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

• Published in: The Journal of immunology (1950) Vol. 181; no. 11; pp. 7948 - 7957
• Main Authors: Bertholet, Sylvie, Ireton, Gregory C, Kahn, Maria, Guderian, Jeffrey, Mohamath, Raodoh, Stride, Nicole, Laughlin, Elsa M, Baldwin, Susan L, Vedvick, Thomas S, Coler, Rhea N, Reed, Steven G
• Format: Journal Article
• Language: English
• Published: England Am Assoc Immnol 01.12.2008
• Subjects: Adjuvants, Immunologic - genetics; Adjuvants, Immunologic - pharmacology; Animals; Antibodies, Bacterial - immunology; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Antigens, Bacterial - pharmacology; CD8-Positive T-Lymphocytes - immunology; Computational Biology; Disease Models, Animal; Female; Humans; Immunoglobulin G - immunology; Interferon-gamma - immunology; Mice; Mycobacterium bovis - immunology; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - immunology; Oligodeoxyribonucleotides - genetics; Oligodeoxyribonucleotides - immunology; Oligodeoxyribonucleotides - pharmacology; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Recombinant Proteins - pharmacology; Th1 Cells - immunology; Tuberculosis Vaccines - genetics; Tuberculosis Vaccines - immunology; Tuberculosis Vaccines - pharmacology; Tuberculosis, Pulmonary - genetics; Tuberculosis, Pulmonary - immunology; Tuberculosis, Pulmonary - prevention & control; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.181.11.7948

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-γ 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-γ, 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.