Immune Netw.  2015 Oct;15(5):213-221. 10.4110/in.2015.15.5.213.

Mechanisms of Cross-protection by Influenza Virus M2-based Vaccines

Affiliations
  • 1Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA. skang24@gsu.edu
  • 2Animal and Plant Quarantine Agency, Anyang 14089, Korea.

Abstract

Current influenza virus vaccines are based on strain-specific surface glycoprotein hemagglutinin (HA) antigens and effective only when the predicted vaccine strains and circulating viruses are well-matched. The current strategy of influenza vaccination does not prevent the pandemic outbreaks and protection efficacy is reduced or ineffective if mutant strains emerge. It is of high priority to develop effective vaccines and vaccination strategies conferring a broad range of cross protection. The extracellular domain of M2 (M2e) is highly conserved among human influenza A viruses and has been utilized to develop new vaccines inducing cross protection against different subtypes of influenza A virus. However, immune mechanisms of cross protection by M2e-based vaccines still remain to be fully elucidated. Here, we review immune correlates and mechanisms conferring cross protection by M2e-based vaccines. Molecular and cellular immune components that are known to be involved in M2 immune-mediated protection include antibodies, B cells, T cells, alveolar macrophages, Fc receptors, complements, and natural killer cells. Better understanding of protective mechanisms by immune responses induced by M2e vaccination will help facilitate development of broadly cross protective vaccines against influenza A virus.

Keyword

Influenza virus; M2e; Universal vaccine; Immune mechanism

MeSH Terms

Antibodies
B-Lymphocytes
Complement System Proteins
Cross Protection
Disease Outbreaks
Hemagglutinins
Influenza A virus
Influenza Vaccines
Influenza, Human*
Killer Cells, Natural
Macrophages, Alveolar
Membrane Glycoproteins
Orthomyxoviridae*
Pandemics
Receptors, Fc
T-Lymphocytes
Vaccination
Vaccines*
Antibodies
Complement System Proteins
Hemagglutinins
Influenza Vaccines
Membrane Glycoproteins
Receptors, Fc
Vaccines

Cited by  1 articles

Evaluation of Protective Immunity of Peptide Vaccines Composed of a 15-mer N-terminal Matrix Protein 2 and a Helper T-Cell Epitope Derived from Influenza A Virus
Jeong-Ki Kim, Sinyoung Cheong, Myung Kyu Lee
Immune Netw. 2019;19(4):.    doi: 10.4110/in.2019.19.e29.


Reference

1. Palese P, Shaw ML. Orthomyxoviridae: the viruses and their replication.: Fields virology. 5th ed. Philadelphia: Williams and Wilkins;2007.
2. Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M, Yang H, Chen X, Recuenco S, Gomez J, Chen LM, Johnson A, Tao Y, Dreyfus C, Yu W, McBride R, Carney PJ, Gilbert AT, Chang J, Guo Z, Davis CT, Paulson JC, Stevens J, Rupprecht CE, Holmes EC, Wilson IA, Donis RO. New world bats harbor diverse influenza A viruses. PLoS Pathog. 2013; 9:e1003657.
Article
3. Chizhmakov IV, Geraghty FM, Ogden DC, Hayhurst A, Antoniou M, Hay AJ. Selective proton permeability and pH regulation of the influenza virus M2 channel expressed in mouse erythroleukaemia cells. J Physiol. 1996; 494(Pt 2):329–336.
Article
4. Pinto LH, Holsinger LJ, Lamb RA. Influenza virus M2 protein has ion channel activity. Cell. 1992; 69:517–528.
Article
5. Long JX, Wang QZ, Lu JH, Liu YL, Liu XF. [Cloning of full-length genes of H5N1 subtype Avian influenza virus strain A/duck/Shandong/093/2004 and analysis of the sequences]. Wei Sheng Wu Xue Bao. 2005; 45:690–696.
6. Ito T, Gorman OT, Kawaoka Y, Bean WJ, Webster RG. Evolutionary analysis of the influenza A virus M gene with comparison of the M1 and M2 proteins. J Virol. 1991; 65:5491–5498.
Article
7. Zebedee SL, Lamb RA. Nucleotide sequences of influenza A virus RNA segment 7: a comparison of five isolates. Nucleic Acids Res. 1989; 17:2870.
Article
8. Fiers W, De FM, Birkett A, Neirynck S, Min JW. A "universal" human influenza A vaccine. Virus Res. 2004; 103:173–176.
Article
9. Kim MC, Song JM, E O, Kwon YM, Lee YJ, Compans RW, Kang SM. Virus-like particles containing multiple M2 extracellular domains confer improved cross-protection against various subtypes of influenza virus. Mol Ther. 2013; 21:485–492.
Article
10. Kim MC, Lee JS, Kwon YM, E O, Lee YJ, Choi JG, Wang BZ, Compans RW, Kang SM. Multiple heterologous M2 extracellular domains presented on virus-like particles confer broader and stronger M2 immunity than live influenza A virus infection. Antiviral Res. 2013; 99:328–335.
Article
11. De FM, Ramne A, Birkett A, Lycke N, Lowenadler B, Min JW, Saelens X, Fiers W. The universal influenza vaccine M2e-HBc administered intranasally in combination with the adjuvant CTA1-DD provides complete protection. Vaccine. 2006; 24:544–551.
Article
12. Fan J, Liang X, Horton MS, Perry HC, Citron MP, Heidecker GJ, Fu TM, Joyce J, Przysiecki CT, Keller PM, Garsky VM, Ionescu R, Rippeon Y, Shi L, Chastain MA, Condra JH, Davies ME, Liao J, Emini EA, Shiver JW. Preclinical study of influenza virus A M2 peptide conjugate vaccines in mice, ferrets, and rhesus monkeys. Vaccine. 2004; 22:2993–3003.
Article
13. Neirynck S, Deroo T, Saelens X, Vanlandschoot P, Jou WM, Fiers W. A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat Med. 1999; 5:1157–1163.
Article
14. Ionescu RM, Przysiecki CT, Liang X, Garsky VM, Fan J, Wang B, Troutman R, Rippeon Y, Flanagan E, Shiver J, Shi L. Pharmaceutical and immunological evaluation of human papillomavirus viruslike particle as an antigen carrier. J Pharm Sci. 2006; 95:70–79.
Article
15. Bessa J, Schmitz N, Hinton HJ, Schwarz K, Jegerlehner A, Bachmann MF. Efficient induction of mucosal and systemic immune responses by virus-like particles administered intranasally: implications for vaccine design. Eur J Immunol. 2008; 38:114–126.
Article
16. Tompkins SM, Zhao ZS, Lo CY, Misplon JA, Liu T, Ye Z, Hogan RJ, Wu Z, Benton KA, Tumpey TM. Matrix protein 2 vaccination and protection against influenza viruses, including subtype H5N1. Emerg Infect Dis. 2007; 13:426–435.
Article
17. Fu TM, Grimm KM, Citron MP, Freed DC, Fan J, Keller PM, Shiver JW, Liang X, Joyce JG. Comparative immunogenicity evaluations of influenza A virus M2 peptide as recombinant virus like particle or conjugate vaccines in mice and monkeys. Vaccine. 2009; 27:1440–1447.
Article
18. Ernst WA, Kim HJ, Tumpey TM, Jansen AD, Tai W, Cramer DV, dler-Moore JP, Fujii G. Protection against H1, H5, H6 and H9 influenza A infection with liposomal matrix 2 epitope vaccines. Vaccine. 2006; 24:5158–5168.
Article
19. Eliasson DG, El BK, Schon K, Ramne A, Festjens E, Lowenadler B, Fiers W, Saelens X, Lycke N. CTA1-M2e-DD: a novel mucosal adjuvant targeted influenza vaccine. Vaccine. 2008; 26:1243–1252.
Article
20. Huleatt JW, Nakaar V, Desai P, Huang Y, Hewitt D, Jacobs A, Tang J, McDonald W, Song L, Evans RK, Umlauf S, Tussey L, Powell TJ. Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin. Vaccine. 2008; 26:201–214.
Article
21. Wu F, Yuan XY, Li J, Chen YH. The co-administration of CpG-ODN influenced protective activity of influenza M2e vaccine. Vaccine. 2009; 27:4320–4324.
Article
22. Kim MC, Lee YN, Hwang HS, Lee YT, Ko EJ, Jung YJ, Cho MK, Kim YJ, Lee JS, Ha SH, Kang SM. Influenza M2 virus-like particles confer a broader range of cross protection to the strain-specific pre-existing immunity. Vaccine. 2014; 32:5824–5831.
Article
23. De FM, Martens W, Roose K, Deroo T, Vervalle F, Bentahir M, Vandekerckhove J, Fiers W, Saelens X. An influenza A vaccine based on tetrameric ectodomain of matrix protein 2. J Biol Chem. 2008; 283:11382–11387.
Article
24. Liu W, Peng Z, Liu Z, Lu Y, Ding J, Chen YH. High epitope density in a single recombinant protein molecule of the extracellular domain of influenza A virus M2 protein significantly enhances protective immunity. Vaccine. 2004; 23:366–371.
Article
25. Heinen PP, Rijsewijk FA, de Boer-Luijtze EA, Bianchi AT. Vaccination of pigs with a DNA construct expressing an influenza virus M2-nucleoprotein fusion protein exacerbates disease after challenge with influenza A virus. J Gen Virol. 2002; 83:1851–1859.
Article
26. Andersson AM, Hakansson KO, Jensen BA, Christensen D, Andersen P, Thomsen AR, Christensen JP. Increased immunogenicity and protective efficacy of influenza M2e fused to a tetramerizing protein. PLoS One. 2012; 7:e46395.
Article
27. Hessel A, Savidis-Dacho H, Coulibaly S, Portsmouth D, Kreil TR, Crowe BA, Schwendinger MG, Pilz A, Barrett PN, Falkner FG, Schafer B. MVA vectors expressing conserved influenza proteins protect mice against lethal challenge with H5N1, H9N2 and H7N1 viruses. PLoS One. 2014; 9:e88340.
Article
28. Zebedee SL, Richardson CD, Lamb RA. Characterization of the influenza virus M2 integral membrane protein and expression at the infected-cell surface from cloned cDNA. J Virol. 1985; 56:502–511.
Article
29. Song JM, Van RN, Bozja J, Compans RW, Kang SM. Vaccination inducing broad and improved cross protection against multiple subtypes of influenza A virus. Proc Natl Acad Sci U S A. 2011; 108:757–761.
Article
30. Kim MC, Lee YN, Ko EJ, Lee JS, Kwon YM, Hwang HS, Song JM, Song BM, Lee YJ, Choi JG, Kang HM, Quan FS, Compans RW, Kang SM. Supplementation of influenza split vaccines with conserved M2 ectodomains overcomes strain specificity and provides long-term cross protection. Mol Ther. 2014; 22:1364–1374.
Article
31. Harris A, Cardone G, Winkler DC, Heymann JB, Brecher M, White JM, Steven AC. Influenza virus pleiomorphy characterized by cryoelectron tomography. Proc Natl Acad Sci U S A. 2006; 103:19123–19127.
Article
32. Zebedee SL, Lamb RA. Influenza A virus M2 protein: monoclonal antibody restriction of virus growth and detection of M2 in virions. J Virol. 1988; 62:2762–2772.
Article
33. Treanor JJ, Tierney EL, Zebedee SL, Lamb RA, Murphy BR. Passively transferred monoclonal antibody to the M2 protein inhibits influenza A virus replication in mice. J Virol. 1990; 64:1375–1377.
Article
34. Song JM, Wang BZ, Park KM, Van RN, Quan FS, Kim MC, Jin HT, Pekosz A, Compans RW, Kang SM. Influenza virus-like particles containing M2 induce broadly cross protective immunity. PLoS One. 2011; 6:e14538.
Article
35. Jegerlehner A, Schmitz N, Storni T, Bachmann MF. Influenza A vaccine based on the extracellular domain of M2: weak protection mediated via antibody-dependent NK cell activity. J Immunol. 2004; 172:5598–5605.
Article
36. Mozdzanowska K, Maiese K, Furchner M, Gerhard W. Treatment of influenza virus-infected SCID mice with nonneutralizing antibodies specific for the transmembrane proteins matrix 2 and neuraminidase reduces the pulmonary virus titer but fails to clear the infection. Virology. 1999; 254:138–146.
Article
37. Wang BZ, Liu W, Kang SM, Alam M, Huang C, Ye L, Sun Y, Li Y, Kothe DL, Pushko P, Dokland T, Haynes BF, Smith G, Hahn BH, Compans RW. Incorporation of high levels of chimeric human immunodeficiency virus envelope glycoproteins into virus-like particles. J Virol. 2007; 81:10869–10878.
Article
38. Ada GL, Jones PD. The immune response to influenza infection. Curr Top Microbiol Immunol. 1986; 128:1–54.
Article
39. Couch RB, Kasel JA. Immunity to influenza in man. Annu Rev Microbiol. 1983; 37:529–549.
Article
40. Lamm ME. Interaction of antigens and antibodies at mucosal surfaces. Annu Rev Microbiol. 1997; 51:311–340.
Article
41. Taylor PM, Wraith DC, Askonas BA. Control of immune interferon release by cytotoxic T-cell clones specific for influenza. Immunology. 1985; 54:607–614.
42. Virelizier JL, Allison AC, Schild GC. Immune responses to influenza virus in the mouse, and their role in control of the infection. Br Med Bull. 1979; 35:65–68.
Article
43. Bachmann MF, Lutz MB, Layton GT, Harris SJ, Fehr T, Rescigno M, Ricciardi-Castagnoli P. Dendritic cells process exogenous viral proteins and virus-like particles for class I presentation to CD8+ cytotoxic T lymphocytes. Eur J Immunol. 1996; 26:2595–2600.
Article
44. Huber VC, Lynch JM, Bucher DJ, Le J, Metzger DW. Fc receptor-mediated phagocytosis makes a significant contribution to clearance of influenza virus infections. J Immunol. 2001; 166:7381–7388.
Article
45. Hashimoto Y, Moki T, Takizawa T, Shiratsuchi A, Nakanishi Y. Evidence for phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and macrophages in mice. J Immunol. 2007; 178:2448–2457.
Article
46. Zharikova D, Mozdzanowska K, Feng J, Zhang M, Gerhard W. Influenza type A virus escape mutants emerge in vivo in the presence of antibodies to the ectodomain of matrix protein 2. J Virol. 2005; 79:6644–6654.
Article
47. El BK, Descamps F, De FM, Smet A, Festjens E, Birkett A, Van RN, Verbeek S, Fiers W, Saelens X. Universal vaccine based on ectodomain of matrix protein 2 of influenza A: Fc receptors and alveolar macrophages mediate protection. J Immunol. 2011; 186:1022–1031.
Article
48. Lee YN, Lee YT, Kim MC, Hwang HS, Lee JS, Kim KH, Kang SM. Fc receptor is not required for inducing antibodies but plays a critical role in conferring protection after influenza M2 vaccination. Immunology. 2014; 143:300–309.
Article
49. Fu TM, Freed DC, Horton MS, Fan J, Citron MP, Joyce JG, Garsky VM, Casimiro DR, Zhao Q, Shiver JW, Liang X. Characterizations of four monoclonal antibodies against M2 protein ectodomain of influenza A virus. Virology. 2009; 385:218–226.
Article
50. Subbarao K, Joseph T. Scientific barriers to developing vaccines against avian influenza viruses. Nat Rev Immunol. 2007; 7:267–278.
Article
51. Simhadri VR, Dimitrova M, Mariano JL, Zenarruzabeitia O, Zhong W, Ozawa T, Muraguchi A, Kishi H, Eichelberger MC, Borrego F. A Human Anti-M2 Antibody Mediates Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Cytokine Secretion by Resting and Cytokine-Preactivated Natural Killer (NK) Cells. PLoS One. 2015; 10:e0124677.
Article
52. Anders EM, Hartley CA, Reading PC, Ezekowitz RA. Complement-dependent neutralization of influenza virus by a serum mannose-binding lectin. J Gen Virol. 1994; 75(Pt 3):615–622.
Article
53. Hirsch RL, Winkelstein JA, Griffin DE. The role of complement in viral infections. III. Activation of the classical and alternative complement pathways by Sindbis virus. J Immunol. 1980; 124:2507–2510.
54. Cooper NR, Jensen FC, Welsh RM Jr, Oldstone MB. Lysis of RNA tumor viruses by human serum: direct antibody-independent triggering of the classical complement pathway. J Exp Med. 1976; 144:970–984.
Article
55. Beebe DP, Schreiber RD, Cooper NR. Neutralization of influenza virus by normal human sera: mechanisms involving antibody and complement. J Immunol. 1983; 130:1317–1322.
56. Wang R, Song A, Levin J, Dennis D, Zhang NJ, Yoshida H, Koriazova L, Madura L, Shapiro L, Matsumoto A, Yoshida H, Mikayama T, Kubo RT, Sarawar S, Cheroutre H, Kato S. Therapeutic potential of a fully human monoclonal antibody against influenza A virus M2 protein. Antiviral Res. 2008; 80:168–177.
Article
57. Gerhard W, Mozdzanowska K, Furchner M, Washko G, Maiese K. Role of the B-cell response in recovery of mice from primary influenza virus infection. Immunol Rev. 1997; 159:95–103.
Article
58. Heusser CH, Anderson CL, Grey HM. Receptors for IgG: subclass specificity of receptors on different mouse cell types and the definition of two distinct receptors on a macrophage cell line. J Exp Med. 1977; 145:1316–1327.
Article
59. Neuberger MS, Rajewsky K. Activation of mouse complement by monoclonal mouse antibodies. Eur J Immunol. 1981; 11:1012–1016.
Article
60. Doherty PC, Topham DJ, Tripp RA, Cardin RD, Brooks JW, Stevenson PG. Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Immunol Rev. 1997; 159:105–117.
Article
61. Heidema J, Rossen JW, Lukens MV, Ketel MS, Scheltens E, Kranendonk ME, van Maren WW, van Loon AM, Otten HG, Kimpen JL, van Bleek GM. Dynamics of human respiratory virus-specific CD8+ T cell responses in blood and airways during episodes of common cold. J Immunol. 2008; 181:5551–5559.
Article
62. McElhaney JE, Xie D, Hager WD, Barry MB, Wang Y, Kleppinger A, Ewen C, Kane KP, Bleackley RC. T cell responses are better correlates of vaccine protection in the elderly. J Immunol. 2006; 176:6333–6339.
Article
63. Bender BS, Croghan T, Zhang L, Small PA Jr. Transgenic mice lacking class I major histocompatibility complex-restricted T cells have delayed viral clearance and increased mortality after influenza virus challenge. J Exp Med. 1992; 175:1143–1145.
Article
64. Jameson J, Cruz J, Ennis FA. Human cytotoxic T-lymphocyte repertoire to influenza A viruses. J Virol. 1998; 72:8682–8689.
Article
65. Gianfrani C, Oseroff C, Sidney J, Chesnut RW, Sette A. Human memory CTL response specific for influenza A virus is broad and multispecific. Hum Immunol. 2000; 61:438–452.
Article
66. Mozdzanowska K, Feng J, Eid M, Kragol G, Cudic M, Otvos L Jr, Gerhard W. Induction of influenza type A virus-specific resistance by immunization of mice with a synthetic multiple antigenic peptide vaccine that contains ectodomains of matrix protein 2. Vaccine. 2003; 21:2616–2626.
Article
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