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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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
Streptococcus pneumoniae; pneumococcal conjugate vaccine; primary vaccination; booster vaccination; DTPa-combined; DTPw-combined; meningococcal conjugate vaccine