title: Nasal immunization with mannan-decorated mucoadhesive HPMCP microspheres containing ApxIIA toxin induces protective immunity against challenge infection with Actinobacillus pleuropneumoiae in mice.
abstract: The development of subunit mucosal vaccines requires an appropriate delivery system or an immune modulator such as an adjuvant to improve antigen immunogenicity. The nasal route for vaccine delivery by microparticles has attracted considerable interest, although challenges such as the rapid mucociliary clearance in the respiratory mucosa and the low immunogenicity of subunit vaccine still remain. Here, we aimed to develop mannan-decorated mucoadhesive thiolated hydroxypropylmethyl cellulose phthalate (HPMCP) microspheres (Man-THM) that contain ApxIIA subunit vaccine - an exotoxin fragment as a candidate for a subunit nasal vaccine against Actinobacillus pleuropneumoniae. For adjuvant activity, mucoadhesive thiolated HPMCP microspheres decorated with mannan could be targeted to the PRRs (pathogen recognition receptors) and mannose receptors (MR) of antigen presenting cells (APCs) in the respiratory immune system. The potential adjuvant ability of Man-THM for intranasal immunization was confirmed by in vitro and in vivo experiments. In a mechanistic study using APCs in vitro, it was found that Man-THM enhanced receptor-mediated endocytosis by stimulating the MR of APCs. In vivo, the nasal vaccination of ApxIIA-loaded Man-THM in mice resulted in higher levels of mucosal sIgA and serum IgG than mice in the ApxIIA and ApxIIA-loaded THM groups due to the specific recognition of the mannan in the Man-THM by the MRs of the APCs. Moreover, ApxIIA-containing Man-THM protected immunized mice when challenged with strains of A. pleuropneumoniae serotype 5. These results suggest that mucoadhesive Man-THM may be a promising candidate for a nasal vaccine delivery system to elicit systemic and mucosal immunity that can protect from pathogenic bacteria infection.
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Hui-Shan
authors.initials: HS
authors.lastname: Li
authors.affiliation: Department of Infectious Disease, College of Veterinary Medicine, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Min-Kyoung
authors.initials: MK
authors.lastname: Shin
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Bijay
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Sushila
authors.initials: S
authors.lastname: Maharjan
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Tae-Eun
authors.initials: TE
authors.lastname: Park
authors.affiliation: Institute of Green-Bio Science & Technology, Seoul National University, Pyeongchang-gun, 232-916, South Korea.
authors.forename: Sang-Kee
authors.initials: SK
authors.lastname: Kang
authors.affiliation: Department of Infectious Disease, College of Veterinary Medicine, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Han-Sang
authors.initials: HS
authors.lastname: Yoo
authors.affiliation: Department of Animal Science, Tianjin Agricultural University, Tianjin 300-384, China.
authors.forename: Zhong-Shan
authors.initials: ZS
authors.lastname: Hong
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea. Electronic address: chocs@snu.ac.kr.
authors.forename: Chong-Su
authors.initials: CS
authors.lastname: Cho
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea; Department of Animal Science, Tianjin Agricultural University, Tianjin 300-384, China. Electronic address: cyjcow@snu.ac.kr.
authors.forename: Yun-Jaie
authors.initials: YJ
authors.lastname: Choi
mesh_terms: D000189:Actinobacillus Infections / Q000517:prevention & control*; D016977:Actinobacillus pleuropneumoniae / Q000276:immunology; D000268:Adhesiveness; D000281:Administration, Intranasal; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000938:Antigen-Presenting Cells / Q000276:immunology; D001426:Bacterial Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D001428:Bacterial Vaccines / Q000008:administration & dosage* / Q000737:chemistry; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002460:Cell Line; D005260:Female; D006460:Hemolysin Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D018928:Immunity, Mucosal; D007114:Immunization / Q000379:methods; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008351:Mannans / Q000008:administration & dosage* / Q000737:chemistry; D008747:Methylcellulose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D020545:Respiratory Mucosa / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D000907:Antibodies, Bacterial; C085361:ApxII toxin, bacteria; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D006460:Hemolysin Proteins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D008351:Mannans; D013438:Sulfhydryl Compounds; D008747:Methylcellulose; C053309:hydroxypropyl methylcellulose phthalate
keywords: Adjuvant; Antigen presenting cells (APCs); Mannan; Mannose receptor targeting; Mucoadhesive microspheres; Nasal vaccine