title: Polymeric penetration enhancers promote humoral immune responses to mucosal vaccines.
abstract: Protective mucosal immune responses are thought best induced by trans-mucosal vaccination, providing greater potential to generate potent local immune responses than conventional parenteral vaccination. However, poor trans-mucosal permeability of large macromolecular antigens limits bioavailability to local inductive immune cells. This study explores the utility of polymeric penetration enhancers to promote trans-mucosal bioavailability of insulin, as a biomarker of mucosal absorption, and two vaccine candidates: recombinant HIV-1 envelope glycoprotein (CN54gp140) and tetanus toxoid (TT). Responses to vaccinating antigens were assessed by measurement of serum and the vaginal humoral responses. Polyethyleneimine (PEI), Dimethyl-β-cyclodextrin (DM-β-CD) and Chitosan enhanced the bioavailability of insulin following intranasal (IN), sublingual (SL), intravaginal (I.Vag) and intrarectal (IR) administration. The same penetration enhancers also increased antigen-specific IgG and IgA antibody responses to the model vaccine antigens in serum and vaginal secretions following IN and SL application. Co-delivery of both antigens with PEI or Chitosan showed the highest increase in systemic IgG and IgA responses following IN or SL administration. However the highest IgA titres in vaginal secretions were achieved after IN immunisations with PEI and Chitosan. None of the penetration enhancers were able to increase antibody responses to gp140 after I.Vag immunisations, while in contrast PEI and Chitosan were able to induce TT-specific systemic IgG levels following I.Vag administration. In summary, we present supporting data that suggest appropriate co-formulation of vaccine antigens with excipients known to influence mucosal barrier functions can increase the bioavailability of mucosally applied antigens promoting the induction of mucosal and systemic antibody responses.
authors.affiliation: Imperial College London, Department of Infectious Diseases, Division of Medicine, Norfolk Place, London W2 1PG, UK.
authors.forename: Katja
authors.initials: K
authors.lastname: Klein
authors.affiliation: Imperial College London, Department of Infectious Diseases, Division of Medicine, Norfolk Place, London W2 1PG, UK.
authors.forename: Jamie F S
authors.initials: JF
authors.lastname: Mann
authors.affiliation: Imperial College London, Department of Infectious Diseases, Division of Medicine, Norfolk Place, London W2 1PG, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Rogers
authors.affiliation: Imperial College London, Department of Infectious Diseases, Division of Medicine, Norfolk Place, London W2 1PG, UK. Electronic address: r.shattock@imperial.ac.uk.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D058956:Administration, Mucosal; D000818:Animals; D048271:Chitosan / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D056724:Immunity, Humoral; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008807:Mice, Inbred BALB C; D011094:Polyethyleneimine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D013745:Tetanus Toxoid / Q000008:administration & dosage / Q000276:immunology* / Q000493:pharmacokinetics; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D047392:beta-Cyclodextrins / Q000737:chemistry; D054299:env Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000276:immunology* / Q000493:pharmacokinetics
chemical_list: D016915:AIDS Vaccines; D004337:Drug Carriers; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011108:Polymers; D013745:Tetanus Toxoid; D014614:Vaccines, Synthetic; D047392:beta-Cyclodextrins; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1; C038119:heptakis(2,6-O-dimethyl)beta-cyclodextrin; D011094:Polyethyleneimine; D048271:Chitosan
keywords: Delivery; Immunity; Insulin; Mucosal; Penetration; Vaccination