title: Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study.
abstract: BACKGROUND
  Efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) was inferred before licensure from an aggregate correlate of protection established for the seven-valent vaccine (PCV7). We did a postlicensure assessment of serotype-specific vaccine effectiveness and immunogenicity in England, Wales, and Northern Ireland to derive the correlates of protection for individual serotypes.
  
  
  METHODS
  We assessed vaccine effectiveness against invasive pneumococcal disease using the indirect cohort method. We measured serotype-specific IgG concentration in infants after they were given two priming doses of PCV7 (n=126) or PCV13 (n=237) and opsonophagocytic antibody titre from a subset of these infants (n=100). We derived correlates of protection by relating percentage protection to a threshold antibody concentration achieved by an equivalent percentage of infants. We used multivariable logistic regression to estimate vaccine effectiveness and reverse cumulative distribution curves to estimate correlates of protection.
  
  
  RESULTS
  For the 706 cases of invasive pneumococcal disease included in the study, PCV13 vaccine effectiveness after two doses before age 12 months or one dose from 12 months was 75% (95% CI 58-84). Vaccine effectiveness was 90% (34-98) for the PCV7 serotypes and 73% (55-84) for the six additional serotypes included in PCV13. Protection was shown for four of the six additional PCV13 serotypes (vaccine effectiveness for serotype 3 was not significant and no cases of serotype 5 infection occurred during the observation period). The vaccine effectiveness for PCV13 and PCV7 was lower than predicted by the aggregate correlate of protection of 0·35 μg/mL used during licensing. Calculated serotype-specific correlates of protection were higher than 0·35 μg/mL for serotypes 1, 3, 7F, 19A, 19F, and lower than 0·35 μg/mL for serotypes 6A, 6B, 18C, and 23F. Opsonophagocytic antibody titres of 1 in 8 or higher did not predict protection.
  
  
  CONCLUSIONS
  PCV13 provides significant protection for most of the vaccine serotypes. Although use of the aggregate correlate of protection of 0·35 μg/mL has enabled the licensing of effective new PCVs, serotype-specific correlates of protection vary widely. The relation between IgG concentration after priming and long-term protection needs to be better understood.
  
  
  BACKGROUND
  Public Health England and UK Department of Health Research and Development Directorate.
authors.affiliation: Statistics, Modelling, and Economics Department, Health Protection Services, Public Health England, London, UK.
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Andrews
authors.affiliation: Immunisation, Hepatitis, and Blood Safety Department, Health Protection Services, Public Health England, London, UK.
authors.forename: Pauline A
authors.initials: PA
authors.lastname: Waight
authors.affiliation: Immunobiology Section, UCL Institute of Child Health, London, UK.
authors.forename: Polly
authors.initials: P
authors.lastname: Burbidge
authors.affiliation: Immunobiology Section, UCL Institute of Child Health, London, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Pearce
authors.affiliation: Immunobiology Section, UCL Institute of Child Health, London, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Roalfe
authors.affiliation: Immunobiology Section, UCL Institute of Child Health, London, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Zancolli
authors.affiliation: Respiratory and Vaccine Preventable Bacteria Reference Unit, Microbiology Services, Public Health England, London, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Slack
authors.affiliation: Immunisation, Hepatitis, and Blood Safety Department, Health Protection Services, Public Health England, London, UK.
authors.forename: Shamez N
authors.initials: SN
authors.lastname: Ladhani
authors.affiliation: Immunisation, Hepatitis, and Blood Safety Department, Health Protection Services, Public Health England, London, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Miller
authors.affiliation: Immunobiology Section, UCL Institute of Child Health, London, UK. Electronic address: d.goldblatt@ucl.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Goldblatt
mesh_terms: D000907:Antibodies, Bacterial / Q000097:blood; D002675:Child, Preschool; D015331:Cohort Studies; D000069443:Heptavalent Pneumococcal Conjugate Vaccine; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007223:Infant; D008004:Licensure; D022242:Pneumococcal Vaccines / Q000276:immunology*; D012703:Serotyping; D018074:Vaccines, Conjugate / Q000276:immunology
chemical_list: C538862:13-valent pneumococcal vaccine; D000907:Antibodies, Bacterial; D000069443:Heptavalent Pneumococcal Conjugate Vaccine; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D018074:Vaccines, Conjugate