TY - JOUR
T1 - Characterization of novel multiantigenic vaccine candidates with pan-HLA coverage against mycobacterium tuberculosis
AU - Kovjazin, Riva
AU - Shitrit, David
AU - Preiss, Rachel
AU - Haim, Ilanit
AU - Triezer, Lev
AU - Fuks, Leonardo
AU - Nader, Abdel Rahman
AU - Raz, Meir
AU - Bardenstein, Ritta
AU - Horn, Galit
AU - Smorodinsky, Nechama I.
AU - Carmona, Lior
PY - 2013/3
Y1 - 2013/3
N2 - The low protection by the bacillus Calmette-Guérin (BCG) vaccine and existence of drug-resistant strains require better anti- Mycobacterium tuberculosis vaccines with a broad, long-lasting, antigen-specific response. Using bioinformatics tools, we identified five 19- to 40-mer signal peptide (SP) domain vaccine candidates (VCs) derived from M. tuberculosis antigens. All VCs were predicted to have promiscuous binding to major histocompatibility complex (MHC) class I and II alleles in large geographic territories worldwide. Peripheral mononuclear cells (PBMC) from healthy naïve donors and tuberculosis patients exhibited strong proliferation that correlated positively with Th1 cytokine secretion only in healthy naïve donors. Proliferation to SP VCs was superior to that to antigen-matched control peptides with similar length and various MHC class I and II binding properties. Tcell lines induced to SP VCs from healthy naïve donors had increased CD44high/ CD62L+ activation/effector memory markers and gamma interferon (IFN-Υ), but not interleukin-4 (IL-4), production in both CD4+ and CD8+ T-cell subpopulations. T-cell lines from healthy naïve donors and tuberculosis patients also manifested strong, dose-dependent, antigen-specific cytotoxicity against autologous VC-loaded or M. tuberculosis-infected macrophages. Lysis of M. tuberculosis-infected targets was accompanied by high IFN-Υ secretion. Various combinations of these five VCs manifested synergic proliferation of PBMC from selected healthy naïve donors. Immunogenicity of the best three combinations, termed Mix1, Mix2, and Mix3 and consisting of 2 to 5 of the VCs, was then evaluated in mice. Each mixture manifested strong cytotoxicity against M. tuberculosis-infected macrophages, while Mix3 also manifested a VC-specific humoral immune response. Based on these results, we plan to evaluate the protection properties of these combinations as an improved tuberculosis subunit vaccine.
AB - The low protection by the bacillus Calmette-Guérin (BCG) vaccine and existence of drug-resistant strains require better anti- Mycobacterium tuberculosis vaccines with a broad, long-lasting, antigen-specific response. Using bioinformatics tools, we identified five 19- to 40-mer signal peptide (SP) domain vaccine candidates (VCs) derived from M. tuberculosis antigens. All VCs were predicted to have promiscuous binding to major histocompatibility complex (MHC) class I and II alleles in large geographic territories worldwide. Peripheral mononuclear cells (PBMC) from healthy naïve donors and tuberculosis patients exhibited strong proliferation that correlated positively with Th1 cytokine secretion only in healthy naïve donors. Proliferation to SP VCs was superior to that to antigen-matched control peptides with similar length and various MHC class I and II binding properties. Tcell lines induced to SP VCs from healthy naïve donors had increased CD44high/ CD62L+ activation/effector memory markers and gamma interferon (IFN-Υ), but not interleukin-4 (IL-4), production in both CD4+ and CD8+ T-cell subpopulations. T-cell lines from healthy naïve donors and tuberculosis patients also manifested strong, dose-dependent, antigen-specific cytotoxicity against autologous VC-loaded or M. tuberculosis-infected macrophages. Lysis of M. tuberculosis-infected targets was accompanied by high IFN-Υ secretion. Various combinations of these five VCs manifested synergic proliferation of PBMC from selected healthy naïve donors. Immunogenicity of the best three combinations, termed Mix1, Mix2, and Mix3 and consisting of 2 to 5 of the VCs, was then evaluated in mice. Each mixture manifested strong cytotoxicity against M. tuberculosis-infected macrophages, while Mix3 also manifested a VC-specific humoral immune response. Based on these results, we plan to evaluate the protection properties of these combinations as an improved tuberculosis subunit vaccine.
UR - http://www.scopus.com/inward/record.url?scp=84875012976&partnerID=8YFLogxK
U2 - 10.1128/CVI.00586-12
DO - 10.1128/CVI.00586-12
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AN - SCOPUS:84875012976
SN - 1556-6811
VL - 20
SP - 328
EP - 340
JO - Clinical and Vaccine Immunology
JF - Clinical and Vaccine Immunology
IS - 3
ER -
