title: Formulation, high throughput in vitro screening and in vivo functional characterization of nanoemulsion-based intranasal vaccine adjuvants.
abstract: Vaccine adjuvants have been reported to induce both mucosal and systemic immunity when applied to mucosal surfaces and this dual response appears important for protection against certain pathogens. Despite the potential advantages, however, no mucosal adjuvants are currently approved for human use. Evaluating compounds as mucosal adjuvants is a slow and costly process due to the need for lengthy animal immunogenicity studies. We have constructed a library of 112 intranasal adjuvant candidate formulations consisting of oil-in-water nanoemulsions that contain various cationic and nonionic surfactants. To facilitate adjuvant development we first evaluated this library in a series of high-throughput, in vitro assays for activities associated with innate and adaptive immune activation in vivo. These in vitro assays screened for the ability of the adjuvant to bind to mucin, induce cytotoxicity, facilitate antigen uptake in epithelial and dendritic cells, and activate cellular pathways. We then sought to determine how these parameters related to adjuvant activity in vivo. While the in vitro assays alone were not enough to predict the in vivo adjuvant activity completely, several interesting relationships were found with immune responses in mice. Furthermore, by varying the physicochemical properties of the surfactant components (charge, surfactant polar head size and hydrophobicity) and the surfactant blend ratio of the formulations, the strength and type of the immune response generated (TH1, TH2, TH17) could be modulated. These findings suggest the possibility of using high-throughput screens to aid in the design of custom adjuvants with unique immunological profiles to match specific mucosal vaccine applications.
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Pamela T
authors.initials: PT
authors.lastname: Wong
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Pascale R
authors.initials: PR
authors.lastname: Leroueil
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Smith
authors.affiliation: NanoBio Corporation, Ann Arbor, Michigan, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Ciotti
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Anna U
authors.initials: AU
authors.lastname: Bielinska
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Katarzyna W
authors.initials: KW
authors.lastname: Janczak
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Mullen
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Groom
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Taylor
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Crystal
authors.initials: C
authors.lastname: Passmore
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Makidon
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: O'Konek
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Myc
authors.affiliation: NanoBio Corporation, Ann Arbor, Michigan, United States of America.
authors.forename: Tarek
authors.initials: T
authors.lastname: Hamouda
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry* / Q000633:toxicity; D000281:Administration, Intranasal; D000818:Animals; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D016207:Cytokines / Q000096:biosynthesis; D004655:Emulsions; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D057166:High-Throughput Screening Assays; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D036103:Nanotechnology; D014612:Vaccines / Q000008:administration & dosage* / Q000737:chemistry*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D004655:Emulsions; D016328:NF-kappa B; D014612:Vaccines