The advantages of pediatric combination vaccines are well documented for the vaccine recipient, the medical staff, and for society as a whole. They facilitate protection against several diseases with a single injection in the context of an increasingly complex pediatric vaccination schedule. The addition of new antigens to existing vaccines with established high coverage rates is an efficient means of promoting rapid uptake and high coverage. The routine use of such combination vaccines has played a vital role in reducing the global burden of childhood diseases,1,2 although regional differences, particularly in terms of using acellular pertussis (aP) versus whole-cell pertussis vaccines or using the inactivated poliovirus vaccine (IPV) versus the oral poliovirus vaccine, are still evident. World Health Organization recommends booster vaccinations for children during the second year of life when coverage levels for primary vaccination are high and supports the use of aP-based vaccines because of their favorable reactogenicity and safety profiles.3,4 Combined vaccines make it easier both to maximize coverage by administering multiple antigens in a single injection and to follow booster recommendations for vaccines against several childhood diseases.
In a previous study,5 an investigational hexavalent DTaP-IPV-Hep B-PRP-T vaccine (Hexaxim, part of Sanofi Pasteur's AcXim family of vaccines) was administered in a 2-, 4-, 6-month primary-series schedule in healthy Argentinean infants. The investigational hexavalent vaccine is a thimerosal-free, fully liquid, ready-to-use formulation and includes the same diphtheria (D), tetanus (T), aP, IPV, and Haemophilus influenzae type b (Hib) polysaccharide conjugated to tetanus protein (PRP-T) antigens as those included in Pentaxim (registered in >100 countries globally6), in combination with a new Hansenula polymorpha–derived hepatitis B antigen (Hep B).7 – 9 The high immunogenicity of the new Hep B antigen, both as a stand-alone vaccine in adolescents and adults10 and in various pediatric primary-series schedules as part of the new hexavalent vaccine,5,11 – 13 has been demonstrated in a range of clinical studies. The previous study demonstrated that the immunogenicity and safety of the new hexavalent vaccine were comparable to an established DTaP-IPV//PRP-T pentavalent vaccine (Pentaxim) coadministered with a stand-alone hepatitis B vaccine (Engerix B Pediatrico).
We conducted our study to describe the antibody persistence after each of the 2 primary-series vaccination regimens5 before the booster vaccination at 18 months of age. Additionally, we describe the effect of a booster vaccination of Pentaxim on the immune response to the D, T, aP, IPV, and polyribosyl-ribitol phosphate (PRP) antigens.
MATERIALS AND METHODS
This Phase III, open-label trial was conducted at the Hospital Materno Neonatal, Córdoba, Argentina (ClinicalTrials.gov identifier: NCT00303316) between February and November 2006. The study was approved by the institutional review board of the study center, the local independent ethics committee, and the Administración Nacional de Medicamentos, Alimentos y Tecnología Médica. The trial complied with the Declaration of Helsinki, International Conference on Harmonisation (ICH), Good Clinical Practice guidelines, and Argentinean regulations. At least 1 parent or a legally acceptable representative, and a witness, gave written informed consent before each participant was included in the trial.
A booster dose of DTaP-IPV//PRP-T vaccine (Pentaxim) was administered at 18 months of age to children who had completed a 3-dose primary-series vaccination of either the investigational DTaP-IPV-HepB-PRP-T vaccine or Pentaxim and Engerix B Pediatrico at 2, 4, and 6 months of age.
Children were excluded if they had any known contraindication to further vaccination with a pertussis vaccine, including axillary temperature >39.4°C, either inconsolable crying for >3 hours or a hypotonic hyporesponsive episode within 48 hours of a previous vaccine injection, encephalopathy, or seizures within 3 days after vaccination. Other exclusion criteria were, as for the primary vaccination, any current or planned involvement in another clinical trial or any involvement in another clinical trial in the 4 weeks preceding our trial; congenital or acquired immunodeficiency or immunosuppressive therapy; hypersensitivity to any of the vaccine components; receipt of blood-derived products; chronic illness that could interfere with conduct or completion of the trial; and history of seizures; vaccination against pertussis, tetanus, diphtheria, polio, Hib, or hepatitis B disease since the end of the primary series or any vaccination in the 4 weeks before the booster vaccination.
Vaccine and Vaccine Administration
The pentavalent booster vaccine (batch Y2213-1, Pentaxim) was produced and supplied by Sanofi Pasteur, France, and stored at 2°C to 8°C. Each 0.5 mL dose of DTaP-IPV//PRP-T contained ≥30 IU of diphtheria toxoid, ≥40 IU of tetanus toxoid, 25 μg of pertussis toxoid (PT), 25 μg of filamentous hemagglutinin (FHA), 40 D antigen units (DU) of poliovirus type 1 (Mahoney), 8 DU of poliovirus type 2 (MEF-1), 32 DU of poliovirus type 3 (Saukett), and 10 μg PRP-T. The lyophilized PRP-T component was reconstituted with the liquid DTaP-IPV vaccine immediately before vaccination.
The vaccination was administered intramuscularly into the anterolateral area of the right thigh.
Two 5-mL blood samples were taken for the assessment of the antibody persistence to the D, T, aP, IPV, Hep B, and PRP antigens (before the booster vaccination) and for the assessment of the booster response to the D, T, aP, IPV, and PRP antigens (1 month after booster vaccination).
Serologic analyses were performed at the Sanofi Pasteur Global Clinical Immunology Laboratory in the United States. Anti-D and antipoliovirus antibody titers were measured by seroneutralization. Anti-T, anti-PT, anti-FHA, and anti-PRP antibody concentrations were measured by enzyme-linked immunosorbent assay. Anti-Hep B antibody titers were measured, before the booster dose only, using an Ortho-Enhanced Chemoluninescence test.
Reactogenicity and Safety
Participants were monitored at the study center for immediate adverse events (AEs) and adverse reactions (an adverse reaction is defined as an AE that is considered to be related to the vaccination) occurring within 30 minutes after injection. In addition, for predefined (solicited) injection site (pain, erythema, swelling) and systemic (pyrexia, vomiting, crying, somnolence, anorexia, irritability) reactions (all solicited events were considered to be related to the vaccination), daily severity (mild, moderate, and severe tenderness were defined as “minor reaction when injection site is touched,” “cries and protests when injection site is touched,” and “cries when injected limb is moved or the movement of the injected limb is reduced.” For erythema and swelling, a diameter of <2.5 cm was assessed as mild, from 2.5 to <5 cm as moderate, and ≥5 cm as severe. Mild, moderate, and severe pyrexia were defined as rectal equivalent temperature 38°C–38.5°C, 38.6°C–39.5°C, and ≥39.6°C, respectively. Other systemic symptoms were defined as follows: vomiting [mild-moderate, 1–5 episodes/d; severe, ≥6 episodes/d], crying [mild-moderate, ≤3 hours; severe, >3 hours], somnolence [mild-moderate, unusually sleepy; severe, sleepy most of the time], anorexia [mild-moderate, missed 1–2 meals; severe, missed ≥3 meals], and irritability [mild-moderate, easily consolable or needs increased attention; severe, inconsolable]), and other pertinent details were recorded by the parent(s)/legally responsible representative using diary cards for 7 days after each vaccination. The parent(s)/legally responsible representative also recorded the start/stop date, severity (mild [noticeable, but does not interfere with daily activities], moderate [interferes with daily activities], or severe [prevents daily activities]), and other pertinent details of any nonsolicited events for approximately 1 month after the booster vaccination. The relationship with the vaccination for nonsolicited systemic events was assessed by the investigators.
For cultural and compliance reasons, axillary rather than rectal temperature was measured; axillary temperature was subsequently converted to a rectal equivalent value by adding 0.6°C. Serious AEs (SAEs, defined according to the International Conference on Harmonisation E2A Guideline for Clinical Safety Data Management as an untoward medical occurrence that results in death, is life-threatening, requires in-patient hospitalization or prolongs existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event) were collected until approximately 1 month after the booster vaccination.
The trial objectives were to describe antibody persistence for all antigens (D, T, aP, IPV, Hep B, PRP-T) at 18 months of age after the 3-dose primary-series vaccination5 as well as the effect of a booster dose of Pentaxim at 18 months of age on the immunogenicity response to the 5 Pentaxim valences (D, T, aP, IPV, PRP-T). All analyses were descriptive.
The antibody persistence and the booster immunogenicity response were described using geometric mean titers (GMTs, for antipolio 1, 2, and 3) and concentrations (GMCs, for anti-T, anti-D, anti–Hep B, anti-PT, anti-FHA, and anti-PRP) and the percentages of participants with a titer above predefined thresholds for anti-T (≥0.01 IU/mL, ≥0.1 IU/mL, and ≥1 IU/mL); anti-D (≥0.01 IU/mL, ≥0.1 IU/mL, and ≥1 IU/mL); anti–Hep B (≥10 mIU/mL) (for persistence only); antipoliovirus 1, 2, and 3 (≥8 [1/dil]); and anti-PRP (≥0.15 μg/mL and ≥1.0 μg/mL). The minimum defined and recognized correlates of protection (seroprotective concentrations) were assumed to be ≥0.01 IU/mL for anti-T and anti-D and ≥0.15 μg/mL for anti-PRP. For the booster response, an antibody level ≥1.0 IU/mL (for anti-T and anti-D) and ≥1.0 μg/mL (for anti-PRP) is associated with long-term persistence of protection. For the other antigens, ≥10 mIU/mL for anti–Hep B, ≥8 1/dil for antipolio 1, 2, and 3 are considered as the minimal levels correlating with both short- and long-term protection. Additionally, as there are no universally accepted correlates of protection for pertussis (PT and FHA antigens), seroconversion (SC) rate for these antigens was predefined as the percentage of participants with a ≥4-fold increase from baseline in anti-PT and anti-FHA antibody concentration and is considered as a surrogate of protection for these antigens.14
Seroprotection (SP) and SC rates were calculated with 95% confidence intervals (CI) using the exact binomial distribution for percentages (Clopper-Pearson method). The normal approximation method was used to calculate the 95% CIs for the GMTs and GMCs.15 For the safety analysis, the percentage of participants with a particular event and the associated 95% CI were calculated using the exact binomial Clopper-Pearson method.15
The intent to treat (ITT) analysis set included all participants who received the booster vaccine. Those who received the booster vaccine and with evaluable safety data after booster administration were included in the safety analysis set. The immunogenicity data were assessed using the ITT analysis set.
All statistical analyses were performed using SAS software, version 8.2 (SAS Institute, Cary, NC).
Of the 604 participants who completed the primary-series vaccination study, 458 returned for the booster vaccination (232 primed with DTaP-IPV-Hep B-PRP-T [group 1] and 226 primed with Pentaxim and Engerix B Pediatrico [group 2]). The mean age of the participants in groups 1 and 2 were 17.6 and 17.7 months, respectively, and the mean weight in each group was 11.1 kg.
Of the 458 participants who received the booster vaccination, 2 participants were withdrawn from group 1 (primed with DTaP-IPV-Hep B-PRP-T) (1 because of noncompliance with the protocol and 1 voluntary withdrawal [not because of an AE]) and 3 participants were withdrawn from group 2 (primed with Pentaxim and Engerix B Pediatrico) (1 lost to follow-up and 2 voluntary withdrawals [not because of AEs]).
All participants were included in the immunogenicity analyses (458 participants; 232 in group 1 and 226 in group 2) (ITT analysis set) and 454 participants were included in the safety analysis (231 in group 1 [includes the participant who withdrew voluntarily, who still provided safety data] and 223 in group 2).
Participant disposition is presented in Figure 1.
The SP rates, SC rates, GMCs, and GMTs before and 1 month after the Pentaxim booster dose administration are summarized in Table 1. The post–primary-series data are also included in this table (already presented in the primary-series article—the population size is slightly different for the primary-series data, as noted in Table 1 [N = 260 for DTaP-IPV-Hep B-PRP-T and N = 271 for Pentaxim + Engerix B]. The primary-series results are not from the subpopulation included in the booster study but are from the participants who were included in the primary-series study).5
Before the booster vaccination, most participants in groups 1 and 2, respectively, showed the minimum defined recognized antibody level that correlates with protection for D (74.1% and 74.7%, ≥0.01 IU/mL), T (100.0% and 100.0%, ≥0.01 IU/mL), polio (99.5% and 100.0% [antipolio 1], 99.1% and 99.5% [antipolio 2], 95.8% and 98.0% [antipolio 3]: ≥8 [1/dil]), invasive Hib disease (anti-PRP) (76.3% and 75.6%, ≥0.15 mIU/mL), and Hep B (85.5% and 99.5%, ≥10 mIU/mL). Antibody persistence at 18 months of age was similar between participants primed with the new hexavalent vaccine and the comparators, with the exception of anti-HBs: the % (95% CI) of participants with an anti–Hep B titer ≥10 mIU/mL was higher in group 2 (99.5% [97.5, 100.0]) than in group 1 (85.5% [80.3, 89.8]). This difference was associated with a higher anti–Hep B antibody GMT in group 2 (197 mIU/mL) than group 1 (87.6 mIU/mL).
One month after the Pentaxim booster vaccination, most participants achieved the predefined minimal antibody seroprotective thresholds against D, T, polio 1, 2, and 3, and invasive Hib disease (98.2%–100%), and for SC for PT and FHA (88.0%–95.7%), independent of the priming vaccine. (There was no Hep B booster, in accordance with the national schedule for Argentina at the time of the study.) Furthermore, after the booster vaccination, between 96% and 100% of participants achieved the thresholds indicative of long-term persistence for D (≥0.1 IU/mL), T (≥0.1 IU/mL), and PRP (≥1.0 mIU/mL), with no difference based on the primary-series vaccine. Strong increases in antibody GMTs against all vaccine valences were observed 1 month after booster administration. Although there were no differences in postbooster SP or SC rates, there were some differences between groups in antibody level (eg, for anti-PT, anti-PRP, and antipolio 1 antibodies; Table 1) that were not considered to be clinically important.
Safety and Tolerability
Overall, 59.7% of the participants reported a solicited injection site reaction within 7 days after the booster vaccination, with no difference observed between the 2 priming groups (Table 2), with 11.9% of participants (overall) experiencing a severe injection site reaction. All injection site reactions occurred and resolved within the first 3 days after the booster vaccination except for one participant with moderate erythema that resolved after 6 days.
Overall, 55.3% of the participants experienced a solicited systemic reaction within 7 days after the booster vaccination, with no difference observed between the 2 priming groups (Table 2). The most frequent systemic reaction in both groups was irritability (overall incidence of 35.9%). Most systemic reactions occurred and resolved within the first 3 days after the booster vaccination. Few study participants experienced severe systemic reactions, the most frequent overall being severe pyrexia (2.9%) and severe anorexia (2.6%).
A total of 65 participants (14.3%) reported an unsolicited AE in the first 7 days after booster vaccination (Table 3), most of which were of mild to moderate severity. Rhinitis, bronchitis, and diarrhea were the most frequent. Only 3 unsolicited AEs were considered by the investigator to be related to the booster vaccine—injection site hemorrhage, injection site induration, and severe systemic convulsions, the latter also being reported as an SAE (described later in the text). Overall, 23.8% of participants experienced an unsolicited AE during the first 30 days after the booster vaccination, with rhinitis and bronchitis being the most frequent.
No deaths occurred during the study. Four participants (0.9%) each experienced an SAE during the study (Table 3), of which only 1 was considered to be related to the Pentaxim booster vaccination. This was an episode of nonfebrile convulsions in a female participant (who had received the investigational DTaP-IPV-HepB-PRP-T vaccine in the primary-series study) on day 3 after Pentaxim administration, which lasted 5 minutes. This participant also had fever on day 1, vomiting on day 2, diarrhea on days 2 to 4, and rhinitis on days 2 to 8 (all nonserious SAEs). The participant received oxygen for 5 minutes on day 3 and amoxicillin at 75 mg/kg/d from days 4 to 7; she recovered within 1 day of the episode of convulsions.
The remaining 3 SAEs were otitis media on day 5 in one participant and pneumonia on day 3 in another who had received the investigational DTaP-IPV-HepB-PRP-T vaccine in the primary series, and febrile convulsion on day 24 in one participant who had received Pentaxim and Engerix B in the primary series. Each of these participants recovered without sequelae after treatment.
This phase III trial assessed antibody persistence and the immune response and safety of a booster dose of Pentaxim in 18-month-old children who had been primed with 3 doses of either an investigational hexavalent DTaP-IPV-Hep B-PRP-T vaccine or Pentaxim and Engerix B Pediatrico at 2, 4, and 6 months of age. Pentaxim was chosen as the booster vaccine because it is widely used as such worldwide with proven immunogenicity and safety6,16 – 18 and also as it contained the same D, T, aP, IPV, and PRP-T antigens as those included in the investigational hexavalent vaccine.
In the primary-series study, the hexavalent vaccine demonstrated noninferiority to the reference vaccines in terms of SP or SC rates at 1 month after the primary-series vaccination for all measured antibodies.5 For hepatitis B, although SP was similar after the primary series, before the booster vaccination this was lower for participants primed with DTaP-IPV-Hep B-PRP-T than those primed with Pentaxim and Engerix B. A factor that potentially could influence observation is a difference in population size between the 2 groups after primary series and before the booster vaccination. Approximately 11% (who had received the new hexavalent vaccine in the primary series) and 17% (who had received Pentaxim in the primary series) of participants did not return for booster vaccination. Although we do not consider this to be a critical factor, this difference could influence the accurate comparison of hepatitis B persistence between the 2 primary-series groups. As no hepatitis B booster dose was administered in our study, it was not possible to evaluate the subsequent booster response in each primary-series group. World Health Organization has commented that efficacy observations have “indicated that the loss of detectable anti-HBs in participants who had responded satisfactorily to a primary series does not necessarily indicate a lack of protection” and that long-term follow-up studies have “confirmed that hepatitis B surface antigen (HBsAg) carrier status or clinical HBV disease rarely occurs in participants who responded to a primary series even when the anti-HBsAg concentrations decline to ≤10 mIU/mL over time,”19,20 Furthermore, HBsAg-specific T- and B-cell memory has been shown in individuals who did not have protective Hep B antibodies after vaccination.21 These data suggest that a waning of anti–Hep B antibodies to below the recognized threshold for SP does not necessarily imply a waning of protection or preclude a strong and adequate anamnestic response if exposed or boosted. Ongoing studies in other regions will further document the response to the new Hep B antigen contained in the investigational hexavalent vaccine after primary series and after booster vaccination, and will be reported in future peer-reviewed articles.
As expected, given the use of the same AcXim family diphtheria, tetanus, aP, polio, and Hib antigens in the 2 primary-series vaccines, the proportions of participants who remained seroprotected/seroconverted before the booster was high and similar in the 2 primary-series vaccine groups.
In our study, the strong increases in GMCs/GMTs for antibodies to each of the 5 Pentaxim antigens after booster vaccination are indicative of satisfactory priming in each group. As expected, high postbooster SP and SC rates were obtained irrespective of the primary-series vaccine. As such, the use of a Pentaxim booster after a primary series of the investigational hexavalent vaccine results in a strong anamnestic response for each Pentaxim antigen.
Consistent with previous Pentaxim studies,16 – 18,22 – 24 as well as the good immunogenicity for each antigen, the Pentaxim booster in our study had a good safety profile, and the priming vaccine did not influence the booster safety profile. One participant experienced vaccine-related convulsions after the booster vaccination but recovered within 1 day after treatment.
Most participants had seroprotective antibody levels at 18 months of age, before the booster vaccination, after priming with the investigational DTaP-IPV-Hep B-PRP-T vaccine. The robust anamnestic responses to all the valences in the Pentaxim booster vaccine, regardless of the vaccine used for priming, demonstrate the suitability of a Pentaxim booster after a primary series of the new hexavalent vaccine. The Pentaxim booster was well tolerated irrespective of the primary-series immunization history.
The authors acknowledge all the investigators who participated in the trial: Maria Gabriela Graña, Paula Carina Vanadía, Miriam Teresa Calvari, Jorge Pablo Tregnaghi, Ana María Baudagna, Sandra Mountford, Susana Carina Barale, Flavia Castelli, and Karina María Llugdar. The authors also thank the trial participants and their parents, and the personnel at the Hospital Materno Neonatal Profesor Doctor Ramón Carrillo de la Ciudad de Córdoba, Argentina.
The authors thank Dr. Michel Scemama for his significant contribution to the realization of this trial when employed as a Clinical Trial Leader at Sanofi Pasteur (Dr. Scemama is now an employee of Sanofi Aventis). Currently at Sanofi Pasteur, the authors thank Dr. Sandrine Lentsch-Graf as Project Leader, Mrs. Siham B'Chir for the statistical analyses, and Dr. Andrew Lane for assistance in the preparation of the manuscript in accordance with the European Medical Writers Association guidelines and Good Publication Practice.
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