title: Safe Recombinant Outer Membrane Vesicles that Display M2e Elicit Heterologous Influenza Protection.
abstract: Recombinant, Escherichia coli-derived outer membrane vesicles (rOMVs), which display heterologous protein subunits, have potential as a vaccine adjuvant platform. One drawback to rOMVs is their lipopolysaccharide (LPS) content, limiting their translatability to the clinic due to potential adverse effects. Here, we explore a unique rOMV construct with structurally remodeled lipids containing only the lipid IVa portion of LPS, which does not stimulate human TLR4. The rOMVs are derived from a genetically engineered B strain of E. coli, ClearColi, which produces lipid IVa, and which was further engineered in our laboratory to hypervesiculate and make rOMVs. We report that rOMVs derived from this lipid IVa strain have substantially attenuated pyrogenicity yet retain high levels of immunogenicity, promote dendritic cell maturation, and generate a balanced Th1/Th2 humoral response. Additionally, an influenza A virus matrix 2 protein-based antigen displayed on these rOMVs resulted in 100% survival against a lethal challenge with two influenza A virus strains (H1N1 and H3N2) in mice with different genetic backgrounds (BALB/c, C57BL/6, and DBA/2J). Additionally, a two-log reduction of lung viral titer was achieved in a ferret model of influenza infection with human pandemic H1N1. The rOMVs reported herein represent a potentially safe and simple subunit vaccine delivery platform.
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Watkins
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: C Garrett
authors.initials: CG
authors.lastname: Rappazzo
authors.affiliation: Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853 USA.
authors.forename: Jaclyn S
authors.initials: JS
authors.lastname: Higgins
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Xiangjie
authors.initials: X
authors.lastname: Sun
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Brock
authors.affiliation: Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853 USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Chau
authors.affiliation: Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Misra
authors.affiliation: College of Agriculture and Life Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Joseph P B
authors.initials: JPB
authors.lastname: Cannizzo
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: King
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Taronna R
authors.initials: TR
authors.lastname: Maines
authors.affiliation: Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Leifer
authors.affiliation: Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Whittaker
authors.affiliation: Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: DeLisa
authors.affiliation: Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA. Electronic address: dap43@cornell.edu.
authors.forename: David
authors.initials: D
authors.lastname: Putnam
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000276:immunology* / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D007074:Immunoglobulin G; D009980:Influenza A virus / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D007074:Immunoglobulin G; D007252:Influenza Vaccines; C509609:M2e-HBc influenza vaccine; D051195:Toll-Like Receptor 2
keywords: M2e; adjuvants; endotoxin; influenza; outer membrane vesicles; subunit vaccine delivery