Vaccination schedule.

<p>The following vaccines were used: PHiD-CV, Synflorix; diphtheria–tetanus–acellular pertussis–hepatitis B–inactivated poliovirus–<i>Haemophilus influenzae</i> type b vaccine (DTPa-HBV-IPV/Hib), Infanrix hexa; DTPa-IPV/Hib, Infanrix-IPV/Hib; hepatitis B, Engerix-B; hepatitis A, Havrix (all by GlaxoSmithKline Vaccines). In addition to these blinded study vaccines, the following vaccines were administered or were recommended: measles–mumps–rubella vaccine at 12 mo of age, hepatitis B vaccination at birth, and hepatitis A vaccination at 12 and 18–21 mo of age, with the second dose given at least 28 days after the study vaccine booster dose. In Argentina, <i>Neisseria meningitidis</i> group C conjugate vaccine (NeisVac-C, Baxter International) was offered at 12 mo of age; in Colombia and Panama, varicella vaccine (Varilrix, GlaxoSmithKline Vaccines) was offered at 12 mo of age; in Colombia, two doses of oral rotavirus vaccine (Rotarix, GlaxoSmithKline Vaccines) were offered within the first 6 mo of life.</p

Trial profile for children included in the analysis of the primary study end point.

<p>Elimination criteria shown for one reason only, although more than one reason for elimination could apply per child. ^aForbidden underlying medical conditions included, but were not limited to, major congenital defects, serious chronic illness, or confirmed or suspected immunosuppressive or immunodeficient conditions.</p

Trial profile for children included in the end-of-study analysis of acute otitis media.

<p>Elimination criteria shown for one reason only, although more than one reason for elimination could apply per child. ^aForbidden underlying medical conditions included, but were not limited to, major congenital defects, serious chronic illness, or confirmed or suspected immunosuppressive or immunodeficient conditions.</p

Inclusion and exclusion criteria.

<p>Inclusion and exclusion criteria.</p

Serious adverse events reported from study start and administration of the first vaccine dose up to study end in at least 1.0% of children (intent-to-treat cohort: all children).

<p>A full listing of SAEs is provided in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001657#pmed.1001657.s011" target="_blank">Table S8</a>.</p

Study objectives.

<p>AOM, acute otitis media; B-CAP, likely bacterial community-acquired pneumonia; C-AOM, clinically confirmed acute otitis media; CAP, community-acquired pneumonia; CRP, C-reactive protein; IPD, invasive pneumococcal disease; PHiD-CV, pneumococcal nontypable <i>Haemophilus influenzae</i> protein D conjugate vaccine; SAE, serious adverse event; VT, vaccine serotype.</p

Efficacy of PHiD-CV against first community-acquired pneumonia and invasive pneumococcal disease episodes.

<p>VE estimated as one minus the hazard ratio and obtained, with its 95% CI, from a Cox regression model based on time to first episode when at least one event was observed in each group and conditional on number of cases when no case in at least one group (i.e., VE equal to zero or −infinite (VE, 1 − [<i>x</i>/0]).</p>a<p>Number of first episodes during the respective follow-up period divided by <i>n</i>, multiplied by 100.</p>b<p>Significant <i>p</i>-value (<i>p</i> = 0.002); one-sided <i>p</i>-value from Cox regression model to test null hypothesis VE ≤ 0% with one-sided alpha of 1.75%.</p>c<p><i>S. pneumoniae</i> was isolated from all culture-confirmed invasive disease cases.</p>d<p>Pneumococcal serotype 6A, 9N, or 19A.</p><p>NC, not calculable.</p

Chest X-ray classification and CAP end point definitions.

<p>Chest X-ray classification and CAP end point definitions.</p

Characteristics of the trial participants included in the analysis of the primary study end point (CAP efficacy cohort; interim analysis), CAP and IPD end-of-study analysis (CAP/IPD efficacy cohort), and AOM end-of-study analysis (AOM efficacy cohort).

a<p>59% of participants were recruited in Argentina (race predominantly white or with European heritage), and the remaining were recruited in Colombia and Panama (participants predominantly mixed race).</p>b<p>Follow-up time calculated as sum of follow-up periods of each child, expressed in years, censored at the first occurrence of a respective end point event.</p>c<p>Recruited in Panama only.</p><p>SD, standard deviation.</p

Efficacy of PHiD-CV against first acute otitis media episodes (end-of-study analysis).

<p>VE estimated as one minus the hazard ratio and obtained, with its 95% CI, from a Cox regression model based on time to first episode.</p>a<p>Number of first episodes during the respective follow-up period divided by <i>n</i>, multiplied by 100.</p>b<p>Pneumococcal serotype 6A, 18B, 19A, or 23A.</p