M2e-Based Universal Influenza A Vaccines

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.

Keywords: influenza; matrix protein 2; vaccines.

Figure 1

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.

Figure 2

M2 from PR8 virus with the identified human T cell epitopes underlined.

Figure 3

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.