title: A Meningococcal Outer Membrane Vesicle Vaccine Incorporating Genetically Attenuated Endotoxin Dissociates Inflammation from Immunogenicity.
abstract: BACKGROUND
  Group BNeisseria meningitidis, an endotoxin-producing Gram-negative bacterium, causes the highest incidence of group B meningococcus (MenB) disease in the first year of life. The Bexsero vaccine is indicated in Europe from 8 weeks of age. Endotoxin components of outer membrane vesicles (OMVs) or soluble lipopolysaccharide (LPS) represent a potential source of inflammation and residual reactogenicity. The purpose of this study was to compare novel candidate MenB vaccine formulations with licensed vaccines, including Bexsero, using age-specific humanin vitroculture systems.
  
  
  METHODS
  OMVs from wild type- and inactivatedlpxL1gene mutant-N. meningitidisstrains were characterized in human neonatal and adultin vitrowhole blood assays and dendritic cell (DC) arrays. OMVs were benchmarked against licensed vaccines, including Bexsero and whole cell pertussis formulations, with respect to Th-polarizing cytokine and prostaglandin E2 production, as well as cell surface activation markers (HLA-DR, CD86, and CCR7). OMV immunogenicity was assessed in mice.
  
  
  RESULTS
  ΔlpxLInative OMVs (nOMVs) demonstrated significantly less cytokine induction in human blood and DCs than Bexsero and most of the other pediatric vaccines (e.g., PedvaxHib, EasyFive, and bacillus Calmette-Guérin) tested. Despite a much lower inflammatory profilein vitrothan Bexsero, ΔlpxLInOMVs still had moderate DC maturing ability and induced robust anti-N. meningitidisantibody responses after murine immunization.
  
  
  CONCLUSIONS
  A meningococcal vaccine comprised of attenuated LPS-based OMVs with a limited inflammatory profilein vitroinduces robust antigen-specific immunogenicityin vivo.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dowling
authors.affiliation: Janssen Vaccines and Prevention B.V. , Leiden , Netherlands.
authors.forename: Holly
authors.initials: H
authors.lastname: Sanders
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Precision Vaccine Program, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Wing Ki
authors.initials: WK
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Precision Vaccine Program, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Sweta
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Precision Vaccine Program, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Brightman
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital , Boston, MA , USA.
authors.forename: Ilana
authors.initials: I
authors.lastname: Bergelson
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Precision Vaccine Program, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Neonatal Intensive Care Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pietrasanta
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Precision Vaccine Program, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Simon D
authors.initials: SD
authors.lastname: van Haren
authors.affiliation: Janssen Vaccines and Prevention B.V. , Leiden , Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: van Amsterdam
authors.affiliation: Janssen Research and Development, LLC , Spring House, PA , USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fernandez
authors.affiliation: Janssen Vaccines and Prevention B.V. , Leiden , Netherlands.
authors.forename: Germie P J M
authors.initials: GP
authors.lastname: van den Dobbelsteen
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Precision Vaccine Program, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
keywords: dendritic cells; group B meningococci; newborn; outer membrane vesicles; vaccine