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.

Efficacy and Effectiveness of the PCV-10 and PCV-13 Vaccines Against Invasive Pneumococcal Disease

“…23 PCV-10 was not effective at reducing vaccine-type carriage when measured 1 month after the primary series of the 2 1 1 schedule (1.3%; 95% CI = 221.2 to 19.8) 25 but was at the other time points examined. 24,25 For both the 3 1 1 and 2 1 1 schedules, when NPC was measured at either the 1-or 6month post-primary series or at the 3-month postbooster time point, PCV-10 VE at reducing NTHi carriage was not statistically significant. 24,25 However, these studies saw low carriage levels in all groups across all time points, resulting in wide CIs.…”

“…Schedule e These 2 studies analyzed data obtained from the same study, using 2 different methodologies: a case-control and an indirect cohort design CI: 5.9 to 43.3) as well as for all episodes of AOM (23.7%; 95% CI: 1.3 to 41). 24 The efficacy tended to fall off in older age groups (Supplemental Table 4). When the analysis was restricted to bacteriologically confirmed AOM, the efficacy estimate in children ,12 months of age was significant when considering the first episode (43.3%; 95% CI: 1.7 to 67.3) but not for all AOM episodes (40.3%; 95% CI: 24 to 65.7) 24 .…”

“…24 The efficacy tended to fall off in older age groups (Supplemental Table 4). When the analysis was restricted to bacteriologically confirmed AOM, the efficacy estimate in children ,12 months of age was significant when considering the first episode (43.3%; 95% CI: 1.7 to 67.3) but not for all AOM episodes (40.3%; 95% CI: 24 to 65.7) 24 . Importantly, VE against NTHi AOM could not be demonstrated in children ,5 years of age who had received at least 1 dose of the vaccine 24 (Supplemental Table 4).…”

Cost-effectiveness analysis of infant universal routine pneumococcal vaccination in Malaysia and Hong Kong

“…Finally the assumption that PCV10 has effectiveness against NTHi disease has been widely and repeatedly challenged. [22][23][24][26][27][28][29][30][31][32] In addition, of note, by definition, IPD is a severe condition caused by streptococcus pnemoniae, not caused by NTHi. The assumption that PCV10 provided protection against invasive NTHi is not supported by any scientific evidence.…”

Impact of protein D-containing pneumococcal conjugate vaccines on non-typeableHaemophilus influenzaeacute otitis media and carriage

“…The occurrence of culture-confirmed nasopharyngeal carriage of H. influenzae and NTHi in Panama for the COMPAS study was much less frequent (4.0-5.7%) than was observed in POET (8.8-16.9%). A trend toward VE against nasopharyngeal carriage of NTHi was observed after the booster dose (Figure 2(b)) and the point estimate was greatest 3 months after the booster dose (NTHi VE: 27.0% [95% CI: (Table 1) [80]. Thus, these two studies share similar trends with respect to nasopharyngeal carriage of NTHi although the difference between groups appeared of smaller magnitude and shorter duration in COMPAS than POET.…”