Effectiveness of the 10-Valent Pneumococcal Nontypeable Haemophilus influenzae Protein 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.

Background: This 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).

Methods: Infants (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]).

Results: The 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.

Conclusions: We observed reduced vaccine-type pneumococcal carriage, a limited increase in non-vaccine-type carriage, and a trend toward AOM reduction.

Keywords: PHiD-CV; Streptococcus pneumoniae; acute otitis media; nasopharyngeal carriage; pneumococcal conjugate vaccine.

Figure 1.

Study design. Syringes indicate vaccination; vials indicate blood sample acquisition. Abbreviations: HAV, hepatitis A vaccine; HBV, hepatitis B vaccine; M, months; NP, nasopharyngeal swab; PHiD-CV, 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D–conjugated vaccine; W, weeks.

Figure 2.

Participant flow chart. Because of an error in treatment number allocation, 3 children had 2 subject numbers allocated each; thus, the actual number of enrolled children was 6178 instead of 6181, corresponding to 5092 children instead of 5093 in the infant total vaccinated cohort for carriage/safety and 1082 instead of 1084 in the catch-up total vaccinated cohort for carriage/safety. Data for these children were recorded only once for the subject number corresponding to the time of participation. Abbreviations: AOM, acute otitis media; ATP, according-to-protocol; M, months; N, number of children in the specified group; PHiD-CV, 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D–conjugated vaccine; TVC, total vaccinated cohort; W, weeks.

Figure 3.

Percentage of children with nasopharyngeal colonization across all visits (total vaccinated cohort for carriage). The occurrence of S pneumoniae serotypes in nasopharyngeal swabs across all visits (including baseline) is shown. No carriage for vaccine serotype 1 and 5 was observed. Abbreviations: M, months; PHiD-CV, 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D–conjugated vaccine; TVC, total vaccinated cohort.

Figure 4.

Percentage of infants with nasopharyngeal colonization (infant total vaccinated cohort for carriage). The percentages of infants, enrolled between 6 weeks and 6 months of age, colonized with S pneumoniae, NTHi, M catarrhalis, or S aureus were assessed at different ages: 3 months (before vaccination, only for a subset of infants), 6 months (1 month after primary vaccination), 11–12 months (before booster), 14–15 months (3 months after booster), and 18–22 months (7–12 months after booster). Mean values with 95% confidence intervals are shown. Vaccine-type S pneumoniae serotypes were 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F; non-vaccine/non–vaccine-related serotypes were any S pneumoniae serotype, excluding vaccine serotypes and excluding serotypes belonging to the same serogroup as vaccine serotypes. Abbreviations: m, months; PHiD-CV, p10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D–conjugated vaccine.

Figure 5.

Vaccine effectiveness against nasopharyngeal carriage at given time points (infant total vaccinated cohort for carriage). Vaccine efficacy against nasopharyngeal carriage of S pneumoniae, NTHi, M catarrhalis, and S aureus was assessed at different ages: 6 months (1 month after primary vaccination), 11–12 months (before booster), 14–15 months (3 months after booster), and 18–22 months (7–12 months after booster). Mean values with 95% confidence intervals are shown. Vaccine-type S pneumoniae serotypes were 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F; non-vaccine/non–vaccine-related serotypes were any S pneumoniae serotype, excluding the vaccine serotypes and any serotype that belonged to the same serogroup as the vaccine serotype. Abbreviation: PHiD-CV, 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D–conjugated vaccine.