title: Nanoformulation of synergistic TLR ligands to enhance vaccination against Entamoeba histolytica.
abstract: Diarrheal infectious diseases represent a major cause of global morbidity and mortality. There is an urgent need for vaccines against diarrheal pathogens, especially parasites. Modern subunit vaccines rely on combining a highly purified antigen with an adjuvant to increase their efficacy. In the present study, we evaluated the ability of a nanoliposome adjuvant system to trigger a strong mucosal immune response to the Entamoeba histolytica Gal/GalNAc lectin LecA antigen. CBA/J mice were immunized with alum, emulsion or liposome based formulations containing synthetic TLR agonists. A liposome formulation containing TLR4 and TLR7/8 agonists was selected based on its ability to generate intestinal IgA, plasma IgG2a/IgG1, IFN-γ and IL-17A. Immunization with a mucosal prime followed by a parenteral boost generated a high mucosal IgA response that inhibited adherence of parasites to mammalian cells. Inclusion of the immune potentiator all-trans retinoic acid in the regimen further improved the mucosal IgA response. Immunization protected from infection with up to 55% efficacy. Our results show that a nanoliposome delivery system containing TLR agonists is a promising prospect for the development of vaccines against enteric pathogens, especially when a multifaceted immune response is desired.
authors.affiliation: Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, United States. Electronic address: mma3a@virginia.edu.
authors.forename: Mayuresh M
authors.initials: MM
authors.lastname: Abhyankar
authors.affiliation: Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, United States.
authors.forename: Zannatun
authors.initials: Z
authors.lastname: Noor
authors.affiliation: 3M Drug Delivery Systems, 3M Center, 275-3E-10, St Paul, MN 55144, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tomai
authors.affiliation: 3M Drug Delivery Systems, 3M Center, 275-3E-10, St Paul, MN 55144, USA.
authors.forename: James
authors.initials: J
authors.lastname: Elvecrog
authors.affiliation: IDRI, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA 98104, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Fox
authors.affiliation: Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, United States. Electronic address: wap3g@virginia.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Petri
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis*; D000953:Antigens, Protozoan / Q000737:chemistry / Q000276:immunology; D004748:Entamoeba histolytica / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D004749:Entamoebiasis / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D018928:Immunity, Mucosal / Q000187:drug effects*; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D037102:Lectins / Q000737:chemistry / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000235:genetics / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D011136:Polysorbates / Q000008:administration & dosage; D016052:Protozoan Vaccines / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D012313:RNA / Q000008:administration & dosage; D013185:Squalene / Q000008:administration & dosage; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D014212:Tretinoin / Q000008:administration & dosage; D022223:Vaccines, Subunit
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D020381:Interleukin-17; D037102:Lectins; D008070:Lipopolysaccharides; D008081:Liposomes; C089950:MF59 oil emulsion; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D011136:Polysorbates; D016052:Protozoan Vaccines; C519703:TLR3 protein, mouse; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D022223:Vaccines, Subunit; C041524:aluminum sulfate; D014212:Tretinoin; D012313:RNA; D013185:Squalene; D007371:Interferon-gamma
keywords: Amebiasis; Entamoeba; Immune response; Liposome; Vaccine