trehalose-6-6--dibehenate and Tuberculosis--Pulmonary

The development of the CAF family adjuvant was initiated around 20 years ago when Statens Serum Institut was preparing its first generation protein based recombinant subunit vaccine against tuberculosis for clinical testing, but realized that there were no clinically relevant adjuvants available that would support the strong CMI response needed. Since then the aim for the adjuvant research at Statens Serum Institut has been to provide adjuvants with distinct immunogenicity profiles correlating with protection for any given infectious disease. Two of the adjuvants CAF01 and CAF09 are currently being evaluated in human clinical trials. The purpose of this review is to give an overview of the immunocorrelates of those CAF adjuvants furthest in development. We further aim at giving an overview of the mechanism of action of the CAF adjuvants.

Topics: Adjuvants, Immunologic; Animals; Glycolipids; Humans; Immunity, Cellular; Immunity, Humoral; Immunogenicity, Vaccine; Lipid A; Liposomes; Mice; Quaternary Ammonium Compounds; Th1 Cells; Th17 Cells; Th2 Cells; Tuberculosis Vaccines; Tuberculosis, Pulmonary

Topics: Adjuvants, Immunologic; Animals; CD4-Positive T-Lymphocytes; Cytokines; Disease Models, Animal; Drug Compounding; Female; Glycolipids; Host-Pathogen Interactions; Immunogenicity, Vaccine; Lipid A; Liposomes; Lung; Mice, Inbred C57BL; Mycobacterium tuberculosis; Quaternary Ammonium Compounds; Receptors, Pattern Recognition; Time Factors; Tuberculosis Vaccines; Tuberculosis, Pulmonary; Vaccination; Vaccines, Subunit; Virulence

Novel vaccination strategies against Mycobacterium tuberculosis (MTB) are urgently needed. The use of recombinant MTB antigens as subunit vaccines is a promising approach, but requires adjuvants that activate antigen-presenting cells (APCs) for elicitation of protective immunity. The mycobacterial cord factor Trehalose-6,6-dimycolate (TDM) and its synthetic analogue Trehalose-6,6-dibehenate (TDB) are effective adjuvants in combination with MTB subunit vaccine candidates in mice. However, it is unknown which signaling pathways they engage in APCs and how these pathways are coupled to the adaptive immune response. Here, we demonstrate that these glycolipids activate macrophages and dendritic cells (DCs) via Syk-Card9-Bcl10-Malt1 signaling to induce a specific innate activation program distinct from the response to Toll-like receptor (TLR) ligands. APC activation by TDB and TDM was independent of the C-type lectin receptor Dectin-1, but required the immunoreceptor tyrosine-based activation motif-bearing adaptor protein Fc receptor gamma chain (FcRgamma). In vivo, TDB and TDM adjuvant activity induced robust combined T helper (Th)-1 and Th-17 T cell responses to a MTB subunit vaccine and partial protection against MTB challenge in a Card9-dependent manner. These data provide a molecular basis for the immunostimulatory activity of TDB and TDM and identify the Syk-Card9 pathway as a rational target for vaccine development against tuberculosis.

Topics: Adaptor Proteins, Signal Transducing; Adjuvants, Immunologic; Animals; B-Cell CLL-Lymphoma 10 Protein; CARD Signaling Adaptor Proteins; Caspases; CD4-Positive T-Lymphocytes; Cytokines; Dendritic Cells; Glycolipids; Immunity, Innate; Immunoglobulin G; Intracellular Signaling Peptides and Proteins; Lung; Lymph Nodes; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Neoplasm Proteins; Protein-Tyrosine Kinases; Receptors, IgE; Signal Transduction; Syk Kinase; T-Lymphocytes, Helper-Inducer; Tuberculosis Vaccines; Tuberculosis, Pulmonary; Vaccines, Subunit