Identification of human T cell antigens for the development of vaccines against Mycobacterium tuberculosis.
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-gamma 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-gamma, 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.
Bertholet
Sylvie
S
Infectious Disease Research Institute, Seattle WA 98104, USA. sbertholet@idri.org
Ireton
Gregory C
GC
Kahn
Maria
M
Guderian
Jeffrey
J
Mohamath
Raodoh
R
Stride
Nicole
N
Laughlin
Elsa M
EM
Baldwin
Susan L
SL
Vedvick
Thomas S
TS
Coler
Rhea N
RN
Reed
Steven G
SG
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019295:Computational Biology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; C408982:CPG-oligonucleotide; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D032581:Tuberculosis Vaccines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma