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Immunogenicity and Safety of 10-valent Pneumococcal Nontypeable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) Administered to Children With Sickle Cell Disease Between 8 Weeks and 2 Years of Age: A Phase III, Open, Controlled Study

Sirima, Sodiomon B. MD, PhD*†; Tiono, Alfred MD, PhD; Gansané, Zakaria MD*; Siribié, Mohamadou MD, PhD*; Zongo, Angèle MD; Ouédraogo, Alphonse MD, PhD; François, Nancy MSc§; Strezova, Ana MD; Dobbelaere, Kurt MD§; Borys, Dorota MD§

The Pediatric Infectious Disease Journal: May 2017 - Volume 36 - Issue 5 - p e136–e150
doi: 10.1097/INF.0000000000001518
Vaccine Reports
Open Access

Background: Immunogenicity, safety and reactogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) were evaluated in children with sickle cell disease (SCD), who are at increased risk for infections.

Methods: In this phase III, open-label, single-center, controlled study in Burkina Faso (NCT01175083), children with SCD (S) or without SCD (NS) were assigned to 6 groups (N = 300): children 8–11 weeks of age (<6 months; <6S and <6NS groups) received 3 primary doses and a booster dose of PHiD-CV coadministered with routine childhood vaccines; children 7–11 months of age (7-11S and 7-11NS groups) received 2 primary doses and a booster dose of PHiD-CV; children 12–23 months of age (12-23S and 12-23NS groups) received 2 catch-up doses of PHiD-CV. Pneumococcal antibody responses were measured using 22F-inhibition enzyme-linked immunosorbent assay and functional opsonophagocytic activity. Responses to other antigens were measured by enzyme-linked immunosorbent assay. Adverse events were recorded.

Results: One month postprimary vaccination, for each vaccine serotype ≥98% of infants in the <6S and <6NS groups had antibody concentrations ≥0.2 µg/mL, except for 6B (≥85%) and 23F (≥89%). Immune responses to PHiD-CV after age-appropriate vaccination in children <2 years did not appear influenced by SCD. All infants were seroprotected/seropositive for diphtheria, tetanus and Bordetella pertussis antigens postprimary and booster vaccination. Safety and reactogenicity profiles were similar in children with or without SCD.

Conclusions: PHiD-CV was immunogenic with an acceptable safety profile in children with and without SCD starting vaccination at 8 weeks to 23 months of age.

Supplemental Digital Content is available in the text.

From the *Groupe de Recherche Action en Santé (GRAS), Ouagadougou, Burkina Faso; Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso; Centre Hospitalier Universitaire Yalgado Ouédraogo (CHUYO), Ouagadougou, Burkina Faso; §GSK, Wavre, Belgium; and XPE Pharma & Science C/O GSK, Wavre, Belgium.

Accepted for publication October 11, 2016.

GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also funded all costs associated with the development and the publishing of the present article. N.F. and D.B. are employed by the GSK group of companies; K.D. was employed by the GSK group of companies; K.D. and D.B. own shares of the GSK group of companies; A.S. works for XPE Pharma & Science as a consultant for the GSK group of companies. The other authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Sodiomon B. Sirima, MD, PhD, 06 BP 10248 Ouagadougou 06, Burkina Faso. E-mail: gras@fasonet.bf.

Children with sickle cell disease (SCD) have increased susceptibility to bacterial infections compared with children of similar age without SCD. Streptococcus pneumoniae and Haemophilus influenzae infections are significant causes of morbidity and mortality in these children and are particularly problematic in early childhood.1 Prophylactic administration of penicillin can reduce the risk of infection and death in children with SCD,2 but prevention by antibiotics is not optimal because penicillin-resistant strains of S. pneumoniae have emerged since the early 1990s.3 Immunization with a pneumococcal vaccine is an important strategy to prevent invasive pneumococcal disease (IPD) and other pneumococcal diseases in children with SCD.4

The 23-valent polysaccharide pneumococcal vaccine (PPSV23), first recommended for children over 2 years of age in high-risk groups including children with SCD, covers approximately 90% of the most frequently reported IPD isolates.5 However, children under the age of 2 years fail to mount an adequate immune response to PPSV23, which led to the development of pneumococcal conjugate vaccines. The 7-valent pneumococcal conjugate vaccine (PCV7), which includes serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, was shown to be highly immunogenic and well tolerated in infants with SCD when administered at 2, 3 and 4 months of age.6 Although antibody titers declined with time after the completion of 3-dose priming, they increased dramatically after administration of a booster dose of PPSV23 given at 15–18 months of age, showing that children with SCD are capable of mounting immune memory.6 Another study evaluating immune responses to PCV7 showed equally robust immune responses after primary immunization in infants with and without SCD.7 Also, PCV7 implementation in the United States was associated with a 68% reduction in the incidence of IPD in children with SCD 10 years of age and younger.8 In these children, PCV7 effectiveness against IPD was estimated to be 84.5% in the first 3 years after licensure.8 The 13-valent pneumococcal conjugate vaccine, which contains 6 additional serotypes (1, 3, 5, 6A, 7F and 19A) compared with PCV7, was immunogenic when administered as a 2-dose regimen in 6- to 17-year-old SCD children primed with PPSV23.9

In 2008, a 10-valent pneumococcal nontypeable H. influenzae protein D conjugate vaccine (PHiD-CV), which extends the coverage of PCV7 to serotypes 1, 5 and 7F, was licensed outside the United States, for immunization of infants and children up to 5 years of age. The aim of this study was to evaluate the immunogenicity, safety and reactogenicity of PHiD-CV in infants and toddlers with SCD.

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MATERIALS AND METHODS

Study Design and Participants

This phase III, open-label, single-center, controlled study was conducted in Burkina Faso between June 2011 and May 2013. Children with SCD (S) and children without SCD (NS) 8 weeks to 23 months of age at the time of first vaccination were assigned to 6 parallel groups: children 8–11 weeks of age (<6 months; <6S and <6NS groups) received 3 primary doses and a booster dose of PHiD-CV (Synflorix, GSK, Belgium) coadministered with diphtheria-tetanus-whole cell pertussis-hepatitis B virus and H. influenzae type b vaccine (DTPw-HBV/Hib, Tritanrix HepB Hib, GSK, Belgium) and oral poliovirus vaccine (OPV, Polio Sabin, GSK, Belgium); children 7–11 months of age (7-11S and 7-11NS groups) received 2 primary doses and a booster dose of PHiD-CV; and children 12–23 months of age (12-23S and 12-23NS groups) received PHiD-CV in a 2-dose catch-up regimen. The study design is presented in Figure 1.

FIGURE 1

FIGURE 1

The study participants were screened in a network of 13 peripheral health care centers and 2 central hospitals in Ouagadougou. Newborns were screened for SCD at the maternities; when a child with SCD was enrolled, a control was selected among the infants without SCD screened the same day at the same maternity. Most older children with SCD had been diagnosed with a hemoglobinopathy before the start of the study and were in active cohorts followed up by a pediatrician in the main hospital of Ouagadougou. Other parents of children with SCD were sent to the study center by their pediatrician. The healthy controls were selected among children attending the health center for routine nutritional status follow-up; during this screening, some new SCD cases were diagnosed.

Written informed consent for study participation was obtained from each child’s parent or legally acceptable representative. For all infants below 6 months of age and for older children without hemoglobin status confirmed by electrophoresis, a specific informed consent form was used for SCD testing. Children from the <6S, 7-11S and 12-23S groups had a diagnosis of SCD [homozygous SCD (hemoglobin SS disease), double heterozygous sickle hemoglobin C disease (hemoglobin SC disease) and sickle β-thalassemia] and confirmed hemoglobin status by hemoglobin chromatography and electrophoresis (<6S group) or electrophoresis only (7-11S and 12-23S groups). Children diagnosed with SCD did not have any known or suspected health problems that would contraindicate routine immunizations. Children from the <6NS, 7-11NS and 12-23NS groups were generally healthy, with negative diagnosis of SCD, and confirmed hemoglobin status by hemoglobin chromatography or electrophoresis.

Children were not eligible if they had received any pneumococcal vaccine or any investigational or nonregistered drug or vaccine between 30 days before the first dose and study end. Locally recommended vaccines were allowed, even if they were concomitantly administered with the study vaccines. Based on medical history and physical examination (no laboratory testing required), children were excluded if they had received immunoglobulin or blood products since birth, were immunosuppressed or immunodeficient for any reason (including human immunodeficiency virus) or had previous vaccination against or history of diphtheria, tetanus, Bordetella pertussis, hepatitis B and H. influenzae (<6S and <6NS groups). Other exclusion criteria were any reaction of hypersensitivity likely to be exacerbated by any component of the vaccines, a birth weight below 1500 g, any major congenital defect, serious chronic illness (other than SCD), history of any neurologic disorder or seizures, or an acute disease or fever at the time of enrollment.

The study was conducted per Good Clinical Practice guidelines, the Declaration of Helsinki and the local rules and regulations of the country. The protocol was approved by the national independent ethics committee and institutional review board of the study center. The study was registered at www.ClinicalTrials.gov (NCT01175083). A summary of the protocol is available at http://www.gsk-clinicalstudyregister.com (GSK study ID 114056). The study vaccines and procedures, the treatment allocation and the immunogenicity and safety assessments are described in Supplemental Digital Content 1, http://links.lww.com/INF/C661.

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Objectives

The primary objective of the study was to assess the immunogenicity of 3 primary doses of PHiD-CV when coadministered with DTPw-HBV/Hib and OPV in infants younger than 6 months of age with SCD.

Secondary objectives included the assessment of immunogenicity of PHiD-CV given as a booster dose coadministered with DTPw-HBV/Hib and OPV vaccines in the <6S and <6NS groups, as 2-dose priming followed by a booster dose in the 7-11S and 7-11NS groups or as a 2-dose catch-up vaccination in the 12-23S and 12-23NS groups. Other secondary objectives were the assessment of safety and reactogenicity after each vaccination in all groups and antibody persistence after primary vaccination in the <6S, <6NS, 7-11S and 7-11NS groups and after the first catch-up dose in the 12-23S and 12-23NS groups. Finally, immune responses to diphtheria, tetanus and B. pertussis antigens after primary and booster vaccinations were also assessed in the <6S and <6NS groups.

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SCD Testing

Testing for SCD was performed on a blood sample of up to 2.5 mL drawn at birth or before the first vaccination. To confirm hemoglobin status, blood samples were analyzed by a local laboratory using an isoelectric focusing technique on agar gels. When SCD was diagnosed in children younger than 6 months of age, high-performance liquid chromatography using the Variant β-thalassemia short program kit (Bio-Rad Laboratories, Inc) was performed as a confirmation test. No confirmation test was needed for children older than 6 months.

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Statistical Analysis

A total of 300 children (50 children per group) were planned to be enrolled, to have 40 evaluable children per group in the according-to-protocol (ATP) cohort for immunogenicity with drop-out and elimination rate of 20%. The study had no confirmatory objectives that would drive its sample size. All objectives including the primary objective were descriptive. For exploratory analysis, the power to rule out the null hypothesis that antibody geometric mean concentration (GMC) ratios (<6NS group over <6S group) were ≥2 ranged from 64.1% to 99.4% for vaccine serotypes and protein D.

Immunogenicity analyses were performed on the ATP cohort. For study groups <6S, <6NS, 7-11S and 7-11NS, the primary (or booster) ATP cohort for immunogenicity included all evaluable children, meeting all eligibility criteria, complying with the protocol-defined procedures and intervals relative to the primary (or booster) vaccination, with no elimination criteria during the primary (or booster) vaccination and for whom data concerning primary (or booster) immunogenicity endpoints were available. For study groups 12-23S and 12-23NS, the ATP cohort for immunogenicity included all evaluable children, meeting all eligibility criteria, complying with the protocol-defined procedures and intervals, with no elimination criteria during the study and for whom data concerning immunogenicity endpoints were available.

The primary safety analysis was performed on the total vaccinated cohort (TVC). For study groups <6S, <6NS, 7-11S and 7-11NS, the primary (or booster) TVC included all vaccinated children who received at least 1 primary dose (or the booster dose) of the study vaccine. For study groups 12-23S and 12-23NS, the TVC included all children who received at least 1 dose of PHiD-CV.

Antibody GMCs and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were calculated for each pneumococcal serotype or antigen with 95% confidence intervals (CIs) by taking the antilog of the mean of the log antibody concentration or titer transformations. Antibody concentrations and OPA titers below assay cutoffs were given an arbitrary value of half the cutoff for GMC and GMT calculations. Seropositivity and seroprotection rates were calculated with exact 95% CIs for each appropriate antigen. The percentage of children with antibody concentrations ≥0.2 µg/mL, equivalent to antibody concentrations ≥0.35 µg/mL measured by the non-22F enzyme-linked immunosorbent assay of the reference laboratory of the World Health Organization, was calculated for each vaccine and vaccine-related pneumococcal serotype.10 Seropositivity was defined as antiinactivated B. pertussis antibody concentrations ≥15 enzyme-linked immunosorbent assay units per milliliter (EU/mL), antiprotein D antibody concentrations ≥100 EU/mL and OPA titers ≥8 against pneumococcal serotypes. Seroprotection rates were ≥0.1 international unit per milliliter (IU/mL) for antidiphtheria and antitetanus antibodies.

In exploratory analyses, 2 groups were considered potentially different in terms of percentages of participants with antibody concentrations and OPA titers above prespecified cutoffs if the asymptotic standardized 95% CI for the difference in rates between groups did not contain the value 0. In terms of GMCs and GMTs, 2 groups were considered potentially different if the 95% CI for the GMC and GMT ratios between groups did not contain the value 1. Exploratory analyses at 1 month postprimary vaccination and catch-up vaccination were performed on GMC and GMT ratios adjusted for baseline concentrations (except for OPA GMTs in the <6S and <6NS groups). The results of exploratory group comparisons should be interpreted with caution considering there was no adjustment for multiplicity and the clinical relevance of the difference is unknown.

Statistical analyses were performed using the Statistical Analysis System Drug Development web portal version 3.5 and Statistical Analysis System version 9.2 (SAS Institute Inc.).

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RESULTS

Study Participants

The study was performed between June 2011 and May 2013. A total of 3505 children were screened, of whom 300 were enrolled and included in the primary TVC (6 study groups). Of these, 198 were included in the booster TVC (4 study groups). The primary and booster ATP cohorts for immunogenicity included 289 and 181 children, respectively. The number of children enrolled in each cohort at different time points and the reasons for elimination are detailed in Figure 2. Within age categories, demographic characteristics were similar between groups of children with and without SCD (Table 1), except for sex distribution. All children were of African heritage.

TABLE 1

TABLE 1

FIGURE 2

FIGURE 2

SCD testing was part of the per-protocol defined study procedures (screening phase) in all children younger than 6 months, while for older children, it was performed only if no confirmation on a hemoglobin status by electrophoresis was available before the study. As reported by the investigators, the vast majority of children in the <6S and 7-11S groups (90% and 74%, respectively) had SC disease, while this percentage was approximately 50% among children from the 12-23S group. Among remaining children with SCD, a majority was diagnosed with SS disease, few with β-thalassemias.

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Immunogenicity Results

Immune Response to PHiD-CV

<6S and <6NS Groups.

One month postprimary vaccination, for each vaccine serotype, ≥97.8% of infants with or without SCD had antibody concentrations ≥0.2 µg/mL, except for serotypes 6B and 23F, and ≥93.2% of infants with SCD and ≥89.7% of infants without SCD had OPA titers ≥8, except for serotypes 1, 6B and 23F (Table 2). Exploratory analyses suggested that OPA GMTs against serotype 19F may be higher in the <6S group than in the <6NS group (558.9 versus 266.1) and that percentages of infants with antibody concentrations ≥0.2 µg/mL for serotype 6A (43.5% versus 20.9%) and with OPA titers ≥8 for serotype 19A (28.9% versus 8.8%) may be higher in the <6S than in the <6NS group (Fig. 3A and B).

TABLE 2

TABLE 2

FIGURE 3

FIGURE 3

Before administration of the booster dose, for each vaccine serotype, ≥92.1% of infants had antibody concentrations ≥0.2 µg/mL, and ≥80.0% of infants had OPA titers ≥8, with the exception of serotypes 1, 5 and 23F.

One month postbooster vaccination, for each vaccine serotype, all infants had antibody concentrations ≥0.2 µg/mL, with the exception of serotypes 14 and 23F, and ≥97.5% of infants with SCD and ≥93.9% of infants without SCD had OPA titers ≥8. The booster dose induced robust increases in antibody GMCs and OPA GMTs against each vaccine serotype. For each of the vaccine-related serotypes 6A and 19A, ≥77.8% of infants with SCD and ≥65.5% of infants without SCD had postbooster antibody concentrations ≥0.2 µg/mL, and ≥42.3% of infants with SCD and ≥40.6% of infants without SCD had OPA titers ≥8. Exploratory analyses suggested that postbooster OPA GMTs for serotype 23F may be higher in the <6S compared with the <6NS group (4231.2 versus 1454.0) (Fig. 3C).

All children had antiprotein D antibody concentrations ≥100 EU/mL at 1 month postprimary and postbooster vaccinations.

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7-11S and 7-11NS Groups.

One month postprimary vaccination, for each vaccine serotype, ≥98.0% of children with SCD and ≥93.9% of children without SCD had antibody concentrations ≥0.2 µg/mL, with the exception of serotypes 6B and 23F, and ≥87.5% of children with SCD and ≥84.4% of children without SCD had OPA titers ≥8 (Table 3). For each of the vaccine-related serotypes 6A and 19A, antibody concentrations ≥0.2 µg/mL were observed in 33.3% and 72.0% of children with SCD and 45.7% and 87.8% of children without SCD, while OPA titers ≥8 were observed in 46.9% and 37.5% of children with SCD and 53.8% and 80.6% of children without SCD, respectively. Exploratory analyses suggested that postprimary vaccination antibody GMCs may be higher for serotype 4 (adjusted GMC of 10.56 versus 7.50 µg/mL) and OPA GMTs lower for serotype 19A (adjusted GMT of 15.2 versus 78.8) in the 7-11S than in the 7-11NS group (Fig. 3D).

TABLE 3

TABLE 3

Before the booster dose administration, for each vaccine serotype, ≥86.0% of children with SCD and ≥91.8% of children without SCD had antibody concentrations ≥0.2 µg/mL, and ≥86.7% of children with SCD and ≥82.6% of children without SCD had OPA titers ≥8, except for serotype 1.

One month postbooster vaccination, for each vaccine serotype, ≥89.8% of children with SCD and ≥93.8% of children without SCD had antibody concentrations ≥0.2 µg/mL, and ≥89.4% of children with SCD and ≥95.1% of children without SCD had OPA titers ≥8. For each of the vaccine-related serotypes, ≥62.5% of children with SCD and ≥77.1% of children without SCD had antibody concentrations ≥0.2 µg/mL, and ≥60.0% of children with SCD and ≥62.8% of children without SCD had OPA titers ≥8. Robust increases in antibody GMCs and OPA GMTs were observed from prebooster to 1 month postbooster vaccination for each vaccine serotype. Exploratory analyses suggested that postbooster OPA GMTs may be lower for serotype 19A (adjusted GMT of 76.1 versus 449.1) in the 7-11S compared with the 7-11NS group (Fig. 3E).

All children had antiprotein D antibody concentrations ≥100 EU/mL at 1 month postprimary vaccination, before and 1 month postbooster vaccination.

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12-23S and 12-23NS Groups.

Before the second dose administration, for each vaccine serotype, ≥91.5% of children without SCD had antibody concentrations ≥0.2 µg/mL, except for serotypes 6B and 23F, and ≥90.7% of children had OPA titers ≥8, except for serotypes 1, 5 and 6B (Table 4). For serotypes 6A and 19A, 51.1% and 83.3% of children with SCD and 34.0% and 78.7% of children without SCD had antibody concentrations ≥0.2 µg/mL, and 65.9% and 52.2% of children with SCD and 57.1% and 51.9% of children without SCD had OPA titers ≥8, respectively.

TABLE 4

TABLE 4

One month postdose 2, for each vaccine serotype, ≥91.7% of children had antibody concentrations ≥0.2 µg/mL, and ≥88.6% of children had OPA titers ≥8, except for serotype 1. Robust increases in antibody GMCs and OPA GMTs were observed from pre- to 1 month postdose 2 for each vaccine serotype. For each of the vaccine-related serotypes, ≥63.8% of children with SCD and ≥56.5% of children without SCD had antibody concentrations ≥0.2 µg/mL, and ≥70.0% of children with SCD and ≥66.7% of children without SCD had OPA titers ≥8. All children with SCD and 97.8% of children without SCD had antiprotein D antibody concentrations ≥100 EU/mL at 1 month postdose 2. Exploratory analyses suggested that antibody GMCs for protein D (adjusted GMC of 1350.08 versus 737.67 EU/mL) and OPA GMTs for serotype 5 (adjusted GMT of 160.1 versus 81.0) may be higher in the 12-23S than in the 12-23NS group (Fig. 3F).

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Immune Response to DTPw-HBV/Hib

One month postprimary, all infants in the <6S and <6NS groups had antidiphtheria and antitetanus antibody concentrations ≥0.1 IU/mL and antiinactivated B. pertussis antibody concentrations ≥15 EU/mL (Table 5). Before booster vaccination, all infants had antidiphtheria and antitetanus antibody concentrations ≥0.1 IU/mL, while 70.5% of infants in the <6S and 78.9% in the <6NS group had antiinactivated B. pertussis antibody concentrations ≥15 EU/mL. One month postbooster vaccination, all infants were seroprotected/seropositive for antidiphtheria, antitetanus and antiinactivated B. pertussis antibodies.

TABLE 5

TABLE 5

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Safety Results

Pain at the injection site (range, 0–24%) was the most frequently reported solicited local symptom (Fig. 4). Swelling was reported in 2 children after the first dose [1 (2%) from 12-23S and 1 (2%) from 12-23NS], in 2 children after the second dose [1 (2%) from <6NS and 1 (2%) from 7-11NS] and in 2 children postbooster [1 (2%) from <6S and 1 (2%) from 7-11S]. No redness, large swelling reactions or grade 3 solicited local symptoms were observed at the injection site after primary or booster vaccination.

FIGURE 4

FIGURE 4

Fever was the most common solicited general symptom (Fig. 4). No grade 3 solicited general adverse events (AEs) were reported, except for fever [1 (2%) infant from <6NS after the booster dose]. Drowsiness was reported in 1 (2%) child from 7-11NS after the first dose. Loss of appetite occurred in 2 children after primary vaccination [1 (2%) child from 12-23NS after the first dose and 1 (2%) infant from <6NS after the third dose]. No drowsiness or loss of appetite was reported after the booster dose. Irritability was reported as follows: in 2 (4%) infants from <6NS and 1 (2%) child from 12-23S after the first dose, 1 (2%) child from 12-23S after the second dose, 3 (6%) infants from <6S and 4 (8%) infants from <6NS after the third dose and 6 (12.2%) infants from <6S after the booster dose.

The most frequent unsolicited AEs reported during the 31-day postprimary vaccination follow-ups were malaria, bronchitis and gastroenteritis (Table, Supplemental Digital Content 2, http://links.lww.com/INF/C662). After booster vaccination, malaria was the most frequently reported unsolicited AE followed by diarrhea and enteritis (Table, Supplemental Digital Content 2, http://links.lww.com/INF/C662).

After primary vaccination, any antipyretic medication was taken after 70.0%, 65.3%, 41.0%, 35.0%, 36.0% and 33.7% of doses in the <6S, <6NS, 7-11S, 7-11NS, 12-23S and 12-23NS groups, respectively. After booster vaccination, these percentages were 79.6%, 63.3%, 12.0% and 14.0% in the <6S, <6NS, 7-11S and 7-11NS groups, respectively.

Three children died during this study: 1 infant from <6S (Salmonella meningitidis occurring 110 days after the third dose), 1 infant from <6NS (worsening of malnutrition occurring 125 days after the third dose) and 1 child from 7-11S group (pyrexia occurring 35 days after the booster dose). Moreover, nonfatal serious AEs were reported for 2 and 8 infants from <6S and <6NS groups, respectively, for 2 and 4 children from 7-11S and 7-11NS groups, respectively, and for 2 children in both 12-23S and 12-23NS groups (Table, Supplemental Digital Content 3, http://links.lww.com/INF/C663). None of these serious AEs was assessed as causally related to vaccination by the investigator.

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DISCUSSION

In this descriptive study, the immune response to PHiD-CV did not appear to be influenced by SCD in infants and toddlers below 2 years of age. PHiD-CV elicited high antibody and functional OPA responses against all vaccine serotypes, when coadministered with DTPw-HBV/Hib and OPV vaccines in infants at 2, 3 and 4 months of age or when given as 2-dose primary vaccination or 2-dose catch-up vaccination in children 7–11 months or 12–23 months of age, respectively.

A decline in antibody GMCs and OPA GMTs was observed at 5–6 months (<6S and <6NS groups) and 2–4 months (7-11S and 7-11NS groups) after the primary vaccination course, indicating that a booster dose may be needed for infants and toddlers. The strong antibody and functional OPA responses observed after booster dose administration in children with or without SCD confirmed the induction of immunologic memory by PHiD-CV, which had been previously observed in healthy children.11–18

PHiD-CV also induced an immune response against vaccine-related serotypes 6A and 19A in infants and toddlers with or without SCD. This is in line with results of previous studies, which showed that PHiD-CV induced an improved OPA response against serotype 19A, compared with PCV7.13,14,18–20 In accordance with previous results obtained in healthy infants, this study suggested that PHiD-CV can be coadministered with DTPw-HBV/Hib and OPV in infants with SCD.13,21,22 All children were seroprotected or seropositive for antibodies against diphtheria, tetanus and inactivated B. pertussis after 3-dose primary and booster vaccinations.

Moreover, PHiD-CV had an acceptable safety profile when coadministered with DTPw-HBV/Hib and OPV in infants below 6 months of age, and when given to toddlers per either a 2 + 1 or a 2-dose catch-up schedule. Previous studies have shown that PCV7 was also well tolerated in children with SCD.6,7 Here, we report lower rates of solicited local AEs after administration of PHiD-CV compared with local AEs after primary vaccination with the same vaccine observed by study physicians in Malian children and field workers in Nigerian children [pain: 80.8% (95% CI 77.7–83.6); redness: 10.9% (95% CI 8.7–13.4); swelling: 65.3% (95% CI 61.7–68.9)]22 or by study staff in Malian children after booster vaccination [pain: 28.4% (95% CI 21.1–36.6); redness: 12.1% (95% CI 7.2–18.6); swelling: 47.5% (95% CI 39.1–56.1)].12 The low level of reactogenicity may in part be due to early administration of antipyretics and may also be explained by the recording of AEs by field workers, who provided information at specific time points (when visiting the child) and not from full-day observations. Thus, solicited AEs occurring before or after this time point may have been missed, or the severity of the AEs may have been underestimated (for instance, if the swelling had already reduced by the time the field worker visited).

Previous studies have shown that the incidence of IPD in children with SCD decreased after introduction of PCV7 into the immunization schedule.4,23 Because PHiD-CV showed efficacy/effectiveness against IPD, pneumonia and acute otitis media in the pediatric population in double-blinded, randomized, controlled trials and when used in universal mass vaccination programs,24–27 the results of the present study suggest that PHiD-CV may also reduce the incidence of these diseases in children with SCD.

This study was limited by its open design, which could have biased the safety results, and by the lack of a control arm in which another vaccine than PHiD-CV would have been administered to children with SCD. Moreover, it was a descriptive study: all comparisons between groups were exploratory, and potential differences should be interpreted with caution and assessed for their clinical relevance. The collection of solicited symptoms by field workers, who could only provide information at specific time points, might be another limitation, although field workers are less biased than parents in assessing reactogenicity. Another limitation of this study was the absence of OPA measurement at prevaccination in the children from the <6S and <6NS groups.

In conclusion, this study showed that PHiD-CV was immunogenic and had an acceptable safety profile in infants and toddlers with or without SCD starting vaccination at 8 weeks to 23 months of age. Immune responses against diphtheria, tetanus and inactivated B. pertussis antigens contained in the DTPw-HBV/Hib vaccine were also elicited in infants included in the <6S and <6NS groups when coadministered with PHiD-CV. These results suggest that PHiD-CV can provide a protective effect in children with SCD as shown in the generally healthy pediatric population. This is an important finding because children with SCD have an increased susceptibility to IPD as compared with healthy children without SCD.1

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ACKNOWLEDGMENTS

The authors thank investigator Dr. Amidou Diarra, Javier Ruiz Guiñazù (GSK) and Marjan Hezareh (Chiltern International for GSK). The authors also thank Nathalie Annez De Taboada (GSK) and Inge Delmotte (SynteractHCR Benelux C/O GSK) for global study management; Claire Verbelen, Iudit-Hajnal Filip and Domenica Majorino (XPE Pharma & Science C/O GSK) for medical writing services and Bram Blomme (XPE Pharma & Science C/O GSK) for manuscript coordination.

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Keywords:

10-valent pneumococcal conjugate vaccine; immunogenicity; safety; sickle cell disease

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