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.

Development of a novel dual-domain nanoparticle antigen construct for universal influenza vaccine

“…This suggests that antibodies induced by DDNFPs against the specific domains (M2e, CD, or FP) may not be strongly neutralizing. These observations are consistent with previous studies with M2e [8,35], while neutralization activity with FP or CD domain did not appear to have been evaluated previously [14–17]. The more sensitive pseudotype neutralization test could be used in future studies to examine the extent of neutralizing activity [5].…”

“…M2e is the 24-aa extracellular domain of the minor envelope protein M2 which is highly conserved among all influenza A viruses, especially within the first nine amino acids [7–8]. M2 has a low copy number per virion, but is present abundantly on infected cells [9].…”

“…M2 has a low copy number per virion, but is present abundantly on infected cells [9]. It is one of the most widely studied targets for the universal influenza vaccine and has been shown to provide strong protection through antibody-dependent cell-mediated cytotoxicity (ADCC) [1,8]. The HA2 makes up the bulk of HA stem and consists of distinct domains including FP, A, B, C, D, E, F, G and H [10].…”

Vaccine approaches conferring cross-protection against influenza viruses

“…It consists of three structural domains: 1) a 24-residue N-terminal ectodomain (M2e) necessary for the incorporation of the M2 into mature virions, 2) a 19-residue transmembrane domain necessary for the ion channel activity, and 3) a 54 amino acids C-terminal intravirion/intracellular domain necessary for the assembly of influenza virions. Unlike HA and NA, M2e is relatively conserved across human influenza A viruses, whereas in H5N1 and H7N9, the first 10 amino acid residues of M2e are same as of H1N1 and H3N2, but the remaining 14 residues have approximately 78 and 42% amino acid identity with H5N1 and H7N9 M2e, respectively[43], therefore, it is a potential candidate for a broadly protective vaccine.…”

“…Along these lines, M2e has been conjugated with carrier proteins including KLH, bovine serum albumin, Neisseria meningitiditis outer membrane protein complex, human papillomavirus L protein, and the leucine zipper domain of yeast transcription factor GCN4 to enhance immunogenicity and protective efficacy of M2e-based vaccines by several investigators[43,49]. DNA and viral vectored vaccines encoding M2 either alone or in combination with other influenza virus proteins have also been evaluated.…”