Widespread use of the 7-valent pneumococcal conjugate vaccine (PCV7; serotypes 4, 6B, 9V, 14, 18C, 19F and 23F) has resulted in dramatic decreases in invasive pneumococcal disease (IPD) caused by PCV7 serotypes among vaccinated children as well as unvaccinated adults.1–4 The emergence of serotypes, particularly serotype 19A, associated with IPD, has led to the development of a 13-valent PCV (PCV13), which adds serotypes 1, 3, 5, 6A, 7F and 19A to those serotypes in PCV7. PCV13 is now approved in >100 countries and used routinely in many countries. In the United States, the Advisory Committee for Immunization Practices (ACIP) recommends routine vaccination with PCV13 as a 4-dose series at ages 2, 4, 6 and 12–15 months. ACIP also recommends that children aged ≤59 months not previously vaccinated with PCV13, or those with an incomplete infant series of PCV7 or PCV13 be vaccinated with ≥1 dose of PCV13, depending on the age of the child.5
IPD incidence is bimodal with peaks occurring in children aged <5 years and the elderly. However, older children at increased risk for pneumococcal infections also may benefit from receipt of PCV13. PCV13 was recently approved in the United States and Europe for healthy children aged 6–18 years who had not previously received the vaccine.6,7 The American Academy of Pediatrics and ACIP recommend 1 dose of PCV13 for children in this age group who are at increased risk of pneumococcal disease regardless of previous vaccination with PCV7 or 23-valent pneumococcal polysaccharide vaccine.5,8
Data on safety and immunogenicity of PCV13 in children aged ≥6 years have not been published previously. We, therefore, report the results from a study to evaluate the safety and immunogenicity of PCV13 in healthy children aged 5–18 years. Results from this study were used to support licensure and recommendations for this age group.
Study Design and Subjects
This prospective, multicenter, open-label phase 3 study was conducted at 29 sites in the United States. The study included 4 age groups: ≥15 months to <2 years; ≥2 to <5 years; ≥5 to <10 years and ≥10 to <18 years. The immunogenicity and safety of PCV13 in the ≥15 months to <2 years and ≥2 to <5 years groups have been reported previously.9 The current article presents the results of a single 0.5 mL dose of PCV13 administered to children in the ≥5 to <10 years and ≥10 to <18 years age groups.
Healthy children aged ≥5 to <10 years, that is, from age 5 years to prior to the 10th birthday (the younger age group), were eligible if they previously had received ≥1 dose of PCV7, with the last dose having been administered ≥56 days before study entry. Healthy children aged from ≥10 to <18 years, that is, from age 10 years to prior to the 18th birthday (the older age group) were eligible if they had never received a dose of pneumococcal vaccine (conjugate or polysaccharide). In these age groups, 17.4% of participating children had a history of asthma, which has been associated with increased risk of IPD.10
Subjects were excluded if they had history of anaphylactic reaction to any vaccine or vaccine-related component, contraindication to vaccination with a PCV or intramuscular injection, history of culture-proven IPD, serious chronic disorder or significant neurologic disorder, receipt of blood products or gamma globulin in the previous 6 months, known or suspected immune deficiency or suppression, participation in another investigational or interventional trial, pregnancy or breast feeding or previous vaccination with PPSV23.
This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki. All relevant study materials were approved by independent ethics committees and/or institutional review boards. Written informed consent was provided by each subject’s parents/legal guardians. Study-specific assent forms were provided to subjects in older age groups as applicable under institutional review board requirements.
PCV13 contains serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, with each saccharide covalently conjugated to 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 serotype 6B, 5 mM succinate buffer, 0.02% polysorbate 80 and 0.125 mg of aluminum as aluminum phosphate. PCV13 was administered intramuscularly into the left arm or leg.
Routine pediatric vaccines could be administered concurrently with PCV13. Other registered, commercially available vaccines could be administered >14 days (nonlive vaccines) or >28 days (live vaccines) before PCV13 or >7 days after PCV13.
Blood was drawn immediately before and 1 month (28–42 days) after vaccination with PCV13. Antipneumococcal immunoglobulin G (IgG) geometric mean concentrations (GMCs) for each of the PCV13 serotypes were determined using the standardized double-absorption enzyme-linked immunosorbent assay. This enzyme-linked immunosorbent assay uses a cell wall extract containing cell wall polysaccharide plus serotype 22F capsular polysaccharide containing cell wall extract containing cell wall polysaccharide 2 for preabsorption of test samples.11–15 Functional serotype-specific antibodies were assessed using microcolony opsonophagocytic activity (OPA) assays and results reported as antibody titers.16,17
Local reactions (redness, swelling and tenderness) at the PCV13 vaccination site, systemic events [fever, decreased appetite, irritability, increased or decreased sleep and hives (urticaria)], and the use of antipyretic medication to prevent or to treat symptoms were recorded by parents/legal guardians in an electronic diary for 7 days postvaccination. Tenderness was recorded as no discernible tenderness, discernible tenderness present or tenderness interfering with limb movement. Parents/legal guardians used a caliper to measure the size of redness and swelling; measurements were categorized as absent, mild (0.5–2.0 cm), moderate (2.5–7.0 cm) or severe (>7.0 cm). Temperature was measured at bedtime or whenever fever was suspected during the 7 days postvaccination, using an age-appropriate method. Fever was categorized as absent (<38.0°C), mild (≥38.0°C to ≤39.0°C), moderate (>39°C to ≤40.0°C) or severe (>40.0°C). Other adverse events (AEs) were collected for 1 month postvaccination and serious AEs were collected for 6 months postvaccination.
Immunogenicity Analysis: Study Cohorts and Comparators
Initially, the study was designed to include 100 children in each of the age groups; however, after consultation with the United States Food and Drug Administration, the design was modified to increase enrollment to 300 children in each group.
Based on consultation with the Food and Drug Administration, the first 100 subjects enrolled in each age group (≥5 to <10 years and ≥10 to <18 years) were designated as the “exploratory” cohort, and the following 200 subjects were designated as the “confirmatory” cohort. Data from the exploratory cohorts were used to establish primary endpoint criteria for testing in the confirmatory cohorts, but only the results of the analyses from the confirmatory cohorts are presented.
In consultation with the Food and Drug Administration, the benchmark for immunogenicity in this study was based on the IgG response of infants who received a 4-dose series (at ages 2, 4, 6 and 12 months) of PCV13 or PCV7 in a previous study (subsequently referred to as the “historical” study).18 This allowed data from the older children and adolescents in the present study to be bridged to data from a population (ie, infants and toddlers) with demonstrated immune responses to PCV13. Infants and toddlers also represent the age group in which the efficacy and effectiveness of PCV7 have previously been demonstrated.2,19–21 The primary comparison for the younger age group (confirmatory cohort) involved demonstration of noninferiority of serotype-specific IgG levels compared with the IgG posttoddler responses from the historical study (bridging). As it is unclear at what age serotype-specific IgG levels are no longer predictive of protection, OPA geometric mean titers (GMTs) were also assessed. Accordingly, the primary comparison for the older age group (confirmatory cohort) involved demonstration of noninferiority comparing the OPA responses in this age group to those that of the younger age group.
Pneumococcal IgG GMCs and geometric mean fold rises (GMFRs) in antibody concentrations (postvaccination/prevaccination) were calculated for each age group. Two-sided 95% confidence intervals (CIs) were constructed by back transformation of the CIs for the mean of the logarithmically transformed assay results and GMFRs, computed using the Student t distribution.
OPA GMTs and GMFRs were calculated for each age group. The proportion of subjects achieving OPA assay titers greater than or equal to the lower limit of quantitation was calculated for each serotype, along with exact, 2-sided, 95% CIs. OPA LLOQs were defined for each serotype as the lowest titer value demonstrating acceptable linearity (relative accuracy) and precision, as defined in a validation protocol.
For the primary endpoint in the younger group, antipneumococcal IgG GMCs following vaccination were compared with values following the toddler dose in the PCV7 and PCV13 groups from the historical study. The geometric mean ratio of the IgG GMCs was calculated for each PCV13 serotype. For the PCV7 serotypes, comparisons were with subjects who received PCV7 in the historical study; for the 6 additional serotypes, comparisons were with subjects who received PCV13 in the historical study. For the primary OPA endpoint in the older group, OPA GMTs following vaccination were compared with the OPA GMTs after vaccination in the younger group, and the geometric mean ratio of the OPA GMTs for each PCV13 serotype was calculated. Two-sided 95% CIs for the GMRs were estimated by back transformation of the CIs for the difference in means of the logarithmically transformed assay results, based on the Student t distribution. For both IgG GMCs and OPA GMTs, noninferiority for a given serotype was met if the lower limit of the 2-sided 95% CI (LCI) for geometric mean ratio was >0.5 (ie, ≤2-fold).
Evaluable immunogenicity populations included subjects who received the required study vaccination, had blood drawn before vaccination and within 27–56 days after vaccination, had ≥1 valid and determinate assay result before and after vaccination and had no major protocol violations.
Safety endpoints included local reactions, systemic events and AEs. Safety data were descriptively summarized, and no formal statistical comparisons were performed. The safety population included all subjects who received 1 dose of PCV13.
Subject Disposition and Demographics
A total of 598 children enrolled, including 199 each in the confirmatory cohorts of the younger and older age groups, respectively. The evaluable immunogenicity populations included 182 and 190 subjects in the younger and older age groups, respectively. Table 1 presents subject demographics for all subjects; demographic data were similar in the confirmatory and evaluable immunogenicity populations. Most subjects (72.2%) were white (Table 1). In a post hoc analysis, no differences in response to PCV13 were noted based on race (data not shown).
Younger Age Group
Subjects in the younger age group responded to PCV13 with IgG GMCs increasing from pre- to postvaccination by ≥4.5-fold for the PCV7 serotypes and by ≥1.4-fold for the 6 additional serotypes (Table 2), and OPA GMTs increasing from pre- to postvaccination by ≥4.2-fold for the PCV7 serotypes and by ≥9.7-fold for the 6 additional serotypes (Table 2). OPA titers ≥ lower limit of quantitation 1 month postvaccination were achieved by 98.9–100% of subjects for the PCV7 serotypes and 97.8–100% for the 6 additional serotypes (Table, Supplemental Digital Content 1, http://links.lww.com/INF/B710).
For the primary comparison of PCV7 serotypes, IgG GMCs were ≥2.5-fold greater than posttoddler dose IgG GMCs in the PCV7 group in the historical study, demonstrating noninferiority and statistically significant greater (95% LCI of the ratio >1.0) responses for all serotypes (Table 3). For the 6 additional serotypes, IgG GMCs were ≥1.2-fold greater than values in the combined PCV13 groups posttoddler dose in the historical study, demonstrating noninferiority and statistically significant greater (95% LCI of the ratio >1.0) responses for all serotypes (Table 3).
Older Age Group
Subjects in the older age group also responded to PCV13, with IgG GMCs increasing from pre- to postvaccination by ≥3.6-fold for the PCV7 serotypes and by ≥1.9-fold for the 6 additional serotypes (Table 4). OPA GMTs increased by ≥8.6-fold for the PCV7 serotypes and by ≥11.8-fold for the 6 additional serotypes (Table 4), and OPA titers ≥ lower limit of quantitation were achieved by 100% of subjects for the PCV7 serotypes and 94.5–100% for the 6 additional serotypes (Table, Supplemental Digital Content 1, http://links.lww.com/INF/B710).
For the primary comparison, OPA GMTs were noninferior in the older age group compared with the younger age group for 12 of 13 serotypes and statistically significantly greater for serotypes 1, 4, 6A, 6B, 9V, 14, 19A, 19F and 23F (Table 5). The one exception was serotype 3, which was lower in the older age group compared with the younger age group (95% LCI <0.5; Table 5).
Similar proportions of subjects in the younger and older age groups reported local reactions (89.6% and 90.5% of subjects, respectively; Table 6). Most local reactions were mild or moderate and lasted for <3 days. Significant tenderness was reported by more subjects in the older age group (43.8%) than the younger age group (19.5%). Both severe redness and severe swelling were reported by 7 (3.3%) and 4 (1.9%) subjects in the younger and older age groups, respectively. Systemic events were reported by similar proportions of subjects in the younger and older age groups (47.2% and 51.4% of subjects, respectively; Table 6). One subject in each age group reported fever >40°C.
AEs were reported by 19.4% and 24.2% of subjects in the younger and older age groups, respectively, and were generally consistent with childhood illnesses expected in these age groups. The most frequently reported AEs in the younger age group were cough (10 subjects, 3.4%), vomiting (8 subjects, 2.7%), pyrexia (7 subjects, 2.4%) and streptococcal pharyngitis (6 subjects, 2.0%). In the older age group, the most frequently reported AEs were headache (10 subjects, 3.4%), cough (5 subjects, 1.7%), pharyngitis (5 subjects, 1.7%), influenza (5 subjects, 1.7%), oropharyngeal pain (5 subjects, 1.7%) and sinusitis (5 subjects, 1.7%). Three subjects in each age group reported AEs considered related studying vaccine. There were no AEs that led to withdrawal from the study, no serious AEs considered related to study vaccine and no deaths.
PCV13 was immunogenic and safe when administered to healthy older children and adolescents, regardless of prior PCV7 vaccination. Antipneumococcal IgG GMCs and OPA GMTs increased from pre- to postvaccination, demonstrating a substantial response to PCV13 in both age groups. For the primary comparison, IgG GMCs in the younger age group were shown to be noninferior and statistically significantly greater compared with posttoddler IgG GMCs in subjects receiving PCV7 or PCV13 in the historic comparison study. Protective levels of antipneumococcal IgG antibodies have not been established in this age group; however, these data bridge the immune responses to PCV13 in this age group to a population with known efficacy, suggesting that a single dose of PCV13 induces a protective immune response in children aged ≥5 to <10 years.
With the exception of serotype 3, OPA GMTs were noninferior in the older age group compared with the younger age group. Despite meeting criteria for noninferiority, the OPA GMTs for serotypes 3, 5, 7F and 18C in the older age group were actually statistically significantly lower than those for the younger age group (nonoverlapping CIs of the OPA GMTs), but the 95% LCIs for the OPA GMRs for serotypes 5, 7F and 18C were >0.5 and, therefore, satisfied the noninferiority criterion; however, for serotype 3, the 95% LCI was <0.5 indicating that this serotype did not achieve noninferiority. Nevertheless, OPA GMTs for serotype 3 increased by approximately 10-fold from pre- to postvaccination in both age groups, demonstrating a functional immune response to this serotype. Notably, for the children in the younger age group, all of whom had been vaccinated previously with PCV7, the single dose of PCV13 represented a booster dose for the serotypes common to PCV7 and PCV13. The OPA responses in children in the older age group, all of whom were pneumococcal vaccine-naïve, were noninferior to those in the younger age group for most serotypes, suggesting that a single dose of PCV13 in children aged >5 years may be sufficient for development of a robust immune response, regardless of past receipt of PCV7.
Comparisons between the younger age group and the historic data permitted bridging of immune responses in this age group to immune responses in the age group in which efficacy of PCV7 has been established.19–23 Similarly, bridging of the antipneumococcal OPA responses in the older age group was achieved by comparison with OPA responses in the younger age group. Concordance between IgG and OPA responses has been demonstrated in previous studies of infants and toddlers,24,25 providing additional justification for using the younger age group as an appropriate basis for comparison of the older age group.
Recent studies have demonstrated the effectiveness of PCV13 in children aged <2 years.26,27 Although risk of pneumococcal diseases is higher among younger children (especially those aged <2 years), healthy older children and adolescents still have some risk of pneumococcal diseases.1,28 In particular, asthma is an independent risk factor for pneumococcal disease.10 In the present study, 17.4% of subjects had a history of asthma, suggesting that a substantial proportion of the population might have been at higher risk of pneumococcal disease. A post hoc analysis suggested the immune responses to PCV13 were similar in subjects with or without asthma (data not shown); thus, a single dose of PCV13 in older children with asthma may provide an adequate protective immune response. Moreover, because pneumococcal pneumonia is a secondary complication of influenza, and risk of pneumococcal pneumonia following influenza in children has been shown to be reduced with PCV7,29 PCV13 is likely to provide a similar protective effect. The American Academy of Pediatrics and ACIP recommend 1 dose of PCV13 for children aged 6 through 18 years who are at increased risk of pneumococcal disease regardless of previous vaccination with PCV7 or 23-valent pneumococcal polysaccharide vaccine.5,8
In conclusion, PCV13 was immunogenic and safe in healthy older children and adolescents. Immune responses were noninferior to those in a population in which efficacy of PCV7 was established. Further studies on immunogenicity, safety and effectiveness of PCV13 in children and adolescents at high risk of pneumococcal disease are ongoing.
The authors thank the members of the 3011 study group (see Appendix, Supplemental Digital Content 2, http://links.lww.com/INF/B711) for their contributions to this study. Medical writing support was provided by Vicki Schwartz, PhD, at Excerpta Medica and was funded by Pfizer Inc.
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