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Immunogenicity and Safety of the 13-Valent Pneumococcal Conjugate Vaccine Administered in a 3 + 1 versus 2 + 1 Dose Schedule Among Infants in China

Zhu, Fengcai MD*; Hu, Yuemei MD*; Li, Jingxin MSC*; Ye, Qiang MD; Young, Mariano M. Jr MD; Liang, John Z. PhD§; Gruber, William C. MD§; Giardina, Peter C. PhD§; Scott, Daniel A. MD

The Pediatric Infectious Disease Journal: November 2019 - Volume 38 - Issue 11 - p 1150–1158
doi: 10.1097/INF.0000000000002458
Vaccine Reports
Free

Background: 13-valent pneumococcal conjugate vaccine (PCV13) was licensed in China based on immunologic noninferiority to 7-valent PCV (PCV7). As part of the noninferiority study, immunogenicity and safety of PCV13 administered as a 3- or 2-dose infant series followed by a toddler dose were examined in healthy Chinese infants.

Methods: Infants (42- to 77-days-old) were randomized to a 3-dose PCV13 or PCV7 infant series administered double-blind at 3, 4 and 5 months or PCV13 administered open-label at 2, 4 and 6 months and a 2-dose open-label series at 3 and 5 months; all subjects received a toddler dose (12 months). Serotype-specific immunoglobulin G (IgG) concentrations were measured 1 month after the infant series and before and after the toddler dose. Opsonophagocytic activity (OPA) was measured in a subset of subjects at each time point. Safety was evaluated.

Results: One month after the infant series, serotype-specific immune responses (IgG ≥ 0.35 µg/mL) were similar for the 2- versus 3-dose schedules, except for serotype 6B, which was significantly lower in the 2-dose group [70.1% in the PCV13 (3, 5 + 12 mo) group vs. 93.2% in the PCV13 (3, 4, 5 + 12 mo) group and 94.7% in the PCV13 (2, 4, 6 + 12 mo) group]. IgG geometric mean concentrations and OPA geometric mean titers trended numerically higher with 3- versus 2-dose schedules. No significant differences in immunogenicity were observed between the 3- versus 2-dose schedules after the toddler dose. PCV13 was well-tolerated across all schedules.

Conclusions: PCV13 administered as a 3- or 2-dose infant series followed by a toddler dose was immunogenic and well tolerated in healthy Chinese infants and likely protective against PCV13 serotypes; immune responses with a 2-dose schedule were lower for some serotypes.

From the *Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China

Division of Respiratory Bacterial Vaccines, NIFDC, Beijing, China

Pfizer Vaccine Clinical Research and Development, Pfizer Inc, Collegeville, Pennsylvania

§Vaccine Clinical Research and Development, Pfizer Inc, Pearl River, New York.

Accepted for publication July 13, 2019.

Research funding for the study was provided to the institutions that employ Drs. F.Z., Y.H., J.L. and Q.Y. Drs. M.Y., J.Z.L., W.C.G., P.C.G. and D.A.S. are employees of Pfizer Inc. This study was funded by Pfizer Inc.

The authors have no conflicts of interest to disclose.

Date of registration: September 25, 2012.

ClinicalTrials.gov: NCT01692886.

Address for correspondence: Mariano M. Young, Jr, MD, Vaccine Clinical Research and Development, Pfizer Inc, 500 Arcola Rd, Collegeville, PA 19426. E-mail: mariano.young-jr@pfizer.com.

Streptococcus pneumoniae is a leading cause of invasive bacterial disease and otitis media in children and is the predominant causative agent of pneumonia.1,2 In 2012, 16% of deaths in children <5 years of age in China were due to pneumonia, which was the second leading cause of death after neonatal causes.3

The 7-valent pneumococcal conjugate vaccine (PCV7) targeting S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F and 23F4 was licensed in China for immunization of infants and young children against invasive pneumococcal disease (IPD).5 In China, PCV7 was administered as a 3-dose primary infant series at 3, 4 and 5 months of age, followed by a toddler dose at 12–15 months of age.6 Importantly, the vaccine was only available on the private market, and surveys estimated coverage for ≥1 dose to be 10%.7 To increase protection against disease, a 13-valent PCV (PCV13; Prevenar 13®, Pfizer Inc, New York, NY) was developed and subsequently approved by the Chinese Food and Drug Administration in November 2016 for active immunization against IPD (including bacteremic pneumonia, meningitis, septicemia and bacteremia) in infants and children 6 weeks to 15 months of age.8 PCV13 contains PCV7 serotypes plus serotypes 1, 3, 5, 6A, 7F and 19A.9

PCV13 was licensed in China based on clinical trial data demonstrating its safety and noninferiority to PCV7.10 In this noninferiority study, the immunogenicity and safety of a 3-dose primary series of PCV13 administered at 3, 4 and 5 months with a booster dose at 12 months was compared with that of PCV7 administered using the same dose schedule.10As part of the noninferiority study, PCV13 was also administered using additional dose schedules to evaluate flexible dosing options. This article reports the immunogenicity, tolerability, and safety of PCV13 administered in 3 different dose schedules used in many countries globally: two 3-dose infant series (vaccination at 3, 4 and 5 months or at 2, 4 and 6 months, both followed by a toddler dose at 12 months) and a 2-dose infant series (vaccination at 3 and 5 months followed by a toddler dose at 12 months). These schedules were evaluated with the aim of expanding PCV13 dosing recommendations in China, with the 2-dose schedule specifically requested for evaluation by regulatory authorities.

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METHODS

Study Design

This phase 3, randomized study evaluated the immunogenicity, tolerability and safety of PCV13 compared with PCV7 in healthy infants in China and compared the immune responses to PCV13 given in different schedules. Chinese infants 42- to 77-days-old were randomized 2:2:2:1 to receive PCV7 [3, 4, 5 + 12 mo] [ie, PCV7 at 3, 4 and 5 months (infant series) and 12 months (toddler dose)], PCV13 [3, 4, 5 + 12 mo], PCV13 [2, 4, 6 + 12 mo] or PCV13 [3, 5 + 12 mo]. The comparison of PCV7 and PCV13, each administered in a 3-dose infant series, has been reported elsewhere.10 The results of PCV13 administered in 3 different infant schedules are presented here.

For the infant series, PCV13 was administered double-blind to the PCV13 [3, 4, 5 + 12 mo] group and open-label to the PCV13 [2, 4, 6 + 12 mo] and PCV13 [3, 5 + 12 mo] groups. All subjects received a toddler dose at 12 months. Details regarding study design, vaccine administration and inclusion/exclusion criteria are reported elsewhere.10 This study was conducted in accordance with local and international laws and regulations, the International Ethical Guidelines for Biomedical Research Involving Human Subjects, the International Conference on Harmonisation Guidelines for Good Clinical Practice, and the Declaration of Helsinki. Institutional review board or independent ethics committee review and written approval were obtained, as was written informed consent from each subject’s parent/legal guardian.

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Study Objectives

The immunogenicity objective was to describe immune responses to the 13 pneumococcal serotypes included in PCV13 measured 1 month after the infant series and 1 month after the toddler dose when administered as a 3-dose infant series [PCV13 (3, 4, 5 + 12 mo) and PCV13 (2, 4, 6 + 12 mo)] or a 2-dose infant series [PCV13 (3, 5 + 12 mo)]. The safety objective assessed rates of local reactions and systemic events for 7 days after each vaccination and adverse event (AE) occurrence throughout the study. Immunogenicity and safety evaluations have been previously reported.10

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Statistical Analysis

Requirements for the evaluable immunogenicity and safety populations for those receiving the primary infant series and toddler dose have been reported.10 The primary immunogenicity endpoints were the percentage of subjects achieving a serotype-specific immunoglobulin G (IgG) concentration ≥0.35 μg/mL and the IgG geometric mean concentrations (GMCs) for each pneumococcal serotype 1 month after the infant series. Other endpoints included the percentage of subjects with opsonophagocytic activity (OPA) geometric mean titers (GMTs) greater than or equal to the lower limit of quantitation (LLOQ; OPA responders) and OPA GMTs 1 month after the infant series, before the toddler dose, and 1 month after the toddler dose. Both for IgG GMCs and OPA GMTs, 95% CIs were calculated for the differences in percentages for responders; values with nonoverlapping 95% CIs were reported to have a statistically significant difference.

Correlations between IgG GMCs and OPA GMTs were derived for each serotype using pooled sera from all PCV13 recipients [PCV13 (3, 4, 5 + 12 mo), PCV13 (2, 4, 6 + 12 mo) and PCV13 (3, 5 + 12 mo)] 1 month after the infant series. The Fisher transformed value was used to evaluate the hypothesis that correlation coefficients are equal between the vaccine groups. Safety endpoints included incidence rates of local reactions and systemic events after PCV13 administration; AEs were summarized by vaccine group.

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RESULTS

Study Subjects

A total of 1196 subjects were randomized to PCV13 [3, 4, 5 + 12 mo] (n = 478), PCV13 [2, 4, 6 + 12 mo] (n = 479) and PCV13 [3, 5 + 12 mo] (n = 239). Fourteen subjects were withdrawn after randomization but before vaccination; 1181 (98.7%) subjects were included in the infant safety population. Overall, 1148 (96.0%) subjects completed the infant series and 1110 (92.8%) were included in the evaluable infant immunogenicity population, which was the primary analysis population. In total, 1088 subjects (91.0%) received a toddler dose and completed the study. All subjects were Asian; there were similar percentages of male and female subjects in each group (data not shown).

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Immunogenicity to PCV13 Serotypes 1 Month After the Infant Series

One month after the infant series, the percentage of subjects achieving serotype-specific IgG ≥0.35 µg/mL was similar across the 3-dose schedules. Among subjects receiving a 2-dose schedule, the percentage of IgG responders was statistically significantly lower for serotype 6B compared with the 3-dose schedules (Table 1). Among the 3-dose recipients, the majority of IgG GMCs were similar for both dosing schedules, with the exception of serotypes 3, 4, 9V and 19A, which were statistically significantly lower, and serotype 6A, which was statistically significantly higher with the PCV13 [2, 4, 6 + 12 mo] compared with the PCV13 [3, 4, 5 + 12 mo] dosing schedule (Table 2). IgG GMCs were numerically lower with the 2-dose compared with the 3-dose schedules for 7 of the 13 serotypes and were statistically significantly lower for serotypes 6B, 14, 18C and 23F.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

For the 3-dose groups, the percentage of OPA responders was high (≥95.0%) and similar for all serotypes 1 month after the infant series; the percentage of responders was statistically significantly lower among 2-dose recipients for serotype 6B (79.8%; Table 1). For 3-dose recipients, OPA GMTs were comparable between dosing schedules, except for serotype 3, which was statistically significantly lower with the PCV13 [2, 4, 6 + 12 mo] schedule. OPA GMTs were numerically lower for 9 of the 13 serotypes with the 2-dose schedule and statistically significantly lower for serotypes 6B and 18C compared with the 3-dose schedules (Table 2).

One month after the infant series, a positive correlation was evident between IgG GMC and OPA GMTs for all 13 serotypes in PCV13 (Fig. 1). Correlations ranged between 0.41 (serotype 4) and 0.72 (serotype 5).

FIGURE 1

FIGURE 1

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Immunogenicity Before the Toddler Dose

During the interval between the infant series and toddler dose, IgG GMCs waned for all serotypes and all dosing schedules, with the exception of serotype 6B in 2-dose recipients (Fig. 2).

FIGURE 2

FIGURE 2

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Immunogenicity to PCV13 Serotypes 1 Month After the Toddler Dose

One month after the toddler dose, the percentage of subjects with serum IgG GMCs ≥0.35 µg/mL was high (≥97.7%) and similar across groups (Table 1). Among the 3-dose recipients, the majority of IgG GMCs were similar for both dosing schedules; exceptions were serotypes 6A, 7F and 18C, which were statistically significantly higher and serotype 3, which was statistically significantly lower with the PCV13 [2, 4, 6 + 12 mo] dosing schedule. There was no significant difference in IgG GMCs between the 2-dose and 3-dose schedules (Table 2). For all dosing schedules, IgG GMCs increased after the toddler dose compared with after the infant series except for serotype 3, which was higher 1 month after the infant series in all groups.

After the toddler dose, the percentage of OPA responders (OPA ≥ LLOQ) was high (≥95.2%) and similar among subjects receiving the 3-dose and 2-dose infant series (Table 1). Among 3-dose recipients, OPA GMTs were comparable after the toddler dose except for serotype 7F, which was statistically significantly lower with the PCV13 [3, 4, 5 + 12 mo] schedule; there were no significant differences in OPA GMTs between the 2-dose and 3-dose schedules (Table 2). For all dosing schedules, OPA GMTs increased after the toddler dose compared with after the infant series except for serotype 3 in the PCV13 [3, 4, 5 + 12 mo] group and serotype 14 in the PCV13 [3, 4, 5 + 12 mo] and PCV13 [3, 5 + 12 mo] groups.

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Safety

Local reactions within 7 days of vaccination were generally infrequent after doses in the infant series (<15% of subjects) and toddler dose (<8% of subjects), mild to moderate in severity, and comparable across groups (Fig. 3A–C). One event each of severe redness and severe swelling was reported in the PCV13 [3, 5 + 12 mo] group after the toddler dose. No severe redness or swelling was reported after any dose in the infant series. Severe local tenderness was reported in <1.5% of subjects in any group after each dose in the infant series and local tenderness interfering with limb movement was reported in <1% of subjects in the PCV13 [3, 4, 5 + 12 mo] and PCV13 [2, 4, 6 + 12 mo] groups after the toddler dose; no local tenderness interfering with limb movement was reported in PCV13 [3, 5 + 12 mo] recipients after the toddler dose.

FIGURE 3

FIGURE 3

Systemic events were reported more frequently after dose 1 (<20% of subjects) than any other dose (<10% of subjects). After dose 1, systemic events were highest in the PCV13 [2, 4, 6 + 12 mo] group compared with the PCV13 [3, 4, 5 + 12 mo] and PCV13 [3, 5 + 12 mo] groups (19.7%, 5.9% and 7.3%, respectively). For subsequent doses, systemic events were comparable across groups. The percentage of subjects with fever was low after all doses in the infant series (<2.5%) and toddler dose (<7%) and was comparable across vaccine groups (Fig. 3D). After the toddler dose, severe fever (ie, temperature >40°C) was reported for 1 subject in the PCV13 [3, 4, 5 + 12 mo] group. No subjects reported severe fever after any dose in the infant series. Across all groups, other systemic events (ie, decreased appetite, irritability, increased sleep and decreased sleep) were reported in <15% of subjects within 7 days of any infant series dose and in <5% of subjects after the toddler dose. After dose 1, irritability was more frequent with PCV13 [2, 4, 6 + 12 mo] compared with PCV13 [3, 4, 5 + 12 mo] and PCV13 [3, 5 + 12 mo] (12.3%, 3.4% and 4.3%, respectively); increased sleep and decreased sleep were slightly higher with PCV13 [2, 4, 6 + 12 mo] after dose 1 (Fig. 3E). The percentage of subjects reporting any systemic event was low and similar between groups after doses 2 and 3 in the infant series and after the toddler dose.

AEs were reported by approximately one-third of subjects in each vaccine group after the infant series. After the toddler dose, AE frequency was low (<8%), similar across groups and mostly mild in severity. Vaccine-related AEs were <1.5% across all groups after the infant series and <1.0% across all groups after the toddler dose; pyrexia was reported in 5 subjects after the toddler dose. The percentage of subjects with serious AEs (SAEs) was <2.5% across all groups after the infant series. After the toddler dose, 1 SAE (bronchiolitis) was reported in a subject receiving PCV13 [3, 4, 5 + 12 mo]; this SAE was considered moderate in severity and not related to the vaccine. No life-threatening AEs were observed, and no deaths were reported after the infant series or after the toddler dose.

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DISCUSSION

This study demonstrates that PCV13 administered as a 3-dose primary infant series at 3, 4 and 5 months and 2, 4 and 6 months or 2-dose primary infant series at 3 and 5 months followed by a booster dose is immunogenic in healthy Chinese children and is likely to be protective against the 13 vaccine-specific serotypes. Alternative dosing offers flexibility for PCV13 administration, particularly in countries such as China that administer routine vaccinations on variable dosing schedules.11 In this study, PCV13 elicited seroprotection after a 3-dose infant series, with >93% of infants responding with anticapsular IgG GMCs at or above the standard threshold for protection (≥0.35 µg/mL) for all serotypes in the vaccine. One month after the infant series, PCV13 recipients receiving a 2-dose schedule achieved a level of protection similar to those receiving 3 doses for most serotypes, with the exception of serotype 6B, which had a statistically significantly lower percentage of IgG and OPA responders and statistically significantly lower IgG and OPA antibodies.

After the infant series, IgG GMCs were generally comparable for the 3-dose schedules, although they were significantly lower or higher for some serotypes when the 2-, 4- and 6-month schedule was compared with the 3-, 4- and 5-month schedule. When PCV13 was administered as a 2-dose infant series, anticapsular IgG GMCs were significantly lower for 4 serotypes. The percentage of 3-dose recipients achieving a functional antibody response (OPA) was high (≥95.0%) for all serotypes and dosing regimens 1 month after the infant series; the percentage of responders was significantly lower among 2-dose recipients for serotype 6B. Functional antibody GMTs were comparable for the 3-dose schedules, with the exception of serotype 3; however, for the 2-dose schedule, GMTs were numerically lower for 9 of the 13 serotypes and statistically significantly lower for serotypes 6B and 18C.

After the toddler dose, PCV13 elicited seroprotection with ≥97.7% of subjects achieving anticapsular IgG GMCs at or above the standard threshold for protection for all serotypes in the vaccine. IgG GMCs were generally similar across 3-dose schedules, with a few exceptions, and did not significantly differ between the 2-dose and 3-dose schedules. The percentage of subjects achieving a functional antibody response above the threshold for protection was similar across dosing schedules. OPA GMTs were comparable except for serotype 7F among 3-dose-schedule recipients and did not significantly differ when comparing 2- and 3-dose schedules. For all dose schedules, an increase in anticapsular IgG GMCs and functional antibody was observed for all serotypes after the booster dose. Among 3-dose recipients, there was a positive linear correlation between binding IgG and OPA (range, 0.41–0.72) for all serotypes in PCV13.

Studies conducted in the United Kingdom12 and Spain13 have raised concerns about the effectiveness of PCV13 against IPD for serotype 3 in particular. However, a recent meta-analysis that included these 2 studies suggested the contrary, with effectiveness estimates of 63.5%–72.4% for ≥1 dose.14 Results also indicated that effectiveness was higher in countries with 3-dose as opposed to 2-dose primary schedules.

In the current study, PCV13 was immunogenic under all 3 schedules evaluated. However, the 3-, 4- and 5-month schedule was associated with significantly higher serotype 3 IgG GMCs and OPA GMTs when compared with the 2-, 4- and 6-month schedule; the same was true for IgG GMCs following the toddler dose. Of note, immune responses in the PCV13 [3, 5 + 12 mo] group were higher than those in the PCV13 [2, 4, 6 + 12 mo] group but lower than those in the PCV13 [3, 4, 5 + 12 mo] group, and OPA GMTs were highest in the PCV13 [3, 5 + 12 mo] group following the toddler dose. A review of PCV13 infant studies similarly found that among studies performed in the European Union, a primary series given at 2, 3 and 4 months of age (ie, 1-month intervals between doses) elicited higher GMCs than a series given at 2, 4 and 6 months of age; a primary schedule given at 3 and 5 months of age also induced robust immune responses.15 These data collectively suggest that immune responses to serotype 3 may vary depending on the specific 3-dose schedule used; future investigation might reveal whether these findings are reflected in effectiveness studies.

Numerous studies have evaluated the immunogenicity and safety of different PCV13 dosing regimens in infants, including 2 large meta-analyses.16,17 The general consensus across studies is that for some serotypes, a 3-dose primary infant series induces a better immune response than a 2-dose series; however, a 2-dose series is effective when used as part of a national immunization program, as seen in studies in the United Kingdom and South Africa.18,19 The higher IgG responses observed with 3 dose regimens could have a greater impact on nasopharyngeal colonization20 and resulting herd effects. Serotypes 6B and 23F generally show the greatest difference between the 3-dose and 2-dose regimens, suggesting that reduced dosing could leave a gap in protection against these serotypes that would not be ameliorated until the 1-year booster dose. Taken together, these data and data presented in the current study indicate that a 3-dose infant series, particularly in areas where pneumococcal burden is high, can maximize vaccine impact and promote herd immunity when used in a universal vaccination program,16,17 although fewer doses can suffice.18,19 In the absence of a universal program, a 3-dose infant series would provide the highest immune response in individual patients.

This study examined the relationship between IgG GMCs and functional antibody. Among these Chinese infants, there was a positive linear correlation between binding IgG and OPA (range, 0.41–0.72) for all PCV13 serotypes. The correlation between IgG GMCs and functional activity has been examined in other clinical studies of PCV13, including a pooled analysis from studies conducted in infants in the European Union (Germany,21 Poland,22 Italy23) and United States.24,25 In a pooled analysis of these studies, the correlation between IgG and OPA was positive, ranging from 0.17 to 0.62. The correlation between IgG and OPA was also positive across individual studies of infants and toddlers conducted in the United Kingdom (rho, 0.07–0.79),26 Poland (rho, 0.15–0.68),27 and Korea (rho, 0.14–0.75).28

Across all subjects, PCV13 was generally well tolerated, and results were consistent with the established PCV13 safety and tolerability profile; no new safety concerns emerged during this study. After the first dose, a notably higher incidence of systemic events was observed among infants receiving PCV13 on a 2-, 4- and 6-month schedule compared with a 3-, 4- and 5-month schedule. This may be an age-related event resulting from infants receiving the first dose of PCV13 at 2 months versus 3 months of age. It is also likely that parents/guardians of younger infants may be more sensitive and therefore more likely to report irritability or changes in sleep patterns.

As the study was performed in Chinese infants, caution must be used when extrapolating these findings to other populations. However, results from this current variable dose schedule study, as well as the previously published noninferiority arm of this study,10 demonstrated anticapsular IgG concentrations and functional antibody in infants after the infant series and booster dose that likely predict effectiveness.

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CONCLUSION

Whether administered as a 3-dose or 2-dose primary infant series followed by a toddler booster dose, PCV13 is immunogenic in healthy Chinese children and is likely to be protective against the 13 vaccine-specific serotypes. Immune responses to some PCV13 serotypes may be lower with a 2-dose compared with 3-dose infant regimen. Across all serotypes, there was a positive correlation between anticapsular IgG concentrations and functional antibody. PCV13 was generally well tolerated, and no new safety signals emerged during this study.

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ACKNOWLEDGMENTS

Editorial/medical writing support was provided by Susan E. DeRocco, PhD, of Complete Healthcare Communications, LLC (West Chester, PA), a CHC Group Company, and was funded by Pfizer Inc.

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Keywords:

PCV7; PCV13; Streptococcus pneumoniae; infants; China

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