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M2e-Based Universal Influenza A Vaccines.

Deng L, Cho KJ, Fiers W, Saelens X - Vaccines (Basel) (2015)

Bottom Line: The successful isolation of a human influenza virus in 1933 was soon followed by the first attempts to develop an influenza vaccine.We address the mechanism of action and the clinical development of M2e-vaccines.Finally, we try to foresee how M2e-based vaccines could be implemented clinically in the future.

View Article: PubMed Central - PubMed

Affiliation: Inflammation Research Center, VIB, Technologiepark 927, B-9052 Ghent, Belgium. Lei.deng@dmbr.vib-ugent.be.

ABSTRACT
The successful isolation of a human influenza virus in 1933 was soon followed by the first attempts to develop an influenza vaccine. Nowadays, vaccination is still the most effective method to prevent human influenza disease. However, licensed influenza vaccines offer protection against antigenically matching viruses, and the composition of these vaccines needs to be updated nearly every year. Vaccines that target conserved epitopes of influenza viruses would in principle not require such updating and would probably have a considerable positive impact on global human health in case of a pandemic outbreak. The extracellular domain of Matrix 2 (M2e) protein is an evolutionarily conserved region in influenza A viruses and a promising epitope for designing a universal influenza vaccine. Here we review the seminal and recent studies that focused on M2e as a vaccine antigen. We address the mechanism of action and the clinical development of M2e-vaccines. Finally, we try to foresee how M2e-based vaccines could be implemented clinically in the future.

No MeSH data available.


Related in: MedlinePlus

Influenza A virus infection cycle and mode of action of M2e based vaccines. The influenza A virions bind to sialic acid containing receptors on the surface of cells. Following endocytosis, the acidification of the endosome triggers the low-pH activation of M2. Then, the viral membrane fuses with the endosomal membrane by a low pH induced conformational change in HA. The interaction between M1 and vRNPs loosens after H+ influx by activated M2 ion channels, resulting in the release of vRNPs into the cytosol. In the nucleus, cRNA(+), vRNA(−) and mRNA(+) are produced, allowing the influenza A virus genome and proteins synthesis. Most likely M2 mediates the lipid recruitment from autophagosome during virus budding. The influenza A virus components and vRNP are packaged at the membrane, allowing the release of newly produced virions from the apical side of airway epithelial cells and the virus spreads. The critical steps in virus replication cycle and the M2(e) vaccine mechanism of action are highlighted in bold and in red. M2e-derived epitopes are presented in the context of MHC II molecules. M2e-specific CD4+ T cells are activated via T cell receptors recognition of these presented M2e epitopes, and release cytokine and chemokine in order to offer bystander help to antibody producing plasma cells or possibly clear infected cells as Cytotoxic CD4+ T lymphocytes. Phagocytes can recognize M2e-specific IgG immune complexes on the surface of infected cells and subsequently kill and eliminate the infected cell. Recognition of M2 on the surface of infected cells by phagocytic cells depends on Fc receptors and opsonizing anti-M2e IgG antibodies.
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vaccines-03-00105-f003: Influenza A virus infection cycle and mode of action of M2e based vaccines. The influenza A virions bind to sialic acid containing receptors on the surface of cells. Following endocytosis, the acidification of the endosome triggers the low-pH activation of M2. Then, the viral membrane fuses with the endosomal membrane by a low pH induced conformational change in HA. The interaction between M1 and vRNPs loosens after H+ influx by activated M2 ion channels, resulting in the release of vRNPs into the cytosol. In the nucleus, cRNA(+), vRNA(−) and mRNA(+) are produced, allowing the influenza A virus genome and proteins synthesis. Most likely M2 mediates the lipid recruitment from autophagosome during virus budding. The influenza A virus components and vRNP are packaged at the membrane, allowing the release of newly produced virions from the apical side of airway epithelial cells and the virus spreads. The critical steps in virus replication cycle and the M2(e) vaccine mechanism of action are highlighted in bold and in red. M2e-derived epitopes are presented in the context of MHC II molecules. M2e-specific CD4+ T cells are activated via T cell receptors recognition of these presented M2e epitopes, and release cytokine and chemokine in order to offer bystander help to antibody producing plasma cells or possibly clear infected cells as Cytotoxic CD4+ T lymphocytes. Phagocytes can recognize M2e-specific IgG immune complexes on the surface of infected cells and subsequently kill and eliminate the infected cell. Recognition of M2 on the surface of infected cells by phagocytic cells depends on Fc receptors and opsonizing anti-M2e IgG antibodies.

Mentions: M2e is a highly conserved target for universal influenza A vaccine development. Different types of M2e-based vaccine, such as DNA vaccine, protein vaccine, VLPs vaccine, and vectored vaccine, are all able to provide a certain level of broad-spectrum protection in animal models. The influenza A virus infection cycle and possible mechanisms of M2e-based vaccine-mediated protection are summarized in Figure 3. M2e-specific antibodies, mainly IgG, are the main actors in immune protection and do so by engaging Fcγ Receptor expressing immune cells such as alveolar macrophages. It is also well documented that mucosal immunization with M2e-based vaccines offers better protection in mouse models compared to parenteral immunization strategies. This improved protection may be attributable to the induction of M2e-specific IgA. The infection-permissive character of M2e-based vaccines can be considered as an advantage when vaccinating immunologically naïve individuals. Because M2e-immunity does not neutralize the virus, the limited virus replication still induces cross-reactive T cell responses against other conserved viral antigens such as NP and M1. However, M2e will likely not be a complete substitute for the currently licensed influenza vaccines that are able to confer much stronger protection, be it against a very narrow antigenic range of viruses. In the future, with many other universal influenza vaccine candidates on the horizon, M2e-conjugate vaccines will likely find a place as part of a vaccine that is a blend of different conserved epitopes that together may offer strong, long lasting, and foremost broad immune protection. Whether such a vaccine will perform better clinically than a fully antigenic matched seasonal vaccine remains to be seen. However, such universal vaccines would prove their value in the case of a pandemic.


M2e-Based Universal Influenza A Vaccines.

Deng L, Cho KJ, Fiers W, Saelens X - Vaccines (Basel) (2015)

Influenza A virus infection cycle and mode of action of M2e based vaccines. The influenza A virions bind to sialic acid containing receptors on the surface of cells. Following endocytosis, the acidification of the endosome triggers the low-pH activation of M2. Then, the viral membrane fuses with the endosomal membrane by a low pH induced conformational change in HA. The interaction between M1 and vRNPs loosens after H+ influx by activated M2 ion channels, resulting in the release of vRNPs into the cytosol. In the nucleus, cRNA(+), vRNA(−) and mRNA(+) are produced, allowing the influenza A virus genome and proteins synthesis. Most likely M2 mediates the lipid recruitment from autophagosome during virus budding. The influenza A virus components and vRNP are packaged at the membrane, allowing the release of newly produced virions from the apical side of airway epithelial cells and the virus spreads. The critical steps in virus replication cycle and the M2(e) vaccine mechanism of action are highlighted in bold and in red. M2e-derived epitopes are presented in the context of MHC II molecules. M2e-specific CD4+ T cells are activated via T cell receptors recognition of these presented M2e epitopes, and release cytokine and chemokine in order to offer bystander help to antibody producing plasma cells or possibly clear infected cells as Cytotoxic CD4+ T lymphocytes. Phagocytes can recognize M2e-specific IgG immune complexes on the surface of infected cells and subsequently kill and eliminate the infected cell. Recognition of M2 on the surface of infected cells by phagocytic cells depends on Fc receptors and opsonizing anti-M2e IgG antibodies.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4494237&req=5

vaccines-03-00105-f003: Influenza A virus infection cycle and mode of action of M2e based vaccines. The influenza A virions bind to sialic acid containing receptors on the surface of cells. Following endocytosis, the acidification of the endosome triggers the low-pH activation of M2. Then, the viral membrane fuses with the endosomal membrane by a low pH induced conformational change in HA. The interaction between M1 and vRNPs loosens after H+ influx by activated M2 ion channels, resulting in the release of vRNPs into the cytosol. In the nucleus, cRNA(+), vRNA(−) and mRNA(+) are produced, allowing the influenza A virus genome and proteins synthesis. Most likely M2 mediates the lipid recruitment from autophagosome during virus budding. The influenza A virus components and vRNP are packaged at the membrane, allowing the release of newly produced virions from the apical side of airway epithelial cells and the virus spreads. The critical steps in virus replication cycle and the M2(e) vaccine mechanism of action are highlighted in bold and in red. M2e-derived epitopes are presented in the context of MHC II molecules. M2e-specific CD4+ T cells are activated via T cell receptors recognition of these presented M2e epitopes, and release cytokine and chemokine in order to offer bystander help to antibody producing plasma cells or possibly clear infected cells as Cytotoxic CD4+ T lymphocytes. Phagocytes can recognize M2e-specific IgG immune complexes on the surface of infected cells and subsequently kill and eliminate the infected cell. Recognition of M2 on the surface of infected cells by phagocytic cells depends on Fc receptors and opsonizing anti-M2e IgG antibodies.
Mentions: M2e is a highly conserved target for universal influenza A vaccine development. Different types of M2e-based vaccine, such as DNA vaccine, protein vaccine, VLPs vaccine, and vectored vaccine, are all able to provide a certain level of broad-spectrum protection in animal models. The influenza A virus infection cycle and possible mechanisms of M2e-based vaccine-mediated protection are summarized in Figure 3. M2e-specific antibodies, mainly IgG, are the main actors in immune protection and do so by engaging Fcγ Receptor expressing immune cells such as alveolar macrophages. It is also well documented that mucosal immunization with M2e-based vaccines offers better protection in mouse models compared to parenteral immunization strategies. This improved protection may be attributable to the induction of M2e-specific IgA. The infection-permissive character of M2e-based vaccines can be considered as an advantage when vaccinating immunologically naïve individuals. Because M2e-immunity does not neutralize the virus, the limited virus replication still induces cross-reactive T cell responses against other conserved viral antigens such as NP and M1. However, M2e will likely not be a complete substitute for the currently licensed influenza vaccines that are able to confer much stronger protection, be it against a very narrow antigenic range of viruses. In the future, with many other universal influenza vaccine candidates on the horizon, M2e-conjugate vaccines will likely find a place as part of a vaccine that is a blend of different conserved epitopes that together may offer strong, long lasting, and foremost broad immune protection. Whether such a vaccine will perform better clinically than a fully antigenic matched seasonal vaccine remains to be seen. However, such universal vaccines would prove their value in the case of a pandemic.

Bottom Line: The successful isolation of a human influenza virus in 1933 was soon followed by the first attempts to develop an influenza vaccine.We address the mechanism of action and the clinical development of M2e-vaccines.Finally, we try to foresee how M2e-based vaccines could be implemented clinically in the future.

View Article: PubMed Central - PubMed

Affiliation: Inflammation Research Center, VIB, Technologiepark 927, B-9052 Ghent, Belgium. Lei.deng@dmbr.vib-ugent.be.

ABSTRACT
The successful isolation of a human influenza virus in 1933 was soon followed by the first attempts to develop an influenza vaccine. Nowadays, vaccination is still the most effective method to prevent human influenza disease. However, licensed influenza vaccines offer protection against antigenically matching viruses, and the composition of these vaccines needs to be updated nearly every year. Vaccines that target conserved epitopes of influenza viruses would in principle not require such updating and would probably have a considerable positive impact on global human health in case of a pandemic outbreak. The extracellular domain of Matrix 2 (M2e) protein is an evolutionarily conserved region in influenza A viruses and a promising epitope for designing a universal influenza vaccine. Here we review the seminal and recent studies that focused on M2e as a vaccine antigen. We address the mechanism of action and the clinical development of M2e-vaccines. Finally, we try to foresee how M2e-based vaccines could be implemented clinically in the future.

No MeSH data available.


Related in: MedlinePlus