title: A dual TLR agonist adjuvant enhances the immunogenicity and protective efficacy of the tuberculosis vaccine antigen ID93.
abstract: With over eight million cases of tuberculosis each year there is a pressing need for the development of new vaccines against Mycobacterium tuberculosis. Subunit vaccines consisting of recombinant proteins are an attractive vaccine approach due to their inherent safety compared to attenuated live vaccines and the uniformity of manufacture. Addition of properly formulated TLR agonist-containing adjuvants to recombinant protein vaccines enhances the antigen-specific CD4(+) T cell response characterized by IFN-γ and TNF, both of which are critical for the control of TB. We have developed a clinical stage vaccine candidate consisting of a recombinant fusion protein ID93 adjuvanted with the TLR4 agonist GLA-SE. Here we examine whether ID93+GLA-SE can be improved by the addition of a second TLR agonist. Addition of CpG containing DNA to ID93+GLA-SE enhanced the magnitude of the multi-functional TH1 response against ID93 characterized by co-production of IFN-γ, TNF, and IL-2. Addition of CpG also improved the protective efficacy of ID93+GLA-SE. Finally we demonstrate that this adjuvant synergy between GLA and CpG is independent of TRIF signaling, whereas TRIF is necessary for the adjuvant activity of GLA-SE in the absence of CpG.
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Orr
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Elyse A
authors.initials: EA
authors.lastname: Beebe
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hudson
authors.affiliation: Center for Immunology and Inflammatory Diseases and Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Moon
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Fox
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, United States of America ; Department of Global Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Rhea N
authors.initials: RN
authors.lastname: Coler
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000276:Adjuvants, Immunologic; D000818:Animals; D000941:Antigens / Q000276:immunology; D023181:Antimicrobial Cationic Peptides / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists*; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000276:Adjuvants, Immunologic; D000941:Antigens; D023181:Antimicrobial Cationic Peptides; D051193:Toll-Like Receptors; D032581:Tuberculosis Vaccines; D014614:Vaccines, Synthetic; C476286:Ticam1 protein, mouse; C045866:peptide-Gly-Leu-amide