The immunization schedules in the first year of life are becoming increasingly complex as new vaccines against preventable diseases are introduced into practice. In the United States, up to 23 separate injections can be necessary to complete the Recommended Childhood Immunization Schedule in the first 2 years of life.1 During some office or clinic visits, the administration of up to 4 or 5 separate injections can be indicated in the first year of life. In the European Union (EU), there is an additional complexity because of the fact that there are a variety of immunization schedules across the 28 member states.2
With the development and use of combination vaccines, multiple antigens can be administered through fewer injections. Use of combination vaccines is associated with higher compliance rates in this age group with the recommended vaccination schedule, presumably caused by reduction in the number of injections needed to deliver the vaccines.3,4 Vaxelis [DTaP5-HB-IPV-Hib vaccine: Diphtheria, tetanus, pertussis (5 acellular components: PT, FHA, PRN and FIM 2&3), hepatitis B (rDNA), poliomyelitis (inactivated) and Haemophilus influenzae type b (Hib) conjugate vaccine (adsorbed); MCM Vaccine B.V., The Netherlands] is a preservative-free, fully liquid, ready to administer, hexavalent vaccine developed to provide active immunization against several infectious diseases caused by 6 pathogens with the convenience of 1 injection.5 During the clinical development of DTaP5-HB-IPV-Hib vaccine, the comparator vaccine (control) was DTaP3-IPV-HepB/Hib (Infanrix hexa; GlaxoSmithKline Biologics S.A., Rixensart, Belgium) in European studies and DTaP5-IPV/Hib (PENTACEL; Sanofi Pasteur, Swiftwater, PA) in North American studies.6,7 The targeted indication for DTaP5-HB-IPV-Hib vaccine is for primary and booster vaccination in infants and toddlers from the age of 6 weeks, against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive diseases caused by Hib.
Presented here is a comprehensive summary and analysis of integrated safety data from 6 phase IIb/III clinical studies (Protocols 004, 005, 006, 007, 008, and PRI01C; Tables, Supplemental Digital Content 1 and 2, http://links.lww.com/INF/D380; http://links.lww.com/INF/D381) conducted in the United States, Canada, and the EU, with the final formulation of DTaP5-HB-IPV-Hib vaccine.3,8–12 These studies provided a rigorous assessment of the overall safety profile of DTaP5-HB-IPV-Hib vaccine across a broad range of geographies, populations and vaccination schedules.
In all 6 studies, the subject’s parent/legal representative was provided a Vaccination Report Card at each vaccination visit with instructions, including severity scales for solicited adverse events (AEs), to record the subject’s temperatures and all AEs. The Primary Investigators at each study site assessed causality (ie, related or not related to vaccination) on all AEs.
While the safety data collection practices were generally similar among the protocols, the studies differed in their vaccination schedules, which reflected local standard-of-care. Protocols 005, 006 and PRI01C administered DTaP5-HB-IPV-Hib vaccine as a 3-dose infant series (all DTaP5-HB-IPV-Hib doses given up to 6 months of age), while Protocols 004, 007 and 008 administered the vaccine as a 2- or 3-dose infant series with a Toddler Dose (given 12–15 months of age). As such, safety summary tables at the Toddler Dose only contain data from Protocols 004, 007 and 008 in the 6-study integration summaries.
The solicited AEs were the same for all studies: solicited injection-site AE terms were redness, pain/tenderness and swelling; solicited systemic AE terms were crying, decreased appetite, pyrexia, irritability, somnolence and vomiting. The length of safety data collection differed slightly among the studies. The 5 phase III studies (Protocols 005, 006, 007, 008 and PRI01C) collected solicited AEs and temperatures day 1 through day 5 post study vaccination while Protocol 004 collected solicited events through 7 days post study vaccination. Any AE (including unsolicited AEs) and concomitant medication occurring day 1 through day 15 post study vaccination was collected for the 5 phase III studies, while Protocol 004 collected such events through 30 days post study vaccination.
Serious AEs (SAEs), or AEs leading to hospitalization, were collected throughout the trial for Protocol 004, regardless of causality. For the US phase 3 studies (Protocols 005 and 006), all SAEs were collected regardless of causality from study entry until 6 months (~180 days) after the last infant series vaccination dose. In the EU phase 3 studies, all SAEs were collected for the first 14 days after any hexavalent vaccination and for the first 28 days after any dose of measles-mumps-rubella-varicella vaccine [ProQuad (Merck & Co., Inc., Kenilworth, NJ), a concomitant vaccine in Protocol 007]. For all studies, deaths and vaccine-related SAEs were collected throughout the study.
Temperature collection methods varied according to local standard practices. The majority of studies measured temperature rectally, while the PRI01C study, conducted in the United Kingdom, used axillary method because of local practice. Consequently, the temperature data from PRI01C was not integrated in the overall temperature analysis.
Numbers and proportions of subjects with AEs were summarized by treatment group. The analysis of integrated safety results followed a prespecified approach. Safety parameters (ie, solicited injection-site/systemic AEs and unsolicited AEs days 1–14 following any vaccination occurring with more than 1% frequency) were to be assessed via point estimates with 95% CIs for difference between the vaccination groups. Other parameters were assessed via point estimates by vaccination group.
The vaccination groups were generally similar with respect to subject disposition (Fig. 1). The overall proportions of subjects who completed follow-up were 86.5% (4584/5250) and 90.1% (2079/2307) for the DTaP5-HB-IPV-Hib and the control group, respectively. The most common reasons for discontinuation were lost to follow-up or withdrawal by subject (parent/guardian) throughout the study periods.
The 2 study groups were similar with respect to gender, age and weight (Table, Supplemental Digital Content 3, http://links.lww.com/INF/D382). Due to EU regulations, race and ethnicity data were not collected for the Protocols 007, 008 and PRI01C. Most subjects with race and ethnicity data collected were white (72.5%) and of non-Hispanic or Latino ethnicity (73.9%). The next most common racial groups were Black (10.4%) and Multiracial (7.8%). The distribution of gender, race, age and weight at enrollment were generally similar between the DTaP5-HB-IPV-Hib vaccine and control groups. The frequency and types of prior and concomitant medications were generally similar between the vaccination groups in each of the studies (data not shown).
A summary of AE parameters for the 6-study integration is presented in Table 1. There were no statistically significant differences between the 2 study groups regarding solicited injection-site AEs, unsolicited systemic AEs, SAEs or AEs leading to discontinuation. However, the analysis showed that DTaP5-HB-IPV-Hib group had a slightly higher incidence of subjects with solicited systemic AEs (estimated percentage difference [DTaP5-HB-IPV-Hib minus Control group] = 1.8; 95% CI: 0.4–3.3). Vaccine-related serious AEs occurred infrequently (0.2% for both groups). A listing of subjects with SAEs related to DTaP5-HB-IPV-Hib vaccine or control (ie, considered by an investigator to have been possibly, probably or definitely related to study therapy) in Protocols 004, 005, 006, 007, 008 and PRI01C is displayed in (Table, Supplemental Digital Content 4, http://links.lww.com/INF/D383).
A detailed analysis regarding individual solicited injection-site AEs after any vaccinations (Fig. 2) showed that the incidence of injection-site pain was similar between the 2 vaccine groups. The incidences of injection-site erythema and injection-site swelling were statistically higher in the DTaP5-HB-IPV-Hib vaccine group; the estimated percentage differences were 5.2 (95% CI: 2.5–7.9) for erythema and 3.1 (95% CI: 0.5–5.8) for swelling. The majority of reported injection-site pain was of mild-to-moderate intensity. The majority of the injection-site erythema and injection-site swelling was <2.5 cm (mild).
A similar detailed analysis regarding solicited systemic AE after any dose vaccination (Fig. 2) showed that the 2 vaccine groups had similar incidences of subjects reporting these events with the exception of pyrexia. The incidence of pyrexia in the DTaP5-HB-IPV-Hib vaccine group was higher; estimated risk difference was 9.4 (95% CI: 6.7–12.0).
A further analysis of temperature revealed that the difference in the incidence of fever was most pronounced in the DTaP5-HB-IPV-Hib vaccine group in Protocols 005 and 006 where the control group using PENTACEL displayed a lower incidence of fever (Fig. 3). Most of the fever was mild-to-moderate as severe fever (>39.5°C) was less than 3% (Fig. 3). The higher rates of fever did not result in an increase in fever-related events such as hospitalization, seizures or febrile seizures (Table 2).
SAEs and AEs leading to discontinuation occurred infrequently and at a similar rate for DTaP5-HB-IPV-Hib and control vaccines (Table 1), and there were no vaccine-related deaths in any of the phase III studies.
The DTaP5-HB-IPV-Hib vaccine phase III studies evaluated a variety of immunization schedules, including 2 key schedules in the EU, that is, the “3 + 1” schedule (3 infant doses followed by 1 Toddler Dose) and the “2 + 1” schedule (2 infant doses followed by 1 Toddler Dose), across a broad geographic distribution including North America and the EU.3,8–12 The phase III program also evaluated the coadministration of DTaP5-HB-IPV-Hib vaccine with licensed pediatric vaccines given at the same age. This integrated safety data from 6 phase II/III studies that used the final formulation of DTaP5-HB-IPV-Hib vaccine provides a comprehensive review of the safety profile of DTaP5-HB-IPV-Hib vaccine when administered as a primary series (N > 5200) and as a booster dose (N > 1500).
The global DTaP5-HB-IPV-Hib vaccine clinical study experience further supports that the overall safety profile of DTaP5-HB-HPV-Hib is similar to the comparator vaccines, is consistent with that of its licensed component vaccines and is considered acceptable. In the 6-study integration (Protocols 004, 005, 006, 007, 008, PRI01C), the majority of AEs were of mild to moderate intensity, not serious, and did not lead to discontinuation. The overall rates of SAEs after any vaccination were similar in the 2 vaccination groups (DTaP5-HB-IPV-Hib vaccine [3.9%] and control [3.7%]) across the 6-study integration. Vaccine-related SAEs were infrequent (0.2% for both vaccination groups) as were discontinuations caused by AEs (0.2% for DTaP5-HB-IPV-Hib, 0.4% for Control).
A higher rate of fever for DTaP5-HB-IPV-Hib vaccine versus control was noted in the 6-study integration and appeared to be driven by a greater difference in fever rates between DTaP5-HB-IPV-Hib vaccine and the pentavalent control regimen in the US studies. Indeed, when the comparison was limited to the studies that compared 2 hexavalent vaccines (Protocols 007 and 008), the fever rates for DTAP5-HB-IPV-Hib and control were comparable (Fig. 3B). Fever after DTaP5-HB-IPV-Hib vaccine was generally mild-to-moderate and self-limited. Consistent with this profile, fever-related medical events (hospitalizations, febrile convulsions or convulsions) occurred at a similar low rate after DTaP5-HB-IPV-Hib vaccination as compared with control vaccine across the 6 studies. For example, within 15 days of vaccination, the incidence of pyrexia SAEs was 0.1% for both groups, and febrile seizure SAEs < 0.1% for both groups (Table 2).
Increased rates of fever have been noted before with multivalent combination vaccines.13,14 Prelicensure studies showed higher rates of fever among infants given DTaP3-HepB-IPV-Hib plus 7-valent pneumococcal conjugate vaccine (PCV-7; Pfizer Inc., Philadelphia, PA) as compared with those given the corresponding component vaccines plus PCV-7, although higher fever (temperature ≥ 39.5°C) was rare and occurred with similar frequency in both groups. Despite some early concern that increased rates of even low-grade fever might prompt emergency department visits, invasive diagnostic work-ups and hospital admissions, a subsequent postmarketing study showed there was no increase in medically attended events associated with fever, including seizure, as compared with a historical control that received the component vaccines.15 As with other licensed vaccines, the safety of DTaP5-HB-IPV-Hib will be continued to be monitored after approval.
In summary, DTaP5-HB-IPV-Hib vaccine administered as a 2- or 3-dose infant series plus Toddler Dose or as 3-dose infant series to over 6,800 children, has an acceptable safety profile generally similar to that of control vaccines, based on a low incidence of severe AEs, vaccine-related SAEs, and AEs leading to discontinuation. Clinically relevant interference has not been seen with concomitant administration of pneumococcal conjugate, rotavirus, meningococcal group C conjugate and measles-mumps-rubella-varicella vaccines.3,8–10 DTaP5-HB-IPV-Hib vaccine provides a new, fully liquid and convenient hexavalent vaccination option for use with various vaccination schedules in Europe.
2. European Centre for Disease Prevention and Control. Vaccine Scheduler: Vaccine schedules in all countries of the European Union. Available at: https://vaccine-schedule.ecdc.europa.eu/
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and immunogenicity of a hexavalent vaccine administered at 2, 4 and 6 months of age with or without a heptavalent pneumococcal conjugate vaccine: a randomized, open-label study. Pediatr Infect Dis J. 2013;32:54–61.
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and immunogenicity of a toddler dose following an infant series of a hexavalent diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae
type b, hepatitis B vaccine administered concurrently or at separate visits with a heptavalent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2014;33:73–80.
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, tolerability and immunogenicity of an investigational hexavalent vaccine in US infants. Pediatr Infect Dis J. 2017;36:202–208.
11. Vesikari T, Becker T, Vertruyen AF, et al. A phase III randomized, double-blind, clinical trial of an investigational hexavalent vaccine given at two, three, four and twelve months. Pediatr Infect Dis J. 2017;36:209–215.
12. Silfverdal SA, Icardi G, Vesikari T, et al. A phase III randomized, double-blind, clinical trial of an investigational hexavalent vaccine given at 2, 4, and 11-12 months. Vaccine. 2016;34:3810–3816.
13. Marin M, Broder KR, Temte JL, et al; Centers for Disease Control and Prevention (CDC). Use of combination measles, mumps, rubella, and varicella vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010;59(RR-3):1–12.
14. Thompson LA, Irigoyen M, Matiz LA, et al. The impact of DTaP-IPV-HB vaccine on use of health services for young infants. Pediatr Infect Dis J. 2006;25:826–831.
15. Zangwill KM, Eriksen E, Lee M, et al. A population-based, postlicensure evaluation of the safety
of a combination diphtheria, tetanus, acellular pertussis, hepatitis B, and inactivated poliovirus vaccine in a large managed care organization. Pediatrics. 2008;122:e1179–e1185.
safety; DTaP5-HB-IPV-Hib Vaccine; integrated analyses
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