title: Outer membrane vesicles harboring modified lipid A moiety augment the efficacy of an influenza vaccine exhibiting reduced endotoxicity in a mouse model.
abstract: Influenza is an acute respiratory disease and a major health problem worldwide. Since mucosal immunity plays a critical role in protection against influenza virus infection, mucosal immunization is considered a promising vaccination route. However, except for live-attenuated vaccines, there are no effective killed or recombinant mucosal influenza vaccines to date. Outer membrane vesicles (OMVs) are nano-sized vesicles produced by gram-negative bacteria, and contain various bacterial components capable of stimulating the immune system of the host. We generated an OMV with low endotoxicity (fmOMV) by modifying the structure of the lipid A moiety of lipopolysaccharide and investigated its effect as an intranasal vaccine adjuvant in an influenza vaccine model. In this model, fmOMV exhibited reduced toll-like receptor 4-stimulating activity and attenuated endotoxicity compared to that of native OMV. Intranasal injection of the vaccine antigen with fmOMV significantly increased systemic antibody and T cell responses, mucosal IgA levels, and the frequency of lung-resident influenza-specific T cells. In addition, the number of antigen-bearing CD103+dendritic cells in the mediastinal lymph nodes was significantly increased after fmOMV co-administration. Notably, the mice co-immunized with fmOMV showed a significantly higher protection rate against challenge with a lethal dose of homologous or heterologous influenza viruses without adverse effects. These results show the potential of fmOMV as an effective mucosal adjuvant for intranasal vaccines.
authors.affiliation: Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Lee
authors.affiliation: Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea; Department of Biochemistry, Chungnam National University, Daejeon, South Korea.
authors.forename: Chang-Ung
authors.initials: CU
authors.lastname: Kim
authors.affiliation: Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Bae
authors.affiliation: Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.
authors.forename: Sang-Hwan
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea; University of Science and Technology (UST), Daejeon, South Korea.
authors.forename: Dae Gwin
authors.initials: DG
authors.lastname: Jeong
authors.affiliation: Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea; University of Science and Technology (UST), Daejeon, South Korea.
authors.forename: Sun-Woo
authors.initials: SW
authors.lastname: Yoon
authors.affiliation: Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Chang
authors.affiliation: Department of Biochemistry, Chungnam National University, Daejeon, South Korea.
authors.forename: Young Sang
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, South Korea. Electronic address: vetmicro@gnu.ac.kr.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea; Department of Biochemistry, Chungnam National University, Daejeon, South Korea; University of Science and Technology (UST), Daejeon, South Korea. Electronic address: golddj@kribb.re.kr.
authors.forename: Doo-Jin
authors.initials: DJ
authors.lastname: Kim
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D000067128:Extracellular Vesicles; D005260:Female; D007070:Immunoglobulin A / Q000032:analysis; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D008050:Lipid A / Q000008:administration & dosage*; D008198:Lymph Nodes / Q000276:immunology; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000276:immunology; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000517:prevention & control*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007070:Immunoglobulin A; D007252:Influenza Vaccines; D008050:Lipid A
keywords: Adjuvant; CD103(+) dendritic cells; Influenza; Intranasal; Outer membrane vesicles; Vaccine