Influenza virus-like particles containing M2 induce broadly cross protective immunity.
BACKGROUND
Current influenza vaccines based on the hemagglutinin protein are strain specific and do not provide good protection against drifted viruses or emergence of new pandemic strains. An influenza vaccine that can confer cross-protection against antigenically different influenza A strains is highly desirable for improving public health.


RESULTS
To develop a cross protective vaccine, we generated influenza virus-like particles containing the highly conserved M2 protein in a membrane-anchored form (M2 VLPs), and investigated their immunogenicity and breadth of cross protection. Immunization of mice with M2 VLPs induced anti-M2 antibodies binding to virions of various strains, M2 specific T cell responses, and conferred long-lasting cross protection against heterologous and heterosubtypic influenza viruses. M2 immune sera were found to play an important role in providing cross protection against heterosubtypic virus and an antigenically distinct 2009 pandemic H1N1 virus, and depletion of dendritic and macrophage cells abolished this cross protection, providing new insight into cross-protective immune mechanisms.


CONCLUSIONS
These results suggest that presenting M2 on VLPs in a membrane-anchored form is a promising approach for developing broadly cross protective influenza vaccines.
Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Jae-Min
JM
Song
Bao-Zhong
BZ
Wang
Kyoung-Mi
KM
Park
Nico
N
Van Rooijen
Fu-Shi
FS
Quan
Min-Chul
MC
Kim
Hyun-Tak
HT
Jin
Andrew
A
Pekosz
Richard W
RW
Compans
Sang-Moo
SM
Kang
D000818:Animals; D000914:Antibodies, Viral; D056738:Cross Protection / Q000276:immunology*; D003713:Dendritic Cells / Q000821:virology; D006801:Humans; D007109:Immunity; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D008264:Macrophages / Q000821:virology; D051379:Mice; D009976:Orthomyxoviridae Infections; D014763:Viral Matrix Proteins / Q000276:immunology*; D014771:Virion / Q000276:immunology*; D000086082:Viroporin Proteins
D000914:Antibodies, Viral; D007252:Influenza Vaccines; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
J Exp Med. 2008 Jul 7;205(7):1635-46
18591411
J Immunol. 2004 May 1;172(9):5598-605
15100303
Vaccine. 2008 Jan 10;26(2):201-14
18063235
J Virol. 2007 Feb;81(3):1083-94
17108046
J Virol. 1988 Aug;62(8):2762-72
2455818
J Virol. 2010 Sep;84(17):8765-76
20573832
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7152-7
12748378
Vaccine. 2009 Feb 25;27(9):1440-7
19146898
Vaccine. 2006 Jan 30;24(5):544-51
16169634
Ann Hematol. 1998 Jun;76(6):231-48
9692811
PLoS One. 2009;4(3):e4667
19252744
Eur J Immunol. 1981 Dec;11(12):1012-6
7327198
Annu Rev Immunol. 1996;14:333-67
8717518
Nature. 2009 Jun 25;459(7250):1122-5
19516283
PLoS One. 2010 Feb 11;5(2):e9161
20161790
Vaccine. 2010 Aug 16;28(36):5817-27
20600476
Virology. 2006 Sep 1;352(2):418-26
16777168
Science. 1996 Apr 5;272(5258):54-60
8600537
Vaccine. 2009 Nov 5;27(47):6512-21
19729082
Vaccine. 1999 May 4;17(18):2237-44
10403591
Annu Rev Immunol. 1997;15:235-70
9143688
N Engl J Med. 2009 Nov 12;361(20):1945-52
19745214
Science. 2004 Jul 16;305(5682):371-6
15218094
Eur J Immunol. 2008 Jan;38(1):114-26
18081037
J Virol. 2007 Apr;81(7):3514-24
17251294
Science. 1999 Dec 3;286(5446):1921-5
10583948
Virology. 1991 Jul;183(1):32-43
2053285
Hum Vaccin. 2007 Sep-Oct;3(5):157-64
17637571
Vaccine. 2004 Aug 13;22(23-24):2993-3003
15297047
PLoS One. 2009 Sep 25;4(9):e7152
19779615
Virus Res. 2009 Aug;143(2):140-6
19374929
J Virol. 2008 Feb;82(3):1350-9
18032492
J Virol. 2007 Apr;81(7):3487-94
17202212
Cell. 1985 Mar;40(3):627-33
3882238
Vaccine. 2008 Feb 26;26(9):1243-52
18243429
Vaccine. 2006 Jun 12;24(24):5158-68
16713037
J Immunol Methods. 1994 Sep 14;174(1-2):83-93
8083541
J Immunol. 2004 Aug 1;173(3):1951-8
15265929
J Immunol. 2005 Nov 15;175(10):6792-801
16272336
J Exp Med. 1977 May 1;145(5):1316-27
300783
Nat Med. 1999 Oct;5(10):1157-63
10502819
Hum Immunol. 2000 May;61(5):438-52
10773346
Lancet. 2003 Nov 22;362(9397):1733-45
14643124
Vaccine. 2001 Jun 14;19(27):3681-91
11395202
J Pharm Sci. 2006 Jan;95(1):70-9
16315228
Virology. 2009 Mar 1;385(1):218-26
19070878
Eur J Immunol. 1991 Nov;21(11):2845-50
1936124
Virol J. 2007 Oct 31;4:118
17974006
J Biol Chem. 2008 Apr 25;283(17):11382-7
18252707
Clin Vaccine Immunol. 2006 Sep;13(9):981-90
16960108
Emerg Infect Dis. 2007 Mar;13(3):426-35
17552096
Expert Rev Vaccines. 2009 Apr;8(4):499-508
19348565
J Immunol. 2001 Jun 15;166(12):7381-8
11390489