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* Adjuvant Research, Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark; and
Cellular Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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-
+IL-2+ and IFN-
+TNF-+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-+IFN-+-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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was funded by the European Commission’s TB Vaccine Cluster (TBVAC) project, contract no. LSHP-CT-2003-503367. Additional funding was provided by Danish Agency for Science Technology and Innovation (Medical Sciences) Grant 271-05-0440.
2 Address correspondence and reprint requests to Dr. Peter Andersen and Dr. Thomas Lindenstrøm, Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark. E-mail addresses: PA{at}ssi.dk and THI{at}ssi.dk
3 Abbreviations used in this paper: TB, tuberculosis; BCG, bacillus Calmette-Guèrin; CAF, cationic adjuvant formulation; DDA, dimethyldioctadecylammonium; ESAT-6, early secreted antigenic target of 6 kDa; icFACS, intracellular FACS; MFI, mean fluorescence intensity; PPD, purified protein derivative; SFU, spot-forming unit; TBD, trehalose 6,6'-dibehenate; TCM, central memory T cell.
4 The online version of this article contains supplemental material.
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