The immunization schedules for infants and toddlers across the European Union countries are diverse, but several countries like the United Kingdom and Germany follow the “accelerated schedule” at 2, 3, 4 and 12 months, to induce early protection against pertussis and Haemophilus influenzae. Most European Union countries prefer to use hexavalent combination vaccines to reduce the number of shots and to improve coverage and timeliness.1–3 A hexavalent vaccine [diphtheria–tetanus toxoids–pertussis, hepatitis B vaccine, inactivated poliovirus vaccine and H. influenzae type b (DTPa3–HBV–IPV/Hib); Infanrix-hexa (GlaxoSmithKline Inc., Mississauga, Ontario, Canada); Control] has been licensed in Europe for over a decade (the only hexavalent vaccine available at the time of the study), a period during which improvement in immunization timeliness and stable effectiveness in disease prevention has been observed.4,5 More recently a fully liquid hexavalent vaccine with a 2-antigen pertussis component (Hexaxim) has been introduced in Europe and elsewhere.6–9
The fully liquid investigational hexavalent vaccine [diphtheria–tetanus toxoids–acellular pertussis 5, hepatitis B, inactivated poliovirus vaccine and H. influenzae type b (DTaP5–HB–IPV–Hib)] reported here contains a 5-antigen pertussis component and has a different carrier protein conjugated to the Hib antigen. This report presents results from a pivotal European Union Phase III study (NCT01341639), assessing the safety, tolerability and immunogenicity of DTaP5–HB–IPV–Hib compared with Control, when administered at 2, 3, 4 and 12 months, concomitantly with Prevenar 13 (PCV13) (Pfizer, Philadelphia, PA), RotaTeq (RV5) (Merck & Co., Inc., Kenilworth, NJ) and ProQuad (MMRV) (Merck & Co., Inc., Kenilworth, NJ). Another study of DTaP5–HB–IPV–Hib and Control when administered in the 2-month, 4-month, and 11-month to 12-month schedule has also been completed and is described in a separate manuscript.10
METHODS
Population
Healthy infants 46–74 days of age were eligible for the study. Participants were excluded if they had (1) participated in another study of an investigational compound or device within 4 weeks of entry, or planned to enroll in another clinical study during this study period; (2) received or were expected to receive immunosuppressive agents; (3) received systemic steroids (greater than the equivalent of 2 mg/kg total daily dose of prednisone) since birth, or any dose within 7 days before study entry, or were expected to receive steroids through the course of the study; (4) a history of leukemia, lymphoma, malignant melanoma or myeloproliferative disorder; (5) known or suspected hypersensitivity to any of the vaccine components; (6) received any hepatitis B, diphtheria, tetanus, pertussis, pneumococcal, rotavirus, measles, mumps, rubella, or varicella vaccines, or combination thereof; (7) a febrile illness, or a rectal temperature ≥38.0°C (≥100.4°F), within 24 hours before enrollment; (8) a coagulation disorder contraindicating intramuscular vaccination; (9) a maternal or personal history of hepatitis B surface antigen seropositivity (e.g., chronic hepatitis B); (10) a history of measles, mumps, rubella, varicella, invasive Hib disease, hepatitis B, diphtheria, tetanus, pertussis, poliomyelitis, rotavirus gastroenteritis or pneumococcal disease; or (11) any contraindication to the concomitant study vaccines. The protocol was conducted in accordance with principles of Good Clinical Practice, including obtaining written informed consent from each participant’s parent(s) or legal guardian(s) before study entry, and was approved by the human studies committees applicable to each study site.
Vaccines
Table, Supplemental Digital Content 1, https://links.lww.com/INF/C585, shows characteristics of the vaccines used in this study. DTaP5–HB–IPV–Hib and PCV13 vaccines were supplied in vials containing 0.5 mL of sterile suspension for intramuscular injection. Control was supplied with a lyophilized Hib powder and reconstituted with the liquid DTPa3–HBV–IPV component for intramuscular injection. RV5 was supplied in a tube containing 2 mL of dose solution for oral administration. MMRV was supplied as a powder and reconstituted as a 0.5-mL sterile diluent (supplied) for subcutaneous injection.
The preferred injection site of any vaccine for infants is the upper anterolateral thigh. DTaP5–HB–IPV–Hib or DTPa3–HBV–IPV was administered in separate limbs from the concomitant vaccines. PCV13 was administered at the lower thigh at 13 months when administered concomitantly with MMRV.
All products were prepared, packaged and labeled in accordance with Good Manufacturing Practice, guidelines for Good Clinical Practice from The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, as well as applicable local laws and regulations. Vaccine supplies were shipped, stored and distributed in accordance with the study protocol and Good Manufacturing Practice.
Design
This was a randomized, double-blind, active comparator-controlled study (NCT01341639) conducted at 40 sites in Belgium (2), Finland (12) and Germany (26) from May 2011 through March 2013. Twenty-one subjects were screened, but not randomized: 18 screen failures, 2 withdrawals by subject and 1 technical issue. A total of 1250 healthy infants were randomized using a computer-generated, site-balanced allocation schedule to receive DTaP5–HB–IPV–Hib or a Control vaccine in a 1:1 ratio. As shown in Table, Supplemental Digital Content 2, https://links.lww.com/INF/C586, the DTaP5–HB–IPV–Hib group received a 0.5-mL dose of DTaP5–HB–IPV–Hib concomitantly with PCV13 and RV5 at 2, 3 and 4 months, followed by DTaP5–HB–IPV–Hib concomitantly with MMRV at 12 months, and MMRV concomitantly with PCV13 at 13 months. The Control group received a 0.5-mL dose of Control at 2, 3, 4 and 12 months and PCV13, RV5 and MMRV doses as per the DTaP5–HB–IPV–Hib group. Blood specimens used to assess immunogenicity were collected via venipuncture within 5 days before administration of dose 1 (~3 mL), approximately 1 month after completion of the infant series (dose 3) (~5 mL), immediately before the toddler dose (~5 mL), and approximately 1 month after the toddler dose (~5 mL). The Hib radioimmunoassay detects antibody to Hib capsular polysaccharide, polyribosylribitol phosphate (PRP); performed by PPD, LLC, Wayne, Pennsylvania.
The hepatitis B enhanced chemiluminescence (ECi) assay detected total antibody to human plasma–derived hepatitis B surface antigen (subtypes ad and ay), the measles enzyme immunoassay is a direct binding assay that detected immunoglobulin G (IgG) antibodies to measles, the mumps enzyme-linked immunosorbent assay (ELISA) detected IgG antibody to mumps virus, the rubella enzyme immunoassay is a direct binding assay that detected IgG antibodies to rubella, and the glycoprotein ELISA detected IgG antibody to varicella-zoster virus; all were performed by PPD, LLC, Wayne, Pennsylvania. Anti-PT, anti-filamentous hemagglutinin, anti-PRN and anti-FIM IgG antibody titers were determined by an indirect ELISA method; anti-diphtheria antibody responses were assayed using the micrometabolic inhibition test; and anti-tetanus antibody titers were determined by ELISA assays; all were performed by the Sanofi Pasteur Inc. GCI platform in Swiftwater, Pennsylvania. Anti-poliovirus types 1, 2 and 3 titers were measured by neutralization assay, performed at Focus Diagnostics, Inc., Cypress, California.
From day 1 (day of vaccination) to day 5 after each vaccination, the following safety measurements were obtained using a vaccination report card: temperature; solicited injection-site adverse events (AEs), including injection-site pain/tenderness, redness and swelling; and solicited systemic AEs, including pyrexia (fever), vomiting, abnormal crying, drowsiness, appetite loss and irritability. Unsolicited injection-site and systemic AEs were collected through day 15 after each vaccination. Serious AEs (SAEs), regardless of causality, were recorded for the duration of the study.
Objectives
The primary objectives were to (1) evaluate the immunogenicity of DTaP5–HB–IPV–Hib when given at 2, 3, 4 and 12 months; and (2) compare the immunogenicity elicited by DTaP5–HB–IPV–Hib to that of Control when given at 2, 3, 4 and 12 months. The endpoints for the primary hypothesis of acceptability of DTaP5–HB–IPV–Hib were vaccine-induced antibody responses to all antigens contained in DTaP5–HB–IPV–Hib at postdose 3 and after the toddler dose. The endpoints for the primary hypothesis of noninferiority of DTaP5–HB–IPV–Hib were vaccine-induced antibody responses against antigens that are common to both DTaP5–HB–IPV–Hib and Control at postdose 3 and after the toddler dose.
The secondary objectives were to (1) evaluate the immunogenicity of MMRV when administered concomitantly with the toddler dose of DTaP5–HB–IPV–Hib or Control; (2) describe the safety profile associated with the administration of each dose of DTaP5–HB–IPV–Hib or Control; (3) describe the fever profile (days 1–5) after each dose of DTaP5–HB–IPV–Hib or Control; (4) describe the percentage of subjects with solicited injection-site AEs (pain, erythema and swelling) and solicited systemic AEs (vomiting, crying, somnolence, decreased appetite and irritability) within 5 days after each and any dose of DTaP5–HB–IPV–Hib or Control; and (5) summarize the incidence of SAEs reported during days 1–15 after each dose of DTaP5–HB–IPV–Hib or Control. The endpoints for the noninferiority and acceptability of MMRV concomitantly administered with DTaP5–HB–IPV–Hib were antibody response rates at 1 month after administration of MMRV at toddler dose. The safety endpoints included: (1) incidence of the daily measurement of temperatures day 1 through day 5 following each hexavalent vaccination; (2) solicited injection-site AEs (i.e., injection-site pain/tenderness, injection-site redness [erythema] and injection-site swelling) from day 1 through day 5 following each hexavalent vaccination; (3) solicited systemic AEs (i.e., vomiting, crying abnormal, drowsiness, appetite loss [decreased appetite] and irritability) from day 1 through day 5 following each hexavalent vaccination; (4) unsolicited AEs (including injection site and systemic) from day 1 through day 15 following each hexavalent vaccination; and (5) SAEs, including death due to any cause, that occurred from day 1 through day 15 following each vaccination. The tertiary objectives were to describe (1) the response rates (%) and geometric mean concentrations for all antigens in DTaP5–HB–IPV–Hib and Control at 1 month after dose 3 and 1 month after the toddler dose with 95% confidence interval (CI); and (2) the percentage of subjects with anti-diphtheria and anti-tetanus antibody ≥1.0 international units per milliliter (IU/mL) after the toddler dose with 95% CI.
It was planned that approximately 620 subjects would be enrolled in each vaccination group. The evaluability was assumed to be 85% at postdose 3 and 80% after the toddler dose. The assumed true response rates and standard deviation were based on previous studies in the program development as well as the studies using component vaccines. With the sample size of this study, the power was 98.8% for the primary hypothesis of acceptability, 94.5% for the primary hypothesis of noninferiority and 89.8% for the secondary hypothesis of concomitant use of MMRV.
Analyses
Immunogenicity
Antibody responses were defined based on accepted immune correlates of protection, or previously accepted definitions of vaccine response for licensed vaccines (Table, Supplemental Digital Content 3, https://links.lww.com/INF/C587). The primary and key secondary endpoints, analysis populations and statistical methods for immunogenicity analyses are provided in Table, Supplemental Digital Content 4, https://links.lww.com/INF/C588. The per-protocol analyses included all participants who met the inclusion criteria, did not have protocol deviations that would potentially impact the immunogenicity results, and had serology results within the specified day ranges. All exclusions from the per-protocol populations were decided before database lock. The Per-Protocol, Original Windows population consisted of subjects who had blood samples collected 28–44 days after dose 2 or the toddler dose. The Per-Protocol, Revised Windows population included subjects who had blood samples collected 28–51 days after dose 2 or the toddler dose. The revised windows were prespecified in an amendment to the protocol and a statistical analysis plan before database lock and knowledge of immunogenicity results. They were based on earlier phase II studies of DTaP5–HB–IPV–Hib and allowed for inclusion of immunogenicity data from more vaccinated participants in the per-protocol analysis. Key immunogenicity summaries and analyses were also provided for all endpoints associated with hypotheses using the Full Analysis Set population, which included all randomized participants with available serology data at postvaccination regardless of protocol deviation.
Safety
All randomized participants who received at least 1 dose of study vaccine and had safety follow-up were included in the safety analysis. The AEs and fever profiles were described for the study vaccine after each hexavalent vaccination and for the entire vaccination period. Incidence rates of each solicited AE occurring from days 1 through 5 after any hexavalent dose, as well as incidence rates of each unsolicited AE from days 1 through 15 after any hexavalent dose and occurring in more than 1% of the participants in either vaccination group, were compared using point estimates and 95% CIs.11 Incidence rates of elevated temperatures (≥38°C) occurring from days 1–5 after any hexavalent dose were compared using point estimates and 95% CIs.11 Other safety endpoints were summarized using frequency counts and percentages.
RESULTS
Results discussed in this section refer to the Per-Protocol, Revised Windows population; results based on the Per-Protocol, Original Windows and Full Analysis Set populations were consistent with the results for Per-Protocol, Revised Windows for all immunogenicity endpoints.
Participant Accounting and Demographics
After blinded trend analysis and subsequent audit at a single study site in Germany, it was identified that safety data from this study site were noted to be far outside of the range of results for the study as a whole (e.g., all temperatures were in the afebrile range and the rate of unsolicited systemic AEs was 0 as compared with >70% of subjects from the other study sites that reported a fever, and >70% of subjects from the other study sites that reported unsolicited systemic AEs), as well as noting major findings in study conduct and monitoring. The probability that such distinct results could have occurred by chance at one particular site as compared with the whole study was exceedingly low, and called into question the veracity of the safety results from this site. Therefore, all data at this site from summaries and analyses were excluded (33 subjects). This decision was made before database lock and was communicated to the regulatory authorities.
A total of 1187/1217 (97.5%) randomized participants (excluding subjects randomized to disqualified study site) received all 3 infant series doses and the toddler dose of DTaP5–HB–IPV–Hib (Fig. 1). Participants in both groups were comparable with respect to baseline characteristics (Table 1). The most common medical history terms included flatulence (15.9% for DTaP5–HB–IPV–Hib group, 13.1% for Control group); rhinitis (3.4% for DTaP5–HB–IPV–Hib group, 6.0% for Control group); and umbilical hernia (3.1% for DTaP5–HB–IPV–Hib group, 3.3% for Control group). The most frequently reported concomitant medications administered during the study were analgesics (74.4% for DTaP5–HB–IPV–Hib group, 73.2% for Control group) and vitamins (56.9% for DTaP5–HB–IPV–Hib group, 55.4% for Control group).
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TABLE 1: Participant Demographics and Baseline Characteristics
FIGURE 1: Participant disposition. aAll data at one site from summaries and analyses were excluded (33). bReasons for discontinuation: not vaccinated (1); protocol violation (1); withdrawal of consent (11). All 598 subjects received all 3 infant doses of DTaP5-IPV-Hib-HepB and all concomitant infant vaccines. cReasons for discontinuation: not vaccinated (1); adverse event (5); lost to follow-up (2); withdrawal of consent (8). Among 590 subjects who received all 3 infant doses of Control, only 589 subjects received all 3 doses of Control and all concomitant infant vaccines. dReasons for discontinuation: lost to follow-up (2); withdrawal of consent (6). eReasons for discontinuation: physician decision (1); protocol violation (1); withdrawal of consent (7). fReasons for discontinuation after Toddler dose: none. Among the 590 subjects who received the Toddler Dose of DTaP5-IPV-Hib-HepB, only 539 subjects received the Toddler Dose of DTaP5-IPV-Hib-HepB and MMRV vaccine. gReasons for discontinuation after Toddler dose: adverse event (2); withdrawal of consent (1). Among the 582 subjects who received the Toddler Dose of Control, only 548 subjects received Toddler Dose of Control and MMRV vaccines. hIncludes 1 subjects who received Control at non-study visit.
There was a slight difference in the percentage of subjects receiving antipyretic, analgesic and antiinflammatory medications within 48 hours after dose 2 (DTaP5–HB–IPV–Hib: 39.3%; Control: 43.6%) and within 48 hours after the toddler dose (DTaP5–HB–IPV–Hib: 40.2%; Control: 29.1%).
Immunogenicity
Acceptability analyses regarding DTaP5–HB–IPV–Hib antigen responses 1 month postdose 3 and 1 month after the toddler dose are provided in Table 2. The lower limit of the 2-sided 95% CI for the response rate (%) was greater than the predetermined lower limit regarding all prespecified endpoints, indicating that the DTaP5–HB–IPV–Hib group met the response rate acceptability criteria.
TABLE 2: Immune Responses: Analysis of Acceptability
Noninferiority analyses regarding DTaP5–HB–IPV–Hib antigen responses 1 month postdose 3 and 1 month after the toddler dose are provided in Table 3. The lower limit of the 2-sided 95% CI for the group difference (DTaP5–HB–IPV–Hib group minus Control group) was above the prespecified noninferiority margin regarding all prespecified endpoints, indicating that DTaP5–HB–IPV–Hib group was noninferior to Control group. Furthermore, the group difference regarding anti-PRP ≥0.15 μg/mL 1 month postdose 3 was 11.37% (95% CI: 8.44%–14.68%) with its entire 95% CI above 0, suggesting a superior anti-PRP response elicited by DTaP5–HB–IPV–Hib postdose 3 (however, the study did not have a formal superiority hypothesis). Prebooster anti-PRP seroprotection rates were much higher with DTaP5–HB–IPV–Hib as compared with Control (95% vs. 64%, respectively). The observed postdose 3 and post-toddler dose immunogenicity responses are summarized in Tables, Supplemental Digital Content 5 and 6, https://links.lww.com/INF/C589 and https://links.lww.com/INF/C590, respectively. After the 3-dose infant series, the response rates for all antigens were similar, with overlapping CIs between DTaP5–HB–IPV–Hib and Control.
TABLE 3: Immune Responses: Analysis of Noninferiority
With regard to co-ad with MMRV, the acceptability analyses regarding MMRV antigen responses 1 month after the Toddler dose are provided in Table 2. The response rate acceptability criteria were met for all MRRV antigens whether it was given with DTaP5–HB–IPV–Hib or Control. Noninferiority analyses regarding MMRV antigen responses 1 month after the toddler dose are provided in Table 5. The lower limit of the 2-sided 95% CI for the group difference in rates (DTaP5–HB–IPV–Hib with MMRV vs. Control with MMRV) was above the prespecified noninferiority margin regarding all prespecified MMRV endpoints, indicating that the DTaP5–HB–IPV–Hib group was noninferior to the Control group.
Adverse Events
Safety follow-up was obtained for ≥97% of participants. As seen in Table 4, 98.9% of participants in the DTaP5–HB–IPV–Hib group and 99.5% in the Control group reported at least 1 AE after any dose. In general, the proportion of participants reporting injection-site AEs (days 1–15), solicited injection-site AEs (days 1–5), systemic AEs (days 1–15) and solicited systemic AEs (days 1–5) were similar between both groups. Most of these reports were mild to moderate in intensity and did not lead to medical intervention. During the entire study, 0 participants in the DTaP5–HB–IPV–Hib group and 4 participants in the Control group discontinued because of vaccine-related AEs.
Table 4 also shows that 2.8% of participants in the DTaP5–HB–IPV–Hib group and 2.2% of participants in the Control group reported at least 1 SAE. There was 1 discontinuation in the Control group due to vaccine-related SAEs (pyrexia and swollen tongue). No deaths were reported during the study.
TABLE 4: Adverse Events After Any Dose in All Participants Who Received ≥1 Dose of Hexavalent Vaccine
There were no significant differences in fever days 1–5 after any dose vaccination between the DTaP5–HB–IPV–Hib group and the Control group (Table 5). In addition, there were no significant differences in the incidence of mild, moderate or severe fever, as the rate difference 95% CI for all fever subcategories included 0. Fever was of brief duration (≤2 days) for the vast majority of subjects.
TABLE 5: Fever Summary (Analysis of Maximum Temperature, Days 1–5 After Any Dose of Vaccine, by Route of Measurement, With Estimated Difference Between DTaP5–HB–IPV–Hib and Control)
AEs associated with the concomitant vaccines were collected after any infant dose and after the toddler dose for PCV13 and MMRV, respectively. Solicited injection-site AEs related to PCV13 were reported by 72.6% of subjects (443/610) in the DTaP5–HB–IPV–Hib group and 73.1% of subjects (441/603) in the Control group during day 1–5 after any infant dose vaccination. Unsolicited injection-site AEs related to PCV13 were reported by 12.0% of subjects (73/610) in the DTaP5–HB–IPV–Hib group and 15.3% of subjects (92/603) in the Control group during day 1–15 after any infant dose vaccination. There was a higher frequency of solicited injection-site AEs related to MMRV in the DTaP5–HB–IPV–Hib group as compared with the Control group during day 1–5 after the toddler dose vaccination: erythema (28.0%, 151/590 vs. 21.4%, 117/581); pain (34.3%, 185/590 vs. 26.1%, 143/581); and swelling (13.4%, 72/590 vs. 8.8%, 48/581). Unsolicited injection-site AEs related to MMRV were reported by 15.4% of subjects (83/539) in the DTaP5–HB–IPV–Hib group and 13.0% of subjects (71/548) in the Control group during day 1–15 after the toddler vaccination.
DISCUSSION
In this study, all primary acceptability and noninferiority immunogenicity comparisons to Control were met, providing evidence to support the use of DTaP5–HB–IPV–Hib at 2, 3, 4 and 12 months of age. The postdose 3 anti-PRP responses at the threshold of ≥0.15 μg/mL were numerically higher than control (98% vs. 87%, ≥0.15 μg/mL, respectively, Table 5), with an estimated difference that excluded 0, suggesting a statistically significant difference. This result is consistent with the literature for monovalent Hib vaccines showing that the PRP antigen conjugated to the OMPC (outer membrane protein complex of Neisseria meningitidis) (contained in DTaP5–HB–IPV–Hib) results in more rapid kinetics of anti-PRP, as compared with the PRP–TT conjugate (contained in Control).12 Additionally, the prebooster difference might be of clinical significance for protection against Hib diseases between ages 4 and 12 months, a time of peak incidence and highest burden of Hib, when DTaP5–HB–IPV–Hib results in more rapid development of protective levels of anti-PRP antibody.13 The higher postinfant and pretoddler anti-PRP responses for DTaP5–HB–IPV–Hib are balanced by a smaller postbooster increase as compared with the Control (geometric mean titers were 6.79 and 21.39 µg/mL, respectively; Table, Supplemental Digital Content 6, https://links.lww.com/INF/C590). However, the risk for Hib disease decreases markedly after 1 year of age, and both vaccines had responses in excess of the threshold associated with long-term protection from Hib disease (≥1.0 µg/mL).
The immunogenicity data also support the administration of the new fully liquid DTaP5–HB–IPV–Hib vaccine with licensed pediatric vaccines (e.g., MMRV). In separate studies, comparable immunogenicity of RV5, RV1 and PCV-13 whether given with DTaP5–HB–IPV–Hib or licensed control was demonstrated.14–16
DTaP5–HB–IPV–Hib was associated with a low rate of vaccine-related SAEs, and no AEs that led to discontinuation from the study. The safety profile for injection-site and systemic adverse reactions, including fever, was similar to that of Control.
The fully liquid formulation of DTaP5–HB–IPV–Hib may also offer additional benefits and convenience during the preparation of the vaccine for administration. A study conducted in Belgium demonstrated that a fully liquid hexavalent vaccine reduces significantly preparation time and risk of handling errors as compared with nonfully liquid hexavalent vaccine.17
Based on its immunogenicity, safety and tolerability to a licensed profile demonstrated in this study, DTaP5–HB–IPV–Hib has the potential to provide a new fully liquid hexavalent option to enhance compliance to the recommended immunization schedules in Europe.
ACKNOWLEDGMENTS
The authors would like to thank all of the study participants, their parents, the study investigators and their staff. They also thank Emilia Jordanov of Sanofi Pasteur; and Laurence Allard, Stéphanie Collomb-Gilbert and Armelle Marais of Sanofi Pasteur MSD.
Following are the members of V419 Protocol 007 Study Group:
Belgium: M. Raes. Finland: T. Korhonen, I. Seppä, A. Ahonen, T. Haapaniemi, A. Forsten, T. Karppa. Germany: A. Bufe, E. Stoeckmann, T. Adelt, B. Becker, G. Bleckmann, P. Bosch, K. Deichmann, M. Donner, T. Fischbach, E. Franke-Beckmann, C. Horn, F. Kaiser, R. Knecht, R. Kollges, N. Luttringhaus, R. Maier, R. Mangeldorf-Taxis, F. Panzer, U. Pfletschinger, B. Sandner, D. Schlegel, A. Schmutte, L. Schroter, P. Soemantri, V. Tempel, W. Otto, C Wolff, R. Clementsen, T. Heising, H. Pabel, M. Vomstein.
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