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