title: Efficacy of pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in young Latin American children: A double-blind randomized controlled trial.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  BACKGROUND
  www.ClinicalTrials.gov NCT00466947.
authors.affiliation: Centro de Desarrollo del Proyectos Avanzados en Pediatría, Córdoba, Argentina.
authors.forename: Miguel W
authors.initials: MW
authors.lastname: Tregnaghi
authors.affiliation: Department of Infectious Diseases, Hospital del Niño, Panama City, Panama.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sáez-Llorens
authors.affiliation: Centro de Estudios en Infectología Pediátrica, Cali, Colombia.
authors.forename: Pio
authors.initials: P
authors.lastname: López
authors.affiliation: Department of Infectious Diseases, Hospital Notti, Mendoza, Argentina.
authors.forename: Hector
authors.initials: H
authors.lastname: Abate
authors.affiliation: Centro de Desarrollo del Proyectos Avanzados en Pediatría, Santiago del Estero, Argentina.
authors.forename: Enrique
authors.initials: E
authors.lastname: Smith
authors.affiliation: Centro de Desarrollo del Proyectos Avanzados en Pediatría, San Juan, Argentina.
authors.forename: Adriana
authors.initials: A
authors.lastname: Pósleman
authors.affiliation: Health Research International, Panama City, Panama.
authors.forename: Arlene
authors.initials: A
authors.lastname: Calvo
authors.affiliation: Instituto de Investigaciones Científicas y Servicios de Alta Tecnología, Panama City, Panama.
authors.forename: Digna
authors.initials: D
authors.lastname: Wong
authors.affiliation: Centro de Estudios en Infectología Pediátrica, Cali, Colombia.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cortes-Barbosa
authors.affiliation: Centro de Desarrollo del Proyectos Avanzados en Pediatría, Córdoba, Argentina.
authors.forename: Ana
authors.initials: A
authors.lastname: Ceballos
authors.affiliation: Centro de Desarrollo del Proyectos Avanzados en Pediatría, Córdoba, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Tregnaghi
authors.affiliation: Centro de Estudios en Infectología Pediátrica, Cali, Colombia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sierra
authors.affiliation: Instituto de Investigaciones Científicas y Servicios de Alta Tecnología, Panama City, Panama.
authors.forename: Mirna
authors.initials: M
authors.lastname: Rodriguez
authors.affiliation: Health Research International, Panama City, Panama.
authors.forename: Marisol
authors.initials: M
authors.lastname: Troitiño
authors.affiliation: Centro de Desarrollo del Proyectos Avanzados en Pediatría, Santiago del Estero, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Carabajal
authors.affiliation: Department of Infectious Diseases, Hospital Notti, Mendoza, Argentina.
authors.forename: Andrea
authors.initials: A
authors.lastname: Falaschi
authors.affiliation: Department of Pediatrics, Hospital del Niño, Panama City, Panama.
authors.forename: Ana
authors.initials: A
authors.lastname: Leandro
authors.affiliation: GlaxoSmithKline Vaccines, Panama City, Panama.
authors.forename: Maria Mercedes
authors.initials: MM
authors.lastname: Castrejón
authors.affiliation: GlaxoSmithKline Vaccines, Buenos Aires, Argentina.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lepetic
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lommel
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: William P
authors.initials: WP
authors.lastname: Hausdorff
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Dorota
authors.initials: D
authors.lastname: Borys
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Javier
authors.initials: J
authors.lastname: Ruiz Guiñazú
authors.affiliation: GlaxoSmithKline Vaccines, Panama City, Panama.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ortega-Barría
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Yarzábal
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Lode
authors.initials: L
authors.lastname: Schuerman
mesh_terms: D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D002675:Child, Preschool; D004311:Double-Blind Method; D006192:Haemophilus Infections / Q000382:microbiology; D006193:Haemophilus influenzae / Q000276:immunology*; D006801:Humans; D007117:Immunization, Secondary; D007072:Immunoglobulin D / Q000276:immunology*; D007223:Infant; D057194:Intention to Treat Analysis; D007843:Latin America; D008074:Lipoproteins / Q000276:immunology*; D010033:Otitis Media / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D011008:Pneumococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D016896:Treatment Outcome; D014611:Vaccination; D018074:Vaccines, Conjugate / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D002352:Carrier Proteins; D007072:Immunoglobulin D; D008074:Lipoproteins; D022242:Pneumococcal Vaccines; D018074:Vaccines, Conjugate; C067989:glpQ protein, Haemophilus influenzae