Evaluation of the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine in a cluster-randomised trial

PLoS One. 2022 Jan 5;17(1):e0261750. doi: 10.1371/journal.pone.0261750. eCollection 2022.


Background: In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes.

Methods: Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009-2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010-2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5-7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010.

Results: From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years.

Conclusions: This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.

Publication types

  • Clinical Trial, Phase III
  • Clinical Trial, Phase IV
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Bacterial Proteins / administration & dosage*
  • Bacterial Proteins / adverse effects
  • Bacterial Proteins / immunology
  • Carrier Proteins / administration & dosage*
  • Carrier Proteins / adverse effects
  • Carrier Proteins / immunology
  • Child
  • Child, Preschool
  • Double-Blind Method
  • Female
  • Haemophilus Infections / immunology
  • Haemophilus Infections / prevention & control*
  • Haemophilus Vaccines / administration & dosage*
  • Haemophilus Vaccines / adverse effects
  • Haemophilus Vaccines / immunology
  • Haemophilus influenzae / immunology*
  • Humans
  • Immunoglobulin D / administration & dosage*
  • Immunoglobulin D / adverse effects
  • Immunoglobulin D / immunology
  • Infant
  • Lipoproteins / administration & dosage*
  • Lipoproteins / adverse effects
  • Lipoproteins / immunology
  • Male
  • Pneumococcal Vaccines / administration & dosage*
  • Pneumococcal Vaccines / adverse effects
  • Pneumococcal Vaccines / immunology
  • Pneumonia, Bacterial / immunology
  • Pneumonia, Bacterial / prevention & control*
  • Vaccines, Conjugate / administration & dosage
  • Vaccines, Conjugate / adverse effects
  • Vaccines, Conjugate / immunology


  • 10-valent pneumococcal conjugate vaccine
  • Bacterial Proteins
  • Carrier Proteins
  • Haemophilus Vaccines
  • Immunoglobulin D
  • Lipoproteins
  • Pneumococcal Vaccines
  • Vaccines, Conjugate
  • glpQ protein, Haemophilus influenzae

Associated data

  • ClinicalTrials.gov/NCT00839254
  • ClinicalTrials.gov/NCT00861380

Grant support

The study was funded by GlaxoSmithKline Biologicals SA and the Finnish Institute for Health and Welfare (THL), Finland. Both parties were involved in all stages of the study planning, conduct, data collection, analyses, and manuscript development. All authors had access to all the data and accept responsibility for its validity. All authors agreed on the final decision to submit for publication. The specific roles of all authors are articulated in the ‘author contributions’ section.