title: Attenuated Bordetella pertussis vaccine protects against respiratory syncytial virus disease via an IL-17-dependent mechanism.
abstract: BACKGROUND
  We attenuated virulent Bordetella pertussis by genetically eliminating or detoxifying three major toxins. This strain, named BPZE1, is being developed as a possible live nasal vaccine for the prevention of whooping cough. It is immunogenic and safe when given intranasally in adult volunteers.
  
  
  OBJECTIVE
  Before testing in human infants, we wished to examine the potential effect of BPZE1 on a common pediatric infection (respiratory syncytial virus [RSV]) in a preclinical model.
  
  
  METHODS
  BPZE1 was administered before or after RSV administration in adult or neonatal mice. Pathogen replication, inflammation, immune cell recruitment, and cytokine responses were measured.
  
  
  RESULTS
  BPZE1 alone did not cause overt disease, but induced efflux of neutrophils into the airway lumen and production of IL-10 and IL-17 by mucosal CD4(+) T cells. Given intranasally before RSV infection, BPZE1 markedly attenuated RSV, preventing weight loss, reducing viral load, and attenuating lung cell recruitment. Given neonatally, BPZE1 also protected against RSV-induced weight loss even through to adulthood. Furthermore, it markedly increased IL-17 production by CD4(+) T cells and natural killer cells and recruited regulatory cells and neutrophils after virus challenge. Administration of anti-IL-17 antibodies ablated the protective effect of BPZE1 on RSV disease.
  
  
  CONCLUSIONS
  Rather than enhancing RSV disease, BPZE1 protected against viral infection, modified viral responses, and enhanced natural mucosal resistance. Prevention of RSV infection by BPZE1 seems in part to be caused by induction of IL-17. Clinical trial registered with www.clinicaltrials.gov (NCT 01188512).
authors.affiliation: 1 Centre for Respiratory Infection, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Corinna
authors.initials: C
authors.lastname: Schnoeller
authors.forename: Xavier
authors.initials: X
authors.lastname: Roux
authors.forename: Devika
authors.initials: D
authors.lastname: Sawant
authors.forename: Dominique
authors.initials: D
authors.lastname: Raze
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Olszewska
authors.forename: Camille
authors.initials: C
authors.lastname: Locht
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Openshaw
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001886:Bordetella pertussis / Q000276:immunology; D001990:Bronchiolitis, Viral / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D007113:Immunity, Innate; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000276:immunology; D010567:Pertussis Vaccine / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000517:prevention & control*; D014613:Vaccines, Attenuated
chemical_list: D020381:Interleukin-17; D010567:Pertussis Vaccine; D014613:Vaccines, Attenuated