Pediatric combination vaccines are pivotal to maintaining coverage of protection against a range of infectious diseases, including diphtheria (D), tetanus (T), pertussis, polio, hepatitis B (HB), Haemophilus influenzae type b (Hib [PRP-T]) and for reducing regional disparities in prevalence.1–3 Vaccines built on a D, T, acellular pertussis (aP) antigenic backbone have been very effective in controlling childhood morbidity and are increasingly a pediatric standard of care globally.4,5 Currently available hexavalent vaccines with a DTaP backbone have been reviewed recently, including their co-administration with other common childhood vaccines as well as practical considerations regarding their implementation6; Sanofi Pasteur’s fully liquid hexavalent DTaP-IPV-HB-PRP-T vaccine (licensed since 2012 as Hexaxim, Hexyon, or Hexacima, depending on the country) has been reviewed separately.7–9
The DTaP-IPV-HB-PRP-T vaccine has the same D, T, aP, IPV, and PRP-T antigens as an established pentavalent vaccine, Pentaxim/Pentavac,2 but includes an additional Hansenula polymorpha-derived HB antigen that includes 10 µg HB surface antigen (HBsAg).10 A strong immune response to each antigen of this fully liquid hexavalent vaccine and a good safety profile has been demonstrated following administration in a wide range of pediatric primary series schedules, on 4 continents, with or without a birth dose of HB, and in co-administration with other common pediatric vaccines.11–19 Good antibody persistence has also been demonstrated for each antigen, and a subsequent booster dose in the second year of life has been shown to be highly immunogenic and safe.12,20–22
This study was requested by the European Medicines Agency to support the use of the DTaP-IPV-HB-PRP-T vaccine in a predominantly Caucasian population in European countries that use a 2, 3, 4 month schedule for primary immunization to supplement European data from study in Sweden and Finland, where a 3, 5 month primary series with a booster at 11–12 months is used.18 The 2, 3, 4 month schedule was also previously assessed in a separate study in Turkey,12 and the present study additionally included an assessment of the coadministration with pneumococcal 13 (PCV13) and rotavirus (RV) vaccines.
MATERIALS AND METHODS
Study Design and Participants
Two phase III, randomized, observer-blind studies were carried out at a total of 40 study sites (15 in Germany and 25 in the Czech Republic): an infant primary series study followed by a booster study in toddlers (World Health Organization Universal Trial Numbers U1111-1122–2329 and U1111-1122–2362, respectively). The study protocol and 1 amendment were approved by local independent ethics committees, and the studies were performed according to local regulations, Good Clinical Practice, applicable International Conference on Harmonization guidelines, and the ethical principles of the Declaration of Helsinki (Edinburgh revision, October 2000). An informed consent form was signed by each participant’s parents or legally acceptable representatives before enrolment into each study. Primary vaccination occurred between January to November 2014 and booster vaccination between November 2014 and November 2015.
Healthy infants aged 55–75 days, born at full term (≥ 37 weeks), and with birth weight ≥ 2.5 kg were eligible for the primary series study. The main exclusion criteria were recent (in the 4 weeks before the first vaccination) or planned participation in another clinical trial or nonstudy vaccination during or in the 4 weeks before the study period (except for routine vaccines administered per the national immunization calendars, including influenza vaccination); previous vaccination against, or history of, DTP, poliomyelitis, HB, Hib, pneumococcal, and rotavirus (RV) infection; receipt of blood products since birth; personal/maternal history of human immunodeficiency virus or hepatitis C infection, or receipt of any immunosuppressive therapy; known hypersensitivity to any vaccine component; bleeding disorder in the 3 weeks before inclusion contraindicating intramuscular injection; history of seizures; any chronic illness that could interfere with study conduct or completion; acute illness or febrile illness. Participants were excluded from the booster study if they had received any nonstudy vaccine in the 2 weeks before booster vaccine or had any planned nonstudy vaccination planned in the 4 weeks after the booster. Additionally, at the time of the booster study, contraindications to pertussis vaccination were assessed based on the temporal association of encephalopathy, temperature ≥ 40°C, hypotonic hyporesponsive episode, persistent inconsolable crying and nonfebrile convulsions.
In the primary series study, participants were randomized to the fully liquid, investigational vaccine (DTaP-IPV-HB-PRP-T) (group 1) or a reconstituted control vaccine (DTaP-HB-IPV//PRP-T) (group 2) at 2, 3, 4 months of age, co-administered with PCV13 (2, 3, 4 months of age) and RV vaccine (2, 3, 4 months of age). Participants who completed the primary series and were eligible for the booster study received either the same investigational vaccine or control vaccine at 11–15 months of age as had been administered in the primary series; all booster vaccinations of the investigational or control vaccine were co-administered with a PCV13 booster (Fig. 1). If a PCV booster had been administered between the primary and booster studies (and outside their scope), no additional PCV13 booster was administered. A permuted block method was used for the primary randomizations to guarantee an approximately similar ratio of participants in each group at any time.
Study vaccines were administered into the right thigh (investigational or control vaccine), left thigh (PVC13) and orally (RV).
The investigational hexavalent vaccine (Hexaxim) was manufactured by Sanofi Pasteur and supplied as a fully liquid, sterile suspension for injection in a prefilled syringe. Each 0.5 mL dose contained ≥ 20 IU (30 limit of flocculation [Lf]) D-toxoid, ≥ 40 IU (10 Lf) T-toxoid, 25 µg PT, 25 µg FHA, 40, 8 and 32 D antigen units of poliovirus type 1, 2 and 3, respectively, 10 µg HBsAg, 12 µg Hib polysaccharide conjugated to 22–36 µg tetanus protein (PRP-T) and 0.6 mg aluminum hydroxide.
The control hexavalent vaccine (Infanrix hexa) was manufactured by GlaxoSmithKline Biologicals and supplied as 2 separate components (a DTaP-HB-IPV suspension in a prefilled syringe and Hib as a white lyophilized pellet in a glass vial) that were reconstituted as a 0.5 mL dose before injection. Each dose contained ≥ 30 IU of D-toxoid, ≥ 40 IU T-toxoid, 25 µg PT, 25 µg FHA, 8 µg pertactin, 40, 8 and 32 antigen units of IPV type 1, 2 and 3, respectively, 10 µg HBsAg, and 10 µg of Hib capsule polysaccharide conjugated to 20–40 µg tetanus toxoid with a total aluminum content of 0.82 mg (0.5 mg hydrated aluminum hydroxide and 0.32 mg aluminum phosphate).
The PCV13 vaccine (Prevenar 13) was manufactured by Pfizer Incorporated and supplied in prefilled 0.5 mL syringes. Each 0.5 mL dose contained 2.2 µg of pneumococcal polysaccharide serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F and 4.4 µg pneumococcal polysaccharide serotype 6B. Each serotype was conjugated to a CRM197 carrier protein.
The RV vaccine (RotaTeq) was manufactured by Merck Sharp & Dohme Corporation and supplied as a prefilled solution in a squeezable tube for oral administration. Each 2 mL dose contained RV type G1 (≥ 2.2 × 106 IU), G2 (≥ 2.8 × 106 IU), G3 (≥ 2.2 × 106 IU), G4 (≥ 2.0 × 106 IU), and P1A (≥ 2.3 × 106 IU).
All vaccines were commercial lots.
In the primary series study, 5 mL blood samples were collected pre-first vaccination (2 months of age) for determination of anti-PT, anti-FHA and anti-RV IgA antibodies and 1 month post-third vaccination (5 months of age) for determination of antibodies to all antigens in the investigational, control, PCV13 and RV vaccines. In the booster study, 5 mL blood samples were collected prebooster to assess antibody persistence for all antigens in the investigational and control vaccines, and 1 month postbooster to assess the booster response to all antigens in the investigational, control and PCV13 vaccines.
All assays were performed at either the Sponsor’s Global Clinical Immunology laboratory (Swiftwater, PA) or at qualified contract laboratories approved by Global Clinical Immunology. Anti-diphtheria antibody concentrations (IU/mL) and anti-polio 1, 2, 3 antibody titers (1/dil) were measured by neutralization assays. Anti-tetanus (IU/mL), anti-PT (EU/mL) and anti-FHA (EU/mL) concentrations were evaluated by enzyme-linked immunosorbent assays (ELISA); the ELISA specifically measured the IgG antibody isotype and validation studies before testing showed that both the PT IgG ELISA and the FHA IgG ELISA were valid and suitable to quantify anti-PT and anti-FHA antibody levels in human serum. Anti-HB concentrations (mIU/mL) were evaluated by a commercially available chemiluminescence assay (VITROS ECi/ECiQ) and anti-PRP-T (µg/mL) concentrations by a radioimmunoassay. Anti-RV IgA and anti-PCV13 antibodies were assessed using ELISA.
Reactogenicity and Safety
Participants were observed for 30 minutes after each vaccination to assess immediate unsolicited adverse events (AEs). For 7 days after each vaccination, parent(s)/legal representative(s) used diary cards to record the duration and intensity of solicited injection site reactions (tenderness, erythema, swelling [recorded separately for the DTaP-IPV-HB-PRP-T or control vaccine and PCV13 vaccination sites] and extensive swelling of the vaccinated limb [Extensive swelling of the vaccinated limb was only assessed after the booster DTaP vaccinations (not PCV13)]) and solicited systemic reactions (fever [defined as ≥ 38.0°C], vomiting, crying abnormal, drowsiness, appetite lost, irritability) reactions. Solicited injection site reactions were assessed as grade 1, 2 and 3 as follows: tenderness grade 1 “minor reaction when injection site touched,” grade 2 “cries of protests when injection site is touched,” and grade 3 “cries when injected limb is moved or the movement of the injected limb is reduced;” erythema and swelling grade 1, 2 and 3, diameter of > 0 to < 25 mm, ≥ 25 to < 50 mm and ≥ 50 mm, respectively; extensive swelling of the vaccinated limb was automatically to have been considered as grade 3. Solicited systemic reactions were assessed as grade 1, 2 and 3 as follows: fever grade 1, 2 and 3, ≥ 38°C to ≤ 38.5°C, > 38.5°C to ≤ 39.5°C and > 39.5°C, respectively; vomiting grade 1, 2 and 3, 1, 2–5 and ≥ 6 episodes per 24 hours (or requiring parenteral nutrition [grade 3]); abnormal crying grade 1, 2 and 3, < 1 hour, 1–3 hours and > 3 hours, respectively; drowsiness grade 1 sleepier than usual or less interested in surroundings, grade 2 not interested in surroundings or did not wake up for a feed/meal, grade 3 sleeping most of the time or difficult to wake up; appetite lost grade 1 eating less than normal, grade 2 missed 1–2 feeds/meals completely, grade 3 refused ≥ 3 feeds/meals or refused most feeds/meals; irritability grade 1 easily consolable, grade 2 required increased attention, grade 3 inconsolable. All solicited reactions were automatically considered to be related to the vaccination. For temperature measurement, the rectal route was preferred.
Unsolicited AEs were recorded using diary cards for 30 days after each vaccination: unsolicited injection site AEs were considered to be related to the vaccination, and the investigator assessed unsolicited systemic AEs for causality. Serious adverse events (SAEs) were collected throughout the study until 1 month after the last primary series vaccination or booster vaccination, and the Investigator assessed their causality.
The primary statistical objective of the primary series study was to demonstrate that the immune response to the investigational vaccine was noninferior to that for the control vaccine in terms of seroprotection (SP) rates for anti-HB and anti-PRP and vaccine response (VR) rates for anti-PT and anti-FHA following co-administration with PCV13 and RV. The noninferiority test was based on the difference (investigational minus control vaccine) in SP/VR rates. Noninferiority was concluded if the lower bound of the 2-sided 95% confidence interval (CI) was greater than −10% for all of the 4 tested antigens (HB, PT, FHA and PRP); the 95% CI of the difference was calculated based on the Wilson score method without continuity correction as quoted by Newcombe.23
Secondary objectives included further description of the immunogenicity of the investigational and control vaccines, the immune response to PCV13 and RV and the overall safety profile in each group. In the booster study, antibody persistence of the investigational and control vaccines at 11–15 months of age and the response to the investigational, control and PCV13 vaccines at 1 month postbooster were compared descriptively.
The antibody thresholds and criteria used to define SP and VR rates are presented for the investigational and control vaccines in Tables 1, 2. For PCV13, SP rates are defined in Table 3 and for RV the SP rates, and seroconversion (SC) rates are defined in Table 4. Additionally, geometric mean titers (GMTs: anti-IPV) and geometric mean concentrations (GMCs: anti-HB, anti-PRP, anti-D, anti-T, anti-PT, and anti-FHA, anti-PCV13, and anti-RV IgG) are presented. All data are presented with their 95% confidence intervals (CIs), calculated using the exact binomial distribution (Clopper-Pearson)24 for proportions and the normal approximation method for GMCs and GMTs.
The sample size calculation was based on the noninferiority test, calculated using the Farrington and Manning formula and based on a type 1 error of 2.5% (1-sided hypothesis) to obtain an overall power of 90% with 424 evaluable participants. With an estimated attrition rate of 20%, the planned sample size was therefore 530 participants.
The primary series and booster analysis of immunogenicity used the per protocol (PP) population (participants with no protocol violation that could have interfered with the evaluation criteria, and analyzed according to the vaccine received). Data from the full analysis set (those who received at least 1 vaccination, and analyzed according to the randomization) supported the evaluation done using the PP population. The safety evaluation used the safety analysis set (participants who received at least 1 primary vaccination and all who received the booster).
The statistical analyses were done under the responsibility of Sanofi Pasteur’s statistical group using SAS software, Version 9.2 or later (SAS Institute, Cary, NC).
Overall, 529 participants were randomized (266 in group 1 and 263 in group 2). In group 1 and group 2, respectively, 266 and 262 participants received at least 1 primary series vaccination, and 264 and 262 participants completed the primary vaccination series. Of these, 234 and 230 participants completed the booster. Participant disposition, including the number of participants included in the PP set and reasons for exclusion for both the primary series and booster analyses is presented in Figure 1. Demographic characteristics were similar in each group at the time of primary series and booster vaccination, and all participants were Caucasian except for 4 Asians, 4 Black/African American and 5 of mixed origin.
Noninferiority postprimary series was demonstrated for the investigational vaccine compared with the control vaccine, with the lower bound of the 95% CI for the difference in response rates being above −10% for anti-HB, anti-PT, anti-FHA and anti-PRP (Table 1).
Table 2 presents the immunogenicity data for the investigational and control vaccine antigens for the primary and booster vaccinations. Descriptively, these data demonstrated an overall similarity in the immune response to each antigen for the investigational and control vaccines, although some differences were observed, for example, anti-HB ≥ 100 mIU/mL was lower for the investigational vaccine compared with the control vaccine (71.9% versus 86.6%) and anti-PRP ≥ 1 was higher for the investigational vaccine compared with the control vaccine (58.9% versus 37.2%). There were some differences between groups for antibody persistence before the booster vaccination, for example, prebooster anti-HB was lower for the investigational vaccine compared with the control vaccine (86.0% versus 97.2% ≥ 10 mIU/mL and GMCs of 74.6 mIU/mL versus 169 mIU/mL) and prebooster anti-PRP was higher for the investigational vaccine compared with the control vaccine (72.0% versus 57.7% ≥ 0.15 µg/mL and GMCs of 0.383 µg/mL versus 0.173 µg/mL). However, the primary series and booster responses were strong and similar for each antigen in the investigational and control vaccines.
For PVC13, the response for each serotype was high and generally similar postprimary series and postbooster in both groups in terms of both SP rate (≥ 0.35 µg/mL) and GMC (Table 3). Seroprotection rate was > 90% for all antigens after both the primary and booster vaccinations except for serotype 3 (group 1, postbooster), serotype 5 (group 1, postprimary), serotype 6B (group 1 and group 2, postprimary).
For RV, the SP rate (≥ 20 U/mL) and GMC were similar in each group preprimary and postprimary series, and SC was similar in each group postprimary series (Table 4).
Safety and Tolerability
For the primary series, immediate AEs (within 30 minutes after vaccination) were experienced by 5 participants in group 1 (single episodes of flatulence and oral candidiasis that were not considered to be related to the investigational vaccine and 5 episodes of cough, of which 2 episodes were considered to be related to the investigational vaccine) and 2 participants in group 2 (abdominal pain and restlessness, both of which were considered to be related to the control vaccine). For the booster, 2 participants reported immediate AEs in group 1 (candidiasis that was not considered to be vaccine-related and pain in both legs that was considered to be related to the vaccination); none was reported in group 2.
The overall incidence of solicited injection site reactions following the investigational and control vaccines was similar for the primary series (83.0% versus 82.0%) and booster vaccination (68.5% versus 68.7%) (Table 5). For PCV13, the incidence was similar to that reported for the investigational and control vaccines and similar between groups. For solicited systemic reactions, the incidence was similar following the investigational and control vaccines for the primary series (97.0% and 95.8%) and booster vaccination (80.4% and 78.9%) (Table 5). Most solicited reactions were grade 1 or 2 in severity and resolved within 3 days. There were no clinically important differences between groups for individual injection site or systemic reactions for either the primary series or booster vaccination.
The incidence of unsolicited AEs in the 30 days postvaccination was similar in each group and slightly higher for the primary series (41.1% in group 1 and 39.5% in group 2) than for the booster vaccination (31.8% in group 1 and 31.1% in group 2). The most frequently reported unsolicited AEs for both the primary series and the booster vaccination were gastrointestinal/respiratory disorders or infections and infestations, but overall few were considered to be vaccine-related for the primary series (5.7% and 3.1%) or booster vaccination (1.3% and 0%).
During the primary series, SAEs were reported for 12 participants in group 1 (12 SAEs) and 9 participants in group 2 (10 SAEs). Of these, an SAE of convulsions occurred in 1 participant in group 1 at 10 days after receiving the second dose of the investigational vaccine, PCV13, and RV, and was considered to be related to the investigational vaccine and RV but unrelated to PCV13. The participant was hospitalized and experienced 3 more episodes of convulsions on the day of hospitalization and a further episode 3 days later. Neurologic findings were normal as was etiologic check-up, and the participant recovered after receiving diazepam and valproate and was discharged from hospital after 4 days. The participant remained in the study but did not receive the third primary series vaccination. Approximately 4 months later, the participant experienced another episode of convulsions, was hospitalized and recovered 4 days after treatment with diazepam, phenytoin sodium and valproate; this episode was not considered to be related to the study vaccines or procedures. Following the booster vaccination, 2 participants in group 1 reported 2 SAEs (bronchopneumonia and foreign body aspiration) and 3 participants in group 2 reported 3 SAEs (head injury [2 participants] and acute pyelonephritis): none was considered to be related to the vaccination.
This study confirmed the good immunogenicity and strong safety profile of DTaP-IPV-HB-PRP-T when administered in a 2, 3, 4 month primary series schedule followed by a booster in the second year of life in a Caucasian population. The response to each antigen was as expected from data obtained previously using a similar vaccination schedule12,25 and noninferiority of the primary series immune response to a hexavalent control vaccine was demonstrated for anti-HB, anti-PRP, anti-FHA and anti-PT. The study was not powered for an assessment of noninferiority for each antigen as this has been established in an extensive clinical development program in a range of countries and vaccine administration and coadministration schedules.8,9,12,18–20 As well as the strong primary series response, good antibody persistence and an anamnestic response following booster vaccination were shown for each of the D, T, aP, IPV, HB and PRP-T antigens that were comparable between the DTaP-IPV-HB-PRP-T and control vaccines.
The HB component of the DTaP-IPV-HB-PRP-T vaccine is the newest antigen included in the vaccine and so is of particular interest. While noninferiority of the primary series anti-HB response was demonstrated in terms of SP rate, anti-HB GMCs before the booster dose were slightly lower for DTaP-IPV-HB-PRP-T compared with the control vaccine. However, it is important to note that adequate priming will result in T and B cell memory even if anti-HB antibody levels decline and that a strong anti-HB response would be expected following exposure to wild-type virus.26,27 According to World Health Organization, “the loss of detectable anti-HBs in participants who had responded satisfactorily to a primary series does not necessarily indicate a lack of protection.”28,29 The strong anti-HB booster response is indicative of good anti-HB priming following the DTaP-IPV-HB-PRP-T primary series.
For PCV13 and RV, the primary and booster responses were strong and comparable with existing data following similar coadministrations.14,18,20
All primary series and booster vaccinations were well tolerated, which would be expected from previous data for the DTaP-IPV-HB-PRP-T vaccine that have consistently shown a good safety profile. One participant experienced an SAE of convulsions that was considered by the investigator to be related to the investigational vaccine and/or RV. This occurred approximately 10 days after the second dose of the primary series and such a latency of onset is more suggestive of a relationship to a live vaccine (RV) than to inactivated vaccines (DTaP-IPV-HB-PRP-T or PCV13).
In conclusion, these data support the use of the investigational vaccine in a 2, 3, 4 month schedule without a birth dose of HB vaccine, followed by a booster dose in the second year of life in Europe and administered with routine childhood vaccines, and add to the extensive scientific literature for this vaccine in a wide range of populations and administration schedules.
The authors thank and acknowledge the contribution and participation of the children and parents/legal guardians, as well as the investigational staff in the Czech Republic at: Brandys nad Labem, Chlumec nad Cidlinou, Chrudim, Holice, Hradec Kralove, Hronov, Jaromer, Jindrichuv Hradec, KolinLibechov, Mseno, Ostrava-Hrabuvka, Ostrava-Poruba, Pardubice, Praha, Sezemice, Smirice, Usti nad Labem; and in Germany at: Berlin, Bochum, Bretten, Erfurt, Hamburg, Karlsruhe, Mainz, Mannheim, Monchengladbach, Oberhausen, Solingen, Stockelsdorf, Stuttgart, Welzheim, Wiesbaden. The authors also acknowledge Severine Paulhac, Estelle Chataigner, Gaelle Soupart, Manon Croix, Nicolas Corde, Catherine Moreau, Jesus Garrido, Christine Manson, Nathalie Chateau-Rivoire, Corinne Terle, Pascale Davaux, Alexandra Jouve, Catherine Forrat, Neil Scheff, Marie Bufferne, Roxane Couty and Vincent Dallery (employed by Sanofi Pasteur); as well as Dajana Neichel (employed by Sanofi). Dr Andrew Lane (Lane Medical Writing) provided medical writing assistance, funded by Sanofi Pasteur, in the preparation and development of the manuscript in accordance with the European Medical Writers Association guidelines and Good Publication Practice and was funded by Sanofi Pasteur.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
hexavalent; vaccine; primary; booster; Europe; coadministration