M2-based influenza vaccines: recent advances and clinical potential

Expert Review of Vaccines

Volumn 16, Issue 2, 2017, Pages 123-136

  Kolpe, Annasaheb ^a,b   Schepens, Bert ^a,b   Fiers, Walter ^a,b   Saelens, Xavier ^a,b  

^a DEPARTMENT OF PLANT SYSTEMS BIOLOGY   (Belgium)

^b GHENT UNIVERSITY   (Belgium)

Author keywords

broadly protecting antibodies; broadly protective vaccines; Clinical trial; influenza A virus; M2e; matrix protein 2

Indexed keywords

INFLUENZA VACCINE; MATRIX PROTEIN; MATRIX PROTEIN 2 VACCINE; UNCLASSIFIED DRUG; M2 PROTEIN, INFLUENZA A VIRUS; RECOMBINANT VACCINE;

ANTIBODY RESPONSE; DRUG EFFICACY; DRUG SAFETY; HUMAN; IMMUNE RESPONSE; IMMUNITY; IMMUNOGENICITY; NONHUMAN; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE; ANIMAL; CLINICAL TRIAL (TOPIC); DISEASE MODEL; DRUG DEVELOPMENT; GENETICS; IMMUNOLOGY; PRECLINICAL STUDY; TRENDS;

ANIMALS; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; DRUG DISCOVERY; DRUG EVALUATION, PRECLINICAL; HUMANS; INFLUENZA VACCINES; VACCINES, SYNTHETIC; VIRAL MATRIX PROTEINS;

EID: 85008517823     PISSN: 14760584     EISSN: 17448395     Source Type: Journal    
DOI: 10.1080/14760584.2017.1240041     Document Type: Review

References (122)

1. Smith W, Andrewes CH, Laidlaw PP., Originally published as volume 2, issue 5732A VIRUS OBTAINED FROM INFLUENZA PATIENTS. The Lancet. 1933;222(5732):66–68.
2. Davenport FM. Current knowledge of influenza vaccine. Jama. 1962;182:11–13.
3. Stokes J, Chenoweth AD, Waltz AD, et al. Results of immunization by means of active virus of human influenza. J Clin Invest. 1937;16(2):237–243.
4. Krammer F, Palese P. Advances in the development of influenza virus vaccines. Nat Rev Drug Discov. 2015;14(3):167–182.
5. Tong S, Li Y, Rivailler P, et al. A distinct lineage of influenza A virus from bats. Proc Natl Acad Sci U S A. 2012;109(11):4269–4274.
6. Tong S, Zhu X, Li Y, et al. New world bats harbor diverse influenza A viruses. PLoS Pathog. 2013;9(10):e1003657.
7. Simonsen L, Clarke MJ, Schonberger LB, et al. Pandemic versus epidemic influenza mortality:a pattern of changing age distribution. J Infect Dis. 1998;178(1):53–60.
8. Schnitzler SU, Schnitzler P. An update on swine-origin influenza virus A/H1N1:a review. Virus Genes. 2009;39(3):279–292.
9. Lamb RA, Choppin PW. Identification of a second protein (M2) encoded by RNA segment 7 of influenza virus. Virology. 1981;112(2):729–737.•• First description of the M2 protein of influenza A
10. Lamb RA, Lai CJ, Choppin PW. Sequences of mRNAs derived from genome RNA segment 7 of influenza virus:colinear and interrupted mRNAs code for overlapping proteins. Proc Natl Acad Sci U S A. 1981;78(7):4170–4174.
11. Chizhmakov IV, Geraghty FM, Ogden DC, et al. 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.
12. Pinto LH, Holsinger LJ, Lamb RA. Influenza virus M2 protein has ion channel activity. Cell. 1992;69(3):517–528.
13. Leiding T, Wang J, Martinsson J, et al. Proton and cation transport activity of the M2 proton channel from influenza A virus. Proc Natl Acad Sci U S A. 2010;107(35):15409–15414.
14. Stauffer S, Feng Y, Nebioglu F, et al. Stepwise priming by acidic pH and a high K+ concentration is required for efficient uncoating of influenza A virus cores after penetration. J Virol. 2014;88(22):13029–13046.
15. Helenius A. Unpacking the incoming influenza virus. Cell. 1992;69(4):577–578.
16. Music N, Reber AJ, Kim MC, et al. Supplementation of H1N1pdm09 split vaccine with heterologous tandem repeat M2e5x virus-like particles confers improved cross-protection in ferrets. Vaccine. 2016;34(4):466–473.
17. Tsybalova LM, Stepanova LA, Kuprianov VV, et al. Development of a candidate influenza vaccine based on virus-like particles displaying influenza M2e peptide into the immunodominant region of hepatitis B core antigen:broad protective efficacy of particles carrying four copies of M2e. Vaccine. 2015;33(29):3398–3406.
18. Black RA, Rota PA, Gorodkova N, et al. Antibody response to the M2 protein of influenza A virus expressed in insect cells. J Gen Virol. 1993;74(Pt 1):143–146.
19. Zhong W, Reed C, Blair PJ, et al. Influenza serology working G. Serum antibody response to matrix protein 2 following natural infection with 2009 pandemic influenza A(H1N1) virus in humans. J Infect Dis. 2014;209(7):986–994.
20. Cho KJ, Schepens B, Moonens K, et al. Crystal structure of the conserved amino terminus of the extracellular domain of matrix protein 2 of influenza a virus gripped by an antibody. J Virol. 2016;90(1):611–615.
21. Cho KJ, Schepens B, Seok JH, et al. Structure of the extracellular domain of matrix protein 2 of influenza A virus in complex with a protective monoclonal antibody. J Virol. 2015;89(7):3700–3711.
22. Schotsaert M, Ysenbaert T, Neyt K, et al. Natural and long-lasting cellular immune responses against influenza in the M2e-immune host. Mucosal Immunol. 2013;6(2):276–287.
23. Neirynck S, Deroo T, Saelens X, et al. A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat Med. 1999;5(10):1157–1163.•• First report on the immune protective potential of M2e against influenza A virus challenge. Also, an example of a non-natural immune response against a pathogen that turns out to be protective.
24. Kim MC, Song JM, Eunju O, et al. Virus-like particles containing multiple M2 extracellular domains confer improved cross-protection against various subtypes of influenza virus. Mol Ther. 2013;21(2):485–492.
25. De Filette M, Martens W, Roose K, et al. An influenza A vaccine based on tetrameric ectodomain of matrix protein 2. J Biol Chem. 2008;283(17):11382–11387.
26. Zeng W, Horrocks KJ, Tan ACL, et al. Chemical synthesis of monomeric, dimeric and tetrameric forms of the ectodomain of influenza matrix 2 protein. European J Org Chem. 2016;2016(5):1054–1059.
27. Eliasson DG, El Bakkouri K, Schon K, et al. CTA1-M2e-DD:a novel mucosal adjuvant targeted influenza vaccine. Vaccine. 2008;26(9):1243–1252.
28. Deng L, Ibanez LI, Van Den Bossche V, et al. Protection against influenza a virus challenge with M2e-displaying filamentous escherichia coli phages. PLoS One. 2015;10(5):e0126650.
29. Rappazzo CG, Watkins HC, Guarino CM, et al. Recombinant M2e outer membrane vesicle vaccines protect against lethal influenza A challenge in BALB/c mice. Vaccine. 2016;34(10):1252–1258.
30. Tompkins SM, Zhao ZS, Lo CY, et al. Matrix protein 2 vaccination and protection against influenza viruses, including subtype H5N1. Emerg Infect Dis. 2007;13(3):426–435.
31. Mayr A, Danner K. Vaccination against pox diseases under immunosuppressive conditions. Dev Biol Stand. 1978;41:225–234.
32. Hessel A, Savidis-Dacho H, Coulibaly S, et al. MVA vectors expressing conserved influenza proteins protect mice against lethal challenge with H5N1, H9N2 and H7N1 viruses. PLoS One. 2014;9(2):e88340.
33. Dabaghian M, Latify AM, Tebianian M, et al. Vaccination with recombinant 4 x M2e.HSP70c fusion protein as a universal vaccine candidate enhances both humoral and cell-mediated immune responses and decreases viral shedding against experimental challenge of H9N2 influenza in chickens. Vet Microbiol. 2014;174(1–2):116–126.
34. Ionescu RM, Przysiecki CT, Liang X, et al. Pharmaceutical and immunological evaluation of human papillomavirus viruslike particle as an antigen carrier. J Pharm Sci. 2006;95(1):70–79.
35. Bessa J, Schmitz N, Hinton HJ, et al. Efficient induction of mucosal and systemic immune responses by virus-like particles administered intranasally:implications for vaccine design. Eur J Immunol. 2008;38(1):114–126.
36. Hashemi H, Pouyanfard S, Bandehpour M, et al. Immunization with M2e-displaying T7 bacteriophage nanoparticles protects against influenza A virus challenge. PLoS One. 2012;7(9):e45765.
37. Fu TM, Grimm KM, Citron MP, et al. Comparative immunogenicity evaluations of influenza A virus M2 peptide as recombinant virus like particle or conjugate vaccines in mice and monkeys. Vaccine. 2009;27(9):1440–1447.
38. Ernst WA, Kim HJ, Tumpey TM, et al. Protection against H1, H5, H6 and H9 influenza A infection with liposomal matrix 2 epitope vaccines. Vaccine. 2006;24(24):5158–5168.
39. Huleatt JW, Nakaar V, Desai P, et al. 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(2):201–214.
40. Mu X, Hu K, Shen M, et al. Protection against influenza A virus by vaccination with a recombinant fusion protein linking influenza M2e to human serum albumin (HSA). J Virol Methods. 2016;228:84–90.
41. Ingrole RS, Tao W, Tripathy JN, et al. Synthesis and immunogenicity assessment of elastin-like polypeptide-M2e construct as an influenza antigen. Nano Life. 2014;4(2):1450004.
42. Zhao G, Miao Y, Guo Y, et al. Development of a heat-stable and orally delivered recombinant M2e-expressing B. subtilis spore-based influenza vaccine. Hum Vaccin Immunother. 2014;10(12):3649–3658.
43. Wibowo N, Hughes FK, Fairmaid EJ, et al. Protective efficacy of a bacterially produced modular capsomere presenting M2e from influenza:extending the potential of broadly cross-protecting epitopes. Vaccine. 2014;32(29):3651–3655.
44. Blokhina EA, Kuprianov VV, Stepanova LA, et al. A molecular assembly system for presentation of antigens on the surface of HBc virus-like particles. Virology. 2013;435(2):293–300.
45. Herve PL, Raliou M, Bourdieu C, et al. A novel subnucleocapsid nanoplatform for mucosal vaccination against influenza virus that targets the ectodomain of matrix protein 2. J Virol. 2014;88(1):325–338.• Elegant design of M2e-displaying nanoparticles derived from respiratory syncytial virus nucleoprotein that protect when used as a mucosal vaccine against influenza A.
46. De Filette M, Min Jou W, Birkett A, et al. Universal influenza A vaccine:optimization of M2-based constructs. Virology. 2005;337(1):149–161.
47. De Filette M, Ramne A, Birkett A, et al. The universal influenza vaccine M2e-HBc administered intranasally in combination with the adjuvant CTA1-DD provides complete protection. Vaccine. 2006;24(5):544–551.
48. Wu F, Yuan XY, Li J, et al. The co-administration of CpG-ODN influenced protective activity of influenza M2e vaccine. Vaccine. 2009;27(32):4320–4324.
49. Andersson AM, Hakansson KO, Jensen BA, et al. Increased immunogenicity and protective efficacy of influenza M2e fused to a tetramerizing protein. PLoS One. 2012;7(10):e46395.
50. El Bakkouri K, Descamps F, De Filette M, et al. Universal vaccine based on ectodomain of matrix protein 2 of influenza A:fc receptors and alveolar macrophages mediate protection. J Immunol. 2011;186(2):1022–1031.• Demonstrates an important role of Fcγ receptors for protection by anti-M2e IgG.
51. Lee YN, Lee YT, Kim MC, et al. Fc receptor is not required for inducing antibodies but plays a critical role in conferring protection after influenza M2 vaccination. Immunology. 2014;143(2):300–309.
52. Jegerlehner A, Schmitz N, Storni T, et al. Influenza A vaccine based on the extracellular domain of M2:weak protection mediated via antibody-dependent NK cell activity. J Immunol. 2004;172(9):5598–5605.
53. Wang R, Song A, Levin J, et al. Therapeutic potential of a fully human monoclonal antibody against influenza A virus M2 protein. Antiviral Res. 2008;80(2):168–177.
54. Kim MC, Lee YN, Ko EJ, et al. Supplementation of influenza split vaccines with conserved M2 ectodomains overcomes strain specificity and provides long-term cross protection. Mol Ther. 2014;22(7):1364–1374.
55. Lee YN, Kim MC, Lee YT, et al. AS04-adjuvanted virus-like particles containing multiple M2 extracellular domains of influenza virus confer improved protection. Vaccine. 2014;32(35):4578–4585.
56. Turley CB, Rupp RE, Johnson C, et al. Safety and immunogenicity of a recombinant M2e-flagellin influenza vaccine (STF2.4xM2e) in healthy adults. Vaccine. 2011;29(32):5145–5152.• Report on a phase I study with a low-dose M2e vaccine antigen.
57. Song JM, Van Rooijen N, Bozja J, et al. Vaccination inducing broad and improved cross protection against multiple subtypes of influenza A virus. Proc Natl Acad Sci U S A. 2011;108(2):757–761.
58. Song JM, Wang BZ, Park KM, et al. Influenza virus-like particles containing M2 induce broadly cross protective immunity. PLoS One. 2011;6(1):e14538.
59. Lalor PA, Webby RJ, Morrow J, et al. Plasmid DNA-based vaccines protect mice and ferrets against lethal challenge with A/Vietnam/1203/04 (H5N1) influenza virus. J Infect Dis. 2008;197(12):1643–1652.
60. Fan J, Liang X, Horton MS, et al. Preclinical study of influenza virus A M2 peptide conjugate vaccines in mice, ferrets, and rhesus monkeys. Vaccine. 2004;22(23–24):2993–3003.
61. Denis J, Acosta-Ramirez E, Zhao Y, et al. Development of a universal influenza A vaccine based on the M2e peptide fused to the papaya mosaic virus (PapMV) vaccine platform. Vaccine. 2008;26(27–28):3395–3403.
62. Alvarez P, Zylberman V, Ghersi G, et al. Tandem repeats of the extracellular domain of matrix 2 influenza protein exposed in Brucella lumazine synthase decameric carrier molecule induce protection in mice. Vaccine. 2013;31(5):806–812.
63. Leclerc D, Rivest M, Babin C, et al. A novel M2e based flu vaccine formulation for dogs. PLoS One. 2013;8(10):e77084.
64. Heinen PP, Rijsewijk FA, de Boer-Luijtze EA, et al. 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(Pt 8):1851–1859.
65. Petukhova NV, Gasanova TV, Stepanova LA, et al. Immunogenicity and protective efficacy of candidate universal influenza A nanovaccines produced in plants by tobacco mosaic virus-based vectors. Curr Pharm Des. 2013;19(31):5587–5600.
66. Pejoski D, Zeng W, Rockman S, et al. A lipopeptide based on the M2 and HA proteins of influenza A viruses induces protective antibody. Immunol Cell Biol. 2010;88(5):605–611.
67. Wolf AI, Mozdzanowska K, Williams KL, et al. Vaccination with M2e-based multiple antigenic peptides:characterization of the B cell response and protection efficacy in inbred and outbred mice. PLoS One. 2011;6(12):e28445.
68. Wei H, Lenz SD, Thompson DH, et al. DNA-vaccine platform development against H1N1 subtype of swine influenza A viruses. Viral Immunol. 2012;25(4):297–305.
69. Park KS, Seo YB, Lee JY, et al. Complete protection against a H5N2 avian influenza virus by a DNA vaccine expressing a fusion protein of H1N1 HA and M2e. Vaccine. 2011;29(33):5481–5487.
70. Kammoun H, Roux X, Raze D, et al. Immunogenicity of live attenuated B. pertussis BPZE1 producing the universal influenza vaccine candidate M2e. PLoS One. 2013;8(3):e59198.
71. Treanor JJ, Tierney EL, Zebedee SL, et al. Passively transferred monoclonal antibody to the M2 protein inhibits influenza A virus replication in mice. J Virol. 1990;64(3):1375–1377.
72. Grandea AG, 3rd, Olsen OA, Cox TC, et al. Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses. Proc Natl Acad Sci U S A. 2010;107(28):12658–12663.
73. Liu W, Zou P, Chen YH. Monoclonal antibodies recognizing EVETPIRN epitope of influenza A virus M2 protein could protect mice from lethal influenza A virus challenge. Immunol Lett. 2004;93(2–3):131–136.
74. 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(8):2762–2772.•• First monoclonal antibody against M2 and, surprisingly, with in vitro antiviral activity.
75. Zebedee SL, Lamb RA. Nucleotide sequences of influenza A virus RNA segment 7:a comparison of five isolates. Nucleic Acids Res. 1989;17(7):2870.
76. Hughey PG, Roberts PC, Holsinger LJ, et al. Effects of antibody to the influenza A virus M2 protein on M2 surface expression and virus assembly. Virology. 1995;212(2):411–421.
77. Hughey PG, Compans RW, Zebedee SL, et al. Expression of the influenza A virus M2 protein is restricted to apical surfaces of polarized epithelial cells. J Virol. 1992;66(9):5542–5552.
78. Hashimoto Y, Moki T, Takizawa T, et al. Evidence for phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and macrophages in mice. J Immunol. 2007;178(4):2448–2457.
79. Huber VC, Lynch JM, Bucher DJ, et al. Fc receptor-mediated phagocytosis makes a significant contribution to clearance of influenza virus infections. J Immunol. 2001;166(12):7381–7388.
80. Zharikova D, Mozdzanowska K, Feng J, et al. 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(11):6644–6654.
81. Nimmerjahn F, Bruhns P, Horiuchi K, et al. FcgammaRIV:a novel FcR with distinct IgG subclass specificity. Immunity. 2005;23(1):41–51.
82. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8(1):34–47.
83. Fu TM, Freed DC, Horton MS, et al. Characterizations of four monoclonal antibodies against M2 protein ectodomain of influenza A virus. Virology. 2009;385(1):218–226.
84. Simhadri VR, Dimitrova M, Mariano JL, et al. 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(4):e0124677.
85. Jegaskanda S, Job ER, Kramski M, et al. Cross-reactive influenza-specific antibody-dependent cellular cytotoxicity antibodies in the absence of neutralizing antibodies. J Immunol. 2013;190(4):1837–1848.
86. Jegaskanda S, Weinfurter JT, Friedrich TC, et al. Antibody-dependent cellular cytotoxicity is associated with control of pandemic H1N1 influenza virus infection of macaques. J Virol. 2013;87(10):5512–5522.
87. Srivastava V, Yang Z, Hung IF, et al. Identification of dominant antibody-dependent cell-mediated cytotoxicity epitopes on the hemagglutinin antigen of pandemic H1N1 influenza virus. J Virol. 2013;87(10):5831–5840.
88. DiLillo DJ, Tan GS, Palese P, et al. Broadly neutralizing hemagglutinin stalk-specific antibodies require FcgammaR interactions for protection against influenza virus in vivo. Nat Med. 2014;20(2):143–151.
89. 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(5):2507–2510.
90. Beebe DP, Schreiber RD, Cooper NR. Neutralization of influenza virus by normal human sera:mechanisms involving antibody and complement. J Immunol. 1983;130(3):1317–1322.
91. Fiers W, De Filette M, Birkett A, et al. A “universal” human influenza A vaccine. Virus Res. 2004;103(1–2):173–176.
92. Wu F, Huang JH, Yuan XY, et al. Characterization of immunity induced by M2e of influenza virus. Vaccine. 2007;25(52):8868–8873.
93. Nimmerjahn F, Ravetch JV. Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science. 2005;310(5753):1510–1512.
94. Zeng W, Tan AC, Horrocks K, et al. A lipidated form of the extracellular domain of influenza M2 protein as a self-adjuvanting vaccine candidate. Vaccine. 2015;33(30):3526–3532.
95. Lee YN, Lee YT, Kim MC, et al. A novel vaccination strategy mediating the induction of lung-resident memory CD8 T cells confers heterosubtypic immunity against future pandemic influenza virus. J Immunol. 2016;196(6):2637–2645.
96. Ramos EL, Mitcham JL, Koller TD, et al. Efficacy and safety of treatment with an anti-m2e monoclonal antibody in experimental human influenza. J Infect Dis. 2015;211(7):1038–1044.•• Proof of principle in human that anti-M2e monoclonal antibody therapy can reduce influenza symptoms.
97. Edenborough KM, Gilbertson BP, Brown LE. A mouse model for the study of contact-dependent transmission of influenza A virus and the factors that govern transmissibility. J Virol. 2012;86(23):12544–12551.
98. Price GE, Lo CY, Misplon JA, et al. Mucosal immunization with a candidate universal influenza vaccine reduces virus transmission in a mouse model. J Virol. 2014;88(11):6019–6030.• Study that demonstrates that a broadly protective vaccine against influenza could have a major, possibly underestimated, impact on viral spread in the community.
99. Doherty PC, Topham DJ, Tripp RA, et al. Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Immunol Rev. 1997;159:105–117.
100. Heidema J, Rossen JW, Lukens MV, et al. Dynamics of human respiratory virus-specific CD8+ T cell responses in blood and airways during episodes of common cold. J Immunol. 2008;181(8):5551–5559.
101. McElhaney JE, Xie D, Hager WD, et al. T cell responses are better correlates of vaccine protection in the elderly. J Immunol. 2006;176(10):6333–6339.
102. Gianfrani C, Oseroff C, Sidney J, et al. Human memory CTL response specific for influenza A virus is broad and multispecific. Hum Immunol. 2000;61(5):438–452.
103. Jameson J, Cruz J, Ennis FA. Human cytotoxic T-lymphocyte repertoire to influenza A viruses. J Virol. 1998;72(11):8682–8689.
104. Mozdzanowska K, Feng J, Eid M, et al. 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(19–20):2616–2626.
105. Zhang J, Fan HY, Zhang Z, et al. Recombinant baculovirus vaccine containing multiple M2e and adjuvant LTB induces T cell dependent, cross-clade protection against H5N1 influenza virus in mice. Vaccine. 2016;34(5):622–629.
106. https://clinicaltrials.gov/ct2/show/NCT00819013?term=Acam-flu-A&rank=1. [cited 2016 Jun 2]
107. http://investors.dynavax.com/releasedetail.cfm?ReleaseID=485548. [cited 2016 Jun 2]
108. Stoloff GA, Caparros-Wanderley W. Synthetic multi-epitope peptides identified in silico induce protective immunity against multiple influenza serotypes. Eur J Immunol. 2007;37(9):2441–2449.
109. http://imutex.com/index.php/flu-vaccine-programme/. [cited 2016 Jul 5]
110. Schmitz N, Beerli RR, Bauer M, et al. Universal vaccine against influenza virus:linking TLR signaling to anti-viral protection. Eur J Immunol. 2012;42(4):863–869.
111. Zhou D, Wu TL, Lasaro MO, et al. A universal influenza A vaccine based on adenovirus expressing matrix-2 ectodomain and nucleoprotein protects mice from lethal challenge. Mol Ther. 2010;18(12):2182–2189.
112. http://www.inovio.com/. [cited 2016 Jul 5]
113. http://www.juvaris.com/news/press/09_11_02.html [cited 2016 Jun 2]
114. http://www.altimmune.com/candidates.html. [cited 2016 Jul 5]
115. Gerhard W, Mozdzanowska K, Zharikova D. Prospects for universal influenza virus vaccine. Emerg Infect Dis. 2006;12(4):569–574.
116. Mardanova ES, Kotlyarov RY, Kuprianov VV, et al. Rapid high-yield expression of a candidate influenza vaccine based on the ectodomain of M2 protein linked to flagellin in plants using viral vectors. BMC Biotechnol. 2015;15:42.
117. Mbewana S, Mortimer E, Pera FF, et al. Production of H5N1 influenza virus matrix protein 2 ectodomain protein bodies in tobacco plants and in insect cells as a candidate universal influenza vaccine. Front Bioeng Biotechnol. 2015;3:197.
118. Krammer F, Palese P. Influenza virus hemagglutinin stalk-based antibodies and vaccines. Curr Opin Virol. 2013;3(5):521–530.
119. Lin YP, Gregory V, Bennett M, et al. Recent changes among human influenza viruses. Virus Res. 2004;103(1–2):47–52.
120. Bianchi E, Liang X, Ingallinella P, et al. Universal influenza B vaccine based on the maturational cleavage site of the hemagglutinin precursor. J Virol. 2005;79(12):7380–7388.
121. Wang Y, Xu H, Wu N, et al. Monoclonal antibody, but not synthetic peptide, targeting the ectodomain of influenza B virus M2 proton channel has antiviral activity. New Microbiol. 2010;33(4):311–317.
122. Chambers Benjamin S, Parkhouse K, Ross Ted M, et al. Identification of hemagglutinin residues responsible for H3N2 antigenic drift during the 2014–2015 influenza season. Cell Reports. 2015;12(1):1–6.