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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

Mutation frequency of amino acids in human, avian, and swine consensus M2e. (A) Percentages of the residues which are different from consensus sequences were calculated based on 14,588 human, 9324 avian, and 3060 swine M2 sequences deposited in the National Center for Biotechnology Information (NCBI) databank; (B) Sequence alignments of M2e derived from different influenza A viruses.
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vaccines-03-00105-f001: Mutation frequency of amino acids in human, avian, and swine consensus M2e. (A) Percentages of the residues which are different from consensus sequences were calculated based on 14,588 human, 9324 avian, and 3060 swine M2 sequences deposited in the National Center for Biotechnology Information (NCBI) databank; (B) Sequence alignments of M2e derived from different influenza A viruses.

Mentions: The high sequence conservation of M2e among all known human influenza A viruses that circulated between 1918 and 2008, was key to its development as a universal human influenza A vaccine candidate (Figure 1A) [32]. A human influenza M2e consensus sequence was deduced, and this suggested that a human type M2 or M2e was somehow a prerequisite for influenza A viruses to be fit in the human host. However, the swine-origin H1N1 2009 pandemic virus proved this assumption wrong. This virus has avian origin gene segments 6 (encoding NA) and 7 (encoding M1/M2) and hence an “avian” type M2e, which differs at 4 positions from M2e of previously circulating human H1N1, H2N2, and H3N2 viruses (Figure 1B) [33]. The genetic relation between M2e and M1 explains the low variability in M2e. Amino acid residues 1–9 of M2e and M1 are encoded by the same nucleotides in the same reading frame. Amino acid residues 10–23 of M2e and 239–252 of M1 are also encoded by the same RNA sequence but are translated by different reading frames. A closer look at M2e shows that its N-terminal 9 amino acids are almost absolutely conserved, even in H17N10 and H18N11 influenza viruses that were recently isolated from bats (Figure 1B). M2e residues 10 to 24 are more variable. Still, in this region, Arg12, Trp15, Cys17, Cys19, and Ser22 are strongly conserved suggesting that these residues in M2e are functionally important. It is important to note that the sequence variation in the membrane proximal part of M2e is not comparable to the amino acid changes that contribute to antigenic drift in HA and NA. In the latter case, nearly any amino acid change is tolerated, whereas in the case of M2e, selection pressure is also imposed by the overlapping M1 codon sequence. An additional element that helps explain the relatively strong sequence conservation of M2e is the fact that M2e-specific antibody responses are hardly induced following an infection. Hence, there is probably only a low natural immune pressure directed against M2e [34].


M2e-Based Universal Influenza A Vaccines.

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

Mutation frequency of amino acids in human, avian, and swine consensus M2e. (A) Percentages of the residues which are different from consensus sequences were calculated based on 14,588 human, 9324 avian, and 3060 swine M2 sequences deposited in the National Center for Biotechnology Information (NCBI) databank; (B) Sequence alignments of M2e derived from different influenza A viruses.
© Copyright Policy
Related In: Results  -  Collection

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

vaccines-03-00105-f001: Mutation frequency of amino acids in human, avian, and swine consensus M2e. (A) Percentages of the residues which are different from consensus sequences were calculated based on 14,588 human, 9324 avian, and 3060 swine M2 sequences deposited in the National Center for Biotechnology Information (NCBI) databank; (B) Sequence alignments of M2e derived from different influenza A viruses.
Mentions: The high sequence conservation of M2e among all known human influenza A viruses that circulated between 1918 and 2008, was key to its development as a universal human influenza A vaccine candidate (Figure 1A) [32]. A human influenza M2e consensus sequence was deduced, and this suggested that a human type M2 or M2e was somehow a prerequisite for influenza A viruses to be fit in the human host. However, the swine-origin H1N1 2009 pandemic virus proved this assumption wrong. This virus has avian origin gene segments 6 (encoding NA) and 7 (encoding M1/M2) and hence an “avian” type M2e, which differs at 4 positions from M2e of previously circulating human H1N1, H2N2, and H3N2 viruses (Figure 1B) [33]. The genetic relation between M2e and M1 explains the low variability in M2e. Amino acid residues 1–9 of M2e and M1 are encoded by the same nucleotides in the same reading frame. Amino acid residues 10–23 of M2e and 239–252 of M1 are also encoded by the same RNA sequence but are translated by different reading frames. A closer look at M2e shows that its N-terminal 9 amino acids are almost absolutely conserved, even in H17N10 and H18N11 influenza viruses that were recently isolated from bats (Figure 1B). M2e residues 10 to 24 are more variable. Still, in this region, Arg12, Trp15, Cys17, Cys19, and Ser22 are strongly conserved suggesting that these residues in M2e are functionally important. It is important to note that the sequence variation in the membrane proximal part of M2e is not comparable to the amino acid changes that contribute to antigenic drift in HA and NA. In the latter case, nearly any amino acid change is tolerated, whereas in the case of M2e, selection pressure is also imposed by the overlapping M1 codon sequence. An additional element that helps explain the relatively strong sequence conservation of M2e is the fact that M2e-specific antibody responses are hardly induced following an infection. Hence, there is probably only a low natural immune pressure directed against M2e [34].

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