Gamma Interferon and Monophosphoryl Lipid A-Trehalose Dicorynomycolate Are Efficient Adjuvants for<i>Mycobacterium tuberculosis</i>Multivalent Acellular Vaccine

The development of novel vaccine strategies supplementing Mycobacterium bovis BCG (BCG) constitutes an urgent research challenge. To identify potential subunit vaccine candidates, we have tested a series of eight recently identified Mycobacterium tuberculosis antigens in M. bovis-infected and BCG-vaccinated cattle. These antigens were characterized on the basis of their ability to induce in vitro gamma interferon responses in infected or BCG-vaccinated calves. We were able to establish a hierarchy of these antigens based on how frequently they were recognized in both groups of animals. In particular, we were able to prioritize frequently recognized proteins like Rv0287, Rv1174, and Rv1196 for future evaluation as subunit vaccines to be used in BCG-protein heterologous prime-boost vaccination scenarios. In addition, the antigen most dominantly recognized in M. bovis-infected cattle in this study, Rv3616c, was significantly less frequently recognized by BCG vaccinees and could be a target to improve BCG, for example, by increasing its secretion, in a recombinant BCG vaccine.

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“…Furthermore, it was part of a hexavalent protein vaccine that protected mice against M. tuberculosis infection (27).…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity ofMycobacterium tuberculosisAntigens inMycobacterium bovisBCG-Vaccinated andM. bovis-Infected Cattle

et al. 2006

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“…Th1-associated Ab responses (24) and CTL induction (25) have been achieved with Ag and TLR agonists. With the discovery of tumor-specific Ags, adjuvants are required to prime the acquired immune system to self/tumor-specific Ags that are poorly immunogenic.…”

mentioning

confidence: 99%

Combined Triggering of Dendritic Cell Receptors Results in Synergistic Activation and Potent Cytotoxic Immunity

Wells

Cowled

Farzaneh

et al. 2008

The Journal of Immunology

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Elimination of malignant cells and intracellular infections involves collaboration between CTLs and Th1 inflammation. Dendritic cells drive this response via costimulation and cytokines. We have defined key signals required for the exponential expansion of specific CD8+ T cells in vivo in mice. Immunization with two or more TLR agonists, anti-CD40, IFN-γ, and surfactant were sufficient to drive unprecedented levels of CD8 response to peptide or protein Ag and highly polarized Th1 CD4 responses. CD40 signaling was required for CD8 expansion but could be provided by a concomitant CD4 Th response in place of anti-CD40. Triggering of these pathways activated migration and activation of myeloid and plasmacytoid dendritic cells and secretion of IL-12. Cross-presentation can thus be exploited to induce potent cytotoxic responses and long-term memory to peptide/protein Ags. When combined with a tumor-associated peptide from tyrosinase-related protein 2, our combined adjuvant approach effectively halted tumor growth in an in vivo melanoma model and was more effective than anti-CD40 and a single TLR agonist. Antitumor immunity was associated with long-lived effector memory CD8 cells specific for the naturally processed and presented tumor Ag, and tumor protection was partially but not entirely dependent on CD8 T cells. This flexible strategy is more effective than existing adjuvants and provides a technological platform for rapid vaccine development.

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“…CLP have also been included in multivalent vaccines. Immunization with vaccines containing Clp1 as a component, either as DNA [28] or protein delivered with monophosphoryl lipid (MPL) and/ or dimethyl-dioctadecylammonium (DDA) [29], stimulated protective immunity against M. tuberculosis. A multivalent protein vaccine containing Clp2 also stimulated a similar degree of protection [31].…”

Section: Discussionmentioning

confidence: 99%

“…The importance of various secreted gene products of M. tuberculosis, in terms of immunogenic potential is established, with some being frequently included in multi-component vaccines, such as Ag85, ESAT-6 and CFP10 [27][28][29]. The success of these secreted proteins in vaccines drives the search for further immunogenic and protective antigens.…”

Section: Discussionmentioning

confidence: 99%

Immunological diversity within a family of cutinase-like proteins of Mycobacterium tuberculosis

West¹,

Wozniak²,

Valenzuela³

et al. 2008

Vaccine

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Secreted proteins of Mycobacterium tuberculosis play key roles in the assembly of the mycobacterial cell wall, with many being major targets of the host immune response. To date, meaningful characterization of a significant proportion of this important group of proteins is lacking. Among the group of putatively secreted proteins of M. tuberculosis are 7 cutinase-like proteins (CLP), not previously characterized in terms of their immunogenicity or vaccine protective efficacy. Although the CLP vary in the degree of homology with one another, they all share a similar active catalytic triad, closely homologous to that of the cutinase of Fusarium solani. By construction of DNA vaccines of all 7 CLP, and expression and purification of soluble, recombinant CLP, this study addresses the immunological responses to these proteins. Clp1, 2, 3 and 6 were found to elicit significant IFN-γ secretion in DNA immunized mice, with the antigens also demonstrating specificity in terms of CLP-generated T cell IFN-γ release, with minimal cross reactivity of humoral responses. Finally, following delivery of DNA vaccines, Clp1, 2 and 6, conferred a moderate yet reproducible and significant level of protection in a murine aerosol model of M. tuberculosis infection.

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Gamma Interferon and Monophosphoryl Lipid A-Trehalose Dicorynomycolate Are Efficient Adjuvants forMycobacterium tuberculosisMultivalent Acellular Vaccine

Cited by 29 publications

References 53 publications

Immunogenicity ofMycobacterium tuberculosisAntigens inMycobacterium bovisBCG-Vaccinated andM. bovis-Infected Cattle

Immunogenicity ofMycobacterium tuberculosisAntigens inMycobacterium bovisBCG-Vaccinated andM. bovis-Infected Cattle

Combined Triggering of Dendritic Cell Receptors Results in Synergistic Activation and Potent Cytotoxic Immunity

Immunological diversity within a family of cutinase-like proteins of Mycobacterium tuberculosis

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