Knuf, Markus MD*; Szenborn, Leszek MD†; Moro, Masnuel MD‡; Petit, Christian MD§; Bermal, Nancy MD¶; Bernard, Laurence MSc∥; Dieussaert, Ilse Ir∥; Schuerman, Lode MD∥
The practice of vaccine coadministration is central to successful childhood immunization programs. Recommendations of the National Vaccine Advisory Committee in the United States for standard immunization practice advocate “Health care professionals simultaneously administer as many indicated vaccine doses as possible.”1 Coadministration of vaccines maximizes the likelihood that children will receive age-appropriate vaccines in a timely manner, reduces the number of vaccination visits required, and allows easier incorporation of new vaccines into existing schedules.2
It is generally considered that multiple inactivated vaccines may be coadministered at the same vaccination visit without compromise of the immune response of the administered vaccines.3 However, combination vaccines including multivalent or combined protein conjugate vaccines are becoming larger and more complex, increasing the risks of immune interference or enhancing effects on the coadministered antigens. A recent review of DTPa and Hib based combination vaccines highlighted that immune responses depend on the nature and quantity of the coadministered antigens, mixed or separated administration of antigens, and the adjuvant used in individual coadministered vaccines.4
The candidate 10-valent pneumococcal non-typeable Haemophilus influenzae [NTHi] Protein D-conjugate vaccine (PHiD-CV) has shown to be immunogenic when administered for primary and booster vaccination in different populations and using different vaccination schedules.5–7 PHiD-CV differs in several key aspects from the currently licensed 7-valent pneumococcal conjugate vaccine (7vCRM). Both vaccines contain a total of 16 μg of pneumococcal capsular polysaccharide, but for PHiD-CV this includes additional pneumococcal serotypes 1, 5, and 7F, besides the 7 serotypes included in the 7vCRM vaccine. Unlike the 7vCRM vaccine in which each pneumococcal polysaccharide is conjugated to mutated diphtheria toxoid (CRM197 protein), the PHiD-CV vaccine uses a recombinant form of protein D (a nonlipidated form of a highly conserved 42 kD cell-surface lipoprotein of non-typeable H. influenzae) as carrier protein for 8 of the 10 vaccine serotypes (1, 4, 5, 6B, 7F, 9V, 14, and 23F), tetanus toxoid as carrier protein for serotype 18C, and diphtheria toxoid as carrier protein for serotype 19F. The choice of protein D as carrier was driven in part by the caution to avoid carrier-mediated suppression and possible bystander interference known to occur with some conjugates that have tetanus toxoid or CRM197 as carrier protein.4,8–12 Using protein D as carrier protein also confers the potential to offer children protection against both pneumococcal and NTHi diseases. In view of the unique formulation of the PHiD-CV vaccine, studies to evaluate the impact of PHiD-CV coadministration on the immunogenicity and safety of routinely used childhood vaccines have been conducted.
This review reports data from the coadministration of PHiD-CV with commonly used pediatric vaccines arising from 3 primary vaccination studies and 2 booster studies. The immune response to the administered pneumococcal vaccines as well as safety and reactogenicity data from the 5 clinical trials are reported elsewhere.5,6,7,13
The design of each study (Studies: 105553/NCT00307554, 107005/NCT00334334, 107007/NCT00344318, 107046/NCT00370396, and 109507/NCT00463437) is summarized in Table 1. Each study assessed immune responses, safety and reactogenicity profiles of commonly used pediatric vaccines when coadministered with either PHiD-CV or 7vCRM (Prevenar™/Prevnar™). All studies were randomized. Study C was double-blind (observer blind), whereas the other studies were conducted in an open (studies B and E) or single-blind fashion (studies A and D).
Immune responses to the following coadministered pediatric vaccines were assessed: combined hexavalent diphtheria-tetanus-acellular pertussis–hepatitis B-inactivated poliovirus and H. influenzae type b conjugate vaccine (DTPa-HBV-IPV/Hib) or DTPa-IPV/Hib, the combined DTPa-HBV-IPV or DTPa-IPV vaccines, combined DTPw (whole-cell pertussis)-HBV/Hib vaccine, standalone IPV and oral live attenuated poliovirus vaccine (OPV), combined Hib-Neisseria meningitidis serogroup C vaccine conjugated to tetanus toxoid (Hib-MenC-TT), monovalent MenC-TT and MenC-CRM vaccines. In accordance with national recommendations in place at the time of each study, hepatitis B vaccine was administered at or soon after birth, in Poland (Studies A, B, and C) and some regions of Spain (Study B).
The studies were conducted according to Good Clinical Practice, the Declaration of Helsinki (Somerset West, 1996 version), applicable local laws, and with the approval of relevant ethics review committees. In each study, written informed consent was obtained from the parents/guardian of each subject before enrolment.
Primary vaccination studies were conducted in healthy infants between 6 and 16 weeks of age at the time of the first vaccine dose. In booster studies, vaccination occurred between 11 and 18 months of age. Infants and children were excluded from participation if they had experienced disease caused by, or had received prior vaccination against pathogens targeted by the study vaccines (with the exception of HBV vaccine in Poland and some regions of Spain, where it was routinely administered at birth). Children with immunosuppression of any cause, serious chronic illness, a history of seizures or progressive neurologic disease, major congenital defects, or who had received immunoglobulin or blood products since birth were also excluded. In booster studies, children were required to have been vaccinated during infancy in the previous clinical trial of PHiD-CV, and were excluded if they had received intercurrent vaccination with antigens present in the booster study vaccines.
The DTPa-HBV-IPV/Hib (Infanrix hexa™), DTPa-HBV-IPV (Infanrix penta™/Pediarix™), DTPw-HBV/Hib (Tritanrix™-HepB/Hib), Hib-MenC-TT (Menitorix™), OPV (Polio Sabin™), and IPV (Poliorix™) vaccines were manufactured by GlaxoSmithKline Biologicals (GSK), Rixensart, Belgium (Table 2). The conjugate meningococcal vaccines MenC-TT (NeisVac-C™) and MenC-CRM (Meningitec™) were manufactured by Baxter Healthcare SA, Zurich, Switzerland and Wyeth, Pearl River, NY, USA, respectively.
All vaccines except OPV were administered intramuscularly. In primary vaccination studies, all vaccines were administered into the thigh. In booster studies, vaccines were administered into the thigh or the deltoid.
Assessment of the Immune Responses of the Coadministered Vaccines
For most antigens, blood samples were collected before commencing primary vaccination, and 1 month after completion of the primary vaccination course in studies A and C, 2 months after the second and 1 month after the third primary vaccination doses in Study B, and before and 1 month after the vaccine dose in booster studies (D and E). In each study, serological testing of the response to coadministered antigens was conducted in a randomly selected subset of subjects. In Study E, the immunologic assessment of coadministered vaccines was limited to Hib and MenC responses.
All assays used to evaluate the immune response to coadministered antigens were performed using standardized, validated procedures with adequate controls.
In Study A, antibodies against hepatitis B surface antigen (anti-HBs) were measured using a commercially available kit (AUSAB® EIA, Abbott Laboratories) with a cut-off for seroprotection of 10 mIU/mL. Analysis of the hepatitis B response in other studies, as well as immune responses to diphtheria and tetanus toxoids, Hib, and pertussis antigens was performed using standard GSK ELISA assays. The assay cut-off for antibody concentrations considered to be associated with seroprotection was 0.1 IU/mL for diphtheria and tetanus,14,15 10 mIU/mL for hepatitis B,16 and 0.15 μg/mL for Hib.17,18 For anti-PRP (Hib) antibodies, the percentage of subjects with an antibody concentration (total Ig) ≥1 μg/mL was also evaluated. For pertussis where no serological correlate of protection currently exists, immune responses were expressed as seropositivity (≥5 EL.U/mL for PT, FHA, and PRN in DTPa vaccines19 and ≥15 EL.U/mL for the response to Bordetella pertussis [killed; BPT] in the DTPw vaccine).
Serum titers of anti-poliovirus types 1, 2, and 3 were measured by viral microneutralization assay test.20 The lowest dilution at which serum samples were tested was 1:8, which is considered to be protective.
Measurement of the immune response to MenC was made by determination of serum bactericidal activity against MenC (SBA-MenC), according to the CDC protocol21 using baby rabbit complement. SBA-MenC titers ≥ the assay cut-off of 1:8 were considered protective.22 A cut-off of 1:128 was also assessed. Specific IgG antibodies against MenC polysaccharide (PSC) were measured by ELISA with an assay cut-off of 0.3 μg/mL.23 The 2 μg/mL threshold was also assessed as it has been suggested by some to be protective against serogroup C.24
Coadministered antigens were tested on a defined subset of vaccinated subjects. Analysis of immunogenicity was performed on the according-to-protocol (ATP) for immunogenicity, for which immunogenicity data on coadministration antigens are available. The ATP cohort for analysis of immunogenicity included all eligible subjects in the immunogenicity subsets for whom assay results were available for antibodies/titers against at least 1 coadministered study vaccine component after vaccination.
Percentage of subjects with antibody concentration/titer equal to or greater than the seropositivity/seroprotection cut-off were calculated with the exact 2-sided 95% confidence intervals (CIs) for each vaccine antigens after each time point.25
Geometric mean antibody concentrations/geometric mean antibody titers (GMCs/GMTs) were calculated (with 95% CIs) by taking the antilog of the mean of the log concentration/titer transformations. Antibody concentrations/OPA titers below the assay cut-off were given an arbitrary value of one-half the cut-off for the purpose of GMC/GMT calculation.
All comparisons were exploratory and statistically significance was based on the observation of nonoverlapping 95% CIs. These exploratory comparisons should therefore be taken with caution and should only be considered indicative of possible differences between groups.
The immune response to antigens coadministered with PHiD-CV was assessed in approximatively 1805 subjects across the 3 primary vaccination studies and in the 2 booster studies, in about 1150 subjects who had received a fourth consecutive vaccination with PHiD-CV. Because of limited quantities of sera, antibody responses could not be measured for all antigens in every subject, resulting in differences in number of subjects tested per antigen.
Primary Vaccination (Studies A, B, C)
Response to Diphtheria and Tetanus Toxoids
One month after completion of primary vaccination in studies A, B, and C, at least 97.9% of PHiD-CV and 7vCRM vaccinees had seroprotective antibody levels against diphtheria and virtually all subjects were seroprotected against tetanus (Table 3). Antidiphtheria antibody GMCs were statistically significantly higher in the 7vCRM group compared with the PHiD-CV group in study A, but the opposite trend was observed in both schedules assessed in study C. Antitetanus antibody GMCs were observed to be consistently higher across most PHiD-CV groups compared with 7vCRM groups (Table 3), with a statistically significant difference in study A, and in the PHiD-CV groups receiving a MenC vaccine conjugated to TT compared with 7vCRM in Study B.
Response to Hepatitis B Antigen
The hepatitis B responses after primary vaccination are given per country in Table 4. Although limited by small numbers in some countries, anti-HBs seroprotection rates and GMCs seem to be influenced by the number of hepatitis B vaccinations given, and the schedule in which they were administered. For each study, the overall seroprotection rate against hepatitis B was more than 96% for subjects who received at least 3 vaccine doses according to the 2-, 4-, and 6-month or 2-, 3-, and 4-month schedules coadministered with PHiD-CV or 7vCRM, versus approximately 90% of the subjects vaccinated according to the 6-, 10-, and 14-week schedule with PHiD-CV or 7vCRM coadministration, in study C in the Philippines.
The highest anti-HBs antibody GMCs were observed in schedules where 4 hepatitis B vaccine doses were provided (Poland and Spain). The lowest anti-HBs antibody GMC was observed in Filipino subjects who received 3 HBV vaccine doses in the accelerated 6-, 10-, and 14-week schedule (all but 6 subjects assessed for hepatitis B immunogenicity did not receive HBV vaccine at birth). Anti-HBs antibody GMCs were also lower in French infants who received only 2 HBV vaccine doses coadministered with PHiD-CV at 2 and 4 months of age. Although a higher anti-HBs antibody GMC was observed in French children who received 7vCRM, conclusions cannot be drawn because of the small sample size (N = 16).
Response to Pertussis Antigens
Virtually all subjects were seropositive for antibodies against PT, FHA, and PRN in studies A and B where DTPa was given (Table 5). In study C where DTPw was administered, 93% to 95% of subjects in Poland and 98% to 99% of subjects in the Philippines were seropositive for anti-BPT antibodies after primary vaccination (Table 6).
In each study/schedule, post-primary antibody GMCs against acellular and whole cell pertussis antigens were within the same range in the PHiD-CV and 7vCRM groups.
Response to Poliovirus Antigens
One month after completion of primary vaccination in studies A, B, and C, more than 96% of PHiD-CV recipients in all 3 studies had antibody concentrations consistent with seroprotection against poliovirus types 1 and 3 (Table 7). Lower seroprotection rates and antibody GMTs against anti-poliovirus types 1 and 3 were observed in 7vCRM recipients compared with PHiD-CV recipients in study C when the 6-, 10-, 14-week schedule was used (only 90.9% [Polio 1] and 84.2% [Polio 3] of 7vCRM vaccinees with titers ≥8, Table 7).
Poliovirus type 2 responses were different between studies but were within the same range for the PHiD-CV and 7vCRM groups in each study (Table 7). More than 97% of PHiD-CV recipients had seroprotective anti-poliovirus type 2 antibody levels in studies B and C, whereas in study A, 91.2% of subjects in the PHiD-CV group and 90.4% of subjects in the 7vCRM group had titers ≥8.
Response to H. influenzae type B Antigens
More than 97% of subjects had antibody concentrations consistent with seroprotection (≥0.15 μg/mL) against Hib for both PHiD-CV and 7vCRM groups (Table 8). The anti-PRP antibody GMC and the percentage of subjects with anti-PRP antibody concentrations ≥1.0 μg/mL was significantly higher in PHiD-CV recipients compared with 7vCRM recipients in study A. Anti-PRP antibody GMCs were markedly higher when PHiD-CV or 7vCRM was coadministered with Hib-MenC-TT, compared with groups receiving MenC-CRM or MenC-TT coadministered with DTPa-HBV-IPV/Hib and PHiD-CV (study B). Anti-PRP antibody GMCs were significantly lower when MenC-CRM was coadministered compared with the group with MenC-TT coadministration in study B.
Response to MenC Antigens (Study B)
SBA-MenC titers ≥8 were observed in at least 97.6% of subjects in study B after primary vaccination and at least 95.0% of all subjects had SBA-MenC titers ≥128 2 months after the second dose of MenC-CRM or MenC-TT vaccines (corresponding to the full primary vaccination course according to existing prescribing information26,27), and 1 month after the third dose of Hib-MenC-TT vaccine (Table 9). All subjects had anti-PSC antibody concentrations ≥0.3 μg/mL 2 months after the second dose of MenC-CRM or MenC-TT vaccines or 1 month after the third dose of Hib-MenC-TT vaccine, and more than 95% had anti-PSC antibody concentrations ≥2.0 μg/mL.
Booster Vaccination (Studies D and E)
One month post-booster vaccination in study D, the seroprotection/seropositivity rates for antibodies against diphtheria, tetanus, pertussis, hepatitis B, and poliomyelitis were within the same range in all 3 vaccine groups (Table 10). More than 99.0% of subjects in each group had seroprotective antibody concentrations against diphtheria, tetanus, poliovirus types 1, 2, and 3, and were seropositive against each pertussis antigen. At least 97.9% had seroprotective antibodies against hepatitis B. Post-booster antibody GMCs/GMTs (Table 10) were globally within the same range in all groups, with the exception of a statistically significantly higher antidiphtheria antibody GMC in the 7vCRM primed group boosted with PHiD-CV compared with other groups, and a significantly higher antitetanus antibody GMC in the PHiD-CV groups compared with other groups.
Booster Response to H. influenzae Antigens
In both studies D and E, at least 97.8% of subjects in all groups had anti-PRP antibody levels ≥1 μg/mL after the booster dose (Table 11). In study D, higher post-booster anti-PRP antibody GMC were observed in subjects primed and boosted with PHiD-CV compared with the other groups (Fig. 1). In study E, groups primed and boosted with PHiD-CV and monovalent MenC-CRM or MenC-TT vaccines had anti-PRP antibody concentrations within the same range as PHiD-CV boosted subjects in study D, whereas groups primed and boosted with Hib-MenC-TT had significantly higher anti-PRP antibody GMCs. The highest anti-PRP antibody GMC was observed in PHiD-CV+Hib-MenC-TT vaccinees (Fig. 1).
Booster Response to MenC Antigens (Study E)
In study E, all subjects were seroprotected (SBA-MenC titer ≥8) and at least 97.4% of subjects had SBA-MenC titers ≥128 after the booster dose of monovalent MenC or Hib-MenC-TT vaccines (Table 11). A higher post-booster SBA-MenC GMT was observed in the PHiD-CV + Hib-MenC-TT group compared with the 7vCRM + Hib-MenC-TT group. Between 93.1% and 98.7% of subjects in PHiD-CV groups who received a booster dose of MenC-CRM, MenC-TT or Hib-MenC-TT had anti-PSC antibody concentrations ≥2.0 μg/mL versus 82.6% of 7vCRM + Hib-MenC-TT recipients. The post-booster anti-PSC antibody GMC was statistically significantly higher in the PHiD-CV + Hib-MenC-TT group compared with the 7vCRM+Hib-MenC-TT group (Table 11).
In Poland, a third primary dose of MenC-CRM or MenC-TT was offered at 7 months of age to comply with MenC-CRM and MenC-TT prescribing information in place at the time of the study. However, this additional dose during primary vaccination course of MenC-CRM or MenC-TT did not appear to have any impact on the booster responses (analyses per country; results not shown).
In 5 controlled clinical trials, immune responses measured against antigens contained in widely used childhood vaccines after coadministration with PHiD-CV did not indicate negative interferences, compared with immune responses measured after coadministration with the licensed 7vCRM vaccine. Lower than expected seroprotection rates and GMTs against poliovirus type 2 were observed in both the PHiD-CV and 7vCRM groups in one of the primary vaccination studies (study A). The clinical significance of this result is uncertain given that booster vaccination of subjects in Study D (booster of study A) induced good booster responses in all groups with seroprotective titers against poliovirus type 2 observed in all children. For all other coadministered antigens, the immune response was high and at least 96% of PHiD-CV recipients had antibody concentrations consistent with seroprotection against diphtheria, tetanus, poliovirus types 1 and 3, Hib (≥0.15 μg/mL), SBA-MenC (≥8), and more than 94% were seropositive for antibodies against pertussis antigens.
In each study, at least 96% of subjects had antibody concentrations consistent with seroprotection against hepatitis B, except for subjects in the Philippines (study C) where seroprotection rates reached about 90%. In general, hepatitis B antibody GMCs varied according to the vaccination schedule employed in each country (2 hepatitis B vaccine doses in France, 3 in Finland, or 4 in Poland), with a tendency to increase according to the number of HBV vaccine doses administered in each country. The lowest seroprotection rates and anti-HBs GMCs were however observed in Filipino infants who, although receiving 3 hepatitis B vaccine doses, were vaccinated in the early and accelerated 6-, 10-, and 14-week schedule. Low anti-HBs immune responses have been reported previously by Gatchalian et al28 after administration of the DTPw-HBV/Hib vaccine in Filipino children at 6, 10, and 14 weeks of age. As well as vaccination schedule, the low responses in Filipino infants may also be because of interference of maternal antibodies as reported by Bravo et al.29 Only 6 subjects in the immunogenicity subset for coadministered vaccines in the Philippines received hepatitis B vaccination at birth. The importance of a birth dose of HBV vaccine when the 6-, 10-, and 14-week schedule is employed has been demonstrated in other studies.30,31 Neonatal vaccination against hepatitis B is now recommended in the Philippines, regardless of whether primary vaccination will be performed with DTPw or DTPa-based vaccines.30
The mechanism of immune interference or enhancement to coadministrated vaccines is poorly understood, difficult to predict and may be the result of carrier-specific T-helper cell interactions or T cell bystander interferences.4,32 Coadministration of CRM-based conjugate vaccines with DTPa and Hib-TT combination vaccines has been associated with reduced responses to the Hib-TT vaccine and also to hepatitis B.4 These effects seem to be dose related,33 are more pronounced with DTPa-based vaccine from some manufacturers than from others.9,10,34 In contrast, coadministration of DTPa and Hib-TT combinations with other TT-conjugate vaccines has led to enhancement of the immune response to Hib.35–37
We observed results consistent with above mentioned observations. In study A, we observed significantly higher anti-PRP (Hib) antibody GMC and percentage of subjects reaching the 1.0 μg/mL cut-off in the PHiD-CV + DTPa-HBV-IPV/Hib group compared with the 7vCRM + DTPa-HBV-IPV/Hib group, suggesting enhancement of the anti-PRP response by the TT-carrier used for serotype 18C in the PHiD-CV vaccine. Similarly, in study B, higher anti-PRP antibody GMCs were observed in subjects primed with 3 doses of PHiD-CV or 7vCRM when these vaccines were coadministered with Hib-MenC-TT conjugate vaccine, compared with the other groups that received the DTPa-HBV-IPV/Hib vaccine.
The generally higher antitetanus antibody GMCs observed in the PHiD-CV groups in all studies is consistent with enhancement of the immune response by the TT-carrier protein for serotype 18C in the PHiD-CV vaccine. The difference between 7vCRM and PHiD-CV groups in term of the antitetanus antibody GMC was less pronounced in study B where the TT present in the Hib-MenC-TT vaccine clearly increased the tetanus response in 7vCRM recipients, as it also did for the anti-PRP response. In study B, the antitetanus antibody GMC in the 7vCRM group was within the same range as that of the PHiD-CV + MenC-CRM group, but remained lower than the other 2 PHiD-CV groups where the overall amount of TT administered was higher (Table 2).
Significantly, higher antidiphtheria antibody GMCs in the 7vCRM group in study A compared with the PHiD-CV group are consistent with the presence of the CRM carrier protein, a mutated diphtheria toxoid, in the 7vCRM vaccine, although this was not consistently observed in all studies.
In study C where OPV was administered to subjects vaccinated at 6, 10, and 14 weeks of age, anti-poliovirus types 1 and 2 GMTs were at least as high or higher than in groups receiving IPV at 2, 4, and 6 months of age, whereas anti-poliovirus type 3 GMTs were significantly lower in the 6-, 10-, and 14-weeks OPV schedule. This is consistent with previous observations comparing OPV and IPV immune responses.38
A booster dose of PHiD-CV and coadministered vaccines given to subjects primed with PHiD-CV or 7vCRM induced high levels of seroprotection/seropositivity against all coadministered vaccine antigens. The significantly higher antitetanus antibody GMCs observed in PHiD-CV primed and boosted subjects in study D compared with the other groups reflects the additional TT content of the vaccine as discussed above. The reason for significantly higher antidiphtheria antibody GMCs in subjects primed with 7vCRM and boosted with PHiD-CV, compared with priming and booster vaccination with 7vCRM remains unclear.
Post-booster Hib responses were consistent with post-primary findings, with the anti-PRP antibody GMCs in PHiD-CV groups, exceeding GMCs in 7vCRM groups when identical vaccines were coadministered. The high anti-PRP and rSBA-MenC responses seen in groups receiving a booster dose of Hib-MenC-TT coadministered with PHiD-CV may be a combined result of TT enhancement and an improved anamnestic response known to occur after primary vaccination with reduced antigen content vaccines.39–41
These studies were not designed to assess the impact of PHiD-CV on the immune responses of coadministered vaccines because none included control groups without coadministration of pneumococcal conjugate vaccines. These studies were rather designed to compare 2 different pneumococcal conjugate vaccines, in the context of coadministration of routine pediatric vaccines. The immune response of pediatric vaccines when coadministered with PHiD-CV is therefore compared with the immune response of the same coadministered vaccines when used in the current routine practice of 7vCRM coadministration. Because no contra-indications currently exist for coadministration of 7vCRM with other pediatric vaccines, immune responses of vaccines when coadministered with 7vCRM should be considered acceptable and can therefore be used as reference. Furthermore, the seroprotection/seropositivity rates observed for the vaccine antigens coadministered with PHiD-CV were within the range of those previously observed for these antigens in other studies using similar schedules,11,28,29,39,42 thereby confirming the preserved immune responses induced by these widely used pediatric vaccines when coadministered with PHiD-CV vaccine.
Also, lacking in these studies are data assessing the immune response to live attenuated viruses other than OPV. However in a controlled booster study enrolling the remaining subjects primed in study A, coadministration of combined measles-mumps-rubella-varicella (MMRV) vaccine with PHiD-CV did not impair immunogenicity and tolerability of the administered vaccines.43
Coadministration of the novel PHiD-CV has not been assessed in every possible schedule or with every possible vaccine. However, data from 5 clinical trials that evaluated 3 different vaccination schedules including the more immunologically challenging 6-, 10-, and 14-week and 2-, 3-, and 4-month schedules, adequately take into account most of the potentially required coadministrations worldwide. Use of protein D as carrier protein did not lead to negative interferences in the immune response to coadministered antigens.
In conclusion, coadministration of commonly used childhood vaccines with PHiD-CV induced high levels of seroprotection/seropositivity against the targeted diseases, without evidence of interference on the immune response to any of the coadministered vaccine antigens compared with immune responses after 7vCRM coadministration.
The authors thank the parents and their children who participated in these trials.
The authors gratefully acknowledge the investigators, clinicians, study nurses, and other staff members for contributing in many ways to these studies, in particular all the investigators involved in these studies: N. Lindblad, T. Vesikari, A. Karvonen, T. Karppa, U. Elonsalo, J. Immonen, T. Korhonen, B. Chevallier, F. Mokdad, JP Arsene, V. Duflo, B. Blanc, F. Thollot, P. Bakhache, PM. Tran, E. Mothe, R. Amar, M. Guy, E. Jacqz-Aigrain, H. Czajka, J. Brzostek, J. Pejcz, B. Pajek, A. Galaj, J. Wysocki, U. Behre, F. Bertholdt, P. Bosch, E. Erdmann, D. Grunert, S. Hetzinger, U. Hörnlein, M. Kimmig, K. Kindler, K. Kirsten, R. Knecht, HP. Loch, KE. Mai, R. Mangelsdorf-Taxis, L. Maurer, S. Noll, H. Pabel, F. Panzer, C. Pauli, U. Pfletschinger, K. Pscherer, HH. Rohé, L. Sander, HC. Sengespeik, M. Steiner, U. Sträubler, KJ. Taube, K. Vogel, M. Völker, M. Vomstein, V. von Arnim, MH. Wagner, W. Olechowski, R. Konior, E. Miszczak-Kowalska, J. Arístegui, A. de Vicente, JM. Merino, X Pérez-Porcuna, E. Muñoz, D. Moreno, M. Méndez, J. de la Flor, JC. Tejedor, J. Marés, F. Barrio, MJ. de Torres, F. Centeno, J. García-Sicilia, F. Omeñaca, A. Chrobot, K. Kulczyk, B. Białynicka-Birula, E. Majda-Stanisławska, U. Wachter, C. Lotz, C. Wittermann, U. Jacob, B. Acosta, M. Moro, C. López, E. Alberto, C. Matela, M. Hernandez, F. Reyes, I. Aquino, L. Casidsid, C. Cuaresma, F. Bajaro, W. Dacasin, and E. La Valle.
In addition, they thank the clinical and serological laboratory teams of GlaxoSmithKline Biologicals, Belgium for their input in various aspects of the studies, Patricia Lommel (GlaxoSmithKline Biologicals) for statistical analyses, Dr. Joanne Wolter (freelance) for providing medical writing and Dr. Christine Vanderlinden (GlaxoSmithKline Biologicals) for editorial assistance and manuscript coordination.
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