Vaccination Inducing Broad and Improved Cross Protection Against Multiple Subtypes of Influenza A Virus

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Dec 29

PMID 21187388

Citations 80

Authors

Jae-Min Song

Nico van Rooijen

Jadranka Bozja

Richard W Compans

Sang-Moo Kang

Affiliations

Soon will be listed here.

Abstract

Development of an influenza vaccine that provides broadly cross-protective immunity has been a scientific challenge for more than half a century. This study presents an approach to overcome strain-specific protection by supplementing conventional vaccines with virus-like particles (VLPs) containing the conserved M2 protein (M2 VLPs) in the absence of adjuvants. We demonstrate that an inactivated influenza vaccine supplemented with M2 VLPs prevents disease symptoms without showing weight loss and confers complete cross protection against lethal challenge with heterologous influenza A viruses including the 2009 H1N1 pandemic virus as well as heterosubtypic H3N2 and H5N1 influenza viruses. Cross-protective immunity was long-lived, for more than 7 mo. Immune sera from mice immunized with M2 VLP supplemented vaccine transferred cross protection to naive mice. Dendritic and macrophage cells were found to be important for this cross protection mediated by immune sera. The results provide evidence that supplementation of seasonal influenza vaccines with M2 VLPs is a promising approach for overcoming the limitation of strain-specific protection by current vaccines and developing a universal influenza A vaccine.

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References

Chen B, Leser G, Morita E, Lamb R . Influenza virus hemagglutinin and neuraminidase, but not the matrix protein, are required for assembly and budding of plasmid-derived virus-like particles. J Virol. 2007; 81(13):7111-23. PMC: 1933269. DOI: 10.1128/JVI.00361-07. View

McGill J, van Rooijen N, Legge K . Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs. J Exp Med. 2008; 205(7):1635-46. PMC: 2442641. DOI: 10.1084/jem.20080314. View

Gomez-Puertas P, Albo C, Vivo A, Portela A . Influenza virus matrix protein is the major driving force in virus budding. J Virol. 2000; 74(24):11538-47. PMC: 112434. DOI: 10.1128/jvi.74.24.11538-11547.2000. View

Huleatt J, Nakaar V, Desai P, Huang Y, Hewitt D, Jacobs A . Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin. Vaccine. 2007; 26(2):201-14. DOI: 10.1016/j.vaccine.2007.10.062. View

de Jong M, Tran T, Truong H, Vo M, Smith G, Nguyen V . Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005; 353(25):2667-72. DOI: 10.1056/NEJMoa054512. View

Quan F, Huang C, Compans R, Kang S . Virus-like particle vaccine induces protective immunity against homologous and heterologous strains of influenza virus. J Virol. 2007; 81(7):3514-24. PMC: 1866067. DOI: 10.1128/JVI.02052-06. View

Fu T, Grimm K, Citron M, Freed D, Fan J, Keller P . 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):1440-7. DOI: 10.1016/j.vaccine.2008.12.034. View

De Filette M, Ramne A, Birkett A, Lycke N, Lowenadler B, Jou W . The universal influenza vaccine M2e-HBc administered intranasally in combination with the adjuvant CTA1-DD provides complete protection. Vaccine. 2005; 24(5):544-51. DOI: 10.1016/j.vaccine.2005.08.061. View

Gessner J, Heiken H, Tamm A, Schmidt R . The IgG Fc receptor family. Ann Hematol. 1998; 76(6):231-48. DOI: 10.1007/s002770050396. View

10.

Bosio C, Dow S . Francisella tularensis induces aberrant activation of pulmonary dendritic cells. J Immunol. 2005; 175(10):6792-801. DOI: 10.4049/jimmunol.175.10.6792. View

11.

Neirynck S, Deroo T, Saelens X, Vanlandschoot P, Jou W, Fiers W . A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat Med. 1999; 5(10):1157-63. DOI: 10.1038/13484. View

12.

Song J, Hossain J, Yoo D, Lipatov A, Davis C, Quan F . Protective immunity against H5N1 influenza virus by a single dose vaccination with virus-like particles. Virology. 2010; 405(1):165-75. PMC: 2925114. DOI: 10.1016/j.virol.2010.05.034. View

13.

Fu T, Freed D, Horton M, Fan J, Citron M, Joyce J . Characterizations of four monoclonal antibodies against M2 protein ectodomain of influenza A virus. Virology. 2008; 385(1):218-26. DOI: 10.1016/j.virol.2008.11.035. View

14.

Latham T, GALARZA J . Formation of wild-type and chimeric influenza virus-like particles following simultaneous expression of only four structural proteins. J Virol. 2001; 75(13):6154-65. PMC: 114331. DOI: 10.1128/JVI.75.13.6154-6165.2001. View

15.

Jegerlehner A, Schmitz N, Storni T, Bachmann M . Influenza A vaccine based on the extracellular domain of M2: weak protection mediated via antibody-dependent NK cell activity. J Immunol. 2004; 172(9):5598-605. DOI: 10.4049/jimmunol.172.9.5598. View

16.

Lamb R, Zebedee S, Richardson C . Influenza virus M2 protein is an integral membrane protein expressed on the infected-cell surface. Cell. 1985; 40(3):627-33. DOI: 10.1016/0092-8674(85)90211-9. View

17.

Feng J, Zhang M, Mozdzanowska K, Zharikova D, Hoff H, Wunner W . Influenza A virus infection engenders a poor antibody response against the ectodomain of matrix protein 2. Virol J. 2006; 3:102. PMC: 1702354. DOI: 10.1186/1743-422X-3-102. View

18.

Eliasson D, Bakkouri K, Schon K, Ramne A, Festjens E, Lowenadler B . CTA1-M2e-DD: a novel mucosal adjuvant targeted influenza vaccine. Vaccine. 2008; 26(9):1243-52. DOI: 10.1016/j.vaccine.2007.12.027. View

19.

van Rooijen N, Sanders A . Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods. 1994; 174(1-2):83-93. DOI: 10.1016/0022-1759(94)90012-4. View

20.

Rangel-Moreno J, Carragher D, Misra R, Kusser K, Hartson L, Moquin A . B cells promote resistance to heterosubtypic strains of influenza via multiple mechanisms. J Immunol. 2007; 180(1):454-63. PMC: 2712821. DOI: 10.4049/jimmunol.180.1.454. View