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Effect of pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3–4 trial

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Summary

Background

Antimicrobial drugs are frequently prescribed to children for respiratory tract infections such as otitis, tonsillitis, sinusitis, and pneumonia. We assessed the effect of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; GlaxoSmithKline) on antimicrobial purchases.

Methods

In this nationwide phase 3–4 cluster-randomised, double-blind trial, children younger than 19 months were randomly assigned to receive PHiD-CV10 in 52 of 78 clusters or hepatitis B or A vaccine as control in 26 clusters according to three plus one or two plus one schedules (infants younger than 7 months) or catch-up schedules (children aged 7–18 months). The main objective for the antimicrobial treatment outcome was to assess vaccine effectiveness against outpatient prescriptions of antimicrobial drugs recommended by national treatment guidelines for acute otitis media in Finland in children who received at least one dose of study vaccine before 7 months of age. Masked follow-up lasted from the date of first vaccination (from Feb 18, 2009, through Oct 5, 2010) to Dec 31, 2011. We obtained data on all purchased antimicrobial prescriptions through the benefits register of the Social Insurance Institution of Finland. This and the nested acute otitis media trial are registered at ClinicalTrials.gov, numbers NCT00861380 and NCT00839254.

Findings

More than 47 000 children were enrolled. In 30 527 infants younger than 7 months at enrolment, 98 436 outpatient antimicrobial purchases were reported with incidence of 1·69 per person-year in the control clusters. Analysis of the main objective included 91% of all antimicrobial purchases: 31 982 in the control and 57 964 in the PHiD-CV10 clusters. Vaccine effectiveness was 8% (95% CI 1–14) and the incidence rate difference 0·12 per person-year corresponding to the number needed to vaccinate of five (95% CI 3–67) to prevent one purchase during the 2 year follow-up for combined PHiD-CV10 three plus one and two plus one infant schedules. The vaccine effectiveness was identical for the two infant schedules. In the catch-up schedules, the vaccine effectiveness was 3% (95% CI −4 to 10).

Interpretation

Despite low relative rate reductions the absolute rate reductions were substantial because of the high incidence of the outcome. This reduction would lead to over 12 000 fewer antimicrobial purchases per year in children younger than 24 months in Finland (birth cohort of 60 000 children).

Funding

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

Introduction

Antimicrobial drugs are frequently prescribed to treat mucosal respiratory infections in children. High incidence of respiratory infections coupled with difficult clinical and causal diagnosis, especially in determining whether the origin is bacterial or viral, and parental expectations for active treatment have led to substantial overuse of antimicrobial drugs. Decreasing trends have been reported,1, 2 but overuse of antimicrobial drugs remains a public health challenge. Although most mucosal respiratory infections are viral, Streptococcus pneumoniae and Haemophilus influenzae are major pathogens in acute otitis media in children,3, 4, 5 and acute otitis media is the most common indication for antimicrobial treatment in children in high-income countries.2, 6, 7

In clinical trials, pneumococcal conjugate vaccines (PCV) have reduced vaccine serotype-specific acute otitis media by roughly 60%;5, 8, 9 however, the effect on overall acute otitis media has been lower (from 0% to 34%). This reduced effect is due to a variety of pathogens causing the disease and also due to replacement by non-vaccine serotypes and by other pathogens. In observational studies otitis media diagnoses have shown reductions of 19% on average after the implementation of national vaccination programmes including the first-licensed seven-valent PCV (PCV7; Prevenar/Prevnar Pfizer, Philadelphia, PA, USA).10

We previously reported the effectiveness of the ten-valent pneumococcal conjugate vaccine PHiD-CV10 (Synflorix, GlaxoSmithKline Vaccines, Rixensart, Belgium) against invasive pneumococcal disease in a cluster randomised clinical trial setting.11 Here, we report its effect on outpatient antimicrobial purchases.

Section snippets

Trial design and participants

The Finnish invasive pneumococcal disease (FinIP) vaccine trial was designed as a phase 3–4 double-blind cluster-randomised, controlled field trial. The detailed trial design was presented earlier.11

Nurses (n>2200) who are responsible for routine health follow-up and immunisations of children did the trial enrolment and vaccinations in collaborating Finnish health-care centres and their local well-baby clinics (n=651). A parallel immunogenicity, carriage, and acute otitis media trial12 done by

Results

We enrolled 47 366 individuals in the 78 clusters between Feb 18, 2009, and Oct 5, 2010 (figure 1). 45 974 participants who received the correctly assigned vaccine were included in the intention-to-treat analyses.

The primary vaccination series was completed in 97–99% of participants in the PHiD-CV10 and control three plus one and two plus one infant cohorts. The mean follow-up was 24 months (range 14–34 months) for infants and 27 months (13–34 months) for participants in the catch-up groups.

Discussion

Results from our nationwide randomised trial showed reduction in outpatient antimicrobial purchases in PHiD-CV10 vaccinated children. Despite low estimates for relative vaccine effectiveness, the absolute reduction was substantial because of the extensive load of antimicrobial use in the study population (panel).

Our analysis also suggested that the vaccine effect was greater in those most susceptible to infections since the vaccine effectiveness estimates increased with the higher number of

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