Kang

et al. 2012

Clin. Vaccine Immunol.

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The extracellular domain of matrix protein 2 (M2e) is conserved among influenza A viruses. The goal of this project is to develop enhanced influenza vaccines with broad protective efficacy using the M2e antigen. We designed a membrane-anchored fusion protein by replacing the hyperimmunogenic region of Salmonella enterica serovar Typhimurium flagellin (FliC) with four repeats of M2e (4.M2e-tFliC) and fusing it to a membrane anchor from influenza virus hemagglutinin (

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“…[4][5][6][7][8] By various self-assembling reactions, antigens can be deposited onto the surfaces of nanoparticles at high density. 9 The repetitive antigen structures can act as multivalent ligands and can cross-link antigen receptors on immune cell surfaces for better targeting and long-term stimulation.…”

Section: Introductionmentioning

confidence: 99%

Dual-linker gold nanoparticles as adjuvanting carriers for multivalent display of recombinant influenza hemagglutinin trimers and flagellin improve the immunological responses in vivo and in vitro

Wang

Zhu

Wang

2017

IJN

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Vaccination is the most cost-effective means of infectious disease control. Although current influenza vaccines are effective in battling closely matched strains, such vaccines have major limitations such as the requirement to produce new vaccines every season, an egg-dependent production system, long production periods, uncertainty in matching the vaccine to circulating strains, and the inability to react to new influenza pandemics resulting from genetic drift or shift. To overcome the intrinsic limitations of the conventional influenza vaccine, we have designed dual-linker gold nanoparticles (AuNPs) conjugated with both recombinant trimetric A/Aichi/2/68 (H3N2), hemagglutinin (HA) and TLR5 agonist flagellin (FliC) as a novel vaccine approach. Click chemistry and metal-chelating reactions were used to couple the two proteins. The conjugated proteins were found to possess high coupling specificity, high stability in harsh environments, high conjugation efficiency, and the ability to keep the appropriate protein conformations for immunogenicity and immunostimulation. Both AuNPs-HA/FliC and AuNPs-HA formulations induced higher levels of antibody responses than a mixture of soluble HA and FliC proteins when administered via a single intranasal immunization in mice. To further investigate the adjuvancy of these nanoparticles, in vitro experiments were conducted in both the JAWS II dendritic cell (DC) line and bone marrow-derived DC (BMDC) models. The results showed that dual-conjugated AuNPs were rapidly targeted and taken up by DCs. Consequently, DCs were induced toward maturation, as demonstrated by high levels of cytokine secretions and membrane costimulatory molecule expression. T cell proliferation was observed when splenic T cells were cocultured with AuNPs-HA/FliC-primed BMDCs. These results suggest that dual-conjugated AuNPs are effective at simultaneously displaying antigens and adjuvants in an oriented, multivalent format and can promote a strong immune response by activating DCs and T cells.

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Incorporation of Membrane-Anchored Flagellin into Influenza Virus-Like Particles Enhances the Breadth of Immune Responses

Abstract: We have designed a membrane-anchored form of the Toll-like receptor 5 ligand flagellin, the major proinflammatory determinant of enteropathogenic Salmonella, which was found to be glycosylated and expressed on cell surfaces. A chimeric influenza virus-like particle (

Cited by 122 publications

References 66 publications

Salmonella enterica Serovar Enteritidis Core O Polysaccharide Conjugated to H:g,m Flagellin as a Candidate Vaccine for Protection against Invasive Infection withS.Enteritidis

Salmonella enterica Serovar Enteritidis Core O Polysaccharide Conjugated to H:g,m Flagellin as a Candidate Vaccine for Protection against Invasive Infection withS.Enteritidis

Enhanced Influenza Virus-Like Particle Vaccines Containing the Extracellular Domain of Matrix Protein 2 and a Toll-Like Receptor Ligand

Dual-linker gold nanoparticles as adjuvanting carriers for multivalent display of recombinant influenza hemagglutinin trimers and flagellin improve the immunological responses in vivo and in vitro

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