With integration of a 7-valent pneumococcal conjugate vaccine (PCV7) into the routine childhood immunization schedule in the United States, the incidence of invasive pneumococcal disease has decreased in both children and adults.1–3 Nevertheless, nonvaccine serotypes of Streptococcus pneumoniae remain an important cause of invasive bacterial and mucosal diseases in children.4–7 A 13-valent PCV (PCV13) has been licensed to provide broader protection against pneumococcal diseases than is afforded by the 7-valent vaccine, and has replaced PCV7 in the infant immunization schedule in the United States and Europe. PCV13 is administered concomitantly with other routine pediatric vaccines at 2, 4, 6 and 12–15 months of age.8 The present combined analysis of 2 studies has assessed whether PCV13 interferes with immune responses to concomitantly administered routine pediatric vaccine antigens.
MATERIALS AND METHODS
Infants were enrolled in 1 of 2 randomized, double-blind, controlled trials in the United States. Study 004 evaluated the safety, tolerability and immunogenic noninferiority of PCV13 (Prevnar 13, Wyeth Pharmaceuticals Inc., Philadelphia, PA; Wyeth was acquired by Pfizer Inc in October 2009) compared with PCV7 (had been licensed in the United States as Prevnar, Wyeth Pharmaceuticals Inc., Philadelphia, PA) in infants at 38 centers. Study 3005 evaluated the safety and tolerability of PCV13 compared with PCV7, and the immunogenic consistency among 3 lots of PCV13 (subjects randomized 2:2:2:1 to receive 1 of 3 lots of PCV13 or PCV7) at 80 centers. Institutional Review Board approval was obtained at each participating site or institution.
In both studies, healthy infants were enrolled at 2 months of age after written, informed consent was obtained from the parent or guardian. Infants with prior pneumococcal immunization, blood transfusion or immune globulin treatment were excluded, as were infants with any significant chronic or congenital disease including immune deficiencies or bleeding disorders.
PCV13 contains the PCV7 saccharides from pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, as well as serotypes 1, 3, 5, 6A, 7F and 19A. As with PCV7, each of the polysaccharides is covalently conjugated to the carrier protein, CRM197, a nontoxic variant of diphtheria toxin. Each 0.5-mL dose of PCV13 contains 2.2 µg of each saccharide (except for 4.4 µg of 6B) in 5.0 mM succinate buffer with 0.125 mg of aluminum as aluminum phosphate. In the 3005 study, the PCV13 formulation also contained 0.02% polysorbate 80, a nonionic detergent used to solubilize proteins, which is included in the final formulation of PCV13. PCV13 and PCV7 were presented in identical, prefilled syringes.
In both trials, infants received concomitant age-appropriate immunization against diphtheria, tetanus, pertussis, hepatitis B (Hep B), polio (PEDIARIX, GlaxoSmithKline Biologicals, Rixensart, Belgium) and Haemophilus influenzae type b (Hib) (ActHIB, Sanofi Pasteur SA, Lyon, France) at 2, 4 and 6 months of age (Table 1). At 12–15 months of age, infants received concomitant age-appropriate immunization against measles, mumps, rubella and varicella (ProQuad in study 004; M-M-R II and VARIVAX in study 3005, all manufactured by Merck & Co., Inc., Whitehouse Station, NJ) and hepatitis A vaccine (VAQTA, Merck & Co., Inc., Whitehouse Station, NJ). Subjects in study 004 also received PedvaxHIB (Merck & Co., Inc., West Point, PA) at 12–15 months of age. Infants in study 3005 received ActHIB (Sanofi Pasteur, Swiftwater, PA) after the 12-month dose.
Immunogenicity to concomitant vaccine antigens was measured 1 month after the third infant dose and 1 month after the toddler dose. In study 004, assays for each concomitant vaccine antigen were performed on all infants who received all study vaccines and had at least 1 valid and determinate assay result. In study 3005, assays were performed on all infants who received all vaccines and who had at least 1 assay result in the PCV7 group and an equal number of eligible subjects in the PCV13 groups who were selected randomly from the 3 different subgroups.
Standard enzyme-linked immunoassay (ELISA) methods were used for determining antibodies to diphtheria, tetanus, Haemophilus infuenzae type B polyribosylribitol-phosphate capsular polysaccharide (Hib-PRP), pertussis toxin, pertussis filamentous hemagglutinin and pertussis pertactin. Serum levels of antibody to Hep B surface antigen were measured using a Food and Drug Administration–approved in vitro diagnostic kit. Poliovirus antibody titers were determined by neutralization assays. Antimeasles immunoglobulin G (IgG), antimumps IgG and antirubella IgG were determined with the use of kits approved for in vitro diagnostic testing by the Food and Drug Administration: Captia Measles IgG and Captia Mumps IgG were manufactured by Trinity Biotech USA (Jamestown, NY), and the rubella IgG assay was performed on the ADVIA Centaur ACM-Pivotal Global Central Laboratory (Rochester, NY). Varicella antibody was assessed in study 004 vaccinees using a whole-cell ELISA kit, Captia VZV IgG (Trinity Biotech). Sera from study 3005 vaccinees were assessed for varicella antibodies using a glycoprotein (gp) ELISA Merck Assay, and were assessed for mumps antibodies using mumps IgG ELISA Merck Assay. Glycoprotein and Merck assays for varicella and mumps became commercially available after the study was initiated. Mumps and varicella titers from study 004 were also measured in a post hoc analysis with these assays, which were used in the licensure of the mumps and varicella vaccines.
Protective antibody levels established for diphtheria toxoid (≥0.1 IU/mL), tetanus toxoid (≥0.1 IU/mL), Hib-PRP antibody (≥0.15 and ≥1.0 µg/mL), poliovirus types 1, 2 and 3 (neutralizing antibody ≥1:8) and antibody to Hep B surface antigen (≥10 mIU/mL) were used to define an immune response. Immune responses to pertussis antigens, including pertussis toxin, pertussis filamentous hemagglutinin and pertussis pertactin were prospectively defined as the antibody levels achieved by 95% of PCV7 vaccinees. IgG antibodies to measles, mumps and varicella were expressed as index values according to instructions provided by the manufacturers of the diagnostic kits, with values of ≥1.10 for measles and mumps and ≥1.09 for varicella considered positive. Rubella antibodies were quantitated against the World Health Organization reference standard (second International Standard Preparation for Antirubella Serum) and reported in international units (IU). Antirubella IgG antibodies of ≥15 IU/mL were considered seroprotective. In post hoc analyses, varicella responses were evaluated at 2 defined cutoffs associated with seroconversion (≥1.25 gp ELISA units/mL) and long-term protection (≥5.00 gp ELISA units/mL), and mumps responses were evaluated at a defined cutoff associated with seroconversion (>10.0 Ab units/mL). Pneumococcal immunogenicity and safety results of these studies have been, or will be, reported elsewhere (study 004 results have been reported by Yeh et al,9 and study 3005 results will be reported by Payton et al [submitted for publication]).
For each concomitant vaccine antigen in each study, the proportion of subjects achieving at least the prespecified antibody concentration was calculated. Noninferiority was demonstrated if the lower limit of the 2-sided 95% confidence interval for the difference in proportions of responders (PCV13–PCV7) was >–0.10. For each antigen, the ratio (PCV13/PCV7) of the IgG antibody geometric mean concentrations (GMCs) or titers (GMTs [for poliovirus]) was calculated. Noninferiority was declared if the lower limit of the 2-sided 95% confidence interval for the GMC or GMT ratio was >0.5 (2-fold criterion).
For study 004, recruitment ran from September 18 to December 14, 2006, with the study ending on June 2, 2008. For study 3005, the recruitment period was August 15, 2007, to December 5, 2007, and the study end date was June 11, 2009. In study 004, 666 infants were randomized to either PCV13 or PCV7 (Table 2). Eighty-eight percent completed the infant series (n = 294 and 290 for PCV13 and PCV7, respectively) and 77% completed the study by receiving the toddler dose and blood draw (n = 264 and 252, respectively). In study 3005, 1712 subjects were randomized, with 88% completing the infant series (n = 1290 and 218 for PCV13 and PCV7, respectively) and 82% completing the study (n = 1203 and 200 for PCV13 and PCV7, respectively) (Table 3).
The evaluable concomitant vaccine immunogenicity populations included 504 infants (n = 252 and 252 for PCV13 and PCV7, respectively) and 462 toddlers (n = 239 and 223, respectively) for study 004, and 385 infants (n = 189 and 196, respectively) and 336 toddlers (n = 163 and 173, respectively) for study 3005.
Black/African–American infants comprised a higher proportion of evaluable study subjects in the 004 group compared with 3005, but the 2 populations were otherwise similar with respect to baseline demographic characteristics (Table 4) and there were not differences between the PCV13 and PCV7 groups within each study.
Proportion of Responders to the Concomitantly Administered Antigens
One month after dose 3 of the infant series, the proportion of PCV13 vaccinees achieving prespecified antibody levels to each measured concomitant vaccine antigen was noninferior to the proportion of responders among PCV7 vaccinees (Table 5). Similarly, 1 month after the toddler dose, the proportions of PCV13 recipients achieving prespecified antibody titers to measles, mumps, rubella, varicella and Hib-PRP were noninferior to the proportions of responders vaccinated with PCV7 (Table 6). In both PCV13 and PCV7 vaccinees, the proportion of responders to Hib-PRP increased posttoddler dose (Table 6) compared with those after the infant series (Table 5).
Even though noninferiority criteria were met for the percentages of responders for all antigens after the toddler dose, the relatively low values observed in study 004 for both the PCV13 and PCV7 groups for responders to mumps (76.5% and 72.9%, respectively) and varicella (26.7% and 21.9%, respectively) suggested that the assays used were not accurately reflecting the actual clinical response. Consequently, for sera from study 3005, assays used in the licensure of the mumps and varicella vaccines which had recently become available were used in the post hoc analysis. Using the Merck mumps (WT) IgG ELISA assay developed to assess seroconversion rates during vaccine development, mumps responses were shown to be 95.7% for PCV13 and 97.6% for PCV7 (Table 6). Similarly, data using the Merck varicella glycoprotein ELISA demonstrated responses of 98.8% for PCV13 and 97.7% for PCV7 (Table 6). Noninferiority criteria were also met in this post hoc analysis.
GMCs/GMTs for the Concomitantly Administered Antigens
Serum antibody GMCs/GMTs among subjects vaccinated with PCV13 were noninferior to those observed in PCV7 recipients for all measured concomitant vaccine antigens. Across all concomitant vaccine antigens, the ratio of IgG antibody GMC or GMT values (PCV13/PCV7) ranged from 0.91 to 1.33 at 1 month after the infant series and met noninferiority criteria (Table 5). One month after the toddler dose, serum antibody GMCs to each measured concomitant vaccine antigen among subjects receiving PCV13 were likewise noninferior to GMCs among subjects receiving PCV7, with GMC ratios (PCV13/PCV7) ranging from 0.83 to 1.03.
PCV13 is now routinely administered concomitantly with other routine pediatric vaccines in many countries around the world. With any new vaccine, it is necessary to assess whether administering it with other vaccines interferes with their immunogenicity. Accordingly, the studies described here included an evaluation of the immune responses of concomitant vaccine antigens as part of routine immunizations when administered with either PCV13 or PCV7. Overall, the results demonstrate that PCV13 does not interfere with concomitant vaccine antigens when administered during the first 6 months of life or at 12–15 months of age; immune responses to all antigens met noninferiority criteria when compared with PCV7. Findings supporting a lack of interference between PCV13 and concomitant vaccine antigens are consistent with those of a phase 3 trial and a combined analysis of 2 other phase 3 trials of PCV13 administered with diphtheria, tetanus, acellular pertussis, hepatitis b virus inactivated polio virus, and Haemophilus influenzae type b vaccine, which demonstrated that PCV13 did not interfere with the immune response to Haemophilus influenzae type b anti-PRP, polio virus types 1, 2 and 3, Hep B, diphtheria, tetanus and the pertussis components of pertussis toxin, pertussis filamentous hemagglutinin and pertussis pertactin.10,11
Although antidiphtheria GMCs were lower than those reported in earlier studies with PCV7,12,13 this is unlikely to be of clinical significance, as nearly all PCV13 and PCV7 recipients developed protective levels of antidiphtheria antibody. In those prior studies, coadministration of diphtheria-containing vaccines with CRM197-based conjugate vaccines including PCV7 resulted in higher diphtheria toxoid responses. However, this carrier protein-mediated enhancement phenomenon was not observed in the current study.
Responses to mumps and varicella antigens in this study were lower than expected. Antibodies were initially measured using kits approved for in vitro diagnostic testing by the Food and Drug Administration. Although these kits conform to rigorous standards, they are intended for determination of immune status based on natural exposure rather than assessment of response after vaccine administration. In post hoc analyses using the assay used in the licensure of the M-M-R II vaccine for mumps and gp ELISA for varicella, responses to mumps and varicella antigens were high in both groups and met noninferiority criteria for PCV13 compared with PCV7.
This study has several limitations. Immune responses to hepatitis A vaccine, which was routinely administered at 12 months of age, were not measured because only the first dose of the 2-dose hepatitis A vaccination series was given concomitantly with PCV. Likewise, this study did not evaluate coadministration of PCV13 with trivalent, inactivated influenza vaccine because of the seasonal nature of influenza vaccine. Also, these studies were not designed to assess coadministration of PCV13 with diphtheria, tetanus or pertussis antigens in toddlers. The Advisory Committee on Immunization Practices recommends reimmunization of toddlers against diphtheria, tetanus and pertussis at 15–18 months of age, although DTaP-containing vaccines may be given as early as 12 months of age. Of note, however, other studies conducted to license PCV13 assessed posttoddler dose DTaP-induced immune responses and consistently showed noninferiority between PCV13 and PCV7 in this regard.10,11 In addition, rotavirus vaccine began to be included in the routine vaccination schedule during the period over which this study was conducted and vaccination rates were fairly high with 56% and 82% of subjects receiving rotavirus vaccine in studies 004 and 3005, respectively, with an acceptable safety profile in both studies. Immune responses to the rotavirus vaccine were not assessed, but it is not likely that coadministration of PCV13 would have an impact on responses to this oral vaccine.
In conclusion, PCV13 did not interfere with the immune response to any concomitantly administered vaccine antigen given routinely at 2, 4, 6 and 12–15 months of age. PCV13 has been approved in the United States and many countries around the world, and has replaced PCV7 in the infant immunization schedule without concerns about diminishing responses to other recommended vaccines.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
13-valent pneumococcal vaccine; concomitant administration; immune response; infants; toddlers