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

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.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.Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice.www.ClinicalTrials.gov NCT00466947

Efficacy of Pneumococcal Nontypable <i>Haemophilus influenzae</i> Protein D Conjugate Vaccine (PHiD-CV) in Young Latin American Children: A Double-Blind Randomized Controlled Trial

<div><p>Background</p><p>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 <i>Haemophilus influenzae</i> 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.</p><p>Methods and Findings</p><p>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, <i>n</i> = 10,295; control, <i>n</i> = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided <i>p</i> = 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, <i>n</i> = 10,211; control, <i>n</i> = 10,140) and AOM (<i>n</i> = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: −1.1%, 30.4%; one-sided <i>p</i> = 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 (<i>n</i> = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (<i>n</i> = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases.</p><p>Conclusions</p><p>Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice.</p><p>Trial registration</p><p><a href="http://www.ClinicalTrials.gov" target="_blank">www.ClinicalTrials.gov</a><a href="http://www.clinicaltrials.gov/ct2/show/NCT00466947" target="_blank">NCT00466947</a></p><p><i>Please see later in the article for the Editors' Summary</i></p></div

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 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

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

Inclusion and exclusion criteria.

<p>Inclusion and exclusion criteria.</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

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

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