title: Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis: protocol for a randomised controlled trial.
abstract: BACKGROUND
  Recurrent protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis are characterised by a chronic wet cough and are important causes of childhood respiratory morbidity globally. Haemophilus influenzae and Streptococcus pneumoniae are the most commonly associated pathogens. As respiratory exacerbations impair quality of life and may be associated with disease progression, we will determine if the novel 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) reduces exacerbations in these children.
  
  
  METHODS
  A multi-centre, parallel group, double-blind, randomised controlled trial in tertiary paediatric centres from three Australian cities is planned. Two hundred six children aged 18 months to 14 years with recurrent PBB, CSLD or bronchiectasis will be randomised to receive either two doses of PHiD-CV or control meningococcal (ACYW₁₃₅) conjugate vaccine 2 months apart and followed for 12 months after the second vaccine dose. Randomisation will be stratified by site, age (<6 years and ≥6 years) and aetiology (recurrent PBB or CSLD/bronchiectasis). Clinical histories, respiratory status (including spirometry in children aged ≥6 years), nasopharyngeal and saliva swabs, and serum will be collected at baseline and at 2, 3, 8 and 14 months post-enrolment. Local and systemic reactions will be recorded on daily diaries for 7 and 30 days, respectively, following each vaccine dose and serious adverse events monitored throughout the trial. Fortnightly, parental contact will help record respiratory exacerbations. The primary outcome is the incidence of respiratory exacerbations in the 12 months following the second vaccine dose. Secondary outcomes include: nasopharyngeal carriage of H. influenzae and S. pneumoniae vaccine and vaccine- related serotypes; systemic and mucosal immune responses to H. influenzae proteins and S. pneumoniae vaccine and vaccine-related serotypes; impact upon lung function in children aged ≥6 years; and vaccine safety.
  
  
  CONCLUSIONS
  As H. influenzae is the most common bacterial pathogen associated with these chronic respiratory diseases in children, a novel pneumococcal conjugate vaccine that also impacts upon H. influenzae and helps prevent respiratory exacerbations would assist clinical management with potential short- and long-term health benefits. Our study will be the first to assess vaccine efficacy targeting H. influenzae in children with recurrent PBB, CSLD and bronchiectasis.
  
  
  BACKGROUND
  Australia and New Zealand Clinical Trials Registry (ANZCTR) number: ACTRN12612000034831.
authors.affiliation: Queensland Children's Medical Research Institute, Royal Children's Hospital, The University of Queensland, Brisbane, QLD, Australia. k.ogrady@uq.edu.au.
authors.forename: Kerry-Ann F
authors.initials: KA
authors.lastname: O'Grady
authors.forename: Keith
authors.initials: K
authors.lastname: Grimwood
authors.forename: Allan
authors.initials: A
authors.lastname: Cripps
authors.forename: Edward K
authors.initials: EK
authors.lastname: Mulholland
authors.forename: Peter
authors.initials: P
authors.lastname: Morris
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Torzillo
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wood
authors.forename: Heidi
authors.initials: H
authors.lastname: Smith-Vaughan
authors.forename: Amber
authors.initials: A
authors.lastname: Revell
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilson
authors.forename: Peter
authors.initials: P
authors.lastname: Van Asperen
authors.forename: Peter
authors.initials: P
authors.lastname: Richmond
authors.forename: Ruth
authors.initials: R
authors.lastname: Thornton
authors.forename: Sheree
authors.initials: S
authors.lastname: Rablin
authors.forename: Anne B
authors.initials: AB
authors.lastname: Chang
mesh_terms: D000293:Adolescent; D000367:Age Factors; D001315:Australia; D001987:Bronchiectasis / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D001991:Bronchitis / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D002985:Clinical Protocols; D003371:Cough / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D018450:Disease Progression; D004311:Double-Blind Method; D006192:Haemophilus Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D007115:Immunization Schedule; D007223:Infant; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011018:Pneumonia, Pneumococcal / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D012008:Recurrence; D012107:Research Design; D062606:Tertiary Care Centers; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C547294:PHiD-CV vaccine; D022242:Pneumococcal Vaccines