title: Controlled and targeted release of antigens by intelligent shell for improving applicability of oral vaccines.
abstract: Conventional oral vaccines with simple architecture face barriers with regard to stimulating effective immunity. Here we describe oral vaccines with an intelligent phase-transitional shielding layer, poly[(methyl methacrylate)-co-(methyl acrylate)-co-(methacrylic acid)]-poly(D,L-lactide-co-glycolide) (PMMMA-PLGA), which can protect antigens in the gastro-intestinal tract and achieve targeted vaccination in the large intestine. With the surface immunogenic protein (SIP) from group B Streptococcus (GBS) entrapped as the antigen, oral administration with PMMMA-PLGA (PTRBL)/Trx-SIP nanoparticles stimulated robust immunity in tilapia, an animal with a relatively simple immune system. The vaccine succeeded in protecting against Streptococcus agalactiae, a pathogen of worldwide importance that threatens human health and is transmitted in water with infected fish. After oral vaccination with PTRBL/Trx-SIP, tilapia produced enhanced levels of SIP specific antibodies and displayed durability of immune protection. 100% of the vaccinated tilapia were protected from GBS infection, whereas the control groups without vaccines or vaccinated with Trx-SIP only exhibited respective infection rates of 100% or >60% within the initial 5 months after primary vaccination. Experiments in vivo demonstrated that the recombinant antigen Trx-SIP labeled with FITC was localized in colon, spleen and kidney, which are critical sites for mounting an immune response. Our results revealed that, rather than the size of the nanoparticles, it is more likely that the negative charge repulsion produced by ionization of the carboxyl groups in PMMMA shielded the nanoparticles from uptake by small intestinal epithelial cells. This system resolves challenges arising from gastrointestinal damage to antigens, and more importantly, offers a new approach applicable for oral vaccination.
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Fresh Water Fisheries Research Institute of Fujian Province, Fuzhou, 350002, China.
authors.forename: Zhanzhuang
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: National Center for Research on Sugarcane Engineering and Technology, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
authors.forename: Chaohua
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Bellis
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, China.
authors.forename: Wendi
authors.initials: W
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, China.
authors.forename: Yintao
authors.initials: Y
authors.lastname: Su
authors.affiliation: Fresh Water Fisheries Research Institute of Fujian Province, Fuzhou, 350002, China.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, China. Electronic address: wuyk@fjirsm.ac.cn.
authors.forename: Yunkun
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D002460:Cell Line; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004197:Disease Reservoirs; D016503:Drug Delivery Systems / Q000379:methods*; D005347:Fibroblasts; D005393:Fish Diseases / Q000517:prevention & control; D005609:Free Radicals; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007408:Intestinal Absorption; D010316:Particle Size; D010538:Peritonitis / Q000517:prevention & control / Q000662:veterinary; D011091:Polyesters; D058105:Polymerization; D011109:Polymethacrylic Acids; D055672:Static Electricity; D013290:Streptococcal Infections / Q000517:prevention & control / Q000635:transmission / Q000662:veterinary; D013292:Streptococcus agalactiae; D017210:Tilapia / Q000276:immunology / Q000382:microbiology; D014357:Trypsin / Q000494:pharmacology; D014612:Vaccines / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology
chemical_list: D000941:Antigens; D000942:Antigens, Bacterial; D001428:Bacterial Vaccines; D003692:Delayed-Action Preparations; D005609:Free Radicals; D011091:Polyesters; D011109:Polymethacrylic Acids; C414463:SIP protein, Streptococcus group B; D014612:Vaccines; C485184:enhanced green fluorescent protein; C000611580:poly((methyl methacrylate)-co-(methyl acrylate)-co-(methacrylic acid))-poly(lactide-co-glycolide); D049452:Green Fluorescent Proteins; D014357:Trypsin
keywords: Controlled release; Oral vaccine; Phase transition; Target; pH responsive