Efficacy of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine against acute otitis media and nasopharyngeal carriage in Panamanian children - A randomized controlled trial

Abstract

We previously reported 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) efficacy in a double-blind randomized trial (ClinicalTrials.gov: NCT00466947) against various diseases, including acute otitis media (AOM). Here, we provide further analyses. In the Panamanian subset, 7,359 children were randomized (1:1) to receive PHiD-CV or control vaccine at age 2/4/6 and 15-18 months. Of these, 2,000 had nasopharyngeal swabs collected. AOM cases were captured when parents sought medical attention for children with AOM symptoms; surveillance was enhanced approximately 2 y into the study through regular telephone calls or home visits by study personnel, who advised parents to visit the clinic if their child had AOM symptoms. Mean follow-up was 31.4 months. Clinical AOM (C-AOM) cases were assessed by physicians and confirmed by otorhinolaryngologists. Middle ear fluid samples, taken from children with C-AOM after specific informed consent, and nasopharyngeal samples were cultured for pathogen identification. For 7,359 children, 2,574 suspected AOM cases were assessed by a primary healthcare physician; 649 cases were C-AOM cases as per protocol definition. From the 503 MEF samples collected, 158 resulted in a positive culture. In the intent-to-treat cohort (7,214 children), PHiD-CV showed VE against first C-AOM (24.0% [95% CI: 8.7, 36.7]) and bacterial (B-AOM) episodes (48.0% [20.3, 66.1]) in children <24 months, which declined thereafter with age. Pre-booster VE against C-AOM was 30.7% [12.9, 44.9]; post-booster, -6.7% [-36.4, 16.6]. PHiD-CV VE was 17.7% [-6.1, 36.2] against moderate and 32.7% [-20.5, 62.4] against severe C-AOM. VE against vaccine-serotype pneumococcal NPC was 31.2% [5.3, 50.3] 3 months post-booster, and 25.6% [12.7, 36.7] across all visits. NTHi colonization rates were low and no significant reduction was observed. PHiD-CV showed efficacy against C-AOM and B-AOM in children younger than 24 months, and reduced vaccine-serotype NPC.

Keywords: acute otitis media; children; efficacy; nasopharyngeal carriage; pneumococcal conjugate vaccination.

Figure 1.

Trial profile for children included in the analysis of acute otitis media (AOM) and nasopharyngeal carriage (NPC). Footnote: Elimination criteria shown for one reason only although more than one reason for elimination could apply per child. For children part of the carriage subset, both efficacy against AOM and impact on nasopharyngeal carriage were assessed. Note that overall, 142 children were excluded from the intent-to-treat cohort due to non-valid informed consent forms, among them; the 79 children excluded also from the NPC intent-to-treat cohort. ^a Forbidden underlying medical conditions included, but were not limited to: major congenital defects or serious chronic illness, and confirmed or suspected immunosuppressive or immunodeficient condition. AOM, acute otitis media; NPC, nasopharyngeal carriage.

Figure 2.

Timing and compliance for nasopharyngeal swab collection (total vaccinated cohort for carriage analysis).

Figure 3.

Vaccine efficacy of PHiD-CV against first or all AOM episodes in the per-protocol and intent-to-treat analyses. Footnote: PP: N = 3010 (PHiD-CV); N = 2979 (Control); ITT: N = 3602 (PHiD-CV); N = 3612 (Control). Error bars depict 95% confidence interval; N, number of children in PP or ITT cohort; PP, per-protocol; ITT, intent-to-treat; AOM, acute otitis media; C-AOM, clinically confirmed AOM; B-AOM, bacteriologically confirmed AOM; Pn, S. pneumoniae; VT, vaccine type; NVT, non-vaccine non-vaccine-related type; NTHi, non typeable H. influenzae. *Vaccine efficacy against first C-AOM in per-protocol analysis was assessed as secondary confirmatory objective.

Figure 4.

Nasopharyngeal carriage rates of S. pneumoniae and H. influenzae in nasopharyngeal swabs following primary and booster vaccination with PHiD-CV or control vaccine (intent-to-treat cohort). Footnote: Error bars: 95% confidence intervals. Any serotype belonging to the same serogroup as the PHiD-CV vaccine serotypes, but different from the vaccine serotypes, was considered as vaccine-related. The observed vaccine-related serotypes were 6A, 6C, 19A, and 23A.

Figure 5.

Vaccine efficacy of different pneumococcal conjugate vaccines against all AOM episodes in double-blind randomized controlled trials (per-protocol analyses). Footnote: Error bars: 95% confidence intervals; AOM, acute otitis media; COMPAS, Clinical Otitis Media and PneumoniA Study; POET, Pneumococcal Otitis Efficacy Trial; FinOM, Finnish Otitis Media trial; N, number of children in the per-protocol cohort; VT, vaccine type; NVT, non-vaccine non-vaccine-related type; Hi, H. influenzae; 11Pn-PD, 11-valent protein D-conjugated PCV (unlicensed); 7vCRM, 7-valent CRM197-conjugated PCV (licensed); 7vOMPC, 7-valent meningococcal outer membrane protein complex-conjugated PCV (unlicensed).

Figure 6.

AOM surveillance and definition of clinically-confirmed AOM (C-AOM) and bacteriologically-confirmed AOM (B-AOM). AOM, acute otitis media.