Effectiveness of the 10-Valent Pneumococcal NontypeableHaemophilus influenzaeProtein D–Conjugated Vaccine (PHiD-CV) Against Carriage and Acute Otitis Media—A Double-Blind Randomized Clinical Trial in Finland

Abstract

After administering the 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D–conjugated vaccine (PHiD-CV) to children aged 2–18 months, we observed a reduction in vaccine-type nasopharyngeal carriage, resulting in a reduction of overall pneumococcal nasopharyngeal carriage, which may be important for indirect vaccine effects. We noted a trend toward reduction of acute otitis media.BackgroundThis trial (ClinicalTrials.gov identifier NCT00839254), nested within a cluster-randomized double-blind invasive pneumococcal disease effectiveness study in Finland (ClinicalTrials.gov identifier NCT00861380), assessed the effectiveness of the 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D–conjugated vaccine (PHiD-CV or PCV10) against bacterial nasopharyngeal carriage and acute otitis media (AOM).MethodsInfants (aged 6 weeks to 6 months) received the PHiD-CV or a control vaccine (hepatitis B) (schedule 3+1 or 2+1). Nasopharyngeal swabs were collected at 4 time points post-vaccination from all of the infants and at pre-vaccination from a subset. Parent-reported physician-diagnosed AOM was assessed from first vaccination until last contact (mean follow-up, 18 months). Vaccine effectiveness (VE) was derived as (1 – relative risk)*100, accounting for cluster design in AOM analysis. Significant VE was assessed descriptively (positive lower limit of the non-adjusted 95% confidence interval [CI]).ResultsThe vaccinated cohort included 5093 infants for carriage assessment and 4117 infants for AOM assessment. Both schedules decreased vaccine-serotype carriage, with a trend toward a lesser effect from the 2+1 schedule ( VE across timpoints 19%–56% [3+1] and 1%–38% [2+1]). Trends toward reduced pneumococcal carriage (predominantly vaccine serotypes 6B, 14, 19F, and 23F), decreased carriage of vaccine-related serotype 19A, and small increases at later time points (ages 14–15 months) in non–vaccine-serotype carriage were observed. No effects on nontypeable Haemophilus influenzae, Staphylococcus aureus, or Moraxella catarrhalis carriage were observed. There were non-significant trends toward a reduction in the number of infants reporting AOM episodes (VE 3+1: 6.1% [95% CI, −2.7% to 14.1%] and 2+1: 7.4% [−2.8% to 16.6%]) and all AOM episodes (VE 3+1: 2.8% [−9.5% to 13.9%] and 2+1: 10.2% [−4.1% to 22.9%]). PHiD-CV was immunogenic and had an acceptable safety profile.ConclusionsWe observed reduced vaccine-type pneumococcal carriage, a limited increase in non–vaccine-type carriage, and a trend toward AOM reduction.

Reduction in antibiotic prescribing for respiratory tract infections in Swedish primary care- a retrospective study of electronic patient records

“…While it should be noted that the introduction of the pneumococcal vaccine in the general vaccination program in Sweden in 2008–2009 may also have played a part in the reduction of AOM in the age group <1 year. [29, 30], taken together these findings suggest an increased adherence to diagnosis and treatment guidelines.…”

Australian Aboriginal Children with Otitis Media Have Reduced Antibody Titers to Specific Nontypeable Haemophilus influenzae Vaccine Antigens

“…Our data suggest that these are important analyses to conduct and understand if we are to know what benefits PHiD-CV10 may elicit. Previous studies in which protection from NTHi-caused AOM by PHiD10-CV was not demonstrated (28–30) were conducted in populations with much lower rates of NTHi carriage, AOM, and NTHi-caused AOM, compared to high-risk indigenous populations such as Australian Aboriginal children (13). Furthermore, there are no data on antigen-specific antibody titers to PD in low-risk PHiD10-CV-vaccinated populations, to determine whether immunological deficiencies exist in these children that may be boosted by using the PHiD10-CV vaccine.…”

“…While licensure of PHiD10-CV was not for NTHi disease, in some trials this vaccine showed the potential to decrease NTHi-associated OM (26, 27), including in Australian Aboriginal children (26). Again, the data are conflicting, with several large randomized controlled trials not being able to demonstrate PHiD10-CV protection against acute OM (AOM) caused by NTHi (28–30). Interestingly, immunization with PHiD10-CV does not appear to significantly reduce nasopharyngeal carriage of NTHi (26–28, 31), suggesting that the effect of this vaccine is compartmental.…”

Immunization with 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) according to different schedules in infants in South Africa: a phase III trial

“…Both schedules have shown effectiveness against culture-confirmed IPD [12], clinically suspected IPD [13], hospital-diagnosed pneumonia [15,16], antimicrobial purchases [37], and a trend toward reduction in the frequency of tympanostomy tube placements [38]. In a nested study in Finland, reductions in vaccine-type carriage, as well as a trend toward a reduction in acute otitis media, were observed with both schedules [39]. Effectiveness of PCVs administered as a 2 + 1 schedule has also been demonstrated in post-marketing studies [40][41][42].…”