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Identification of Human T Cell Antigens for the Development of Vaccines against Mycobacterium tuberculosis¹

Infectious Disease Research Institute, Seattle WA 98104

Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) depends on the identification of Ags that induce appropriate T cell responses. Using bioinformatics, we selected a panel of 94 Mtb genes based on criteria that included growth in macrophages, up- or down-regulation under hypoxic conditions, secretion, membrane association, or because they were members of the PE/PPE or EsX families. Recombinant proteins encoded by these genes were evaluated for IFN- recall responses using PBMCs from healthy subjects previously exposed to Mtb. From this screen, dominant human T cell Ags were identified and 49 of these proteins, formulated in CpG, were evaluated as vaccine candidates in a mouse model of tuberculosis. Eighteen of the individual Ags conferred partial protection against challenge with virulent Mtb. A combination of three of these Ags further increased protection against Mtb to levels comparable to those achieved with bacillus Calmette-Guérin vaccination. Vaccine candidates that led to reduction in lung bacterial burden following challenge-induced pluripotent CD4 and CD8 T cells, including Th1 cell responses characterized by elevated levels of Ag-specific IgG2c, IFN-, and TNF. Priority vaccine Ags elicited pluripotent CD4 and CD8 T responses in purified protein derivative-positive donor PBMCs. This study identified numerous novel human T cell Ags suitable to be included in subunit vaccines against tuberculosis.

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 work was supported by National Institutes of Health (NIH) Grants AI-044373 and AI-067251 (to S.G.R.), Infectious Disease Research Institute, and by the NIH TB Vaccine Testing and Research Materials Contract N01-AI-40091 (to Colorado State University).

² S.B. and G.C.I. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Sylvie Bertholet, Infectious Disease Research Institute, 1124 Columbia Street, Suite 400, Seattle WA 98104. E-mail address: sbertholet{at}idri.org

⁴ Abbreviations used in this paper: TB, tuberculosis; BCG, bacillus Calmette-Guérin; GrB, granzyme B; ICS, intracellular cytokine staining; Mtb, Mycobacterium tuberculosis; PPD, purified protein derivative.