The introduction of 7-valent pneumococcal conjugate vaccine (PCV7), containing serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, has been associated with a dramatic reduction in incidence of invasive pneumococcal disease (IPD).1 – 3 However, a substantial burden of disease caused by non-PCV7 serotypes remains. In some regions where PCV7 vaccination has been implemented, incidence of disease caused by non-PCV7 serotypes, sometimes associated with antibiotic resistance (principally serotype 19A), has increased.2,4 – 9
To broaden protection and further decrease incidence of pneumococcal disease, 13-valent PCV (PCV13), adding serotypes 1, 3, 5, 6A, 7F, and 19A to those in PCV7, was developed and recently licensed in the United States, Canada, the European Union, and other countries. Based on post-PCV7 surveillance data, PCV13 has the potential to prevent up to 68% of IPD in children <5 years of age in the United States.2 With licensure of PCV13, infant vaccination series have been adjusted to replace PCV7 with PCV13. An important issue, however, is the safety and immunogenicity of PCV13 when administered to children who have already received PCV7. Such supplemental vaccination could provide protection against the 6 additional serotypes in PCV13, and has been recommended by the Advisory Committee on Immunization Practices (ACIP).10 This article reports the results of a study in which healthy children <5 years of age who had been previously vaccinated with PCV7 were vaccinated with 1 or 2 doses of PCV13, according to their age. These data supported ACIP recommendations.
Study Design and Subjects
This prospective, multicenter, open-label, phase 3 study was conducted at 32 sites in the United States. Healthy children between 15 months and 5 years of age who had previously been vaccinated with ≥3 doses of PCV7 were eligible to participate. Group 1 composed of children aged between 15 months and 2 years (ie, up to the second birthday), whereas group 2 composed of children older than 2 years of age up to their fifth birthday. Excluded were children with any contraindications to vaccination with a PCV, including history of an anaphylactic reaction to any vaccine or vaccine-related component, previous vaccination with 23-valent pneumococcal polysaccharide vaccine, or a documented episode of IPD. The last dose of PCV7 must have been received at least 56 days prior to study entry.
Subjects in group 1 received 2 doses of PCV13, given at least 56 days apart, and subjects in group 2 received 1 dose of PCV13. Blood was collected from study subjects prior to the first dose of PCV13 and 28 to 42 days after the last dose of PCV13.
The primary objective was to assess pneumococcal immune responses induced by PCV13 when measured after the last scheduled study vaccination in each age group, in children who had previously been vaccinated with at least 3 doses of PCV7. The safety objective was to evaluate the safety profile of PCV13 as measured by rates of local reactions, systemic events, and adverse events (AEs).
PCV13 contains the polysaccharides of pneumococcal serotypes in PCV7 (4, 6B, 9V, 14, 18C, 19F, and 23F), as well as serotypes 1, 3, 5, 6A, 7F, and 19A. Each polysaccharide is covalently conjugated to CRM197, a nontoxic variant of diphtheria toxin. PCV13 contains 2.2 μg of each polysaccharide, except for 4.4 μg of 6B, 5 mM succinate buffer, 0.02% polysorbate 80, and 0.125 mg of aluminum as aluminum phosphate per 0.5-mL dose.
Immunologic response to PCV13 was evaluated by measuring serotype-specific anticapsular polysaccharide immunoglobulin G (IgG) for each of the 13 pneumococcal serotypes using an enzyme-linked immunosorbent assay. IgG concentrations were measured against an international reference serum, 89-SF.11 Assay specificity was enhanced by preabsorbing serum samples with PnA, a crude pneumococcal cell wall extract, and purified nonvaccine serotype 22F to prevent nonspecific antibody binding.12,13 Enzyme-linked immunosorbent assay results were summarized by serotype using geometric mean concentrations (GMCs) and percentage of responders at ≥0.35 μg/mL, the World Health Organization-defined reference antibody concentration for assessment of vaccine efficacy against IPD in infants.14
Local reactions (injection site redness, swelling, and tenderness) and systemic events (including fever and use of antipyretic medications) were monitored and recorded daily by the parent/legal guardian for 7 days after each vaccination using an electronic diary. Tenderness was recorded as no discernible tenderness, present, or significant (interfered with limb movement). For redness and swelling, the parent/legal guardian measured the actual size of the reaction with a caliper, with each caliper unit representing 0.5 cm. Redness and swelling were categorized as absent; mild, 1 to 4 caliper units (0.5–2.0 cm); moderate, 5 to 14 caliper units (2.5–7.0 cm); or severe, >14 caliper units (>7.0 cm). Temperature was measured at bedtime and any time that fever was suspected, using an age-appropriate method. Only the highest recorded temperature for the day was entered in the electronic diary. Fever was defined as mild (≥38°C but ≤39°C), moderate (>39°C but ≤40°C), or severe (>40°C). Unsolicited AEs and serious AEs (SAEs) were monitored throughout the study. Final assessment of AEs and SAEs was conducted at approximately 6 months after the last scheduled study vaccination.
It was estimated that a final evaluable population of 100 and 145 subjects in groups 1 and 2, respectively, would be needed to achieve a margin of error of ±5% for the proportion of subjects achieving an antibody concentration ≥0.35 μg/mL with a 95% confidence interval (CI) and type I error = 0.05. Assuming a 20% dropout rate, 125 and 182 subjects were to be enrolled in groups 1 and 2, respectively. Subjects were included in the immunogenicity population if they received the required study vaccination(s) and had valid pre- and postvaccination immunogenicity data.
The primary immunogenicity end point was the proportion of responders, ie, the proportion of subjects achieving anticapsular IgG concentration ≥0.35 μg/mL for each of the pneumococcal serotypes 1 month after the last scheduled study vaccination. This end point was based on the World Health Organization guideline for postinfant series immunogenicity assessment for pneumococcal serotypes.14 Additional end points were the antipneumococcal serotype-specific GMCs measured before dose 1 and 1 month after the last scheduled study vaccination, and geometric mean fold rises in antibody concentration (post-/prevaccination). The CI for the single proportions was computed using the F distribution. For the geometric means, 2-sided 95% CIs were constructed by back transformation of the CIs for the mean of the logarithmically transformed assay results, computed using the Student t distribution. There were no formal statistical comparisons between age groups.
Safety data were descriptively summarized. In addition to the overall safety population (defined as those subjects who received at least 1 dose of PCV13), a prespecified exploratory analysis evaluated the effect on safety of the number of previous doses of PCV7 that subjects had received. Subjects in each age group were categorized into subgroups depending on whether they had received 3 or 4 doses of PCV7 prior to enrollment, and were analyzed if they contained >20% of subjects in an age group.
This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and was designed and performed in compliance with Good Clinical Practice and the applicable regulatory requirements. The protocol was approved by the Institutional Review Boards at the various sites. Informed consent was provided by each subject's parent or legal guardian.
The first subject was enrolled on November 18, 2008. Enrollment was completed on March 2, 2009, and the last 6-month follow-up was completed on June 16, 2009. A total of 307 subjects were enrolled (Fig., Supplemental Digital Content 1, http://links.lww.com/INF/A987); 284 subjects, including 109 in group 1 and 175 in group 2, were eligible for the immunogenicity analysis. Table, Supplemental Digital Content 2, http://links.lww.com/INF/A988, shows the baseline demographic characteristics of all study subjects. No subjects discontinued for safety-related reasons.
Prevaccination with PCV13, the percentages of subjects with IgG concentrations ≥0.35 μg/mL, and the GMCs for the serotypes in PCV7 were generally numerically higher in group 1 than in group 2 (Tables 1 and 2). However, for the 6 additional serotypes in PCV13, the percentages of subjects with IgG concentrations ≥0.35 μg/mL and the GMCs were numerically lower in group 1 than in group 2.
After receipt of PCV13, the proportion of responders (definition is mentioned in Methods section) increased for all 13 serotypes in both groups (Table 1). IgG GMCs increased postvaccination by ≥2-fold for each of the 13 serotypes in both groups (Table 2). In both groups, the largest fold rises were observed for serotypes 1 and 7F, which increased by 108- to 124-fold in group 1 and by 28- to 35-fold in group 2.
Most local reactions and systemic events (Fig., Supplemental Digital Content 3, http://links.lww.com/INF/A989) were mild or moderate. In group 1, 70 subjects (63.6%) reported local reactions after dose 1 and 58 (64.4%) reported local reactions after dose 2. In group 2, 112 subjects (70.9%) reported local reactions postvaccination. Six subjects (8.8%) in group 1 and 15 (10.6%) in group 2 reported significant tenderness; no subjects reported severe swelling or severe redness. No subjects in group 1 had fever >40°C after dose 1 or dose 2; in group 2, 1 subject did experience fever >40°C after dose 1 (Fig., Supplemental Digital Content 3, http://links.lww.com/INF/A989).
Unsolicited AEs were considered generally consistent with illnesses common in these age groups. Two SAEs were reported in group 1 after dose 2 and 2 SAEs were reported in group 2, but none was considered related to the study vaccine. No deaths occurred during the study.
A subgroup analysis was conducted to compare safety outcomes among subjects who had received 3 or 4 doses of PCV7 prior to enrollment. In group 1, 29.4% of subjects had received 3 doses of PCV7 and 70.6% of subjects had received 4 doses prior to enrollment (Table, Supplemental Digital Content 2, http://links.lww.com/INF/A988). In group 2, only 4.4% of subjects had received 3 prior doses of PCV7; therefore, the subgroup analysis was not conducted in group 2.
Rates of local reactions, systemic events, and AEs did not increase with number of prior doses of PCV7. Indeed, rates of local reactions tended to be higher in the 3-dose subgroup than the 4-dose subgroup, after both dose 1 (tenderness: 53.1% vs. 50.0%; swelling: 35.5% vs. 21.2%; redness: 46.9% vs. 36.6%) and dose 2 (tenderness: 76.0% vs. 50.0%; swelling: 29.2% vs. 20.4%; redness: 44.0% vs. 31.4%). Rates of systemic events tended to be higher in the 3-dose subgroup than the 4-dose subgroup, but no clear pattern could be discerned. A slightly higher proportion of AEs occurred in the 3-dose subgroup than the 4-dose subgroup after dose 1, and a lower proportion of AEs occurred in the 3-dose subgroup than the 4-dose subgroup after dose 2 (data not shown).
This study demonstrated that PCV13 was immunogenic, safe, and well tolerated in healthy children aged <5 years who had been previously vaccinated with 3 or 4 doses of PCV7. PCV13 boosted anticapsular IgG responses to the 7 serotypes of PCV7 and induced significant immune responses to the 6 additional serotypes in PCV13.
The primary end point of this study was the proportion of subjects with IgG concentration ≥0.35 μg/mL against each serotype in PCV13 after receipt of the vaccine. For both groups, ≥98% of subjects had IgG titers ≥0.35 μg/mL postvaccination with PCV13 for each of the serotypes in PCV13, with the exception of serotype 3, for which 94.5% and 92% of subjects in group 1 and group 2, respectively, had postvaccination titers ≥0.35 μg/mL. An additional indicator of immunogenicity was the at least 2-fold rise in geometric mean fold rises of post- versus prevaccination IgG titers, for each serotype contained in PCV7. Antibody responses to the 6 additional serotypes compared favorably to responses seen after 3-dose infant series in pivotal studies of PCV13, suggesting that they will be protective.15,16 A similar comparison to postinfant series antibody responses was used previously to determine the number of recommended doses of PCV7 for children 7 months to 5 years of age who were naive to PCV.17
Although all postvaccination titers in both groups for all 13 serotypes in PCV13 were well in excess of the serologic correlate of immunity of IgG ≥0.35 μg/mL, there was a marked variation in response between serotypes as well as to the response in group 1 as compared with group 2. For the serotypes in PCV7, postvaccination GMC were higher for each serotype in subjects in group 2 as compared with group 1. However, for the 6 additional serotypes in PCV13, the responses were more variable. For serotypes 1 and 5, postvaccination GMCs in group 1 were higher than group 2, GMCs for serotypes 6A and 19A were higher in group 2, and GMCs for serotypes 3 and 7F were similar. The reasons for these differences are not clear and are beyond the scope of this project.
Not unexpectedly, a high proportion of subjects in both groups had IgG titers ≥0.35 μg/mL against PCV7 serotypes prior to receipt of PCV13, likely because of the inclusion criterion requiring prior receipt of at least 3 doses of PCV7. Additionally, the proportion of subjects with antipneumococcal IgG ≥0.35 μg/mL was much higher for many of the PCV7 serotypes in group 1 than in group 2, probably due to the more recent receipt of PCV7 in among children in group 1. Prior to receipt of PCV13, IgG titers varied for the 6 additional serotypes, being much lower for serotypes 1, 3, and 7F than for 5, 6A, and 19A. The differences in IgG concentrations to serotypes 1, 3, and 7F between group 1 (0.04–0.06 μg/mL) and 2 (0.09–0.22 μg/mL) before receipt of PCV13 may represent a shorter duration of natural exposure to these serotypes in the younger age group. IgG titers to serotypes 5, 6A, and 19A before receipt of PCV13, in contrast, were higher than expected in a population that had not been directly immunized against these serotypes. This has been previously described for serotypes 6A and 19A, and is due to cross-reactive antipolysaccharide antibody responses to those serotypes.18,19 Although anti-6A antibodies elicited by PCV7 are somewhat associated with antipneumococcal opsonophagocytic assay activity, cross-reactive antibodies to types 5 and 19A are not, in contrast to the opsonophagocytic assay activity that is elicited subsequent to PCV13 immunization.15,16,20 Evidence suggests that certain Escherichia coli and Klebsiella antigens show some cross-reactivity with serotype 5 polysaccharide.21,22 Nonetheless, vaccination with PCV13 resulted in significant increases in proportions of responders and IgG concentrations to all 13 serotypes, including those serotypes with high titers before receipt of PCV13.
In this study, PCV13 was generally well tolerated. Local reactions and fever were generally mild or moderate, with no reports of severe redness or swelling, and only 1 report of severe fever. Rates of significant tenderness (8.8%–10.6%) were similar to rates following the toddler dose of PCV13 in a German study (dosing schedule: 3, 4, 5, and 12 months) and an US study (dosing schedule 2, 4, 6, and 12 months) (10.8% and 15.4%, respectively).15,16 There were no clinically significant differences in safety results between subjects receiving 3 prior doses of PCV7 and those receiving 4 prior doses. These results allay the theoretical concern of an Arthus reaction associated with an excessive number of inoculations with vaccines containing components of diphtheria (ie, the CRM component of PCV7 and PCV13). In fact, this study demonstrated, even after 5 doses of PCV, no increase in rates of local reactions or other adverse reactions with increasing number of doses.
A limitation of our study was the inability to determine antibody levels of subjects in group 1 after the first dose of PCV13, as blood was only collected after the final dose of vaccine. Thus, this study does not provide data on whether a single dose of PCV13 would be sufficient in the younger age group, which might be relevant in countries with reduced dosing schedules. Nonetheless, the robust response of group 2 subjects to 1 dose of PCV13 suggests there may be a similar response in the younger age group. In a study of PCV13 conducted in French children,23 infants were randomized to receive either 4 doses of PCV13 at 2, 3, 4, and 12 months of age; 4 doses of PCV7 at the same ages; or 3 doses of PCV7 at 2, 3, and 4 months of age; and 1 dose of PCV13 at 12 months of age. As compared with children who received PCV7, children who received PCV13, including those who received only a single dose of PCV13 at 12 months of age, had higher GMCs to the 6 additional serotypes in PCV13 when tested at 13 months of age.
The ACIP has recommended to the Centers for Disease Control and Prevention that PCV13 be included in the routine immunization schedule, replacing PCV7.10 The ACIP also recommends a single supplemental dose of PCV13 for all children 14 to 59 months of age who have received a complete PCV7 schedule.10 Similar recommendations have been made in other countries.
Evidence from several epidemiologic studies supports the use of a supplemental dose of PCV13 in children who have received 3 or 4 previous doses of PCV7. First, although the overall incidence of IPD is decreasing, the incidence of IPD due to nonvaccine serotypes is increasing, particularly serotype 19A.3 – 6,24 – 28 Besides increasing in frequency, serotype 19A is becoming less susceptible to commonly used first-line antimicrobial agents and many second-line agents.4,6 A manifestation of the disease burden associated with serotype 19A is the increase in hospitalizations due to complicated pneumococcal pneumonia.29 – 32 The older age of children with complicated pneumococcal pneumonia supports the perspective that a supplemental dose of PCV13 may be particularly beneficial in this age group.30,31,33 However, no clinical data are yet available that address this issue. Current guidelines recommend the use of a single dose of PCV13 in children aged 6 to 18 years with underlying conditions predisposing them to IPD, who have not received PCV13 previously.10 Ongoing studies are evaluating PCV13 as a catch-up vaccination in healthy children aged 6 to 18 years.
In conclusion, we have demonstrated that PCV13 is immunogenic and safe in children previously vaccinated with PCV7. By eliciting high antibacterial immune responses to the 6 additional serotypes, PCV13 may provide protection against these serotypes, which are important causes of pneumococcal disease globally.
The authors thank the members of the 3011 study group for their contributions to this study (mentioned in Appendix).
A.T., M.S., S.P., W.G., E.E., D.S., and A.G. are employees of Pfizer Inc. Study design was conducted by A.T., M.S., S.P., W.G., E.E., D.S., and A.G. Study recruitment and conduct were performed by R.F., S.Y., A.L., and the Wyeth 3011 Study group. Study physicians were reimbursed for expenses associated with conduct of the study but not directly paid for participation. Analysis of study data was performed by R.F. and S.Y. in collaboration with W.G., D.S., and A.G. Primary writing of the manuscript was performed by R.F. and S.Y. with the assistance of Vicki Schwartz, PhD, of Excerpta Medica.
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APPENDIX 3011 Study Group: Contributing Physicians and Practices
Gerald Bader, MD (The Vancouver Clinic, Inc., Vancouver, WA); John Frey, MD (Monroe Medical Foundation, Monroe, WI); Kristina Bryant, MD (University of Louisville, Pediatric Clinical Trials Unit, Louisville, KY); Susan Keathley, MD (Little Rock Children's Clinic, P.A., Little Rock, AR); Richard Rupp, MD (University of Texas Medical Branch at Galveston, Department of Pediatrics, Galveston, TX); Anthony Johnson, MD (Arkansas Pediatric Clinic, Little Rock, AR); Kevin Rouse, MD (The Children's Clinic of Jonesboro, P.A., Jonesboro, AR); Shelly Senders, MD (Senders Pediatrics, Cleveland, OH); Michael Martin, MD (Advanced Pediatrics, Vienna, VA); Malcolm Sperling, MD (Edinger Medical Group, Fountain Valley, CA); Wilson Andrews, MD (Pediatrics and Adolescent Medicine, P.A., Woodstock, GA); Terry Payton, MD (Northwest Arkansas Pediatric Clinic, Fayetteville, AR); Michael Pichichero, MD (Research Institute, Rochester General Hospital, Rochester, NY); David Hurley, MD (Cottonwood Pediatrics, Murray, UT); Carina A. Rodriguez, MD (University of South Florida, Department of Pediatrics, Tampa, FL); William Kennedy, MD (Loma Linda University Health Care, Loma Linda, CA); Umesh Goswami, MD (Northern Illinois Research Associates, Dekalb, IL); Robbie Rhodes, MD (Central Arkansas Pediatric Clinic, Benton, AR); Matthew Cox, MD (Families First Pediatrics, South Jordan, UT); Laurie Harris-Ford, MD (Alpha Clinical Research, Clarksville, TN); Janet Tillisch, MD (Innovis Health/Odyssey Research, Fargo, ND); Todd Twogood, MD (Odyssey Research, Bismarck, ND); Stanley Grogg, MD (Oklahoma State University Center for Health Sciences Physicians, Pediatrics, Tulsa, OK); Henry Bernstein, MD (General Academic Pediatrics, Dartmouth Hitchcock Medical Center, Lebanon, NH); Carrie Byington, MD (University of Utah Hospitals and Clinics, Pediatric Clinic, Salt Lake City, UT); Christopher Chambers, MD (Thomas Jefferson University, Department of Family and Community Medicine, Philadelphia, PA); Mark Simpson, MD (Cary Pediatric Center, Cary, NC); Marshall Benbow, MD (Southwest Children's Research Associates, San Antonio, TX).