title: Haemophilus influenzae type b vaccine failure in children is associated with inadequate production of high-quality antibody.
abstract: BACKGROUND
  Despite the excellent immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines, breakthrough cases of Hib disease still affect a small proportion of vaccinated children in the United Kingdom. We performed a retrospective study to compare the avidity of antibody directed against the Hib polysaccharide capsule (PRP) in children who experienced Hib vaccine failure in the United Kingdom among 3 historical cohorts and with age-matched healthy control subjects.
  
  
  METHODS
  Serum samples from vaccinated children with invasive Hib disease were collected beginning in 1992 as part of enhanced surveillance for Hib disease following vaccine introduction. A total of 251 children who experienced Hib vaccine failure were identified from 3 historical cohorts (1992-1995, 1996-1999, and 2000-2003). The anti-PRP antibody concentration and avidity from healthy age-matched control subjects was obtained for the 3 contemporary time points (1995, 1999, and 2002). Serum anti-PRP antibody concentration was measured in each of the samples using a standard Hib ELISA, and antibody avidity was determined using thiocyanate elution.
  
  
  RESULTS
  Within the first 60 days after disease onset, there was no change in the anti-PRP antibody avidity, and there was no statistically significant difference in the geometric mean Hib antibody avidity over the 3 study periods. However, the children who experienced Hib vaccine failure had significantly lower Hib antibody avidity than did healthy control subjects, despite a marked antibody response following infection.
  
  
  CONCLUSIONS
  Children who experience Hib disease despite vaccination appear to have a defect in immunological priming, leading to a qualitative difference in Hib-specific memory B cells. Low anti-PRP antibody avidity decreases the functional activity of anti-PRP antibody in the sera of these children experiencing vaccine failure, leading to disease susceptibility.
authors.affiliation: University Department of Paediatrics, University of Oxford, Oxford, UK. lyehchen@yahoo.com
authors.forename: Yeh Chen
authors.initials: YC
authors.lastname: Lee
authors.forename: Dominic F
authors.initials: DF
authors.lastname: Kelly
authors.forename: Ly-Mee
authors.initials: LM
authors.lastname: Yu
authors.forename: Mary P E
authors.initials: MP
authors.lastname: Slack
authors.forename: Robert
authors.initials: R
authors.lastname: Booy
authors.forename: Paul T
authors.initials: PT
authors.lastname: Heath
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Siegrist
authors.forename: Richard E
authors.initials: RE
authors.lastname: Moxon
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
mesh_terms: D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology*; D000915:Antibody Affinity / Q000276:immunology; D016667:Bacterial Capsules; D002675:Child, Preschool; D015331:Cohort Studies; D004198:Disease Susceptibility; D005260:Female; D006192:Haemophilus Infections / Q000097:blood / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D018073:Haemophilus Vaccines / Q000276:immunology* / Q000627:therapeutic use; D019741:Haemophilus influenzae type b / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D011135:Polysaccharides, Bacterial / Q000276:immunology* / Q000627:therapeutic use; D012189:Retrospective Studies; D017211:Treatment Failure; D018074:Vaccines, Conjugate / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000907:Antibodies, Bacterial; D018073:Haemophilus Vaccines; C044237:Haemophilus influenzae type b polysaccharide vaccine; D011135:Polysaccharides, Bacterial; D018074:Vaccines, Conjugate