title: Evaluation of mucosal adjuvants and immunization routes for the induction of systemic and mucosal humoral immune responses in macaques.
abstract: Delivering vaccine antigens to mucosal surfaces is potentially very attractive, especially as protection from mucosal infections may be mediated by local immune responses. However, to date mucosal immunization has had limited successes, with issues of both safety and poor immunogenicity. One approach to improve immunogenicity is to develop adjuvants that are effective and safe at mucosal surfaces. Differences in immune responses between mice and men have overstated the value of some experimental adjuvants which have subsequently performed poorly in the clinic. Due to their closer similarity, non-human primates can provide a more accurate picture of adjuvant performance. In this study we immunised rhesus macaques (Macaca mulatta) using a unique matrix experimental design that maximised the number of adjuvants screened while reducing the animal usage. Macaques were immunised by the intranasal, sublingual and intrarectal routes with the model protein antigens keyhole limpet haemocyanin (KLH), β-galactosidase (β-Gal) and ovalbumin (OVA) in combination with the experimental adjuvants Poly(I:C), Pam3CSK4, chitosan, Thymic Stromal Lymphopoietin (TSLP), MPLA and R848 (Resiquimod). Of the routes used, only intranasal immunization with KLH and R848 induced a detectable antibody response. When compared to intramuscular immunization, intranasal administration gave slightly lower levels of antigen specific antibody in the plasma, but enhanced local responses. Following intranasal delivery of R848, we observed a mildly inflammatory response, but no difference to the control. From this we conclude that R848 is able to boost antibody responses to mucosally delivered antigen, without causing excess local inflammation.
authors.affiliation: a Tulane National Primate Research Center; Tulane University School of Medicine ; Covington , LA USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.affiliation: b Mucosal Infection & Immunity Group; Section of Virology; Imperial College London; St. Mary's Campus ; London , UK.
authors.forename: Asna
authors.initials: A
authors.lastname: Siddiqui
authors.affiliation: b Mucosal Infection & Immunity Group; Section of Virology; Imperial College London; St. Mary's Campus ; London , UK.|c Present affiliation: University of Western Ontario ; Ontario , Canada.
authors.forename: Katja
authors.initials: K
authors.lastname: Klein
authors.affiliation: b Mucosal Infection & Immunity Group; Section of Virology; Imperial College London; St. Mary's Campus ; London , UK.
authors.forename: Viviana
authors.initials: V
authors.lastname: Buffa
authors.affiliation: b Mucosal Infection & Immunity Group; Section of Virology; Imperial College London; St. Mary's Campus ; London , UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Fischetti
authors.affiliation: a Tulane National Primate Research Center; Tulane University School of Medicine ; Covington , LA USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Doyle-Meyers
authors.affiliation: b Mucosal Infection & Immunity Group; Section of Virology; Imperial College London; St. Mary's Campus ; London , UK.|d Present affiliation: IAVI Human Immunology Lab; Chelsea and Westminster; Imperial College London ; London , UK.
authors.forename: Deborah F
authors.initials: DF
authors.lastname: King
authors.affiliation: b Mucosal Infection & Immunity Group; Section of Virology; Imperial College London; St. Mary's Campus ; London , UK.
authors.forename: John S
authors.initials: JS
authors.lastname: Tregoning
authors.affiliation: b Mucosal Infection & Immunity Group; Section of Virology; Imperial College London; St. Mary's Campus ; London , UK.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
mesh_terms: D000276:Adjuvants, Immunologic; D000281:Administration, Intranasal; D000818:Animals; D000906:Antibodies / Q000097:blood* / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology*; D048271:Chitosan / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D006433:Hemocyanins / Q000276:immunology; D007093:Imidazoles / Q000276:immunology; D018928:Immunity, Mucosal / Q000276:immunology*; D007114:Immunization / Q000379:methods*; D007070:Immunoglobulin A / Q000097:blood* / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D007273:Injections, Intramuscular; D055666:Lipopeptides / Q000276:immunology; D008253:Macaca mulatta; D009092:Mucous Membrane / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D011070:Poly I-C / Q000276:immunology; D001616:beta-Galactosidase / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000276:Adjuvants, Immunologic; D000906:Antibodies; D016207:Cytokines; D007093:Imidazoles; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D010047:Ovalbumin; D048271:Chitosan; D006433:Hemocyanins; D001616:beta-Galactosidase; C032808:keyhole-limpet hemocyanin; D011070:Poly I-C; C402365:resiquimod; D000094632:Thymic Stromal Lymphopoietin
keywords: Macaque; Mucosal; TLR ligand; adjuvant; inflammation; intranasal