title: Tuberculosis subunit vaccination provides long-term protective immunity characterized by multifunctional CD4 memory T cells.
abstract: Improved vaccines capable of promoting long-term cellular immunity are urgently required for a number of diseases that remain global health problems. In the present study, we demonstrate that a tuberculosis subunit vaccine, Ag85B-ESAT-6/CAF01 (where ESAT-6 is early secreted antigenic target of 6 kDa and CAF01 is cationic adjuvant formulation 01), induces very robust memory CD4 T cell responses that are maintained at high levels for >1 year postvaccination. This long-term, vaccine-induced memory response protects against a challenge with Mycobacterium tuberculosis at levels that are comparable to or better than those of bacillus Calmette-Guérin. Characterization of the CD4 memory T cells by multicolor flow cytometry demonstrated that the long-lived memory population consisted almost exclusively of TNF-alpha(+)IL-2(+) and IFN-gamma(+)TNF-alpha(+)IL-2(+) multifunctional T cells. In addition, memory cells isolated >1 year postvaccination maintained a strong, vaccine-specific proliferative potential. Long-term memory induced by the BCG vaccine contained fewer multifunctional T cells and was biased toward effector cells mainly of the TNF-alpha(+)IFN-gamma(+)-coexpressing subset. Ag85B-ESAT-6/CAF01 vaccination very efficiently sustained multifunctional CD4 T cells that accumulated at the site of infection after M. tuberculosis challenge, whereas the response in unvaccinated animals was characterized by CD4 effector T cells. Our data demonstrate that adjuvanted subunit vaccines can promote long-term protective immune responses characterized by high levels of persisting multifunctional T cells and that the quality and profile of this response is sustained postinfection.
authors.affiliation: Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lindenstrøm
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Agger
authors.forename: Karen S
authors.initials: KS
authors.lastname: Korsholm
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Darrah
authors.forename: Claus
authors.initials: C
authors.lastname: Aagaard
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
authors.forename: Ida
authors.initials: I
authors.lastname: Rosenkrands
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology; D021122:Protein Subunits / Q000276:immunology; D013997:Time Factors; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D032581:Tuberculosis Vaccines / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D021122:Protein Subunits; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma