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Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e31827e22e3
Vaccine Reports

A Combined Haemophilus influenzae Type B Neisseria meningitidis Serogroup C Tetanus Toxoid Conjugate Vaccine Is Immunogenic and Well-tolerated When Coadministered With Diphtheria, Tetanus, Acellular Pertussis Hepatitis B–inactivated Poliovirus at 3, 5 and 11 Months of Age: Results of an Open, Randomized, Controlled Study

Vesikari, Timo MD*; Forstén, Aino MD*; Desole, Maria Guiseppina MD; Ferrera, Giuseppe MD; Caubet, Magalie MA§; Mesaros, Narcisa MD§; Boutriau, Dominique MD§

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Author Information

From the *Vaccine Research Center, University of Tampere, Finland; Servizio di Igiene Pubblica ASL n.1 di Sassari, Sassari, Italy; Servizio di Epidemiologia, Dipartimento di Prevenzione AUSL n.7, Ragusa, Italy; and §Glaxo-SmithKline Biologicals, Wavre, Belgium.

Accepted for publication November 14, 2012.

GlaxoSmithKline Biologicals was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals also funded all costs associated with the development and the publishing of the present manuscript. The corresponding author had full access to the data and was responsible for submission of the publication. All authors contributed to the study and were involved in writing and reviewing the manuscript and approved the final content. TV declares having received honoraria and lecture fees from GlaxoSmithKline Biologicals, MedImmune, Novartis, Merck and Sanofipasteur-MSD. MC, NM and DB are employees of GlaxoSmithKline Biologicals. Dominique Boutriau and Narcisa Mesaros own Glaxo-SmithKline Biologicals stock options. DB is also an inventor of certain GSK patents. The authors have no other funding or conflicts of interest to disclose.

Address for correspondence: Timo Vesikari, MD, University of Tampere Medical School, Vaccine Research Center, Biokatu 10, 33520 Tampere, Finland. E-mail: timo.vesikari@uta.fi.

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Abstract

Background: This study evaluated the immunogenicity, reactogenicity and safety of the combined Haemophilus influenzae type B Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine (Hib-MenC-TT) coadministered with diphtheria, tetanus, acellular pertussis hepatitis B–inactivated poliovirus (DTPa-HBV-IPV) as 2 primary and 1 booster doses at 3, 5 and 11 months of age.

Methods: In this phase III open study (NCT00327184), 709 infants were randomized in 2 parallel groups (1:1) to receive either Hib-MenC-TT coadministered with DTPa-HBV-IPV or control vaccines (MenC-TT coadministered with DTPa-HBV-IPV/Hib). Serum bactericidal activity for MenC (rSBA-MenC) and antibody concentrations against polyribosylribitol phosphate from Hib (anti-PRP) and hepatitis B (anti-HBs) were measured at 1 month after dose 2, before booster and 1 month after booster dose. Solicited (local/general) and unsolicited symptoms were assessed up to 4 and 31 days, respectively, after each vaccination. Serious adverse events were recorded throughout the study.

Results: One month after dose 2, high percentages of infants in both groups had rSBA-MenC titers ≥8 (≥99.1%), anti-PRP concentrations ≥0.15 μg/mL (≥96.5%) and anti-HBs concentrations ≥10 mIU/mL (≥95.3%), which persisted up to the booster vaccination (≥94.5%, ≥86.1%, ≥94.2%) and increased again after the booster dose (100%, 100%, ≥99%). Exploratory analyses indicated that rSBA-MenC geometric mean titers were lower and anti-PRP geometric mean concentrations were higher in the infants vaccinated with Hib-MenC-TT compared with the control vaccines at all time points. The safety profiles of the coadministered vaccines were similar in both groups.

Conclusions: The Hib-MenC-TT and DTPa-HBV-IPV vaccines are immunogenic with a clinically acceptable safety profile when coadministered as 2 primary doses during infancy and 1 booster dose at 11 months of age.

Neisseria meningitidis and Haemophilus influenzae type B (Hib) are 2 major causes of invasive bacterial infections worldwide, with the majority of the cases occurring in infants and young children and with the highest disease burden in the first year of life.1–4 Serogroups B and C of N. meningitidis are responsible for the majority of invasive meningococcal disease in Europe.2 Although the development of vaccines against serogroup B has been hindered by the poor immunogenicity of its capsular antigens in humans,5 conjugate vaccines against meningococcal serogroup C (MenC) are available and have been widely used since 1999.6–8 In addition, immunization of infants with Hib conjugate vaccines has been recommended in most industrialized countries since the 1990s.9 Conjugate vaccines against MenC and Hib are immunogenic in infants and young children, and their use has resulted in a dramatic decline in the incidence of invasive diseases caused by these pathogens.6,9–11

GlaxoSmithKline (GSK) Biologicals has developed a combined Hib-MenC conjugate vaccine using tetanus toxoid (TT) as the carrier protein (Hib-MenC-TT). The Hib-MenC-TT vaccine has been investigated according to various vaccination schedules in infants and toddlers, because these are the age groups at highest risk for both diseases.12–20 In the United Kingdom, the Hib-MenC-TT vaccine has been used as a booster vaccination for the Hib and MenC antigens in the second year of life since September 2006. The vaccine is currently approved in some European countries, Brazil and New Zealand for 3-dose primary vaccination in infants from the age of 2 months up to 12 months and for booster vaccination in toddlers up to the age of 2 years. The vaccine also is approved in Australia for 1-dose vaccination in toddlers previously primed with Hib but naïve for MenC.12

The coadministration of Hib-MenC-TT with combined diphtheria, tetanus, acellular pertussis (DTPa)-based vaccines offers an interesting alternative to the DTPa/Hib combinations coadministered with stand-alone meningococcal vaccines, which are administered routinely to infants in various European countries. Previous studies have shown that primary vaccination with DTPa/Hib combinations induces a lower Hib antibody response compared with Hib vaccine administered alone, although this may not translate to lower efficacy if a booster dose is administered in the second year of life.21–25 The coadministration of the Hib-MenC-TT vaccine with a DTPa hepatitis B–inactivated poliovirus (DTPa-HBV-IPV) vaccine previously was shown to be immunogenic and to have a clinically acceptable safety profile when both vaccines were administered as a 3-dose primary vaccination at 2, 3 and 4 months of age or at 2, 4 and 6 months of age.15–17,19,20 High responses to both Hib and MenC antigens were observed after the second dose in these studies, suggesting a potential 2-dose primary vaccination schedule during infancy, followed by a booster dose in the second year of life. This schedule would facilitate the inclusion of the Hib-MenC-TT vaccine in some countries such as Italy, Scandinavian countries, and some Eastern European countries, which are administering routine childhood vaccines as 2 primary doses at 3 and 5 months of age with a booster dose at 11 to 12 months of age.26,27

The purpose of this study was to evaluate the immunogenicity, reactogenicity and safety of the Hib-MenC-TT vaccine coadministered with DTPa-HBV-IPV versus control vaccines when administered as 2 primary doses at 3 and 5 months of age and 1 booster dose at 11 months of age.

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MATERIALS AND METHODS

Study Design

This was an open, phase III, randomized, controlled study conducted in 12 clinics of the Vaccine Research Center of the University of Tampere in Finland and 4 independent centers in Italy between April 2006 and June 2007. This study was conducted according to the International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki. In Finland, the study protocol was approved by the Ethics Review Committee of the Pirkanmaa University Hospital District. In Italy, the study protocol was approved by the Ethics Review Committees of the study centers. Written informed consent was obtained from the parents or guardians of the participants before the study entry. This study has been registered at www.clinicaltrials.gov NCT00327184. A summary of the protocols is available at http://www.gsk-clinicalstudyregister.com (GSK study ID 106388 and 106390).

Infants were randomized (1:1) in 2 parallel groups to receive either Hib-MenC-TT coadministered with DTPa-HBV-IPV (HibMenC group) or a MenC conjugate vaccine using TT as the carrier protein (MenC-TT) coadministered with DTPa-HBV-IPV/Hib (control group) (Fig. 1). The study was conducted in 2 phases. Infants received 2 doses of the vaccines at 3 and 5 months of age in the primary vaccination phase, and they received a booster dose of the same vaccines at 11 months of age in the booster vaccination phase. The immune responses were evaluated in all the participants at 1 month after dose 2, just before the booster dose and at 1 month after booster dose.

Figure 1
Figure 1
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The randomization list was generated at GSK Biologicals using a standard Statistical Analysis System (SAS) program to number the vaccines. A 1:1 randomization and a block scheme of 4 were used to ensure that the balance between treatments was maintained. The treatment allocation at the investigator site was performed using a central randomization system on the Internet developed by GSK and the randomization algorithm used a minimization procedure accounting for center.

The primary objectives of the study were to demonstrate the noninferiority of the MenC and the Hib immune responses induced by the 2-dose primary vaccination course in the HibMenC group versus the control group. The secondary objectives were: (1) to demonstrate the noninferiority of the persistence of the MenC and the Hib immune responses in the HibMenC group versus the control group; (2) to evaluate the MenC and Hib immunogenicity of the 2 primary vaccination doses and of the booster dose of Hib-MenC-TT coadministered with DTPa-HBV-IPV compared with the control vaccines at 1 month after dose 2, just before the booster dose and at 1 month after booster dose; (3) to evaluate the hepatitis B immunogenicity of the 2 primary vaccination doses and of the booster dose of DTPa-HBV-IPV coadministered with Hib-MenC-TT compared with the control vaccines at 1 month after dose 2, just before the booster dose and at 1 month after booster dose; and (4) to assess the local reactogenicity up to 4 days after vaccination and the safety throughout the study period for the 2 vaccines administered in each group.

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Study Participants

Study participants were healthy infants aged between 6 and 12 weeks at the time of the first vaccination and who were born after a gestation period of 36 to 42 weeks. Participants were excluded if they had the following: previous administration since birth or planned administration during the study period of any investigational or nonregistered product, of immunoglobulin or any blood product or of a vaccine not foreseen by the study protocol (with exception of Bacillus Calmette-Guérin); previous vaccination against any of the diseases targeted by the study vaccines; immunosuppression from any cause; history of Hib or MenC disease, of allergic reactions or reactions likely to be exacerbated by any component of the vaccine or of any neurologic disorders or seizures; or major congenital defects, a serious chronic illness or an acute disease at the time of enrollment.

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Vaccines

Each dose of the Hib-MenC-TT vaccine (Menitorix; GSK Biologicals, Rixensart, Belgium) contained 5 μg polyribosylribitol phosphate (PRP) from Hib and 5 μg MenC polysaccharide, and each polysaccharide (PRP and MenC polysaccharide) was conjugated to TT (no adjuvant added). One dose of the MenC-TT vaccine (NeisVac-C; Baxter, Volketswil, Switzerland) contained 10 μg capsular polysaccharide conjugated to TT and adjuvanted with 500 μg aluminum.28 The compositions of DTPa-HBV-IPV (Infanrix penta; GSK Biologicals) and DTPa-HBV-IPV/Hib (Infanrix hexa; GSK Biologicals) have been described elsewhere, both adjuvanted with aluminum as salts.29 All the vaccines were administered intramuscularly into the thigh of the infants.

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Assessment of Immunogenicity

Functional meningococcal antibodies against MenC were measured by a serum bactericidal activity assay using rabbit complement as the exogenous complement source (rSBA).30 The cut-off of the assay was an rSBA-MenC titer of 8, predictive for short-term protection. The more conservative correlate of protection value of rSBA titers ≥128 also was evaluated.31,32 The concentrations of antibodies against PRP from Hib (anti-PRP IgG) were evaluated by an enzyme-linked immunosorbent assay with a cut-off concentration of 0.15 μg/mL, indicative of short-term protection against Hib, and the percentages of infants with anti-PRP concentrations ≥1.0 μg/mL, indicative of long-term protection, also were evaluated.33–35 Enzyme-linked immunosorbent assay was used to measure concentrations of antibodies against hepatitis B antigens (anti-HBs IgG) with a cut-off concentration of 10 mIU/mL.36 All assays were performed at the GSK Biologicals laboratories.

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Assessment of Safety

Solicited local symptoms at the injection site (pain, redness and swelling) and general symptoms (drowsiness, fever [rectal temperature >38.0°C], irritability and loss of appetite) were recorded up to 4 days after administration of each vaccine dose. Unsolicited adverse events (AEs) were recorded up to 31 days after each vaccination. For all reported symptoms, intensity was scored on a 3-grade scale. Pain at the injection site was considered to have a grade 3 intensity if the limb was spontaneously painful or if the child cried when the limb was moved; redness and swelling at the injection site if the diameter was >30 mm; fever if rectal temperature was >40.0°C; loss of appetite if the child did not eat at all; and irritability if the child cried and could not be comforted. Drowsiness and unsolicited AEs were considered of grade 3 intensity if they prevented normal activity. All solicited local symptoms were defined in the protocol to be considered as causally related to vaccination. Using their clinical judgment, the investigators assessed the presence or absence of a possible causal relationship to vaccination for all other AEs.

Serious AEs were reported and described in detail throughout the entire study period. Serious AEs were defined as any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability or incapacity or was an important medical event.

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Statistical Analyses

With a target sample size of 580 infants evaluable for immunogenicity (290 per group), the study power to demonstrate both co-primary objectives was 94.9%. Considering that up to 15% of the participants enrolled might be excluded, enrolling 684 infants was planned. Demographic characteristics were summarized by group using descriptive statistics.

Immunogenicity was assessed for the according to protocol (ATP) immunogenicity cohorts. These included all infants who met eligibility criteria, complied with protocol defined procedures and for whom immunogenicity data for antibodies against at least 1 vaccine antigen were available. In line with the study design, infants were assigned to 3 distinct ATP immunogenicity cohorts based on compliance with the study protocol up to a given time point (primary ATP immunogenicity cohort, booster ATP cohort for persistence and booster ATP immunogenicity cohort) (Fig. 2).

Figure 2
Figure 2
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The geometric mean titers (GMTs), the geometric mean concentrations (GMCs) and the percentages of infants with titers or concentrations above the prespecified cut-offs were calculated with exact 95% confidence intervals (CIs) at 1 month after dose 2, just before the booster dose and at 1 month after booster dose. GMTs and GMCs were calculated by taking the anti-log of the mean of the log10 titer/concentration transformations. Antibody titers or concentrations below the cut-off of the assay were given an arbitrary value of half the cut-off for the purpose of GMTs/GMCs calculation.

The co-primary objectives of noninferiority were met if at 1 month after dose 2, the lower limit of the standardized asymptotic 95% CI for the difference between the HibMenC and the control groups in terms of percentages of infants with rSBA-MenC titers ≥8 was >−5% and anti-PRP concentrations ≥0.15 μg/mL was >−10% (inferential analyses). The secondary noninferiority objectives for antibody persistence were met if, just before the booster vaccination, the lower limit of the standardized asymptotic 95% CI for the difference between the HibMenC and the control groups in terms of percentages of infants with rSBA-MenC titers ≥8 was >−10% and anti-PRP concentrations ≥0.15 μg/mL was >−10% (inferential analyses).

Exploratory analyses were conducted at 1 month after dose 2, just before the booster dose and at 1 month after booster dose to detect significant differences between the 2 groups if the standardized asymptotic 95% CI for the difference between groups (HibMenC minus control group) in terms of the percentages of infants with titers/concentrations greater than or equal to the specified cut-offs did not include the value “0,” or if the 95% CIs for the GMT-to-GMC ratios between groups (HibMenC over control group) did not include the value “1.” The computation of the ratios was performed using an analysis of variance (ANOVA) model on the log10 transformation of the titers/concentrations. The results of the exploratory group comparisons should be interpreted with caution considering that there was no adjustment for multiplicity for these comparisons and considering that the clinical relevance of the differences is unknown.

In the primary and the booster vaccination phases, safety analyses were performed for the primary total vaccinated cohort, which included all infants who received at least 1 vaccine dose, and for the booster total vaccinated cohort, which included all infants with booster dose administration documented. The incidence (any, grade 3, related to vaccination and grade 3 and related to vaccination) of each solicited and unsolicited symptom was calculated overall per dose with exact 95% CI after each vaccination. The software SAS (version 8.2) and StatXact version 5.0 were used for the statistical analyses.

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RESULTS

Study Participants

A total of 709 infants were enrolled and vaccinated in the study, and 695 of them completed the primary vaccination phase. Of these, 690 infants participated in the booster phase of the study, and 683 infants completed the study (Fig. 2). Three infants in the HibMenC group were withdrawn from the primary vaccination phase because of a serious AE (Bardet Biedl syndrome, neonatal tremor and congenital heart defect). None of these events was considered by the investigator to be related to the vaccination. In the primary vaccination phase, 2 infants, who were randomized to the control group, received the study vaccines (Hib-MenC-TT and DTPa-HBV-IPV) and were reassigned to the HibMenC group for the analyses. In the booster vaccination phase they received the control vaccines (MenC-TT and DTPa-HBV-IPV/Hib) as planned in the randomization and they were eliminated from the booster ATP immunogenicity cohort.

The mean age of the infants in the total vaccinated cohort was 10.8 weeks at the time of the first vaccine dose administration and 11.6 months at the time of the booster dose administration (Table 1). In the primary vaccination phase, the proportion of female participants was 46.3% (328/709) and the majority of the participants were white or Caucasian (98.9%, 701/709). The demographic characteristics in the booster vaccination phase were consistent with those in the primary vaccination phase and were comparable in both groups.

Table 1
Table 1
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Immunogenicity

At 1 month after the 2 primary doses and just before the booster dose, the Hib-MenC-TT vaccine met the per-protocol prespecified noninferiority criteria when compared with the control vaccines for both Hib and MenC antigens (Table 2).

Table 2
Table 2
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Immune Response to MenC At 1 month after dose 2, the percentages of infants with rSBA-MenC titers ≥8 reached 99.1% in the HibMenC group and 100% in the control group (Table 2). Just before the booster dose administration, the percentages of infants with rSBA titers ≥8 were still as high as 94.5% in the HibMenC group and 100% in the control group. At 1 month after the booster dose, all infants in both groups had rSBA titers ≥8, whereas 98.1% and 100% of them had rSBA titers ≥128 in the HibMenC and the control groups, respectively. The booster vaccination induced a robust increase of the rSBA-MenC GMTs in both groups (15.3-fold in the HibMenC group and 14.2-fold in the control group). The rSBA-MenC GMTs after the booster were higher than those measured after the 2 primary doses (4.0-fold in the HibMenC group and 3.2-fold in the control group).

Exploratory analyses indicated that the rSBA-MenC GMTs and the percentage of infants with rSBA-MenC titers ≥128 were lower in the HibMenC group than in the control group at 1 month after dose 2, just before the booster vaccination and at 1 month after booster vaccination (Table 2).

Immune Response to Hib The percentages of infants with anti-PRP concentrations ≥0.15 μg/mL reached 96.9% in the HibMenC group and 95.5% in the control group at 1 month after dose 2, and decreased to 86.1% and 87.4% in the HibMenC and the control groups just before the booster dose administration (Table 2). The percentages of infants with anti-PRP concentrations ≥1.0 μg/mL at 1 month after dose 2 were 78.8% and 73.6%, and at prebooster were 50.3% and 32.3% in the HibMenC and the control groups, respectively. At 1 month after booster vaccination, 100% and 99.4% of the participants in both groups reached anti-PRP concentrations ≥0.15 μg/mL and ≥1.0 μg/mL, respectively. The booster dose induced a robust increase of the anti-PRP GMCs in both groups (33.2-fold in the HibMenC group and 30.6-fold in the control group). The postbooster anti-PRP GMCs were higher than those measured after the 2 primary doses (7.2-fold in the HibMenC group and 7.0-fold in the control group).

Exploratory analyses indicated that the anti-PRP GMCs were higher in the HibMenC group than in the control group at 1 month after dose 2, just before the booster vaccination and at 1 month after booster vaccination (Table 2).

Immune Response to HBs At 1 month after dose 2, the seroprotection rates (anti-HBs concentrations ≥10 mIU/mL) reached 98.3% in the infants who received DTPa-HBV-IPV (HibMenC group), which was higher than 95.3% in the infants who received DTPa-HBV-IPV/Hib (control group) (Table 2). Just before the booster vaccination, they were still as high as 98.1% and 94.2%, and at 1 month after booster vaccination they increased to 99.7% and 99.0% in the HibMenC and the control groups, respectively.

Exploratory analyses indicated that in addition to anti-HBs seroprotection rates, the anti-HBs GMCs were higher in the HibMenC group than in the control group at 1 month after dose 2 and just before booster dose (Table 2). Robust increases of the anti-HBs GMCs were observed from prebooster to postbooster vaccinations in both groups (27.1-fold and 27.2-fold for the infants who received DTPa-HBV-IPV and DTPa-HBV-IPV/Hib, respectively). Still, anti-HBs GMCs were higher in the infants who received DTPa-HBV-IPV compared with those who received DTPa-HBV-IPV/Hib at 1 month after booster dose.

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Safety

In both groups, the most frequently reported solicited local symptom overall per dose, regardless of the injection vaccine site and the number of doses, was redness (after 34.1% [239/701] and 39.3% [277/705] of doses in the primary vaccination phase [Fig. 3A] and after 46.8% [159/340] and 50.3% [176/350] of the booster doses [Fig. 3B] for the HibMenC group and the control group, respectively). Each grade 3 symptom was reported infrequently (after maximum 5.9% of the doses; swelling in the HibMenC group after the booster dose).

Figure 3
Figure 3
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Irritability was the most frequently reported solicited general symptom overall per dose in both groups (after 51.8% [363/701] and 58.6% [413/705] of the doses in the primary vaccination phase [Fig. 3A], and after 51.8% [176/340] and 56.9% [199/350] of the booster doses [Fig. 3B] for the HibMenC group and the control group, respectively). Fever (rectal temperature >38.0°C) was reported after 20.5% (144/701) of Hib-MenC-TT/DTPa-HBV-IPV primary doses versus 37.7% (266/705) of MenC-TT/DTPa-HBV-IPV/Hib primary doses (Fig. 3B). Grade 3 general symptoms were reported after no more than 2.3% of the doses (irritability in the control group after primary vaccinations).

Unsolicited symptoms were reported after a similar percentage of doses in both groups (up to 27% in the primary vaccination phase and up to 42% in the booster phase). After primary vaccination, 1 grade 3 unsolicited symptom that was considered related to vaccination was reported in 3 participants in the HibMenC group (insomnia, Bacillus Calmette-Guérin injection site infection, infection of Bacillus Calmette-Guérin injection scar near the injection site of the Hib-MenC-TT vaccine at 1 day after dose 1 of the Hib-MenC vaccine, and hiccups) and in 1 participant in the control group (convulsion). Serious AEs (all nonfatal events) were reported in 44 infants throughout the entire study. None of these was considered related to the vaccination.

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DISCUSSION

This study evaluated the immunogenicity and safety of the Hib-MenC-TT vaccine coadministered with DTPa-HBV-IPV versus control vaccines (MenC-TT coadministered with DTPa-HBV-IPV/Hib) when administered as 2 primary doses at 3 and 5 months of age and 1 booster dose at 11 months of age. Although the Hib-MenC-TT vaccine previously has been evaluated on multiple 3-dose priming schedules,15–17,19,20 the immunogenicity of this vaccine administered according to a 2-dose primary vaccination schedule was evaluated for the first time here. The co-primary objectives of the study were met because the two primary doses of the Hib-MenC-TT vaccine were not inferior to the 2 primary doses of control vaccines, both in terms of seroprotection rates for MenC and Hib.

One month after administration of the 2 primary doses of the Hib-MenC-TT and MenC-TT vaccines, 99.1% and 100% of the infants had seroprotective rSBA-MenC titers that which persisted up to the booster vaccination at 11 months of age in 94.5% and 100% of the vaccinees, respectively, which is consistent with previous studies.13,14,16,18 However, in another study, much lower percentages of MenC-TT–primed toddlers retained seroprotective rSBA-MenC levels up to the booster administration (48%).37 The reasons for this discrepancy between studies are unclear, although potential explanations include differences between studies in vaccination schedules, assay methodology and study populations. The booster dose of the Hib-MenC-TT vaccine in the present study elicited a further robust increase of the rSBA-MenC GMTs (15.3-fold), which were well above those achieved after the 2 primary vaccine doses (4.0-fold). These results were in line with findings of a previous study in which primary vaccination with Hib-MenC-TT was shown to induce immune memory for MenC after administration of a polysaccharide challenge in the second year of life.16 The postbooster rSBA-MenC GMTs, which are strongly dependent on the vaccine used for both primary and booster vaccinations,37,38 were in the same range as those measured after the booster dose in previous studies using 3-dose primary vaccination with Hib-MenC-TT.14,16,18

The Hib-MenC-TT vaccine induced lower rSBA-MenC GMTs than the MenC-TT vaccine after primary and booster vaccination. This also was observed in a previous study after the second dose of a 3-dose primary vaccination course at 2, 4 and 6 months of age with Hib-MenC-TT compared with MenC-TT or MenC-CRM197.17 In contrast, the rSBA GMTs measured after the third dose of Hib-MenC-TT in the same study were higher compared with those measured after 3 doses of MenC-CRM197. Two other studies using an accelerated 3-dose primary vaccination schedule at 2, 3 and 4 months of age showed lower rSBA-MenC GMTs at 1 month after the third primary dose of Hib-MenC-TT compared with MenC-CRM197.15,16 The reasons for the higher rSBA-MenC GMTs observed in the MenC-TT recipients compared with the Hib-MenC-TT recipients are unclear. This observation may not be explained by the difference in MenC antigen content between the 2 vaccines (10 μg versus 5 μg). A previous study comparing 2 different formulations of the Hib-MenC-TT vaccine showed that rSBA-MenC titers were higher with the formulation with the lower (5 μg) antigen content.16 However, the higher rSBA-MenC GMTs induced by MenC-TT may be attributable to the use of the de-O-acetylated polysaccharide in MenC-TT, which has been suggested to be more immunogenic than the O-acetylated form used in Hib-MenC-TT and MenC-CRM197.37,39 Other potential explanations include the use of aluminum hydroxide as adjuvant in MenC-TT or other differences in vaccine composition, such as conjugation method or polysaccharide sizing.40,41 Nonetheless, the difference in postprimary vaccination rSBA-MenC GMTs between the 2 groups in the present study may not be clinically significant because rSBA-MenC GMTs achieved were high in both groups, and because most vaccinees still had protective levels of rSBA titers up to the time of booster vaccination.6

The two primary doses of the Hib-MenC-TT vaccine also induced high seroprotection rates (anti-PRP concentrations ≥0.15 μg/mL) against the Hib antigen (96.9%), which persisted up to the booster vaccination at 11 months of age in 86.1% of the infants and were higher compared with those induced by the DTPa-HBV-IPV/Hib vaccine. The 0.15 μg/mL threshold was chosen to evaluate the persistence of the immune response up to the administration of the booster dose because this threshold is considered as the minimal concentration required for protection at a given moment in time.34 The booster dose of the Hib-MenC-TT vaccine elicited a robust increase of the anti-PRP GMCs (33.2-fold), which were well above those achieved after the 2 primary vaccine doses. This confirms that the Hib-MenC-TT vaccine induces immune memory for Hib. The Hib response measured here after 2 primary doses of the Hib-MenC-TT vaccine was similar to that seen after the second dose in previous studies with a 3-dose primary vaccination schedule with Hib-MenC-TT.16,17 The Hib response measured before the booster here also was in the same range or even higher when compared with the response reported after priming with 3 doses of a Hib conjugate vaccine coadministered with a DTPa-HBV-IPV vaccine.42 At all the time points, the Hib-MenC-TT vaccine induced higher anti-PRP concentrations than the DTPa-HBV-IPV/Hib vaccine. This was expected because it has been well-documented that the Hib response is reduced when Hib is combined with DTPa-based vaccines.21–23 Previous studies already had shown higher anti-PRP concentrations after 3 doses of the Hib-MenC-TT vaccine compared with DTPa-IPV/Hib or DTPa-HBV-IPV/Hib coadministered with MenC-CRM197.15–17 However, the MenC-TT vaccine, which was used as the control vaccine in the present study, is well-known to enhance the Hib response of DTPa/Hib combination vaccines.43

In this study, we showed that the immune response to hepatitis B, against which infants are not routinely vaccinated in Scandinavia, was higher in the recipients of DTPa-HBV-IPV coadministered with Hib-MenC-TT compared with the recipients of DTPa-HBV-IPV/Hib coadministered with MenC-TT after both primary and booster vaccination. It could be proposed that the removal of the Hib antigen from the combination had an effect on the anti-HBs immune response, but this is in contrast with results from a previous study in which the anti-HB immune responses measured after vaccination with DTPa-HBV-IPV/Hib were similar to those measured after vaccination with DTPa-HBV-IPV.44 However, the clinical relevance of the observed difference in the present study may be limited, because the anti-HB seroprotection rates were high in both groups at the different time points. The anti-HB immune responses elicited here after the 2 primary doses in the infants who received DTPa-HBV-IPV coadministered with Hib-MenC-TT were similar to those seen after a 3-dose primary vaccination schedule with the same vaccines in terms of anti-HB seroprotection rates (98.3% versus 98.2%) and GMCs (704.7 versus 742.9 mIU/mL).17

This study also showed that the Hib-MenC-TT vaccine may be coadministered with the licensed DTPa-HBV-IPV combination vaccine without much impact on the reactogenicity or safety profiles. The rates of reported solicited adverse events were observed to be in the same range or lower in the children who received the Hib-Men-C-TT vaccine compared with the control vaccines.

This study was limited by the necessity for an open design because of differences in presentation between the vials containing the Hib-MenC-TT and the DTPa-HBV-IPV/Hib vaccines and the vials containing the control vaccines. Other limitations were the numerous exploratory statistical comparisons performed without adjustment for multiplicity. Nonetheless, the study was powered to demonstrate the 2 co-primary end points, so the conclusions drawn from those statistical evaluations are reliable.

In summary, seroprotection rates induced by the Hib-MenC-TT vaccine coadministered with DTPa-HBV-IPV were high for both meningococcal serogroup C and Hib at 1 month after the 2 primary doses (99.1% and 96.9%), just before the booster dose (94.5% and 86.1%) and at 1 month after the booster dose (each 100%). However, the magnitude of the rSBA-MenC GMTs was observed to be lower after administration of the Hib-MenC-TT vaccine compared with the MenC-TT vaccine. Conversely, the magnitude of the anti-PRP GMCs was lower when Hib was administered as part of the DTPa-based combination than when it was combined in the Hib-MenC-TT vaccine. Moreover, anti-HBs antibody GMCs induced by the DTPa-HBV-IPV vaccine were observed to be higher when compared with those induced by the DTPa-HBV-IPV/Hib vaccine. The clinical significance of these interactions, if any, is unknown at present. These results suggest that the Hib-MenC-TT and the DTPa-HBV-IPV vaccines can be administered safely as a 2-dose primary vaccination schedule at 3 and 5 months of age with a booster dose in second year of life.

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ACKNOWLEDGMENTS

The authors thank the participants and their parents/guardians who participated in the study, the study nurses and other staff members, without whom this study would not have been possible. T.Vesikari and A. Forstén thank Tiina Karppa, Tiina Korhonen, Ilkka Seppä and Anne Salomäki from the Vaccine Research Center, University of Tampere, Finland, for their contributions to this study. The authors also thank Federico Marchetti (Medical Advisor Pediatric Vaccines) and Chiara Triban (Study Manager, GlaxoSmithKline [GSK] Italy) for the local support from the Italian GSK office. The authors also thank Nancy Van Driessche and Wouter Houthoofd (XPE Pharma & Science, Belgium on behalf of GSK Biologicals) for publication management and Claire Verbelen (XPE Pharma & Science, Belgium on behalf of GSK Biologicals) for drafting the manuscript. Menitorix, Infanrix penta and Infanrix hexa are trademarks of the GlaxoSmithKline group of companies. NeisVac-C is a trademark of Baxter Healthcare.

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conjugate vaccine; Haemophilus influenzae type B; immunization schedule; infants; Neisseria meningitidis serogroup C

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