Infections caused by Streptococcus pneumoniae are a major cause of morbidity and mortality worldwide. Globally, pneumococcal disease has been estimated to account for up to 1 million deaths annually in children aged <5 years.1 S. pneumoniae is the most frequent cause of pediatric meningitis in Korea, causing 41% of cases of meningitis in infants and children aged 3 months to 18 years in 1996 to 2005.2 Treatment is complicated by pneumococcal antimicrobial resistance, which is common in Korea. During 1995 to 2005, nonsusceptibility rates were 9.1% to penicillin and 94.8% to erythromycin among invasive isolates in Korean children.3
The 7-valent pneumococcal conjugate vaccine (PCV7; serotypes 4, 6B, 9V, 14, 18C, 19F and 23F) is efficacious in preventing pediatric pneumococcal disease caused by vaccine serotypes.4–6 PCV7 covers the serotypes most common in North America, which differ from those frequently encountered in Korea. The most common serotypes in Korea during 1991 to 2006 were serotypes 19F (21%), 23F (17.8%), 19A (10.8%), 6B (9.3%), 6A (8%) 14 (7.4%), and 9V (4.5%); these 7 serotypes accounted for 79% of the total isolates. Overall, PCV7 serotypes accounted for 64.1% of total isolates and 62.7% of invasive isolates.7
To broaden coverage, a 13-valent PCV (PCV13; PCV7 serotypes and additional serotypes 1, 3, 5, 6A, 7F and 19A) has been developed and is now licensed in many countries, including Korea. In Korea, PCV13 is estimated to provide approximately 81% coverage of invasive serotypes in children aged <5 years, based on a surveillance study conducted at a tertiary care center in Seoul from 1991 to 2006;7 notably, this study demonstrated an increase in the percentage of serotype 19A found in invasive isolates from 0% during the period 1991 to 1994 to 18% during 2001 to 2004, concurrent with a decrease in the prevalence of serotype 19F, indicating a need for coverage of serotype 19A.
This study compared the immunogenicity, safety and tolerability of PCV13 with PCV7 when administered with recommended routine vaccines to healthy infants in Korea.
MATERIALS AND METHODS
This was a parallel-group, randomized, double-blind trial conducted at 6 sites in Korea. Subjects were randomly assigned in a 1:1 ratio to receive PCV13 or PCV7 at ages 2, 4, 6 and 12 months (Table 1). The study was conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice and the ethical principles that have their origins in the Declaration of Helsinki.
Inclusion criteria included healthy infants and previous vaccination with hepatitis B virus vaccine at birth and age 1 month. All infants had been vaccinated with Bacillus Calmette-Guerin before 1 month of age, before enrollment in the study. Exclusion criteria included: previous vaccination with any required study vaccines; contraindication to any vaccine-related component; bleeding diathesis or a condition associated with prolonged bleeding time that would contraindicate intramuscular injection; immune deficiency or suppression; history of culture-proven S. pneumoniae disease; major known congenital malformation or serious chronic disorder; receipt of blood products or gamma globulins or participation in another interventional trial.
PCV13 contains saccharides from pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, all individually conjugated to cross-reactive material 197, a nontoxic variant of diphtheria toxin. PCV7 contains saccharides from pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, all individually conjugated to cross-reactive material 197. PCV13 and PCV7 are formulated to contain 2.2 µg of each saccharide, except for 4.4 µg of 6B per 0.5-mL dose and 0.125mg of aluminum phosphate (adjuvant) per 0.5-mL dose. PCV13 and PCV7 were identical in appearance.
Pediatric vaccines which were required to be given as part of the study included: diphtheria, tetanus and acellular pertussis vaccine administered concomitantly with PCV; inactivated poliovirus vaccine and Haemophilus influenzae type b vaccine administered at 7–21 days after PCV and hepatitis B virus vaccine administered 7–21 days after dose 3 of PCV (Table 1). Costs for these vaccines, which were provided by the investigator, were reimbursed by the sponsor.
The PCVs were administered intramuscularly in the anterolateral aspect of the left thigh. Concomitant diphtheria, tetanus and acellular pertussis vaccine was administered similarly into the right thigh. Inactivated poliovirus, Haemophilus influenzae type b and hepatitis B virus vaccines were administered according to Korean standard vaccination practice.
Other recommended vaccines were permitted, including rotavirus; measles, mumps, and rubella; influenza; varicella and inactivated Japanese encephalitis vaccines.
Blood samples were obtained 28–42 days after dose 3 of the infant series and after the toddler dose (Table 1). The World Health Organization–standardized enzyme-linked immunosorbent assay (ELISA) was used to determine the serum concentrations of anticapsular polysaccharide binding IgG antibodies for each of the pneumococcal serotypes included in PCV13, using the international reference serum 89-SF.8–11 The double-absorption ELISA used a cell wall extract containing cell wall polysaccharide plus serotype 22F capsular polysaccharide containing cell wall polysaccharide-2.
As a post hoc analysis, functional antibody activity was measured by an opsonophagocytic activity (OPA) assay. Functional antibody activity responses, as measured by OPA, are thought to contribute to vaccine-induced protection against pneumococcal disease.12 The microcolony OPA assay used in this study was a modification of the method of Romero-Steiner and coworkers,13 and was based on previously described methods.14 This assay has a more stringent qualification and validation process for the quantitation of a serum response. To quantify functional antibody titers with appropriate precision and accuracy, the lowest limit of quantitation (LLOQ) was determined for each serotype-specific microcolony OPA assay during assay validation. Determination of LLOQ is described in the Supplemental Digital Content 1, http://links.lww.com/INF/B358. OPA titers above the LLOQ were considered accurate, and their quantitated values were reported. Titers below the LLOQ were set to 0.5 times the limit of detection (0.5 × limit of detection) for analysis.
Using an electronic diary, parents/legal guardians recorded local reactions (tenderness, redness and swelling) at the PCV injection site, systemic events (fever, decreased appetite, irritability, increased sleep and decreased sleep) and use of antipyretic medications to treat or prevent symptoms for 4 days after each vaccination. Tenderness was recorded as none, present or interfered with limb movement. The actual size of redness or swelling was measured with a caliper (1 caliper unit represents 0.5cm). Redness and swelling were categorized as mild (0.5–2.0cm), moderate (2.5–7.0cm) or severe (>7.0cm). Axillary temperature was collected daily at bedtime for 4 days after each vaccination, and at any time fever (axillary temperature ≥38°C) was suspected. In the event of a fever, temperature was collected daily until the fever had resolved. Fever was categorized as absent (<38°C), mild (≥38°C to ≤39°C), moderate (>39°C to ≤40°C) or severe (>40°C). Adverse events (AEs) were assessed at each visit throughout the study. All nonserious AEs were documented on the case report form during the infant series (over an approximate 4-month period) and after the toddler dose (over an approximate 1-month period); between the infant series and the toddler dose (over a 5-month period between vaccinations) all AEs were assessed, but only newly diagnosed chronic medical conditions were documented on the case report form. Serious AEs (SAEs) were reported and documented on the case report form throughout the study.
Sample Size Estimation
Sample size estimation was based on the proportion of responders for each serotype, using data from the PCV13 group in a previous study.15 With a type I error of 0.05 (2-sided), 75 evaluable subjects per treatment group allowed estimation of the proportion of subjects achieving an antibody concentration ≥0.35 μg/mL for each serotype to be within ±7.3% precision. Assuming a dropout rate of at most 15%, enrollment of 180 subjects would ensure 150 evaluable subjects. For the post hoc OPA analysis, subjects in the IgG group who had sufficient sera were included.
Subjects were randomly assigned in a 1:1 ratio to receive either PCV13 or PCV7 based on a random assignment schedule prepared by the sponsor. Assignment of eligible subjects to vaccine groups was to be performed during visit 1 through the sponsor’s Clinical Operations Randomization Environment II system. The randomization schedule was generated using a randomized block design for each site separately, with vaccine groups randomly ordered within each block.
The evaluable infant and toddler pneumococcal immunogenicity populations included eligible subjects who adhered to the protocol requirements and had at least 1 valid and determinate assay result. The all-available immunogenicity population included all subjects who had at least 1 valid and determinate assay result. As results in the all-available population were similar to those of the evaluable immunogenicity population, data are only presented for the evaluable immunogenicity population.
The primary endpoint was the proportion of subjects achieving a serotype-specific IgG antibody concentration ≥0.35 μg/mL measured 1 month after dose 3 (responders), based on the World Health Organization reference antibody concentration for assessment of vaccine efficacy against invasive pneumococcal disease (IPD) in infants.8 For each pneumococcal serotype, the proportion of responders was computed, and the exact, unconditional, 2-sided 95% confidence intervals (CIs) on the proportions were calculated. To assess differences between the two vaccine groups for each of the 13 serotypes, the difference in proportions (PCV13–PCV7) was calculated. Exact, unconditional, 2-sided 95% CIs on the difference in proportions were computed with the Chan and Zhang16 procedure. For the secondary endpoint, antibody geometric mean concentrations (GMCs) were calculated, and 2-sided 95% CIs were constructed by back transformation of the CIs for the mean of the logarithmically transformed assay results computed by Student t distribution. To assess differences between vaccine groups, the ratios of the GMCs (PCV13/PCV7) were calculated, and 2-sided 95% CIs for the geometric mean ratio were computed using the Student t distribution for the mean difference of the measures on the log scale.
For the post hoc analyses of the OPA data, similar statistical comparisons between groups were applied to the proportion of responders achieving OPA titers of at least the LLOQ and OPA geometric mean titers (GMTs).
The proportions of subjects with local reactions and systemic events and use of antipyretic medications reported on any day within 4 days after each vaccination were summarized. The incidence of AEs and SAEs was summarized.
Enrollment and Demographics
Subjects were recruited beginning July 22, 2008, and the last toddler blood draw was completed December 11, 2009. The disposition of subjects is illustrated in Figure 1. Of the 180 subjects who consented, 91 were randomly assigned to PCV13 and 89 to PCV7. A total of 168 subjects (PCV13: n = 83; PCV7: n = 85) were included in the evaluable infant immunogenicity population. A total of 164 subjects (PCV13: n = 80; PCV7: n = 84) were included in the evaluable toddler immunogenicity population.
The two vaccine groups were well balanced with respect to demographic characteristics, although the percentage of male subjects was slightly higher in the PCV7 group (56.2%) than in the PCV13 group (50.5%; Table 2). Receipt of recommended nonstudy pediatric vaccines was generally equally distributed across vaccine groups, with the exception of rotavirus vaccine (83.5% in the PCV13 group and 93.5 % in the PCV7 group). The demographics of the evaluable infant population were similar to those of the overall population.
Immune Responses After the Infant Series
For each of the 7 common serotypes, the proportion of subjects achieving IgG concentrations ≥0.35 μg/mL (ie, the proportion of responders) was similar and ≥97.6% in both the PCV13 and PCV7 vaccine groups; ≥92.3% achieved LLOQs, except for serotype 19F which was lower (78.6%). IgG GMCs and OPA GMTs were generally similar across groups, but there was a trend toward lower responses in the PCV13 group for some serotypes (Table 3). For the 6 additional serotypes unique to PCV13, the proportion of responders in the PCV13 group was 100% for all serotypes except serotype 6A (97.6%); ≥96.0% achieved LLOQs. IgG GMCs and OPA GMTs were notably higher in the PCV13 group than in the PCV7 group (Table 4). Of note, although PCV7 elicited IgG responses to nonvaccine serotypes 5 and 19A, OPA functional antibody responses were minimal (GMTs: 4 and 7, respectively). In contrast, PCV7 elicited both IgG and OPA functional responses (GMT 492) to serotype 6A; however, the OPA responses were 4.5-fold less than those in response to PCV13 (GMT 2208; Table 4).
Immune Responses After the Toddler Dose
For the 7 common serotypes, PCV13 generally resulted in an increase in immune responses after the toddler dose. For serotype 14, however, which showed the highest IgG response after the infant series (GMC 14.83 µg/mL), the posttoddler response (GMC 11.51 µg/mL) was less than that after the infant series; in contrast, the OPA GMTs were higher after the toddler dose (GMT increase from 1236 to 1542). For 5 of the 6 additional serotypes, the toddler dose of PCV13 resulted in increases in IgG GMCs; the exception was serotype 3, which showed similar IgG GMCs postinfant series (1.60 µg/mL) and posttoddler dose (1.65 µg/mL). However, OPA GMTs for serotype 3 showed a notable increase from after the infant series to after the toddler dose (GMT increase from 153 to 256).
Safety and Tolerability
The percentages of subjects with local reactions were similar in both groups after doses 1–3 of the infant series and after the toddler dose (Table 5). Most local reactions were mild or moderate in severity.
Incidence of systemic events was generally similar in both groups (Table 6). Fever was mostly mild, and there were no cases of severe fever. The frequency of medication use to treat symptoms (3.6% versus 17.7%; P = 0.018) and to treat or prevent symptoms (5.5% versus 22.2%; P = 0.016) was significantly lower in the PCV13 group than in the PCV7 group after dose 2. The incidence of irritability was significantly lower in the PCV13 group than the PCV7 group after dose 1 (49.4% versus 70.9%; P = 0.009) and dose 3 (21.0% versus 41.7%; P = 0.019).
Overall, the types and frequencies of other AEs were generally similar in the PCV13 and PCV7 groups. AEs were reported for 88.6% and 84.3% of subjects in the PCV13 and PCV7 groups, respectively, during the infant series; 27.3% and 28.1% of subjects, respectively, after the infant series and before the toddler dose (a 5-month interval between vaccinations, during which only newly diagnosed chronic medical conditions and SAEs were documented), and 33.3% and 43.2% of subjects, respectively, after the toddler dose (a 1 month period). Only 4 AEs were considered related to study vaccine (injection site induration and rash in 1 subject each in the PCV13 group, and pyrexia in 2 subjects in the PCV7 group); all occurred during the infant series. The types of AEs reported were generally childhood illnesses common in this age group, and were mainly infections. Of these AEs, 20 were reported in 17 subjects as serious and required hospitalization; there were no deaths. Most of the SAEs were infections; one SAE of Kawasaki disease that occurred on day 49 after dose 1 of PCV13 led to withdrawal of the subject from the study. Careful review of this case and the other SAEs showed no causal associations with the study vaccines.
This study showed that PCV13 elicited a robust immune response in Korean infants as measured by ELISA antipolysaccharide binding IgG antibodies and OPA antibacterial functional antibodies. Consistent with data from other studies,15,17–19 immune responses elicited by the 7 common serotypes were generally similar after PCV13 and PCV7, with trends toward lower responses after PCV13; for the additional serotypes unique to PCV13 responses were notably higher after PCV13. For both vaccines, the IgG responses generally mirrored the OPA functional antibody response with the exception of PCV13-unique serotypes 19A, 6A and 5. For serotype 19A, PCV7 elicited IgG responses, but OPA responses were minimal. These findings underlie the known lack of PCV7 effectiveness against serotype 19A disease.20 IgG and OPA antibody responses to serotype 6A were observed in the PCV7 group, consistent with at least some protection against serotype 6A-mediated IPD.20 Of note, OPA responses in the PCV13 group were 4.5-fold greater than in the PCV7 group, with notably higher proportions of infants with OPA above LLOQ for PCV13 (97.3%) than for PCV7 (84.4%). The clinical relevance of this is unclear as there are no defined protective OPA titer thresholds, and lower titers have been shown to be protective.20 For serotype 5, despite the IgG antibody response, which may have arisen from cross-reactivity with antigens of Klebsiella pneumoniae and Escherichia coli rather than from vaccination with PCV7,21,22 there were only minimal OPA responses. The data further support reports that OPAs may provide a better functional correlate of vaccine-induced protection, and may better reflect effectiveness as compared with responses measured by ELISA.12,23 Of interest, PCV13 serotypes 6A and 7F have also been shown to elicit cross-functional OPA antibodies against nonvaccine serotypes 6C and 7A, respectively, with similar potential for cross protection.14
In general, the PCV13 posttoddler IgG responses were substantially greater than those seen after the infant series, with the exception of serotype 3, which showed similar IgG responses at both time points, and serotype 14, which had the highest postinfant IgG response, but showed a lower posttoddler response. Nonetheless, functional OPA antibody responses showed an increase after the toddler dose for all serotypes, including serotypes 3 and 14. Whether this finding will predict effectiveness in particular for serotype 3 will require further surveillance studies of IPD data over time. To date, PCV13 effectiveness data have shown a reduction in rates of IPD, particularly IPD caused by serotypes 7F and 19A.24–26
PCV13 was highly immunogenic in this Asian population compared with populations in Europe and the United States.15,17–19,27,28 Previous studies in Korea29 and Taiwan30–32 have also reported higher levels of response to PCV7 in Asian populations compared with populations in Europe or the United States. These differences might arise from multiple factors including: regional cultural or ethnic differences; the background use of PCV7 in Korea, which may affect the S. pneumoniae strains circulating in the community; naturally acquired antibodies arising from maternal exposure to toxigenic strains of Corynebacterium diphtheriae,33–35 which may affect the immune responses to cross-reactive material 197, the conjugate protein component of PCV13 and PCV7; use of antipyretic medication36 and breast-feeding practices.37,38
In this study, PCV13 was well tolerated overall. Local reactions and systemic events were generally reported at similar frequencies in the PCV13 and PCV7 groups. Of note, the use of antipyretic medications in this Korean trial was low compared with rates observed in trials of similar design conducted in the United States and Germany.17,18 Overall, the types and frequencies of other AEs were similar in the PCV13 and PCV7 groups, and were generally the types of childhood illnesses commonly occurring in this age group. One subject was withdrawn from the study because of Kawasaki disease, which occurred on day 49 after dose 1 of PCV13. Careful review of this case and the other SAEs showed no evidence of a causal association with vaccine administration.
PCV13 elicited a robust immune response and a satisfactory safety profile in Korean children, comparable with PCV7. PCV13 should be as effective as PCV7 in preventing pneumococcal disease caused by the 7 common serotypes, and should provide protection against the 6 additional serotypes.
This study was sponsored by Wyeth, which was acquired by Pfizer Inc in October 2009. Medical writing support was provided by Vicki Schwartz, PhD, at Excerpta Medica and was funded by Pfizer Inc. The authors thank Norbert Ahlers, PhD, Pfizer Pharma GmbH (Global team lead for management of the study).
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
13-valent pneumococcal conjugate vaccine; Korea; immunogenicity; safety; pediatric