The universal influenza vaccine M2e-HBc administered intranasally in combination with the adjuvant CTA1-DD provides complete protection

Filette, Marina De; Ramne, Anna; Birkett, Ashley; Lycke, Nils; Löwenadler, Björn; Jou, Willy Min; Saelens, Xavier; Fiers, Walter

doi:10.1016/j.vaccine.2005.08.061

Cited by 115 publications

(84 citation statements)

References 36 publications

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“…2) comparable with those obtained with the M2e-HBc vaccine described previously (6,20). The titers of M2e-specific serum IgG2a were highest in the group immunized intranasally with M2e-tGCN4 plus CTA1-DD, in agreement with our previous results using the same mucosal adjuvant (21). Unlike for IgG1, the IgG2a titers were lower compared with the M2e-HBc vaccine.…”

Section: Discussionsupporting

confidence: 91%

“…BALB/c mice were immunized three times with M2e-tGCN4 together with alum, Ribi, or CTA1-DD adjuvants as described previously for the M2e-HBc vaccine (6,20,21). BM2e-tGCN4 was used as a control.…”

Section: Resultsmentioning

confidence: 99%

“…Additional experiments using an optimized M2e-tGCN4 construct, vaccine formulation, and delivery protocol are needed to evaluate the merit of this vaccine relative to that of the M2e-HBc vaccine documented previously (6,20,21). The correct assembly of oligomeric extracellular domains of membrane proteins by virtue of a heterologous oligomerizing domain attached to their C or N terminus leads to a surrogate structure that mimics the oligomeric ectodomain of a natural oligomeric protein.…”

Section: Discussionmentioning

confidence: 99%

“…At the age of 8 weeks they were injected intraperitoneally with 10 g of M2e-or BM2e-tGCN4 with trehalose dicorynomycolate ϩ monophosphoryl lipid A (Sigma) or Alhydrogel (Brenntag Biosector A/S) adjuvant or intranasally with the mucosal adjuvant CTA1-DD and boosted twice at 3-week intervals, as described previously (6,20,21).…”

Section: Estimation Of Molecular Weight By Nondenaturing Page-mentioning

confidence: 99%

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An Influenza A Vaccine Based on Tetrameric Ectodomain of Matrix Protein 2

Filette

Martens

Roose

et al. 2008

Journal of Biological Chemistry

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120

109

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Matrix protein 2 (M2) of influenza A is a tetrameric type III membrane protein that functions as a proton-selective channel. The extracellular domain (M2e) has remained nearly invariable since the first human influenza strain was isolated in 1933. By linking a modified form of the leucine zipper of the yeast transcription factor GCN4 to M2e, we obtained a recombinant tetrameric protein, M2e-tGCN4. This protein mimics the quaternary structure of the ectodomain of the natural M2 protein. M2e-tGCN4 was purified, biochemically characterized, and used to immunize BALB/c mice. High M2e-specific serum IgG antibody titers were obtained following either intraperitoneal or intranasal administration. Immunized mice were protected fully against a potentially lethal influenza A virus challenge. Antibodies raised by M2e-tGCN4 immunization specifically bound to the surface of influenza-infected cells and to an M2-expressing cell line. Using a M2e peptide competition enzymelinked immunosorbent assay with M2-expressing cells as target, we obtained evidence that M2e-tGCN4 induces antibodies that are specific for the native tetrameric M2 ectodomain. Therefore, fusion of an oligomerization domain to the extracellular part of a transmembrane protein allows it to mimic the natural quaternary structure and can promote the induction of oligomer-specific antibodies.Influenza has one of the highest infection rates of all human viruses and can kill healthy persons of all ages (1). It is estimated that influenza infection during seasonal epidemics kills 1 in 1000 infected individuals, whereas an unpredictable pandemic is likely to kill millions. In addition, increased hospitalization and absenteeism from school and work are direct consequences of the flu. At present, the best way to protect against influenza is to vaccinate against the ever-mutating strains (2). However, antigenic drift and occasional shift of the two major membrane glycoproteins, hemagglutinin and neuraminidase, make vaccine production cumbersome and necessitate yearly revision of the vaccine seed strains by the World Health Organization.Influenza A also encodes a third integral membrane protein, M2, 2 a homotetramer, the subunit of which has a small external domain (M2e) of 23 amino acid residues (3). Natural M2 protein is present in a few copies in the virus particle but in abundance on virus-infected cells (4). In contrast to hemagglutinin and neuraminidase, M2e is almost nonimmunogenic (5), and its sequence is highly conserved. Capitalizing on these properties, we developed a universal influenza A vaccine by linking the M2e peptide to a virus-like particle based on the hepatitis B virus core (HBc) (6). In this context, M2e is highly immunogenic, and the M2e-HBc vaccine induces antibodies that protect mice against influenza-induced death and morbidity.Oligomeric proteins found in vaccines derived by inactivating or attenuating a pathogen often function as their major antigenic determinant. Conformational epitopes embedded in the quaternary structures may critically con...

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Estimation Of Molecular Weight By Nondenaturing Page-mentioning

confidence: 99%

See 2 more Smart Citations

An Influenza A Vaccine Based on Tetrameric Ectodomain of Matrix Protein 2

Filette

Martens

Roose

et al. 2008

Journal of Biological Chemistry

Self Cite

120

109

View full text Add to dashboard Cite

show abstract

“…More recently, M2e-HBc was combined with the mucosal adjuvant CTA1-DD to optimize intranasal administration. This adjuvant was selected because it can promote Th1-directed immune responses without exhibiting toxicity [50][51][52].…”

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

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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The fight against new types of influenza virus

Romanova¹

2006

Biotechnology Journal

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In 1997, during an outbreak in chickens in Hong Kong the avian H5N1 influenza virus crossed the species barrier and infected 18 people, of which 6 cases were fatal. The virus also infected wild birds and continued to circulate and mutate in geese and ducks in southeastern China. Since this occurrence, new antigenic variants that are highly pathogenic for humans as well as wild, domestic, and exotic waterfowl continue to appear in Hong Kong. This virus is spreading across Asia, and is encroaching upon Europe and other continents. Wild birds are now considered as the main reservoir of H5N1 virus. Humans become infected with this H5N1 virus usually via close contact with infected birds or a highly contaminated environment. The very low transmissibility of this virus prevented further person-to-person dissemination in spite of the complete absence of immunity in the human population to H5N1 viruses. Viruses of the H5N1 subtype are characterized by an exceptionally high pathogenicity for humans. The cause of the viral virulence is not known so far; however, several virulence factors are considered. The unprecedented capability of H5N1 viruses to kill humans intensifies the concern about its pandemic potential with catastrophic consequences. The effectiveness of existing antivirals as well as vaccines for humans and birds are reviewed.

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The universal influenza vaccine M2e-HBc administered intranasally in combination with the adjuvant CTA1-DD provides complete protection

Cited by 115 publications

References 36 publications

An Influenza A Vaccine Based on Tetrameric Ectodomain of Matrix Protein 2

An Influenza A Vaccine Based on Tetrameric Ectodomain of Matrix Protein 2

The Influenza Matrix Protein 2 as a Vaccine Target

The fight against new types of influenza virus

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