High epitope density in a single recombinant protein molecule of the extracellular domain of influenza A virus M2 protein significantly enhances protective immunity

Liu, Wanli; Zou, Peng; Liu, Zuqiang; Lu, Yun; Ding, Jun; Chen, Yinghua

doi:10.1016/j.vaccine.2004.05.028

Cited by 122 publications

(88 citation statements)

References 25 publications

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“…The BCR is composed of a membrane-bound form of the Ig and a noncovalently associated heterodimer of Iga and Igb in a 1:1 membrane-bound form of the Ig/Iga-Igb heterodimer stoichiometry (2,3). It is well appreciated that Ags show great diversity based on their presentation formats, including Ag density (4,5), Ag affinity (4,5), Ag valency (6)(7)(8), and Ag mobility (9). The initiation of B cell activation has been shown to be sensitive to each type of these Ag presentation formats.…”

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confidence: 99%

“…The initiation of B cell activation has been shown to be sensitive to each type of these Ag presentation formats. For example, early studies extensively investigated how Ag valency can affect B cell activation (10)(11)(12) and the subsequent Ab responses (6)(7)(8). It is generally observed that multivalent Ags with high valency are more potent in inducing Ab responses as compared with monovalent Ags with low valency.…”

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confidence: 99%

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B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Wan

Zhang

Fan

et al. 2013

The Journal of Immunology

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109

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B lymphocytes are activated upon Ag sensing by BCRs. The substrate presenting the Ag can show different degrees of stiffness. It is not clear whether B cells can respond to changes in substrate stiffness. In this study we use high-resolution, high-speed live cell imaging techniques to capture the molecular events in B cell activation after the recognition of Ags tethered to polyacrylamide gel substrates with variable degrees of stiffness as quantified by Young’s modulus (2.6–22.1 kPa). We show that the initiation of B cell activation is extremely sensitive to substrate stiffness. B cells exhibit much stronger activation responses when encountering Ags tethered to substrates with a high degree of stiffness as measured by the accumulation of BCR, phospho-spleen tyrosine kinase, and phosphotyrosine molecules into the B cell immunological synapse. Ags tethered to stiff substrates induce the formation of more prominent BCR and phospho-spleen tyrosine kinase microclusters with significantly enhanced colocalization as compared with Ags tethered to soft substrates. Moreover, the expression of the B cell activation marker CD69 is enhanced in B cells encountering Ags on stiffer substrates. Through time-lapse live cell imaging, we find that the different responses of B cells to substrate stiffness are only demonstrated 5 min after BCR and Ag recognition. Using a series of cytoskeleton inhibitors, we determine that the mechanosensing ability of B cells is dependent on microtubules, and only mildly linked to the actin cytoskeleton. These results suggest the importance of the mechanical properties mediated by substrate stiffness in B cell activation.

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confidence: 99%

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confidence: 99%

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Wan

Zhang

Fan

et al. 2013

The Journal of Immunology

Self Cite

109

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“…However, we subsequently demonstrated that the chemical fusion construct was not superior to our improved, genetically linked M2e-HBc construct [49]. Both chemical and genetic fusions have been exploited by other groups to link M2e to various carriers, such as bovine serum albumin, glutathione-S-transferase, keyhole limpet hemocyanin, bacterial outer-membrane complexes, a synthetic, multiple antigen peptide and a 'proprietary hydrophobic domain' (Table 1) [36,37,[55][56][57][58]. Most experimental influenza vaccines (including M2e-based vaccines), novel adjuvants and fundamental immunological questions related to influenza are first explored in laboratory mice.…”

Section: M2e-specific Antibodies Protect Against Influenza a Virus Inmentioning

confidence: 96%

“…However, the reduction in virus yield by the 14C2 antibody observed in vitro was strain dependent, whereas the efficacy of M2e-based vaccine candidates has been documented for multiple Influenza A virus subtypes and strains (Table 1). [46] hM2e HBc Genetic Mouse H1N1, H3N2 [47] hM2 deletion constructs -/GST Genetic Mouse H1N1, H2N2, H3N2 [53] hM2e HBc, NP Genetic Pig H1N1 [60] hM2e HBc Genetic, chemical Mouse H1N1 [61] hM2e BSA Chemical H3N2 (in vitro) [36] hM2e Multiantigen peptide Chemical Mouse H3N2 [37] hM2e GST Genetic Mouse H1N1 [55] hM2e KLH, OMPC Chemical Mouse, ferret, rhesus monkey H1N1, H3N1, H1N1, none [57] hM2e Hydrophobic domain Genetic Mouse H1N1, H5N1, H6N2, H9N2 [56] hM2e Protection induced by M2e-based vaccines probably depends mostly on the killing of M2-expressing cells by antibody-dependent cytotoxicity (ADCC). Elimination of infected cells at an early phase of the infection cycle would reduce new virus production, consistent with the reported drop in lung virus titers of M2e-immune mice.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

The Influenza Matrix Protein 2 as a Vaccine Target

Saelens

2008

Future Virol.

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Matrix protein (M)2 is an Influenza A, type III membrane protein with an extracellular domain (ectodomain of M2 [M2e]) of 23 amino acid residues, which is strongly conserved across virus strains. M2 fulfills an important biological function in the life cycle of the Influenza A virus and has been a target of antiviral drugs. M2e has generated much interest as a potential vaccine target, and a clinical M2e vaccine trial was initiated in 2007. The advantage of M2e compared with hemagglutinin, the prime antigen target in conventional influenza vaccines, is that its sequence is conserved. This means that a stable, efficacious and easily produced M2e-based vaccine would provide protection not only against drifting seasonal influenza epidemic strains, but would also make it possible to vaccinate in anticipation of an emerging pandemic. Furthermore, most reported M2e-based vaccines are produced by economical and safe technologies. IgG subtype antibodies directed against M2e can prevent death from influenza and reduce morbidity in animal models for influenza disease. The immunological mechanism that mediates protection by anti-M2e antibodies is not completely understood, but it probably involves antibody-mediated cellular cytotoxicity. This review summarizes the findings on M2e vaccine candidates and addresses some of the key unanswered questions about this promising Influenza A vaccine target: what is its likely mechanism of action? Which measurable parameters correlate with protection? And what can be expected from clinical use of an M2e-based vaccine?

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“…Many studies have been focused on the M2 protein (okuda et al, 2001;Fan et al, 2004;liu et al, 2004;DeFilette et al, 2006;hoelscher et al, 2006;DeFilette et al, 2008a,b;huleatt et al, 2008;Zhang et al, 2009;li et al, 2011;Park et al, 2011;Staneková et al, 2011), but recently also the conserved part of hA, hA2 gp, was used as an inductor of cross-protective immunity (okuno et al, 1993;horváth et al, 1998;Gocník et al, 2008;Sui et al, 2009;Bommakanti et al, 2010;Steel et al, 2010;Wang et al, 2010;Staneková et al, 2011). The latter was the subject of our interest for several years.…”

Section: Introductionmentioning

confidence: 99%

Two distinct regions of HA2 glycopolypeptide of influenza virus hemagglutinin elicit cross-protective immunity against influenza

Janulíková¹,

Staneková²,

Mucha³

et al. 2012

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Summary. -currently, a new trend in development of vaccines against influenza with broader spectrum of efficacy is focused on conserved antigens of influenza virus. The hA2 glycopolypeptide (hA2 gp) is one of conserved antigens, potentially suitable as immunogens inducing cross-protection against influenza. We selected two distinct domains of hA2 gp originating from influenza A virus (IAv) of h3 subtype for induction of antiviral immune response: the ectodomain (ehA2) comprising aa 23-185 and the fusion peptide (FP) comprising n-terminal aa 1-38. BAlB/c mice were immunized with three doses of ehA2 and FP, respectively, and subsequently challenged with 2 lD 50 of IAv of homologous (h3) or heterologous (h7) hA subtype. Both peptides induced significant antibody response and protected mice against the lethal infection. The most efficient protection was achieved with ehA2 against homologous virus.Keywords: influenza A virus; cross-protection; hA2 glycopolypeptide; hA2 ectodomain; fusion peptide; mice; vaccine * corresponding author. e-mail: viruevar@savba.sk; phone: +4212-59302427. Abbreviations: A/chicken/Germany/34 (h7n1) virus, rostock strain; A/Miss = A/Mississippi/1/85 (h3n2) virus; A/rostock = avian hA = hemagglutinin; ehA2 = ectodomain of hA2 gp; FA = Freund΄s adjuvant; FP = fusion peptide; hA0 = hA precursor; hA1 = hA1 glycopolypeptide; hA2 = hA2 glycopolypeptide; IAv(s) = influenza A virus(es); MAb = monoclonal antibody; vrnA = viral rnA; p.i. = post infection

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High epitope density in a single recombinant protein molecule of the extracellular domain of influenza A virus M2 protein significantly enhances protective immunity

Cited by 122 publications

References 25 publications

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

The Influenza Matrix Protein 2 as a Vaccine Target

Two distinct regions of HA2 glycopolypeptide of influenza virus hemagglutinin elicit cross-protective immunity against influenza

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