Elsevier

The Lancet

Volume 381, Issue 9862, 19–25 January 2013, Pages 214-222
The Lancet

Articles
Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial

https://doi.org/10.1016/S0140-6736(12)61854-6Get rights and content

Summary

Background

The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was designed to assess the effectiveness of a pneumococcal vaccine containing ten serotype-specific polysaccharides conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid as the carrier proteins (PHiD-CV10) against invasive pneumococcal disease.

Methods

In this cluster-randomised, double-blind trial, children aged younger than 19 months received PHiD-CV10 in 52 clusters or hepatitis vaccines as control in 26 clusters. Infants aged younger than 7 months at the first vaccination received either a 3+1 or a 2+1 vaccination schedule, children aged 7–11 months received a 2+1 schedule, and those 12–18 months of age received a two-dose schedule. The primary and secondary objectives were to assess vaccine effectiveness against culture-confirmed invasive pneumococcal disease due to any of the ten vaccine serotypes for the 3+1 and 2+1 schedules, respectively, in children who received at least one PHiD-CV10 dose before 7 months of age. Masked follow-up of pneumococcal disease lasted from the first vaccination (from February, 2009, to October, 2010) to January 31, 2012. Invasive disease data were retrieved from data accumulated in the national infectious diseases register. This trial and the nested acute otitis media trial are registered with ClinicalTrials.gov, numbers NCT00861380 and NCT00839254, respectively.

Findings

47 366 children were enrolled from February, 2009, to October, 2010. 30 527 participants were assessed for the primary objective. 13 culture-confirmed vaccine-type cases of invasive pneumococcal disease were detected: none in the PHiD-CV10 3+1 group, one in the PHiD-CV10 2+1 group, and 12 in the control groups. The estimates for vaccine effectiveness were 100% (95% CI 83–100) for PHiD-CV10 3+1 and 92% (58–100) for PHiD-CV10 2+1 groups. Two cases of any culture-confirmed invasive disease irrespective of serotype were detected in combined PHiD-CV10 infant cohorts compared with 14 in the corresponding control cohorts (vaccine effectiveness 93%, 75–99). In catch-up cohorts, seven cases of invasive disease were reported, all in the control group: two cases in the children enrolled at 7–11 months of age; and five cases in children enrolled at 12–18 months of age (vaccine effectiveness 100%, 79–100). Non-fatal serious adverse events suspected to be vaccine-related were reported via routine post-immunisation safety surveillance in 18 children.

Interpretation

This nationwide trial showed high PHiD-CV10 effectiveness against invasive pneumococcal disease when given in different schedules. For the first time, effectiveness of a 2+1 schedule in infants was confirmed in a clinical trial.

Funding

GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare, Finland.

Introduction

Widespread use of the first seven-valent pneumococcal non-toxic diphtheria-toxin analogue-conjugate vaccine (PCV7; Prevenar/Prevnar, Pfizer, Philadelphia, PA, USA) has resulted in significant reduction of invasive pneumococcal disease among vaccinated children on several continents.1, 2, 3, 4, 5, 6 Invasive pneumococcal disease has also decreased among unvaccinated populations (herd protection). However, an increase in invasive disease caused by pneumococcal serotypes other than those contained in the vaccine (replacement) has been detected both in vaccinated and unvaccinated populations.4, 5, 6, 7

Another pneumococcal vaccine containing ten serotype-specific polysaccharides conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid as the carrier proteins was developed (PHiD-CV10).8, 9, 10 The vaccine was licensed in the European Union in March, 2009, (Synflorix, GlaxoSmithKline Vaccines, Rixensart, Belgium) on the basis of PHiD-CV10 immunological data according to criteria recommended by WHO11 for licensure for protection against invasive pneumococcal disease, PHiD-CV10 safety data, and efficacy results of the 11-valent precursor formulation against acute otitis media.12

The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was designed to assess the clinical vaccine effectiveness of PHiD-CV10 against invasive pneumococcal disease. To enable unbiased assessment of the total effectiveness in vaccinated children and subsequently the indirect effectiveness in unvaccinated populations we used a cluster randomised clinical field-trial design. Here, we report the effectiveness of PHiD-CV10 against invasive pneumococcal disease in vaccinated children.

Section snippets

Trial design and participants

The FinIP vaccine trial is a controlled, cluster-randomised, double-blind, field trial done in Finnish health-care centres. The study was designed to assess the effectiveness of the PHiD-CV10 against invasive pneumococcal disease in infants. A parallel acute otitis media trial done by the Tampere University Vaccine Research Centre (TAUVRC) had the same cluster-randomised design and its participants were also assessed in this study.13

In August, 2008, public municipal health-care centres in

Results

From February 18, 2009, to October 5, 2010, a total of 47 366 children were enrolled (figure). Of the roughly 125 000 children invited to participate, 38% were finally enrolled. Enrolment proportion ranged from 21–61% in the 72 well-baby-clinic clusters and from 8–16% in the six TAUVRC-only clusters.

All 45 974 participants who received at least one dose of correct vaccine were included in intention-to-treat analyses. 1392 children were excluded from effectiveness analysis: 1381 children did not

Discussion

The FinIP trial showed effectiveness of the PHiD-CV10 vaccine against invasive pneumococcal disease for all vaccination schedules assessed. The effectiveness of the infant 2+1 schedule used in many national programmes was shown for the first time in a clinical-trial setting (panel). Effectiveness was also shown against the two most common serotypes 6B and 14. We were not able to show serotype-specific effectiveness for any of the other serotypes (including the additional serotypes 1, 5, and 7F

References (29)

  • J Leal et al.

    Eradication of invasive pneumococcal disease due to the seven-valent pneumococcal conjugate vaccine serotypes in Calgary, Alberta

    Pediatr Infect Dis J

    (2012)
  • T Pilishvili et al.

    Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine

    J Infect Dis

    (2010)
  • B Chevallier et al.

    Safety and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when coadministered with routine childhood vaccines

    Pediatr Infect Dis J

    (2009)
  • T Vesikari et al.

    Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared to the licensed 7vCRM vaccine

    Pediatr Infect Dis J

    (2009)
  • Cited by (196)

    • Bacterial capsules

      2023, Molecular Medical Microbiology, Third Edition
    View all citing articles on Scopus
    View full text