Efficacy of pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in young Latin American children: A double-blind randomized controlled trial.

BACKGROUND: The relationship between pneumococcal conjugate vaccine-induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed. METHODS AND FINDINGS: This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15-18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization-defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28-30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: -1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases. CONCLUSIONS: Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT00466947.

Antibody persistence after a primary series of a new DTaP-IPV-Hep B-PRP-T combined vaccine or separate DTaP-IPV//PRP-T and hepatitis B vaccines at 2, 4, and 6 months of age and the effect of a subsequent DTaP-IPV//PRP-T booster vaccination at 18 months of age in healthy Argentinean infants.

OBJECTIVE: To assess antibody persistence after vaccination with a new, fully liquid, hexavalent DTaP-IPV-Hep B-PRP-T vaccine at 18 months of age versus licensed DTaP-IPV//PRP-T and hepatitis B (Hep B) vaccines, and to assess the immunogenicity and safety of a subsequent DTaP-IPV//PRP-T booster. METHODS: A phase III, open-label, single-center study was conducted. Infants previously primed with 3 doses of DTaP-IPV-Hep B-PRP-T (Hexaxim: N = 232 [group 1]) or DTaP-IPV//PRP-T and hepatitis B vaccine (Pentaxim + Engerix B Pediatrico: N = 226 [group 2]) at 2, 4, and 6 months of age received a DTaP-IPV//PRP-T booster at 18 months of age. Antibodies were measured before and 1 month after booster vaccination. Safety was evaluated from parental reports. Analyses were descriptive. RESULTS: Antibody persistence was high and similar in each group for each antigen except for Hep B, for which the percentage (95% confidence interval) of participants with a titer of ≥ 10 mIU/mL was higher in group 2 (99.5% [97.5%, 100.0%]) than in group 1 (85.5% [80.3%, 89.8%]). Postbooster seroprotection (diphtheria, tetanus, inactivated poliovirus, polyribosyl-ribitol phosphate) and serconversion (pertussis toxoid, filamentous hemagglutinin) rates were high and similar in each group, and geometric mean antibody concentrations increased markedly in both groups. Safety after the booster vaccination was good and independent of the primary-series vaccine, although one serious adverse event of convulsions was considered to be vaccine related. CONCLUSIONS: The DTaP-IPV/PRP-T booster vaccination at 18 months of age was similarly immunogenic and well tolerated after primary-series vaccination with either the investigational hexavalent vaccine or the reference pentavalent vaccine. This confirms the suitability of a booster vaccination of DTaP-IPV//PRP-T after a primary series of the new DTaP-IPV-Hep B-PRP-T vaccine.