Immunogenicity and safety of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) co-administered with DTPa vaccine in Japanese children: A randomized, controlled study

Abstract

This phase III, randomized, open-label, multicenter study (NCT01027845) conducted in Japan assessed the immunogenicity, safety, and reactogenicity of 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, given intramuscularly) co-administered with diphtheria-tetanus-acellular pertussis vaccine (DTPa, given subcutaneously). Infants (N=360 ) were randomized (2:1) to receive either PHiD-CV and DTPa (PHiD-CV group) or DTPa alone (control group) as 3-dose primary vaccination (3-4-5 months of age) and booster vaccination (17-19 months of age). Immune responses were measured before and one month after primary/booster vaccination and adverse events (AEs) were recorded. Post-primary immune responses were non-inferior to those in pivotal/efficacy European or Latin American pneumococcal protein D-conjugate vaccine studies. For each PHiD-CV serotype, at least 92.6% of infants post-primary vaccination and at least 97.7% of children post-booster had pneumococcal antibody concentrations ≥0.2 μg/ml, and at least 95.4% post-primary and at least 98.1% post-booster had opsonophagocytic activity (OPA) titers ≥8 . Geometric mean antibody concentrations and OPA titers (except OPA titer for 6B) were higher post-booster than post-priming for each serotype. All PHiD-CV-vaccinated children had anti-protein D antibody concentrations ≥100 EL.U/ml one month post-primary/booster vaccination and all were seroprotected/seropositive against each DTPa antigen. Redness and irritability were the most common solicited AEs in both groups. Incidences of unsolicited AEs were comparable between groups. Serious AEs were reported for 47 children (28 in PHiD-CV group); none were assessed as vaccine-related. In conclusion, PHiD-CV induced robust immune responses and was well tolerated when co-administered with DTPa in a 3-dose priming plus booster regimen to Japanese children.

Keywords: 7vCRM, 7-valent pneumococcal CRM-conjugate vaccine; AE, adverse event; AOM, acute otitis media; ATP, according-to-protocol; CAP, community-acquired pneumonia; CI, confidence interval; COMPAS, Clinical Otitis Media and PneumoniA Study; DTPa, diphtheria-tetanus-acellular pertussis; ELISA, enzyme-linked immunosorbent assay; GMC, geometric mean concentration; GMT, geometric mean titer; HBV, hepatitis B virus; Hib, Haemophilus influenzae type b; IPD, invasive pneumococcal disease; Japan; NTHi, nontypeable Haemophilus influenzae; OPA, opsonophagocytic activity; PCV, pneumococcal conjugate vaccine; PHiD-CV, 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine; POET, Pneumococcal Otitis Efficacy Trial; SAE, serious adverse event; SAS, Statistical Analysis System; SDD, SAS Drug and Development; WHO, World Health Organization; children; co-administration; immunogenicity; pneumococcal conjugate vaccine; safety.

Figure 1.

Trial profile. Withdrawals from the study: Primary phase, PHiD-CV group; allergic reaction to the study vaccines of grade 1 intensity (one child), SAE (Kawasaki's disease, one child), simultaneous participation in another clinical trial (one child), sudden infant death syndrome (one child). Primary phase, control group: move from the study area (one child). Booster phase, PHiD-CV group: consent withdrawal not due to an AE (one child), move from the study area (one child).

Figure 2.

22F-ELISA antibody geometric mean concentrations (GMCs) or opsonophagocytic activity (OPA) geometric mean titers (GMTs), with 95% confidence intervals, against individual pneumococcal serotypes before and one month after vaccination with PHiD-CV co-administered with DTPa (logarithmic scale, ATP cohorts for immunogenicity). Pre-vacc, before the first dose (at approximately 3 months of age); Post-priming, one month after 3-dose priming (at approximately 6 months of age); Pre-booster, before booster dose (17 to 19 months of age); Post-booster, one month after booster dose (18 to 20 months of age).

Figure 3.

Study design. *Children in the control group were allowed catch-up vaccination with 7vCRM (2 doses administered between the second blood sampling time point and 7 d before the DTPa booster dose). Children in both groups were allowed to receive Haemophilus influenzae type b (Hib) and hepatitis b virus (HBV) vaccines concomitantly with the study vaccines. Administration of Bacille Calmette-Guérin, oral polio, measles-rubella, varicella and mumps vaccines was allowed, according to local recommendations, up to 28 d before or at least 7 d after DTPa or PHiD-CV administration.