title: Combined local and systemic immunization is essential for durable T-cell mediated heterosubtypic immunity against influenza A virus.
abstract: The threat from unpredictable influenza virus pandemics necessitates the development of a new type of influenza vaccine. Since the internal proteins are highly conserved, induction of T cells targeting these antigens may provide the solution. Indeed, adenoviral (Ad) vectors expressing flu nucleoprotein have previously been found to induce short-term protection in mice. In this study we confirm that systemic (subcutaneous (s.c.) immunization rapidly induced heterosubtypic protection predominantly mediated by CD8 T cells, but within three months clinical protection completely disappeared. Local (intranasal (i.n.)) immunization elicited delayed, but more lasting protection despite relatively inefficient immunization. However, by far, the most robust protection was induced by simultaneous, combined (i.n. + s.c.) vaccination, and, notably, in this case clinical protection lasted at least 8 months without showing any evidence of fading. Interestingly, the superior ability of the latter group to resist reinfection correlated with a higher number of antigen-specific CD8 T cells in the spleen. Thus, detailed analysis of the underlying CD8 T cell responses highlights the importance of T cells already positioned in the lungs prior to challenge, but at the same time underscores an important back-up role for circulating antigen-specific cells with the capacity to expand and infiltrate the infected lungs.
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ida E M
authors.initials: IE
authors.lastname: Uddback
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Line M I
authors.initials: LM
authors.lastname: Pedersen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Pedersen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Steffensen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Holst
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Thomsen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Christensen
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004333:Drug Administration Routes; D005260:Female; D007109:Immunity; D007114:Immunization; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology*; D010641:Phenotype; D013045:Species Specificity; D013997:Time Factors; D014611:Vaccination
chemical_list: D000956:Antigens, Viral; D007252:Influenza Vaccines
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