https://orcid.org/0000-0003-1314-3468
ABSTRACT
Introduction
The benefits of vaccine co-administration include improved vaccine acceptance and uptake resulting in an increased coverage and protection against multiple childhood diseases, with minimal medical visits. The diphtheria-tetanus-acellular pertussis-hepatitis B-poliomyelitis-Haemophilus influenzae type b vaccine (DTaP-HBV-IPV/Hib) has been available for more than 19 years and is recommended for co-administration with several other infant vaccines.
Areas covered
This is a comprehensive review (34 studies, 21,000 participants) describing the immunogenicity and safety of DTaP-HBV-IPV/Hib when co-administered with 12 different vaccines in infants including pneumococcal, meningococcal, rotavirus or measles-mumps-rubella-varicella.
Expert opinion
Interactions among co-administered vaccines are complex. Therefore, co-administration data are critical before a vaccination regimen can be recommended. Co-administration of DTaP-HBV-IPV/Hib with other routinely administered vaccines was associated with high percentages of children achieving seroprotection/vaccine response against DTaP-HBV-IPV/Hib antigens. In addition, co-administration was not associated with clinically significant interference in immune responses to co-administered vaccines and was well tolerated. Increased systemic reactions observed with some combinations (DTaP-HBV-IPV/Hib + pneumococcal conjugate or meningococcal serogroup B vaccines) were mitigated by prophylactic paracetamol administration. The data reported here, which represent the most frequently used co-administrations of DTaP-HBV-IPV/Hib worldwide, support the concomitant administration of DTaP-HBV-IPV/Hib with other routinely recommended infant vaccines.
1. Introduction
In the first years of life, infant immunization programs may include vaccines against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, disease caused by Haemophilus influenzae type b (Hib), meningococcal disease (meningitis and septicemia) due to Neisseria meningitidis serogroups A, B, C, W, and Y, pneumococcal disease, rotavirus gastroenteritis, measles, mumps, rubella, and varicella. This list may expand as new vaccines are developed and become available and recommended – for instance, infant immunization programs in several countries also include hepatitis A and influenza vaccination nowadays [Citation1]. Multiple antigens may be administered at the same site as a combination vaccine or co-administered during the same medical visit at different injection sites. Both strategies minimize the required number of vaccine visits to achieve full coverage, improve timeliness of vaccination and allow for a programmatic fit across different vaccine regimens used in the respective country [Citation2–Citation5]. These benefits are crucial to increase protection of infants, especially in the first months of life when they are most vulnerable to vaccine-preventable diseases.
The benefits of combination vaccines extend to the recipients (improved compliance and reduced pain through fewer injections); to parents (increased productivity, time management and vaccine acceptance); to vaccine providers (improved practice efficiency and reduced risk of needle-stick injuries); and to the public health system (simplified infant immunization schedule and reduced costs associated with storage and handling) [Citation6]. Nevertheless, combination vaccines are complex to develop and manufacture [Citation6,Citation7]. Additionally, the shortage of one component during production may impact the availability of the entire vaccine.
Interactions among vaccines administered concomitantly are complex and may cause positive or negative effects on the immune response [Citation8–Citation12]. Therefore, the benefit versus risk of specific vaccine co-administrations needs to be evaluated in clinical trials before the widespread use of a particular co-administration regimen can be recommended [Citation8,Citation12].
The largest currently available combination vaccines contain antigens targeting six diseases (hexavalent vaccines): diphtheria, tetanus, pertussis, hepatitis B, Hib, and poliomyelitis. At the time of writing, three acellular pertussis-containing hexavalent vaccines were licensed for use in several countries: Infanrix hexa (GSK, DTaP-HBV-IPV/Hib), first licensed in 2000 and containing three acellular pertussis components (pertussis toxoid [PT], filamentous hemagglutinin [FHA] and pertactin [PRN]) [Citation13]; Hexaxim/Hexyon/Hexacima (Sanofi Pasteur), first licensed in 2012 and containing two acellular pertussis components (PT and FHA) [Citation14–Citation16]; and Vaxelis (MCM Vaccine B.V.), approved in Europe in 2016 and in the United States in 2018 and containing five acellular pertussis components (PT, FHA, PRN and fimbriae types 2 and 3) [Citation17,Citation18]. For GSK´s hexavalent vaccine extensive clinical trial and real-world experience exist in different countries, different populations (healthy, preterm and low birth weight infants), with different vaccination schedules, and when co-administered with other pediatric vaccines [Citation19–Citation22]. Interchangeability with other DTaP-containing vaccines manufactured by GSK has been demonstrated [Citation22], thus allowing for generalization of the finding to other (less valent) Infanrix combinations.
While DTaP-containing hexavalent combination vaccines make up the backbone of pediatric immunization schedules in many developed countries, most infant vaccination calendars also include numerous other vaccines scheduled to be administered at the same time [Citation1,Citation23,Citation24]. The present review focusses on co-administration of routine childhood vaccines with GSK’s hexavalent vaccine, DTPa-HBV-IPV/Hib – a more detailed assessment of other combination vaccines is out of the scope of this review. As more vaccines are added to infant schedules, evaluation of the immunogenicity and safety of co-administration regimens will remain of clinical importance. Here, we review the immunogenicity and safety reported in 34 studies and 21,513 subjects, in which GSK’s DTaP-HBV-IPV/Hib was co-administered with other routinely recommended childhood vaccines.
2. Methods
In order to capture all studies where GSK’s DTaP-HBV-IPV/Hib was used, we conducted a literature search on Pubmed using the search terms ‘DTPa-HBV-IPV/Hib OR Infanrix hexa OR DTPa-HBV-IPV//Hib OR DTaP-HBV-IPV/Hib’ with no limits on date or language. All the retrieved studies that did not include GSK’s DTaP-HBV-IPV/Hib were excluded. Of the 153 hits that resulted, all abstracts were reviewed and 36 publications in English were identified and included that presented immunogenicity and/or safety data pertaining to DTaP-HBV-IPV/Hib when co-administered with other licensed pediatric vaccines. Four additional papers were identified during the review of references. We limited this review to currently licensed vaccines, therefore studies of DTaP-HBV-IPV/Hib co-administered solely with the 7-valent pneumococcal conjugate vaccine (PCV7) were not included (PCV7 was replaced with the 13-valent pneumococcal conjugate vaccine [PCV13] by manufacturer).
3. Studies of DTaP-HBV-IPV/Hib co-administration
In total, 40 publications describing 34 studies were included in the review, of which 14 and 7 studies were sponsored and supported by GSK, respectively, and 13 studies were sponsored by other pharmaceutical companies or institutions (for one study [Study 19], no sponsorship/funding was disclosed). The 34 studies were conducted in 22 countries in Europe, North and South America, and Asia using a variety of common vaccination schedules, and evaluated co-administration with 12 different vaccines (). Immunogenicity data pertaining to the DTaP-HBV-IPV/Hib antigens were reported in 31 studies.
Table 1. Overview of studies on pediatric vaccines co-administered with DTaP-HBV-IPV/Hib.
Few studies were specifically designed to evaluate the immunogenicity of the co-administered vaccines, and only some of them included groups that received DTaP-HBV-IPV/Hib and the co-administered vaccine(s) both together and separately. In most studies, co-administration occurred in the context of the evaluation of other study objectives (usually the assessment of the immunogenicity and safety of a novel vaccine administered with or without routine vaccines).
3.1. Evaluation of immunogenicity
Immunogenicity for DTaP-HBV-IPV/Hib was evaluated in 31 studies. Blood samples were collected 1–2 months after completion of primary vaccination or after booster vaccination in the second year of life. The assays used to measure antibody levels for DTaP-HBV-IPV/Hib antigens and the seroprotective/vaccine response cutoffs used across the studies are provided in . Assays used to measure the levels or functionality of antibodies to the antigens in the co-administered vaccines are provided in Supplementary Table S 1. For each DTaP-HBV-IPV/Hib antigen except for pertussis antigens, seroprotection was defined as antibody levels greater than or equal to the following cutoffs: anti-diphtheria and anti-tetanus antibody concentrations ≥ 0.1 IU/ml; anti-hepatitis B surface (anti-HBs) antibody concentrations ≥ 10 mIU/ml; poliovirus neutralizing titers ≥ 1:8; and anti-polyribosyl-ribitol phosphate (anti-PRP) antibody concentrations ≥ 0.15 µg/ml (see for details and exceptions). For pertussis antigens, the definitions of vaccine response used in individual studies are presented in .
Table 2. Assays used to measure the immunogenicity of DTaP-HBV-IPV/Hib in co-administration studies.
Immunogenicity data from relevant study groups in each study were extracted and tabulated. Responses to DTaP-HBV-IPV/Hib are provided in for diphtheria and tetanus; for hepatitis B; and Supplementary Table S 2 for pertussis antigens; for poliovirus types 1, 2 and 3; and for Hib. Due to the large amount of data, and to ease the reading, immunogenicity data in each table are grouped by the type of vaccine co-administered with DTaP-HBV-IPV/Hib (see bold headings in first column of each table), which is the same structure used to present results in the text.
Results pertaining to the immunogenicity of the co-administered vaccines were also extracted and are provided in detail in the supplementary Table S 4 to Table S 12. Co-administration with DTaP-HBV-IPV/Hib generally did not impact the immunogenicity of the other vaccines, even though variations are observed across studies, with high percentages of subjects achieving seroprotection/seropositivity/seroconversion against the targeted diseases, thus supporting an inclusion of DTaP-HBV-IPV/Hib in co-administration schedules.
3.2. Evaluation of safety
Reactogenicity and safety were assessed in 33 studies. Periods for recording the occurrence of solicited local and general signs and symptoms (at least 4 days post-vaccination), as well as the type of symptoms, differed between studies. Thirty-three studies reported serious adverse events (SAEs) and/or adverse events (AEs) of medical significance and their potential relationship to vaccination as determined by the study investigator.
4. Co-administration with meningococcal conjugate vaccines
Immunogenicity and safety of DTaP-HBV-IPV/Hib has been studied when co-administered with monovalent meningococcal serogroup C (MenC) vaccines conjugated to the nontoxic mutant of diphtheria toxin (CRM197) or tetanus toxoid (TT), and with the quadrivalent vaccine including serogroups A, C, W and Y conjugated to TT (MenACWY-TT) in 13 studies (). Throughout this section, immunogenicity results for the DTaP-HBV-IPV/Hib antigens are shown under the heading ‘Co-administered MenC-CRM/MenC-TT/MenACWY-TT/4CMenB’ in through 7 (each DTaP-HBV-IPV/Hib antigen in a separate table).
4.1. Monovalent meningococcal serogroup C conjugate vaccines
Study 1 was designed to demonstrate non-inferiority of the immune response when DTaP-HBV-IPV/Hib and MenC-CRM (Meningitec) were co-administered at 2, 4 and 6 months of age compared to their separate administration (DTaP-HBV-IPV/Hib at 2, 4 and 6 months of age and MenC-CRM at 3, 5 and 7 months of age) [Citation45]. One month after the third primary vaccination dose, the percentage of subjects in the separate and co-administration groups with seroprotective antibody concentrations was 100% for diphtheria and tetanus (), 99.1% (separate group) and 97.8% (co-administration group) for hepatitis B (), and ranged between 99.1% and 100% for the three poliovirus types () and Hib () in both groups. The percentage of subjects in both groups with a vaccine response ranged from 99.1% to 100% for each pertussis antigen (). Non-inferiority between the co-administration group and the separate group in terms of the immune response to DTaP-HBV-IPV/Hib antigens was demonstrated according to pre-defined criteria (Table S 3) [Citation45]. Study 2 showed that the percentage of subjects with seroprotective antibodies was similar in both groups at 18 months of age, except for diphtheria, for which persisting responses were higher in the separate group (98.7% versus 82.4% of subjects with anti-diphtheria antibody concentrations ≥ 0.1 IU/ml; , heading ‘Co-administered MenC-CRM’) [Citation46].
Other co-administration studies of DTaP-HBV-IPV/Hib and monovalent MenC vaccines were not designed to compare separate versus combined vaccine administration (). In these studies (Studies 4–6, 8, 13), the percentage of subjects with seroprotective antibodies for diphtheria, tetanus, hepatitis B, poliovirus, and Hib ranged from 76.9% to 100% after two priming doses, and from 93.2% to 100% after three priming doses of DTaP-HBV-IPV/Hib co-administered with MenC-CRM or MenC-TT. The percentage of subjects with a vaccine response for pertussis antigens after two or three priming doses ranged from 82.4% to 100%. After the booster dose of DTaP-HBV-IPV/Hib co-administered with monovalent MenC vaccines in the second year of life, ≥ 97.9% of subjects were seroprotected against diphtheria, tetanus, hepatitis B, poliovirus, and Hib, and ≥ 92.2% of subjects had a vaccine response for pertussis antigens.
Table 3. Antibody responses – co-administered diphtheria and tetanus toxoids (According-to-protocol immunogenicity cohorts).
Table 4. Antibody responses – co-administered hepatitis B surface antigen (According-to-protocol immunogenicity cohorts).
4.2. Quadrivalent ACWY conjugate vaccines
Co-administration of DTaP-HBV-IPV/Hib with MenACWY-TT was evaluated in Studies 8 and 10. In Study 8, infants received two (or three) primary doses of MenACWY-TT at 2, (3) and 4 months of age and a booster dose at 12 months of age co-administered with DTaP-HBV-IPV/Hib and the 10-valent pneumococcal conjugate vaccine (PHiD-CV). One month after the third dose of DTaP-HBV-IPV/Hib, 100% of subjects had seroprotective antibody concentrations for diphtheria, tetanus (), hepatitis B (), and Hib (), and 98.6% to 100% had seroprotective antibody titers for poliovirus types 1, 2 and 3 (; heading ‘Co-administered MenACWY-TT’ in all tables mentioned). The percentage of subjects with a vaccine response was 90.3% to 95.1% for each pertussis antigen (; heading ‘Co-administered MenACWY-TT’). A booster dose administered at 12 months of age induced increases of up to 43.8-fold in the GMC/Ts for each DTaP-HBV-IPV/Hib vaccine antigen compared with pre-booster levels, indicating effective priming and development of immune memory after vaccine co-administration during infancy [Citation47].
Study 10 was designed to show non-inferiority between concomitantly and separately administered DTaP-HBV-IPV/Hib and MenACWY-TT [Citation48]. Children 12–23 months of age received either DTaP-HBV-IPV/Hib co-administered with MenACWY-TT, DTaP-HBV-IPV/Hib followed by MenACWY-TT one month later, or MenACWY-TT followed by DTaP-HBV-IPV/Hib one month later. One month after DTaP-HBV-IPV/Hib vaccination, 98.2% to 100% of subjects in the separate and co-administration groups had seroprotective antibody concentrations for diphtheria, tetanus (), hepatitis B (), the three poliovirus types (), and Hib (; heading ‘Co-administered MenACWY-TT’ in all tables mentioned). A vaccine response was observed in ≥ 94.2% of subjects in each group for PT, ≥ 91.9% in each group for FHA, and ≥ 97.2% in each group for PRN (; heading ‘Co-administered MenACWY-TT’). Pre-specified criteria for non-inferiority in terms of the immunogenicity of DTaP-HBV-IPV/Hib following co-administration versus separate administration were reached (Table S 3).
Table 5. Antibody responses – co-administered pertussis antigens (According-to-protocol immunogenicity cohorts).
4.3. Reactogenicity and safety: MenC-CRM, MenC-TT and MenACWY-TT vaccines
Thirty-three studies evaluated the reactogenicity and safety of DTaP-HBV-IPV/Hib co-administered with meningococcal conjugate vaccines. In Study 1, the reactogenicity profile was similar in groups receiving concomitant versus separate administration of DTaP-HBV-IPV/Hib and MenC-CRM (Meningitec) [Citation45].
Table 6. Antibody responses – co-administered poliovirus antigens (According-to-protocol immunogenicity cohorts).
Table 7. Antibody responses – co-administered Hib (According-to-protocol immunogenicity cohorts).
Study 10 evaluated concomitant versus separate administration of DTaP-HBV-IPV/Hib and MenACWY-TT. Drowsiness, fever and pain at the injection site occurred significantly more frequently when MenACWY-TT was co-administered with DTaP-HBV-IPV/Hib than when MenACWY-TT was administered alone. However, there were no statistically significant differences in the incidences of solicited local or general symptoms after DTaP-HBV-IPV/Hib and MenACWY-TT co-administration versus DTaP-HBV-IPV/Hib administered alone [Citation48].Groups were similar in terms of the occurrence of grade 3 solicited local and general symptoms, and in terms of the occurrence of other adverse events and SAEs. No SAEs were considered to be causally related to vaccination by the investigator [Citation48]. The authors concluded that the co-administration regimen had a clinically acceptable safety profile.
4.4. Summary: MenC-CRM, MenC-TT and MenACWY-TT vaccines
In total, more than 4000 infants and toddlers have received DTaP-HBV-IPV/Hib co-administered with a monovalent or quadrivalent meningococcal conjugate vaccine in the clinical studies reported here (). Immunological non-inferiority between separate and combined administration of DTaP-HBV-IPV/Hib with MenC-CRM and MenACWY-TT has been demonstrated. No SAEs were considered to be related to vaccination by the study investigators in the described co-administration groups. The data support co-administration of DTaP-HBV-IPV/Hib with monovalent or quadrivalent meningococcal conjugate vaccines.
4.5. Multicomponent meningococcal serogroup B vaccine, 4CMenB
Co-administration of DTaP-HBV-IPV/Hib with the 4-component meningococcal serogroup B vaccine (4CMenB) was evaluated in three large studies (Studies 11, 12, and 13) conducted in infants from 2 months of age. All subjects also received PCV7 co-administered.
One of the objectives of Study 11 was to evaluate the immunogenicity of DTaP-HBV-IPV/Hib when co-administered with 4CMenB compared to DTaP-HBV-IPV/Hib administered alone in an accelerated 2, 3, 4 month schedule [Citation49]. One month post-dose 3, ≥ 93% of subjects in the separate and co-administration groups had seroprotective antibody concentrations for diphtheria, tetanus (), hepatitis B (), poliovirus types 1, 2 and 3 (), and Hib (; heading ‘Co-administered 4CMenB’ in all tables mentioned). The percentage of subjects in each group with a vaccine response to pertussis antigens (4-fold increase in concentration) was 74% to 89% (; heading ‘Co-administered 4CMenB’). Pre-specified non-inferiority criteria for immunogenicity of DTaP-HBV-IPV/Hib antigens in the co-administration versus the separate group were met (Table S 3).
One month after the third primary dose in all three studies, the percentage of subjects in the co-administration groups with seroprotective antibody concentrations was 100% for diphtheria and tetanus (), 97.0% to 98.0% for hepatitis B (), 88% to 100% for each poliovirus type (), and 98% to 99% for Hib (; heading ‘Co-administered 4CMenB’ in all tables mentioned). When measured, the percentage of subjects with a vaccine response was at least 76% for each pertussis antigen (; heading ‘Co-administered 4CMenB’). Increases in seroprotection rates and antibody GMC/Ts were observed after a booster dose of DTaP-HBV-IPV/Hib co-administered with 4CMenB (and PCV7) at 12 months of age.
4.6. Reactogenicity and safety: 4CMenB
Studies of 4CMenB co-administered with routine vaccines, including DTaP-HBV-IPV/Hib and others (Studies 11, 12 and 13), showed an increase in the occurrence of fever, irritability, changes in eating habits and injection site pain after vaccination compared to when DTaP-HBV-IPV/Hib was administered alone [Citation49–Citation53]. In Study 11, body temperature ≥ 38°C after any vaccination was reported by 80% of infants who received DTaP-HBV-IPV/Hib co-administered with PCV7 and 4CMenB, versus 51% who received only DTaP-HBV-IPV/Hib and PCV7 [Citation49]. In Study 13, temperature ≥ 38.5°C after any vaccination was reported by 65.3% of subjects who received DTaP-HBV-IPV/Hib co-administered with PCV7 and 4CMenB versus 32.2% of subjects who received only DTaP-HBV-IPV/Hib and PCV7, although the incidence of medically attended fever was the same in both groups [Citation52].
4.6.1. The impact of prophylactic anti-pyretics on fever and immunogenicity: 4CMenB
In order to assess whether the cumulative effect of co-administration, such as increase in fever and other solicited reactions, could be mitigated, Prymula et al, 2014 (Study 13) [Citation54] evaluated the impact of prophylactic paracetamol (just prior to vaccination with two further doses at 4–6 hour intervals) on the incidence of local and general symptoms when 4CMenB was co-administered with DTaP-HBV-IPV/Hib and PCV7. The occurrence of solicited symptoms and fever were significantly reduced in subjects who received prophylactic paracetamol. Moreover, there was no evidence of an impact of prophylactic paracetamol on the immune response to vaccination. One month after the third vaccination, the percentage of infants with seroprotective antibodies for diphtheria, tetanus (), hepatitis B (), poliovirus types 1, 2 and 3 () and Hib (; heading ‘Co-administered 4CMenB’ in all tables mentioned) was ≥ 96% with or without receipt of prophylactic paracetamol. Booster vaccination induced rises in antibody GMCs/GMTs that were similar with or without concurrent receipt of paracetamol [Citation54].
4.7. Summary: 4CMenB
Currently, DTaP-HBV-IPV/Hib is the only hexavalent vaccine that has been evaluated in co-administration with 4CMenB. More than 3000 infants have received DTaP-HBV-IPV/Hib co-administered with 4CMenB and PCV7 in clinical trials (Studies 11, 12, 13). The majority of children reached antibody levels for DTaP-HBV-IPV/Hib antigens consistent with seroprotection/vaccine response. Administration of prophylactic paracetamol to infants receiving DTaP-HBV-IPV/Hib with 4CMenB and PCV7 reduced the incidence and severity of local and systemic reactogenicity without impairing the immune response or development of immune memory.
5. Co-administration with pneumococcal conjugate vaccines
5.1. PHiD-CV
The recommended schedule for pneumococcal conjugate vaccines usually coincides with that of DTaP-HBV-IPV/Hib, and in real-world practice DTaP-HBV-IPV/Hib and PHiD-CV are usually co-administered. This could explain why, to the best of our knowledge, studies of DTaP-HBV-IPV/Hib + PHiD-CV designed to evaluate the immunogenicity of the vaccines when administered separately have not been performed. Additionally, at the time of PHiD-CV clinical development, PCV7 was licensed for use and was used as the control vaccine in PHiD-CV studies rather than placebo.
Twelve studies assessed primary and/or booster vaccination of DTaP-HBV-IPV/Hib when co-administered with PHiD-CV, of which 10 provided immunogenicity data for DTaP-HBV-IPV/Hib (). In some studies, DTaP-HBV-IPV/Hib and PHiD-CV were also co-administered with other vaccines, such as MenC-TT, MenC-CRM, MenACWY-TT or human rotavirus vaccine (HRV) (). Throughout this section, immunogenicity results for the DTaP-HBV-IPV/Hib antigens are shown under the heading ‘Co-administered PHiD-CV’ in through 7 (each DTaP-HBV-IPV/Hib antigen in a separate table).
One month after the third dose of DTaP-HBV-IPV/Hib co-administered with PHiD-CV (Studies 5, 14–23), the percentage of subjects with seroprotective antibody concentrations was 100% for diphtheria and tetanus (), at least 95.2% for hepatitis B () and 96.1% to 100% for Hib (; heading ‘Co-administered PHiD-CV’ in all tables mentioned). Between 95.3% and 100% of subjects had seroprotective antibodies titers for the three poliovirus types at one month after dose 3, although lower responses were observed in Study 16 compared to the other studies (82.7% to 84.5% of subjects with anti-polio antibody titers ≥ 1:8, increasing to ≥ 97.6% after the booster dose [Citation55]).
Two of the arms in Study 16 evaluated the immunogenicity of PHiD-CV co-administered with DTaP-IPV-Hib (Pediacel, Sanofi Pasteur), and PHiD-CV co-administered with DTaP-HBV-IPV/Hib in infants vaccinated at 2, 3, 4 months of age [Citation55]. One month after the third dose, the percentage of subjects in the DTaP-HBV-IPV/Hib and DTaP-IPV-Hib groups with seroprotective antibody concentrations was 97.2% to 100% for diphtheria, tetanus, and Hib ( and ; heading ‘Co-administered PHiD-CV’). Seroprotective antibody levels for polioviruses were similar in the two groups (range 82.7% to 84.5% in the DTaP-HBV-IPV/Hib group and 70.0% to 84.5% in the DTaP-IPV-Hib group) (; heading ‘Co-administered PHiD-CV’). Pre-defined non-inferiority criteria for immunogenicity of DTaP-HBV-IPV/Hib compared with DTaP-IPV-Hib in co-administration with PHiD-CV were met (Table S 3).
Seven studies assessed the immunogenicity of a booster dose of DTaP-HBV-IPV/Hib co-administered with PHiD-CV after primary vaccination with the same combination (Studies 16, 17, 19, 22, 23). The booster dose induced a marked increase in antibody concentrations/titers. Post-booster antibody GMCs/GMTs reached higher levels than those achieved after primary vaccination, indicative of a booster response.
5.2. PCV13
Seven studies assessed primary and/or booster vaccination with DTaP-HBV-IPV/Hib co-administered with PCV13 (). In some of these studies, DTaP-HBV-IPV/Hib and PCV13 were also co-administered with other vaccines, such as MenC-TT, MenC-CRM, or a rotavirus vaccine (either HRV or human-bovine reassortant rotavirus vaccine [HBRV]). Throughout this section, immunogenicity results for the DTaP-HBV-IPV/Hib antigens are shown under the heading ‘Co-administered PCV13’ in through 7 (each DTaP-HBV-IPV/Hib antigen in a separate table).
One month after two or three priming doses of DTaP-HBV-IPV/Hib co-administered with PCV13, between 89.7% and 100% of subjects had seroprotective antibody concentrations for diphtheria and tetanus for all studies. For the other antigens, the percentage of subjects with seroprotective antibody concentrations was 93.8% to 99.2% for hepatitis B (), 95.6% to 100% for poliovirus types 1, 2 and 3 (), and 85.6% to 96.7% for Hib (; heading ‘Co-administered PCV13’ in all tables mentioned). In two studies in which a vaccine response to pertussis antigens was calculated, a vaccine response to the three pertussis antigens was observed in ≥ 91.9% of subjects (; heading ‘Co-administered PCV13’).
Booster vaccination with DTaP-HBV-IPV/Hib co-administered with PCV13 induced increases in seroprotection/vaccine response rates and antibody GMC/GMTs. These results indicate that the co-administration of DTaP-HBV-IPV/Hib and PCV13 using different primary schedules induced effective priming and immune memory.
5.3. Reactogenicity and safety
The reactogenicity and safety of DTaP-HBV-IPV/Hib co-administered with PHiD-CV or PCV13 compared to the same vaccines administered separately has not been assessed to our knowledge, however, epidemiological investigations to assess the risk of febrile seizure for the influenza vaccine when co-administered with PCV13 revealed an independent risk of febrile seizure with the influenza vaccine and also PCV13 but the greatest risk was observed when both vaccines were concomitantly administered [Citation56]. Moreover, an increased risk with PCV7 (PCV7 was found to present a comparable risk to PCV13 [Citation57]) 2 days post-vaccination regardless of concomitant vaccination was demonstrated in a different study [Citation58] (the studies on febrile seizure are not part of this literature review). Additional reactogenicity and safety data for the different vaccines was presented in the Clinical Otitis Media and Pneumonia Study (COMPAS- not part of this literature review), which was designed to investigate the impact of PHiD-CV compared to standard of care (Study groups PHiD-CV + DTaP-HBV-IPV/Hib versus hepatitis B + DTaP- IPV/Hib) suggesting reduced all-cause mortality due to PHiD-CV vaccination [Citation59]. Moreover, the reactogenicity of DTaP-HBV-IPV/Hib co-administered with PHiD-CV or PCV7 has been reviewed in 4004 infants who participated in five studies [Citation60]. The incidences and intensity of solicited local reactions were similar in subjects who received DTaP-HBV-IPV/Hib co-administered with PHiD-CV or PCV7 in all studies. The incidence and intensity of general symptoms was also similar between groups, with the exceptions of irritability and loss of appetite (any, but not severe), which were observed to occur more frequently in the PHiD-CV than the PCV7 co-administration group in two studies. The nature and incidence of other (unsolicited) symptoms and SAEs reported after vaccination was similar when DTaP-HBV-IPV/Hib was co-administered with PHiD-CV or PCV7.
Study 15 was designed to show that DTaP-HBV-IPV/Hib co-administered with PHiD-CV did not induce more febrile convulsions compared with DTaP-HBV-IPV/Hib co-administered with PCV7 [Citation60,Citation61]. The primary objective was met; according to pre-specified statistical criteria, there was no evidence that DTaP-HBV-IPV/Hib co-administered with PHiD-CV induced more post-immunization febrile reactions (fever ≥ 39.0°C) than when DTaP-HBV-IPV/Hib was co-administered with PCV7 (Table S 3).
While no specific imbalances were noted in the clinical trials reported here, post-marketing analyzes indicate an increased risk of convulsions (with or without fever) and hypotonic-hyporesponsive episodes in subjects who were vaccinated with DTaP-HBV-IPV/Hib and PCV13 compared to DTaP-HBV-IPV/Hib alone [Citation13]. This information is noted in the DTaP-HBV-IPV/Hib prescribing information and physicians are advised that vaccinees with a history of febrile convulsions should be closely followed up as such adverse events may occur within 2 to 3 days post vaccination [Citation51].
5.3.1. The impact of prophylactic anti-pyretics on fever and immunogenicity
Three studies assessed the impact of prophylactic antipyretics (paracetamol or ibuprofen) on post-vaccination reactogenicity when DTaP-HBV-IPV/Hib was co-administered with PHiD-CV or PCV13 (Studies 17, 23 and 26) [Citation62–Citation64]. Administration of paracetamol at the time of, or soon after vaccination reduced the incidence and severity of solicited local and general symptoms after vaccination, with the greatest impact observed during the primary series [Citation63,Citation64]. The effect of ibuprofen on reactogenicity and fever was less marked than that of paracetamol [Citation62,Citation64], though this may be dosage dependent [Citation54,Citation62–Citation64]. There was a statistically significant reduction in fever when paracetamol was administered at the time of DTaP-HBV-IPV/Hib and PHiD-CV vaccination followed by two further doses at 6–8-hour intervals.
All studies demonstrated a reduction in the magnitude of the immune responses to some DTaP-HBV-IPV/Hib antigens when paracetamol was administered at the time of vaccination with DTaP-HBV-IPV/Hib and PHiD-CV or PCV13, although the percentage of subjects who achieved seroprotection/seropositivity rates was not affected. This reduction of immune responses was mainly confined to primary vaccination, was substantially less marked after the booster dose and did not impact the booster response in infants primed with or without prophylactic paracetamol [Citation63] suggesting that prophylactic paracetamol could also be used at the time of the booster dose during the second year of life when the risk of febrile convulsion is highest [Citation65]. Ibuprofen also reduced responses to some DTaP-HBV-IPV/Hib antigens, mainly filamentous hemagglutinin from pertussis and tetanus [Citation62,Citation64]. By contrast, when DTaP-HBV-IPV/Hib was co-administered with 4CMenB and PCV7 in Study 13, there was no impact of prophylactic paracetamol on the immune responses to any of the co-administered vaccines [Citation54].
5.4. Summary
DTaP-HBV-IPV/Hib and pneumococcal conjugate vaccines are usually recommended for administration at the same visit. The immunogenicity and safety of schedules where DTaP-HBV-IPV/Hib was co-administered with either PHiD-CV or PCV13 for primary and booster vaccination of infants/toddlers were evaluated in 16 studies. Co-administration induced high levels of seroprotection after primary vaccination, which further increased after the booster dose administered in the second year of life. Prophylactic administration of paracetamol before or soon after vaccine administration can reduce the incidence and intensity of post-vaccination reactions, including fever, and is recommended for children with seizure disorders or with a prior history of febrile seizures [Citation51]. The administration of paracetamol at the time of vaccination was associated with reduced immune responses to some antigens in some studies, but it did not affect the seroprotection rates.
6. Co-administration with rotavirus vaccines
The immune responses to a rotavirus vaccine co-administered with DTaP-HBV-IPV/Hib were measured in three studies (Study 28, 29 and 30) [Citation66–Citation68]. Throughout this section, immunogenicity results for the DTaP-HBV-IPV/Hib antigens are shown under the heading ‘Co-administered HRV or HBRV’ in through 7 (each DTaP-HBV-IPV/Hib antigen in a separate table).
Study 30 was a controlled study that assessed immunogenicity and safety of DTaP-HBV-IPV/Hib co-administered with three doses of HBRV or placebo. The immune responses to HBV and Hib were non-inferior in the co-administration group versus the placebo group according to pre-specified criteria (Table S 3) [Citation68].
Across all three studies (Study 28, 29 and 30), the percentage of subjects with seroprotective antibody concentrations after three doses of DTaP-HBV-IPV/Hib (either 3 primary doses or 2 primary doses followed by a booster dose in the second year of life) was 71.63 to ~100% for diphtheria and tetanus (), ~95% to 98.72% for hepatitis B (), ~96% to 100% for poliovirus types 1, 2 and 3 (), and 91.4% to 99.37 for Hib (; heading ‘Co-administered HRV or HBRV’ in all tables mentioned). In Study 28, vaccine responses to pertussis antigens were observed in ≥ 91.58% of subjects after primary vaccination and ≥ 98.25% after the booster dose (; heading ‘Co-administered HRV or HBRV’).
6.1. Reactogenicity and safety
The co-administration of DTaP-HBV-IPV/Hib with a rotavirus vaccine was well tolerated. In Study 30, the incidence of adverse events following DTaP-HBV-IPV/Hib co-administered with HBRV or placebo was comparable, with the exception of conjunctivitis and rash which were more common in the co-administration group, although the number of these reports was small (4.0% versus 0.5% for conjunctivitis and 2.0% versus 0.0% for rash) [Citation68].
There was a case of intussusception reported in a 4-month-old child on day 8 after the second dose of HRV in Study 29, with a reasonable possibility that the intussusception may have been caused by the vaccine but with no data to allow for any conclusion [Citation67]. The child underwent surgery and recovered. There were no cases of intussusception in the other studies. One child in Study 28 who had received DTaP-HBV-IPV/Hib co-administered with a rotavirus vaccine withdrew from the study due to an SAE (Kawasaki disease), which was considered as related to vaccination by the investigator [Citation66].
6.2. Summary
Co-administration of DTaP-HBV-IPV/Hib with a rotavirus vaccine resulted in high antibody levels and high seroprotection rates against antigens contained in DTaP-HBV-IPV/Hib. The reactogenicity and safety profile of DTaP-HBV-IPV/Hib co-administered with a rotavirus vaccine was clinically acceptable.
7. Co-administration with measles-mumps-rubella-varicella vaccines
Three studies (Studies 31, 33 and 34) report immunogenicity data for DTaP-HBV-IPV/Hib co-administered with a single dose of measles-mumps-rubella-varicella vaccine (either MMRV [GSK] or MMRVII [Merck]) during the second year of life [Citation69–Citation71]. Immunogenicity was assessed 42–56 days after vaccination. Throughout this section, immunogenicity results for the DTaP-HBV-IPV/Hib antigens are shown under the heading ‘Co-administered MMRV/MMRVII’ in through 7 (each DTaP-HBV-IPV/Hib antigen in a separate table).
The percentage of subjects with seroprotective antibody concentrations after a booster dose of DTaP-HBV-IPV/Hib co-administered with a measles-mumps-rubella-varicella vaccine was 90.55% to 100% for diphtheria and tetanus (), 98.1% to 100% for hepatitis B (), 99.81% to 100% for poliovirus types 1, 2 and 3 (), and 98.2% to 100% for Hib (; heading ‘Co-administered MMRV/MMRVII’ in all tables mentioned). A vaccine response to pertussis antigens was observed in 98.47% to 99.81% of subjects (; heading ‘Co-administered MMRV/MMRVII’).
Statistical comparisons showed no differences between the co-administration or separate groups in terms of seroprotection rates or GMC/GMTs. In Study 33, non-inferiority between the co-administration and separate groups in terms of antibody response rates to HBV, Hib and pertussis antigens was demonstrated based on pre-specified criteria (non-inferiority criteria were not specified for diphtheria, tetanus or poliovirus) (Table S 3).
7.1. Reactogenicity and safety
Fever was recorded during 28 to 43 days after vaccination and peaks in fever incidence were observed at day 0–2 in DTaP-HBV-IPV/Hib recipients, day 4–12 in MMRV recipients, and at both time points in subjects who received DTaP-HBV-IPV/Hib co-administered with MMRV [Citation69]. In Study 31, the fever was transient and the incidence of fever after vaccination was higher in subjects who received DTaP-HBV-IPV/Hib and MMRV compared to DTaP-HBV-IPV/Hib alone, but was similar to incidences observed in subjects who only received MMRV [Citation71]. No SAEs considered to be related to vaccination were reported in the co-administration groups in any of the studies.
7.2. Summary
In three studies of 1877 subjects, coadministration of MMRV or MMRVII with DTaP-HBV-IPV/Hib did not impair the immune response to DTaP-HBV-IPV/Hib antigens and was well tolerated.
8. Trademark statement
Bexsero, Infanrix hexa, Menjugate, Synflorix, Priorix Tetra and Rotarix are registered trademarks of the GSK group of companies. Meningitec is a registered trademark of Nuron Biotech. Nimenrix, Prevenar and Prevenar13 are registered trademarks of Pfizer. Pediacel, ProQuad, Hexaxim, Hexyon and Hexacima are registered trademarks of Sanofi Pasteur. NeisVac C is a registered trademark of Baxter. RotaTeq is registered trademark of Merck & Co. Vaxelis is a registered trademark of MCM Vaccine B.V.
9. Expert opinion
This review presents the immunogenicity, reactogenicity and overall safety profile of DTaP-HBV-IPV/Hib when co-administered with routine pediatric vaccines. The data from the 34 clinical trials across 22 countries reported here represent common co-administration schedules worldwide. Co-administration of DTaP-HBV-IPV/Hib with other vaccines did not negatively impact its immunogenicity, with high seroprotection/seropositivity vaccine response rates against the DTaP-HBV-IPV/Hib antigens. Furthermore, co-administration was not associated with any clinically significant interference in the immune response to the co-administered vaccines. Co-administration regimens were well tolerated. For vaccine combinations where the risk of fever after vaccination may be increased (DTaP-HBV-IPV/Hib co-administered with PCV or 4CMenB), paracetamol appears to be more effective in reducing fever than ibuprofen. The clinical significance of the decrease in immunogenicity to some DTaP-HBV-IPV/Hib antigens – but not seroprotection/seropositivity rates – linked to prophylactic use of paracetamol remains unknown [Citation62–Citation64].
Of note, some of the serological data compiled in this review have been obtained at different laboratories using several assays, each with their own robustness (assessed and confirmed by regulatory authorities). While this constitutes a faithful representation of the available data, the potential methodological variations across studies have to be taken into account when interpreting the data presented here and trying to make comparisons across studies.
Vaccine co-administration provides benefits at all levels of the healthcare system by improving vaccine acceptance and handling costs and by maximizing coverage [Citation6,Citation72]. Co-administration regimens have been in place for several decades. Evidence from disease surveillance networks suggests that co-administration regimens remain highly effective in preventing disease due to pathogens targeted by the vaccines. For diphtheria and tetanus, the 2017 incidence in the European Union was <0.01 cases per 100,000 population and 0.02 cases per 100,000 population, respectively, with the highest proportion of cases occurring in older adults [Citation73,Citation74]. In 2017 in the European Union, the incidence of HBV was highest in adults older than 25 years of age and acute HBV was uncommon in children below 5 years of age (<0.1 per 100,0000 population) [Citation75]. Outbreaks of pertussis continue to occur but the highest incidences are observed in infants who are too young to be vaccinated [Citation76,Citation77]. No cases of poliomyelitis were reported in Europe in 2017 [Citation78]. Hib disease remains well controlled in Europe, with 141 reports of invasive Hib disease in 2017 [Citation79]. Nowadays, most Hib disease cases occur in older adults who present underlying co-morbidities [Citation80].
Some concerns were raised that the immune system is ‘overloaded’ by the administration of multiple antigens at one time, and that this could potentially lead to an increased frequency of other infections [Citation81,Citation82]. However, large observational studies conducted in the United States and the United Kingdom have found no association between the administration of multiple vaccine antigens at one time and subsequent infections [Citation83–Citation85]. Moreover, the results of this review did not indicate safety concerns regarding co-administration of GSK’s DTaP-HBV-IPV/Hib with other pediatric vaccines, compared to separate administration. Additionally, children in industrialized countries are exposed to a lower number of antigens via vaccination than in the past, due to the high purity of currently available subunit vaccines [Citation81].
The addition of new antigens into infant vaccination schedules is likely to continue, and could include vaccines targeting respiratory syncytial virus, cytomegalovirus or Escherichia coli. The advantages of introducing new vaccines into existing schedules include rapid uptake and greater acceptance, which means that the number of vaccines/antigens being co-administered is likely to increase. Caution should be exercised when extrapolating co-administration data from one vaccine with another due to clinically relevant potential interferences in the antibody response inherent to the properties of each vaccine. For instance, while a varicella vaccine may be co-administered with the DTaP-HBV-IPV/Hib vaccine, combined administration of a varicella vaccine with the DTaP-IPV-HB-Hib (Hexyon, Sanofi Pasteur) vaccine is not recommended [Citation86]. Comprehensive evaluation of the safety and immunogenicity of co-administration regimens in the general infant population, as well as in special populations such as premature infants, needs to continue as schedules evolve, to ensure the continued effectiveness of infant immunization programs.
Article highlights
Co-administration of vaccines at the same healthcare visit can improve coverage and vaccine acceptance. Evaluation of the immunogenicity and safety of vaccine co-administrations are needed to ensure the ongoing effectiveness of infant immunization programs.
The immunogenicity and safety of infant vaccines in co-administration cannot be directly extrapolated from other vaccines of the same class due to differences in antigens and excipients. Future assessments in clinical trials may help to provide data supporting recommendations for co-administration.
GSK’s DTaP-HBV-IPV/Hib vaccine has been licensed since 2000. Co-administration of DTaP-HBV-IPV/Hib with 12 commonly administered infant vaccines has been described in 34 clinical trials.
The available evidence supports that DTaP-HBV-IPV/Hib can be co-administered with other vaccines without altering the immunogenicity or safety profile of the vaccines.
Author contribution statement
J Dolhain: development of concept and design of this study, data collection and interpretation, critical review and approval of manuscript; W Janssens: study design, data collection, data analysis and interpretation, critical review and approval of manuscript; V Dindore: study design, data collection, data analysis and interpretation, critical review and approval of manuscript; A Mihayli: study design, data collection, data analysis and interpretation, critical review and approval of manuscript.
Declaration of interest
W Janssens, V Dindore and A Mihalyi are employees of GlaxoSmithKline. W Janssens and A Mihalyi own shares of GlaxoSmithKline group of companies. J Dolhain was an employee of GlaxoSmithKline at the time of the study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
A reviewer on this manuscript discloses that they are employed by Sanofi Pasteur who are manufacturing a similar vaccine to the one in this review. A reviewer on this manuscript discloses that they perform, on behalf of Public Health England, contract research for GlaxoSmithKline, Pfizer, and Sanofi Pasteur. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.
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The authors thank Lauriane Harrington for her insightful and critical comments. Writing support was provided by Joanne Wolter and Claire Verbelen (Modis on behalf of GlaxoSmithKline) and editorial support and publication management was provided by Michaela Conrad and Fabienne Danhier (Modis on behalf of GlaxoSmithKline).
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References
- World Health Organization. WHO vaccine-preventable diseases: monitoring system, 2019 global summary. Immunization schedule by disease covered by antigens within age range selection centre; [cited 2020 Jan 29]. Available from: https://apps.who.int/immunization_monitoring/globalsummary/diseases
- General Recommendations on Immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011;60(2):1–64.
- Kalies H, Grote V, Verstraeten T, et al. The use of combination vaccines has improved timeliness of vaccination in children. Pediatr Infect Dis J. 2006;25(6):507–512.
- Happe LE, Lunacsek OE, Kruzikas DT, et al. Impact of a pentavalent combination vaccine on immunization timeliness in a state Medicaid population. Pediatr Infect Dis J. 2009;28(2):98–101.
- Marshall GS, Happe LE, Lunacsek OE, et al. Use of combination vaccines is associated with improved coverage rates. Pediatr Infect Dis J. 2007;26(6):496–500.
- Maman K, Zöllner Y, Greco D, et al. The value of childhood combination vaccines: from beliefs to evidence. Hu Vacc Immunother. 2015;11(9):2132–2141.
- Van Hoof J. Manufacturing issues related to combining different antigens: an industry perspective. Clin Infect Dis. 2001;33(Suppl 4):S346–350.
- Dagan R, Poolman J, Siegrist CA. Glycoconjugate vaccines and immune interference: A review. Vaccine. 2010;28(34):5513–5523.
- Knuf M, Szenborn L, Moro M, et al. Immunogenicity of routinely used childhood vaccines when coadministered with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV). Pediatr Infect Dis J. 2009;28(4 Suppl):S97–S108.
- Dagan R, Poolman JT, Zepp F. Combination vaccines containing DTPa-Hib: impact of IPV and coadministration of CRM197 conjugates. Expert Rev Vaccines. 2008;7(1):97–115.
- Findlow H, Borrow R. Interactions of conjugate vaccines and co-administered vaccines. Hum Vaccin Immunother. 2016;12(1):226–230.
- Knuf M, Kowalzik F, Kieninger D. Comparative effects of carrier proteins on vaccine-induced immune response. Vaccine. 2011;29(31):4881–4890.
- European Medicines Agency. Infanrix hexa product information. [cited 2019 Sept 6]. Available from: https://www.ema.europa.eu/en/documents/product-information/infanrix-hexa-epar-product-information_en.pdf
- European Medicines Agency. Hexaxim product information. [cited 2020 Jan 29]. Available from: https://www.ema.europa.eu/documents/medicine-outside-eu/hexaxim-h-w-2495-p46-021-assessment-report_en.pdf
- European Medicines Agency. Hexacima product information. [cited 2020 Jan 29]. Available from: https://www.ema.europa.eu/documents/product-information/hexacima-epar-product-information_en.pdf
- European Medicines Agency. Hexyon product information. [cited 2020 Jan 29]. Available from: https://www.ema.europa.eu/documents/product-information/hexyon-epar-product-information_en.pdf
- European Medicines Agency. Vaxelis product information. [cited 2020 Jan 29]. Available from: https://www.ema.europa.eu/documents/product-information/vaxelis-epar-product-information_en.pdf
- Food and Drug Administration. Vaxelis package insert. [cited 2020 Jan 29]. Available from: https://www.fda.gov/media/119465/download
- Van Der Meeren O, Kuriyakose S, Kolhe D, et al. Immunogenicity of InfanrixTM hexa administered at 3, 5 and 11 months of age. Vaccine. 2012;30(17):2710–2714.
- Omenaca F, Vazquez L, Garcia-Corbeira P, et al. Immunization of preterm infants with GSK’s hexavalent combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine: A review of safety and immunogenicity. Vaccine. 2018;36(7):986–996.
- Zepp F, Schmitt H-J, Cleerbout J, et al. Review of 8 years of experience with Infanrix hexa (DTPa-HBV-IPV/Hib hexavalent vaccine). Expert Rev Vaccines. 2009;8(6):663–678.
- Dolhain J, Janssens W, Mesaros N, et al. Hexavalent vaccines: increasing options for policy-makers and providers. A review of the data supporting interchangeability (substitution with vaccines containing fewer antigens) and mixed schedules from the same manufacturer. Expert Rev Vaccines. 2018;17(6):513–524.
- European Centre for Disease Prevention and Control. Vaccination schedules for individual European countries and specific age groups. [cited 2020 Jan 29]. Available from: https://www.ecdc.europa.eu/en/immunisation-vaccines/EU-vaccination-schedules
- World Health Organization. Summary of WHO position papers - recommended routine immunizations for children. [cited 2020 Jan 29]. Available from: https://www.who.int/immunization/policy/Immunization_routine_table2.pdf
- Schmitt HJ, Steul KS, Borkowski A, et al. Two versus three doses of a meningococcal C conjugate vaccine concomitantly administered with a hexavalent DTaP-IPV-HBV/Hib vaccine in healthy infants. Vaccine. 2008;26(18):2242–2252.
- Tejedor JC, Moro M, Ruiz-Contreras J, et al. Immunogenicity and reactogenicity of primary immunization with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type B vaccine coadministered with two doses of a meningococcal C-tetanus toxoid conjugate vaccine. Pediatr Infect Dis J. 2006;25(8):713–720.
- Szenborn L, Czajka H, Brzostek J, et al. A randomized, controlled trial to assess the immunogenicity and safety of a heptavalent diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, hib and meningococcal serogroup C combination vaccine administered at 2, 3, 4 and 12-18 months of age. Pediatr Infect Dis J. 2013;32(7):777–785.
- Thollot F, Scheifele D, Pankow-Culot H, et al. A randomized study to evaluate the immunogenicity and safety of a heptavalent diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, haemophilus influenzae b, and meningococcal serogroup C combination vaccine administered to infants at 2, 4 and 12 months of age. Pediatr Infect Dis J. 2014;33(12):1246–1254.
- Habermehl P, Leroux-Roels G, Sänger R, et al. Combined Haemophilus influenzae type b and Neisseria meningitidis serogroup C (HibMenC) or serogroup C and Y-tetanus toxoid conjugate (and HibMenCY) vaccines are well-tolerated and immunogenic when administered according to the 2, 3, 4 months schedule with a fourth dose at 12-18 months of age. Hum Vaccines. 2010;6(8):640–651.
- Merino Arribas JM, Carmona Martinez A, Horn M, et al. Safety and Immunogenicity of the quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine coadministered with routine childhood vaccines in European infants: an open, randomized trial. Pediatr Infect Dis J. 2017;36(4):e98–e107.
- Vesikari T, Forstén A, Desole MG, et al. A combined haemophilus influenzae type b-neisseria meningitidis serogroup C-Tetanus Toxoid conjugate vaccine (Hib-MenC-TT) is Immunogenic and well-tolerated when co-administered with DTPa-HBV-IPV at 3, 5, and 11 months of age: results of an open, randomized, controlled study. Pediatr Infect Dis J. 2013;32:521–529.
- Esposito S, Prymula R, Zuccotti GV, et al. A phase 2 randomized controlled trial of a multicomponent meningococcal serogroup B vaccine, 4CMenB, in infants (II). Hu Vacc Immunother. 2014;10(7):2005–2014.
- Lagos RE, Munoz AE, Levine MM, et al. Safety and immunogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in Chilean children. Hum Vaccin. 2011;7(5):511–522.
- van den Bergh MR, Spijkerman J, Francois N, et al. Immunogenicity, safety and reactogenicity of a booster dose of the 10-valent pneumococcal nontypeable H. influenzae protein D conjugate vaccine coadministered with DTPa-IPV-Hib in Dutch children: a randomized controlled trial. Pediatr Infect Dis J. 2016;35(7):e206–219.
- Lin TY, Lu CY, Chang LY, et al. Immunogenicity and safety of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co-administered with routine childhood vaccines in Taiwan. J Formos Med Assoc. 2012;111(9):495–503.
- Wijmenga-Monsuur AJ, van Westen E, Knol MJ, et al. Direct comparison of immunogenicity induced by 10- or 13-valent pneumococcal conjugate vaccine around the 11-month booster in Dutch infants. PLoS One. 2015;10(12):e0144739.
- Ruiz-Palacios GM, Guerrero ML, Hernandez-Delgado L, et al. Immunogenicity, reactogenicity and safety of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in Mexican infants. Hum Vaccin. 2011;7(11):1137–1145.
- Huu TN, Toan NT, Tuan HM, et al. Safety and reactogenicity of primary vaccination with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine in Vietnamese infants: a randomised, controlled trial. BMC Infect Dis. 2013;13:95.
- Prymula R, Szenborn L, Silfverdal SA, et al. Safety, reactogenicity and immunogenicity of two investigational pneumococcal protein-based vaccines: results from a randomized phase II study in infants. Vaccine. 2017;35(35Pt B):4603–4611.
- Esposito S, Tansey S, Thompson A, et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine compared to those of a 7-valent pneumococcal conjugate vaccine given as a three-dose series with routine vaccines in healthy infants and toddlers. Clin vaccin immunol. 2010;17(6):1017–1026.
- Martinón-Torres F, Gimenez-Sanchez F, Gurtman A, et al. 13-valent pneumococcal conjugate vaccine given with meningococcal C-tetanus toxoid conjugate and other routine pediatric vaccinations: immunogenicity and safety. Pediatr Infect Dis J. 2012;31(4):392–399.
- Kieninger DM, Kueper K, Steul K, et al. Safety, tolerability, and immunologic noninferiority of a 13-valent pneumococcal conjugate vaccine compared to a 7-valent pneumococcal conjugate vaccine given with routine pediatric vaccinations in Germany. Vaccine. 2010;28(25):4192–4203.
- Gimenez-Sanchez F, Kieninger DM, Kueper K, et al. Immunogenicity of a combination vaccine containing diphtheria toxoid, tetanus toxoid, three-component acellular pertussis, hepatitis B, inactivated polio virus, and Haemophilus influenzae type b when given concomitantly with 13-valent pneumococcal conjugate vaccine. Vaccine. 2011;29(35):6042–6048.
- 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(2):209–215.
- Tejedor JC, Omeñaca F, García-Sicilia J, et al. Immunogenicity and reactogenicity of a three-dose primary vaccination course with a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-haemophilus influenzae type b vaccine coadministered with a meningococcal C conjugate vaccine. Pediatr Infect Dis J. 2004;23(12):1109–1115.
- Tejedor J-C, Omeñaca F, García-Sicilia J, et al. Antibody persistence after primary vaccination with a hexavalent DTPa-HBV-IPV/HiB vaccine coadministered with a meningococcal C-CRM197 vaccine and response to a DTPa-IPV/HiB booster at 18 months of age. Pediatr Infect Dis J. 2006;25(10):943–945.
- Merino Arribas JM, Carmona Martinez A, Horn M, et al. Immunogenicity and reactogenicity of DTPa-HBV-IPV/Hib and PHiD-CV when coadministered with MenACWY-TT in infants: results of an open, randomized trial. Pediatr Infect Dis J. 2018;37(7):704–714.
- Knuf M, Pantazi-Chatzikonstantinou A, Pfletschinger U, et al. An investigational tetravalent meningococcal serogroups A, C, W-135 and Y-tetanus toxoid conjugate vaccine co-administered with Infanrix™ hexa is immunogenic, with an acceptable safety profile in 12-23-month-old children. Vaccine. 2011;29(25):4264–4273.
- Gossger N, Snape MD, Yu L-M, et al. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA. 2012;307(6):573–582.
- Findlow J, Borrow R, Snape MD, et al. Multicenter, open-label, randomized phase ii controlled trial of an investigational recombinant meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy. Clin Infect Dis. 2010;51(10):1127–1137.
- Snape MD, Dawson T, Oster P, et al. Immunogenicity of two investigational serogroup B meningococcal vaccines in the first year of life: a randomized comparative trial. Pediatr Infect Dis J. 2010;29(11):e71–79.
- Vesikari T, Esposito S, Prymula R, et al. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. Lancet. 2013;381(9869):825–835.
- Leder K, Tong S, Weld L, et al. Illness in travelers visiting friends and relatives: a review of the GeoSentinel surveillance network. Clin Infect Dis. 2006;43(9):1185–1193.
- Prymula R, Esposito S, Zuccotti GV, et al. A phase 2 randomized controlled trial of a multicomponent meningococcal serogroup B vaccine (I). Hu Vacc Immunother. 2014;10(7):1993–2004.
- van den Bergh MR, Spijkerman J, François N, et al. Immunogenicity, safety, and reactogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine and DTPa-IPV-Hib when coadministered as a 3-dose primary vaccination schedule in The Netherlands: a randomized controlled trial. Pediatr Infect Dis J. 2011;30(9):e170–178.
- Tse A, Tseng HF, Greene SK, et al. Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011. Vaccine. 2012;30(11):2024–2031.
- Tseng HF, Sy LS, Liu IL, et al. Postlicensure surveillance for pre-specified adverse events following the 13-valent pneumococcal conjugate vaccine in children. Vaccine. 2013;31(22):2578–2583.
- Duffy J, Weintraub E, Hambidge SJ, et al. Febrile seizure risk after vaccination in children 6 to 23 months. Pediatrics. 2016;138:1.
- Tregnaghi MW, Sáez-Llorens X, López P, et al. Efficacy of pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in young Latin American children: A double-blind randomized controlled trial. PLoS Med. 2014;11(6):e1001657–e1001657.
- Chevallier B, Vesikari T, Brzostek J, et al. Safety and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when coadministered with routine childhood vaccines. Pediatr Infect Dis J. 2009;28(4 Suppl):S109–118.
- Wysocki J, Tejedor JC, Grunert D, et al. Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when coadministered with different neisseria meningitidis serogroup C conjugate vaccines. Pediatr Infect Dis J. 2009;28(4 Suppl):S77–88.
- Wysocki J, Center KJ, Brzostek J et al. A randomized study of fever prophylaxis and the immunogenicity of routine pediatric vaccinations. Vaccine. 2017;35(15):1926–1935.
- Prymula R, Siegrist C-A, Chlibek R, et al. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet. 2009;374(9698):1339–1350.
- Falup-Pecurariu O, Man SC, Neamtu ML, et al. Effects of prophylactic ibuprofen and paracetamol administration on the immunogenicity and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugated vaccine (PHiD-CV) co-administered with DTPa-combined vaccines in children: an open-label, randomized, controlled, non-inferiority trial. Hum Vaccin Immunother. 2017;13(3):649–660.
- Leung AK, Robson WL. Febrile seizures. J Pediatr Health Care. 2007;21(4):250–255.
- 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(33):3810–3816.
- Vesikari T, Karvonen A, Prymula R, et al. Immunogenicity and safety of the human rotavirus vaccine Rotarix co-administered with routine infant vaccines following the vaccination schedules in Europe. Vaccine. 2010;28(32):5272–5279.
- Ciarlet M, He S, Lai S, et al. Concomitant use of the 3-dose oral pentavalent rotavirus vaccine with a 3-dose primary vaccination course of a diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type b vaccine: immunogenicity and reactogenicity. Pediatr Infect Dis J. 2009;28(3):177–181.
- Zepp F, Behre U, Kindler K, et al. Immunogenicity and safety of a tetravalent measles-mumps-rubella-varicella vaccine co-administered with a booster dose of a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine in healthy children aged 12-23 months. Eur J Pediatr. 2007;166(8):857–864.
- Deichmann KA, Ferrera G, Tran C, et al. Immunogenicity and safety of a combined measles, mumps, rubella and varicella live vaccine (ProQuad (R)) administered concomitantly with a booster dose of a hexavalent vaccine in 12-23-month-old infants. Vaccine. 2015;33(20):2379–2386.
- Vesikari T, Karvonen A, Lindblad N, et al. Safety and immunogenicity of a booster dose of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine coadministered with measles-mumps-rubella-varicella vaccine in children aged 12 to 16 months. Pediatr Infect Dis J. 2010;29(6):e47–56.
- Orsi A, Azzari C, Bozzola E, et al. Hexavalent vaccines: characteristics of available products and practical considerations from a panel of Italian experts. J Prev Med Hyg. 2018;59(2):E107–E119.
- European Centre for Disease Prevention and Control. Annual epidemiological report for 2017. Diphtheria; [cited 2020 Jan 21]. Available from: https://ecdc.europa.eu/en/publications-data/diphtheria-annual-epidemiological-report-2017
- European Centre for Disease Prevention and Control. Tetanus - annual epidemiological report for 2017. [cited 2020 Jan 21]. Available from https://ecdc.europa.eu/en/publications-data/tetanus-annual-epidemiological-report-2017.
- European Centre for Disease Prevention and Control. Hepatitis B - annual epidemiological report for 2017; [cited 2020 Jan 21]. Available from: https://ecdc.europa.eu/en/publications-data/hepatitis-b-annual-epidemiological-report-2017.
- European Centre for Disease Prevention and Control. Annual epidemiological report for 2017. Pertussis; [cited 2020 Jan 21]. Available from: https://ecdc.europa.eu/en/publications-data/pertussis-annual-epidemiological-report-2017
- Sealey KL, Belcher T, Preston A. Bordetella pertussis epidemiology and evolution in the light of pertussis resurgence. Infect Genet Evol. 2016;40:136–143.
- European Centre for Disease Prevention and Control. Annual epidemiological report for 2017. Poliomyelitis; [cited 2020 Jan 21]. Available from: https://www.ecdc.europa.eu/en/publications-data/poliomyelitis-annual-epidemiological-report-2017
- European Centre for Disease Prevention and Control. Haemophilus influenzae - annual epidemiological report for 2017. [cited 2020 Jan 21]. Available from: https://www.ecdc.europa.eu/en/publications-data/haemophilus-influenzae-annual-epidemiological-report-2017
- Collins S, Ramsay M, Campbell H, et al. Invasive Haemophilus influenzae type b disease in England and Wales: who is at risk after 2 decades of routine childhood vaccination? Clin Infect Dis. 2013;57(12):1715–1721.
- Offit PA, Quarles J, Gerber MA, et al. Addressing parents’ concerns: do multiple vaccines overwhelm or weaken the infant’s immune system? Pediatrics. 2002;109(1):124–129.
- Nicoli F, Appay V. Immunological considerations regarding parental concerns on pediatric immunizations. Vaccine. 2017;35(23):3012–3019.
- Miller E, Andrews N, Waight P, et al. Bacterial infections, immune overload, and MMR vaccine. Measles, mumps, and rubella. Arch Dis Child. 2003;88(3):222–223.
- Glanz JM, Newcomer SR, Daley MF, et al. Association between estimated cumulative vaccine antigen exposure through the first 23 months of life and non-vaccine-targeted infections from 24 through 47 months of age. JAMA. 2018;319(9):906–913.
- Stowe J, Andrews N, Taylor B, et al. No evidence of an increase of bacterial and viral infections following measles, mumps and rubella vaccine. Vaccine. 2009;27(9):1422–1425.
- Summary of Product Characterstics. Hexyon. [ updated 22 May 2018; cited 2019 Feb 27]. Available from: https://www.ema.europa.eu/documents/product-information/hexyon-epar-product-information_en.pdf