title: A virosomal respiratory syncytial virus vaccine adjuvanted with monophosphoryl lipid A provides protection against viral challenge without priming for enhanced disease in cotton rats.
abstract: BACKGROUND
  Non-replicating respiratory syncytial virus (RSV) vaccine candidates could potentially prime for enhanced respiratory disease (ERD) due to a T-cell-mediated immunopathology, following RSV infection. Vaccines with built-in immune response modifiers, such as Toll-like receptor (TLR) ligands, may avoid such aberrant imprinting of the immune system.
  
  
  METHODS
  We developed reconstituted RSV envelopes (virosomes) with incorporated TLR4 ligand, monophosphoryl lipid A (RSV-MPLA virosomes). Immune responses and lung pathology after vaccination and challenge were investigated in ERD-prone cotton rats and compared with responses induced by live virus and formaldehyde-inactivated vaccine (FI-RSV), a known cause of ERD upon RSV challenge.
  
  
  RESULTS
  Vaccination with RSV-MPLA virosomes induced higher levels of virus-neutralizing antibodies than FI-RSV or live virus infection and provided protection against infection. FI-RSV, but not RSV-MPLA virosomes, primed for increases in expression of Th2 cytokines IL-4, IL-5, IL-13, and Th1 cytokine IL-1b, 6 hour-5 days after infection. By contrast, RSV-MPLA virosomes induced IFN-γ transcripts to similar levels as induced by live virus. Animals vaccinated with FI-RSV, but not RSV-MPLA virosomes showed alveolitis, with prominent neutrophil influx and peribronchiolar and perivascular infiltrates.
  
  
  CONCLUSIONS
  These results show that RSV-MPLA virosomes represent a safe and immunogenic vaccine candidate that warrants evaluation in a clinical setting.
authors.affiliation: Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kamphuis
authors.forename: Toon
authors.initials: T
authors.lastname: Stegmann
authors.forename: Tjarko
authors.initials: T
authors.lastname: Meijerhof
authors.forename: Jan
authors.initials: J
authors.lastname: Wilschut
authors.forename: Aalzen
authors.initials: A
authors.lastname: de Haan
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008168:Lung / Q000473:pathology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D022261:Respiratory Syncytial Virus Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D016205:Sigmodontinae; D022721:Vaccines, Virosome / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D008050:Lipid A; D022261:Respiratory Syncytial Virus Vaccines; D022721:Vaccines, Virosome; C048436:monophosphoryl lipid A
keywords: Adjuvant; cotton rat; enhanced respiratory disease; monophosphoryl lipid A; respiratory syncytial virus; vaccine; virosomes