title: Haemophilus influenzae type b-outer membrane protein complex glycoconjugate vaccine induces cytokine production by engaging human toll-like receptor 2 (TLR2) and requires the presence of TLR2 for optimal immunogenicity.
abstract: Conjugate vaccines consisting of the capsular polysaccharide (PS) of Haemophilus influenzae type b (Hib) covalently linked to carrier proteins, unlike pure PS, are immunogenic in infants and have significantly reduced Hib infections in the United States, but require multiple doses to induce protective anti-PS Ab titers. Hib-meningococcal outer membrane protein complex (OMPC) conjugate vaccine, however, elicits protective anti-PS Ab titers after one dose. We found that OMPC and Hib-OMPC engaged human Toll-like receptor 2 (TLR2) expressed in human embryonic kidney (HEK) cells, inducing IL-8 production, and engaged mouse TLR2 on bone marrow-derived dendritic cells, inducing TNF release. Hib conjugated to the carrier proteins CRM(197) and tetanus toxoid did not engage TLR2 on HEK or dendritic cells. Engagement of TLR2 by Hib-OMPC was MyD88 dependent, as Hib-OMPC-induced TNF production was ablated in MyD88 knockout (KO) mice. Hib-OMPC was significantly less immunogenic in TLR2 KO mice, inducing lower Hib PS IgG and IgM titers compared with those in wild-type mice. Splenocytes from OMPC-immunized TLR2 KO mice also produced significantly less IL-6 and TNF-alpha than those from wild-type mice. Hib-OMPC is unique among glycoconjugate vaccines by engaging TLR2, and the ability of Hib-OMPC to elicit protective levels of Abs after one dose may be related to TLR2-mediated induction and regulation of cytokines produced by T cells and macrophages in addition to the peptide/MHC II-dependent recruitment of T cell help commonly afforded by carrier proteins. TLR2 engagement by an adjuvant or carrier protein may be a useful strategy for augmentation of the anti-PS Ab response induced by glycoconjugate vaccines.
authors.affiliation: Department of Medicine, University of Massachusetts Medical Center, Worcester, MA 01605, USA.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Jennifer
authors.initials: J
authors.lastname: Franko
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: John R
authors.initials: JR
authors.lastname: Schreiber
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis / Q000097:blood; D000943:Antigens, Differentiation / Q000502:physiology; D001425:Bacterial Outer Membrane Proteins / Q000008:administration & dosage / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000008:administration & dosage / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018073:Haemophilus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D009345:Neisseria meningitidis / Q000276:immunology*; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000907:Antibodies, Bacterial; D000943:Antigens, Differentiation; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D016207:Cytokines; D018073:Haemophilus Vaccines; C061964:Haemophilus influenzae-type b polysaccharide-Neisseria meningitidis outer membrane protein conjugate vaccine; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011135:Polysaccharides, Bacterial; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018074:Vaccines, Conjugate