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Immunogenicity and Reactogenicity of a 13-Valent-pneumococcal Conjugate Vaccine Administered at 2, 4, and 12 Months of Age

A Double-blind Randomized Active-controlled Trial

Snape, Matthew D. MB BS, MD*; Klinger, Chaam L. MB BS*; Daniels, Elvis D. MD, PhD; John, Tessa M. RN*; Layton, Helen BA*; Rollinson, Llinos RN*; Pestridge, Sarah BSc; Dymond, Sandra RN§; Galiza, Eva BSc, MB BS; Tansey, Susan MB ChB; Scott, Daniel A. MD; Baker, Sherryl A. PhD; Jones, Thomas R. PhD; Yu, Ly-Mee MSc; Gruber, William C. PhD; Emini, Emilio A. PhD; Faust, Saul N. PhD; Finn, Adam PhD§; Heath, Paul T. FRACP, FRCPCH; Pollard, Andrew J. MB BS, PhD*

Author Information
The Pediatric Infectious Disease Journal: December 2010 - Volume 29 - Issue 12 - p e80-e90
doi: 10.1097/INF.0b013e3181faa6be
  • Free

Abstract

Streptococcus pneumoniae is a major cause of morbidity and mortality in children worldwide, resulting in up to 1 million pediatric deaths every year.1,2 In addition to causing invasive disease such as septicemia and meningitis, S. pneumoniae is also an important cause of pneumonia and otitis media.1

A pneumococcal conjugate vaccine covering 7 of the most common disease causing serotypes (4, 6B, 9V, 14, 18C, 19F, 23F) has reduced the burden of invasive pneumococcal disease (IPD) in many developed countries through both direct and indirect protection.3–5 Despite the success of the PCV7 immunization campaigns, there remains a significant burden of disease due to serotypes that are not covered by the current vaccine5 such as serotype 19A, a substantial proportion of which is penicillin resistant in the United States.6

Recently, a pneumococcal conjugate vaccine directed against 13 serotypes (PCV13) has been licensed in the United States and Europe.7,8 In the United States, the vaccine has been recommended for use at 2, 4, 6, and 12 months of age,8 a schedule that has been shown to be immunogenic and well tolerated.9 In the United Kingdom, the vaccine is recommended for use at 2, 4, and 12 to 13 months of age,10 a schedule that may well be employed by countries such as France and Belgium currently immunizing with PCV7 at these ages.11 We therefore performed a study to assess the immunogenicity and tolerability of PCV13 given according to this reduced dose schedule.

METHODS

Study Design and Participant Selection

This phase III, randomized, double-blind, active-controlled study was conducted from October 2006 to October 2008. The study was performed in the United Kingdom across 9 sites; ethical approval was obtained from Oxfordshire Research Ethics Committee (Reference Number 06/Q1604/67). Potential participants were identified either via child health computer databases or directly by general practitioners. Healthy 6- to 14-week-old infants were enrolled; exclusion criteria included previous immunization with any of the study vaccines, previous anaphylactic reactions to vaccinations, bleeding diathesis, culture proven sepsis with S. pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b (Hib), any serious or chronic ill health (including immune deficiency), and receipt of blood transfusions.

Participants were randomly allocated to receive either PCV13 or PCV7 in a 1:1 ratio using a web-based randomization system with a block size of 4 for each site separately. If study visits were to be conducted in participant's homes, randomization numbers were allocated at the study center following telephone discussion of the study with parents but prior to enrolment of the study participant. If consent was not obtained, these randomization numbers were discarded and the participant was considered as not enrolled.

All study sites, participants and relevant sponsor staff remained blinded to the vaccines received during the study.

Vaccines and Interventions

The pneumococcal conjugate vaccines were administered at 2, 4, and 12 months of age. In addition to pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F contained in PCV7, PCV13 contains the saccharides from serotypes 1, 3, 5, 6A, 7F, and 19A. As with PCV7, each of the polysaccharides is covalently conjugated to a common carrier protein, CRM197. PCV13 contains 2.2 μg of each saccharide (4.4 μg for 6B) in 5.0 mM succinate buffer with 0.125 mg of aluminum as aluminum phosphate per 0.5-mL dose. PCV13 and PCV7 were presented in identical prefilled syringes.

As part of the routine UK immunization program participants also received the serogroup C meningococcal (MenC) vaccine NeisVac-C (Baxter Healthcare Corporation, Beltsville, MD) at 2 and 4 months of age and the DTaP-IPV-Hib combination vaccine (Pediacel, Sanofi-Pasteur-MSD, Maidenhead, United Kingdom) at 2, 3, and 4 months of age. DTaP-IPV-Hib contains diphtheria and tetanus-toxoid, pertussis filamentous hemagglutinin (FHA), pertussis-toxoid (PT), pertactin (PRN), and fimbrial agglutinogens (FIM), inactivated polio virus types 1, 2, and 3 and Hib polysaccharide conjugated to tetanus-toxoid. At 12 months of age, participants received a combined conjugated Hib and MenC vaccine (Hib-MenC-TT, Menitorix, GlaxoSmithKline Biologicals, Rixensart, Belgium). All vaccines were administered intramuscularly and concomitant vaccines were administered in the opposite leg to the pneumococcal vaccines.

For the first 4 days after each immunization, parents recorded any local tenderness, swelling or redness, fever, decreased appetite, altered sleep, irritability, and use of antipyretics, as well as a daily axillary temperature (with additional measurements if the child felt feverish). Swelling and redness were classified as absent, mild (diameter, 0.5–2.0 cm), moderate (2.5–7.0 cm), or severe (>7.0 cm). Local tenderness was classified as not discernable, present, or interfering with limb movement. All data were collected via an electronic diary that allowed data entry only on the day of assessment. Unsolicited adverse events were also recorded, including visits to physicians or hospitals. The causal relationship between serious adverse events and the study vaccines was determined by the principal investigators, who remained blinded to the study group.

Serologic Responses

Blood samples were obtained from participants at 5, 12, and 13 months of age. MenC serum bactericidal assays (SBA) were performed at the Manchester Medical Microbiology partnership, Health Protection Agency, using the C11 meningococcal strain and baby rabbit serum as the complement source.12 IgG responses to the acellular pertussis antigens (PT, FHA, PRN, and FIM) and Hib capsule (polyribosylribitol phosphate, PRP) were determined by ELISA at Rijksinstituut voor Volksgezondheid en Milieu (RIVM).13 Remaining sera were tested by ELISA for pneumococcal serotype-specific antipolysaccharide IgG concentrations14,15 against an international reference serum 89-SF16 at Wyeth Laboratories, Pearl River, NY. The reference and test sera were preabsorbed with a crude pneumococcal cell wall extract (PnA), containing cell wall polysaccharide, and purified serotype 22F polysaccharide (test and control sera) to enhance the specificity of the assay by removal of nonspecific antibodies.17,18

Complement-mediated phagocytic killing of pneumococcal bacteria was measured at Wyeth Laboratories by an opsonophagocytic activity (OPA) assay on remaining sera at 5, 12, and 13 months, using a modification of the method of Romero-Steiner et al.19 Heat-inactivated sera were serially incubated with live S. pneumoniae, baby rabbit complement, and differentiated HL60 cells. The OPA titers were determined as the reciprocal of the highest serum dilution that caused a 50% or greater reduction of the colony forming units when compared with the control wells, which lacked human serum.20

The correlate of protection for MenC was an SBA titer of 1:8,21 and for Hib was an anti-PRP IgG concentration ≥0.15 and ≥1.0 μg/mL (short- and long-term protection, respectively).13 The threshold of response to the pneumococcal vaccines was a serotype-specific IgG concentration of ≥0.35 μg/mL, as per the World Health Organization recommendations.18,22 OPA responders were defined as a titer ≥1:8.23 Anti-PT, FHA, and PRN IgG concentrations of ≥5 EU/mL and anti-FIM levels ≥2.2 EU/mL were used as markers of pertussis-vaccine response24 along with an additional, more stringent, threshold for PCV13 participants of the concentration of IgG to pertussis antigens achieved by 95% of PCV7 recipients.

Laboratory analyses were performed following completion of the study visits for the infant (5 month) and toddler (13 month) stages of the study; laboratory staff remained blinded to the study groups at both these stages.

Objectives

For PCV13 immunogenicity, the primary objective was to determine the proportion of participants achieving IgG ≥0.35 μg/mL for each PCV13 serotype at each blood sampling time point. The percentages of PCV7 recipients achieving IgG ≥0.35 μg/mL for the PCV13 serotypes at these times were evaluated as a post hoc analysis. Additionally, given the increasing understanding of the importance of the vaccine-elicited functional antibody response, a post hoc assessment of the OPA response to immunization with PCV7 and PCV13 was carried out on any remaining sera. The safety objective was to measure the incidence of adverse events and local reactions and systemic events following immunization with PCV13 and PCV7.

The primary objective for the concomitant vaccines was to evaluate the proportions of participants in each group achieving the predetermined thresholds for PRP (Hib), MenC, and the pertussis antigens 1 month after primary immunization with DTaP-IPV-Hib and MenC vaccine.

Statistical Analysis

The percentage of participants achieving the prespecified antibody concentrations was calculated and the associated 2-sided 95% confidence intervals (CI) determined using the F distribution method.25 The difference in the percentages between the study groups was calculated for the concomitant vaccine responses (PCV13 group − PCV7 group), and the associated 95% CI calculated using Chan and Zhang's noninferiority procedure.26 Geometric mean IgG concentrations (GMCs) and titers (GMTs) were calculated and their 2-sided 95% CI constructed by back transformation of the CI for the mean logarithmically transformed assay results computed using Student t distribution. Geometric mean ratios (GMRs) of the concomitant vaccine GMCs/GMTs were calculated (PCV13 group: PCV7 group) and the CI determined using the Student t distribution for the mean difference on the log scale. Post hoc comparisons of pneumococcal vaccine immunogenicity were descriptive.

All participants who received at least 1 dose of pneumococcal vaccine were included in the safety analysis according to the treatment received. The primary immunogenicity analysis was conducted on the per-protocol immunogenicity population, consisting of all participants who had at least 1 valid assay result for the proposed analysis at 5 months (for postinfant series analysis), at 12 and 13 months (for 12-month analysis) and at 13 months (for the 13-month analysis) and who received the randomized treatment at expected doses, had blood drawn within protocol specified timeframes, and had no protocol violations. Limitations in serum availability meant that the number of participants in these populations potentially differed for each antigen (including the different pneumococcal serotypes).

Sample Size Calculation

This study's original sample size of approximately 600 was intended to assess immunogenic noninferiority of the PCV13 group relative to PCV7 for the concomitant vaccine's thresholds of response. However, due to slow recruitment the sample size was reconsidered and the analysis modified to be descriptive. Using data from previous studies,9,27,28 the precision of the estimates of the proportion of participants expected to achieve the prespecified antibody levels determined that at a sample size of 125 evaluable participants per treatment group, a 2-sided, type I error of 0.05 and a drop-out rate of approximately 12%, precision of the estimates to within plus or minus 1.9% (pertactin) to 8.1% (Hib) was predicted, and hence recruitment was stopped at 286 participants.

RESULTS

Of the 286 infants randomized in this study, 141 were assigned to receive PCV13 and 145 to receive PCV7 (Fig. 1). Of these, 2 participants (PCV13) and 6 participants (PCV7) were not enrolled since parental consent was declined after treatment assignment. Seventy nine (56.0%) of the PCV13 recipients were male, as were 65 (46.8%) of PCV7 recipients; participant's mean age at enrollment in both groups was 2.1 months (standard deviation: 0.3 months). Over 90% of enrolled participants completed all study visits.

FIGURE 1.
FIGURE 1.:
Study flowchart. *Sites conducting home visits randomized participants before the visit to enable vaccine to be taken to the participant's home. In 8 such cases, consent was subsequently not obtained at the home visit. Participant received an additional dose of meningococcal serogroup C glyco-conjugate vaccine from their general practitioner. PCV13 indicates 13-valent-pneumococcal conjugate vaccine; PCV7, 7-valent-pneumococcal conjugate vaccine; w/d, withdrew.

Immunogenicity of Pneumococcal Vaccines

After primary immunization, the percentage of PCV13 recipients with serotype-specific IgG concentrations of ≥0.35 μg/mL for the 6 non-PCV7 serotypes ranged from 79.2% (serotype 6A) to 97.2% (serotype 1) (Table 1). No more than 17.5% of PCV7 recipients reached this threshold for 5 of these 6 serotypes, however, for serotype 19A the proportion was 88.9%. Of note, the IgG GMC for serotype19A after PVC7 was less than half that observed in PCV13 recipients (Table 2). Over 85% of PCV7 and PCV13 recipients achieved the threshold of response for 5 of the 7 shared serotypes, with lower proportion of participants achieving this threshold for serotypes 6B and 23F.

TABLE 1
TABLE 1:
Percentage of Participants With Pneumococcal Serotype Specific IgG ≥0.35 μg/mL (per Protocol Pneumococcal Immunogenicity Populations)
TABLE 2
TABLE 2:
Pneumococcal Serotype Specific IgG Geometric Mean Concentrations (μg/mL)—per Protocol Pneumococcal Immunogenicity Populations

Following immunization at 12 months of age, ≥88.2% of PCV13 recipients had IgG concentrations ≥0.35 μg/mL for the 6 non-PCV7 serotypes. Although this threshold was reached by ≥60% of PCV7 participants for serotypes 5, 6A, and 19A, IgG GMCs in PCV13 recipients were at least double those observed in PCV7 recipients for these serotypes (Table 2). At least 97% of recipients of both vaccines achieved the threshold of IgG response for all 7 shared serotypes after the 12-month booster dose with these proportions being similar between both groups. IgG GMCs were similar between the 2 groups after boosting, with the exception of serotypes 4 and 23F, which tended to be lower in PCV13 recipients (Table 2).

Following immunization with PCV13 at 2 and 4 months of age, OPA titers of ≥1:8 were seen in ≥88% of participants for each of the 13 vaccine serotypes. Although these percentages fell below 50% for serotypes 4, 18C, 19F, and 19A by 12 months of age, following the 12-month dose of PCV13 they were ≥93% for all serotypes (Fig. 2A–C). Despite the relatively high percentages of PCV7 recipients with IgG concentrations of ≥0.35 μg/mL for serotypes 5, 6A, and 19A at 13 months of age, the percentage of participants with OPA titers of ≥1:8 for these serotypes was considerably lower in the PCV7 group than the PCV13 group, as were OPA GMTs (Fig. 3A–C). At 13 months of age, 96.7% of PCV7 recipients had serotype 7F OPA titers of 1:8 or greater, however, the OPA GMT in this group (304.44; 95% CI, 215.23–430.62) was substantially lower than in PCV13 recipients (6702.70; 95% CI, 5260.98–8541.12).

FIGURE 2.
FIGURE 2.:
Percentage of participants with pneumococcal serotype-specific opsonophagocytic assay titres ≥1:8 following dose 2 of the infant series (A), prior to the 12-month immunization (B) and 1 month following the 12-month immunization (C). The numbers of participants included in the per-protocol immunogenicity population with serum available for OPA analysis varied according to serotype in (A) from 70 to 73 (PCV13 recipients) and 62 to 65 (PCV7 recipients), in (B) from 70 to 73 (PCV13 recipients) and 62 to 65 (PCV7 recipients) and in (C) from 71 to 77 (PCV13 recipients) and 59 to 60 (PCV7 recipients).
FIGURE 3.
FIGURE 3.:
Pneumococcal serotype-specific opsonophagocytic assay geometric mean titres following dose 2 of the infant series (A), prior to the 12-month immunization (B) and 1 month following the 12-month immunization (C).

Immunogenicity of Concomitant Vaccines

Over 99% of participants in both groups had MenC-specific SBA titers ≥1:8 at 5 months of age, while over 96% of participants achieved anti-PRP concentrations ≥0.15 μg/mL. The percentages of participants achieving the prespecified antibody concentration thresholds for Hib, MenC, and pertussis antigens after infant immunization were similar in both groups (Table 3), as were the IgG GMC/GMTs (Table 4).

TABLE 3
TABLE 3:
Comparison of Participants Achieving a Prespecified Antibody Level for Concomitant Vaccine Antigens After Dose 2 of the Infant Series (5 Months of Age)—per Protocol Infant Immunogenicity Population
TABLE 4
TABLE 4:
Comparison of Concomitant Vaccine Antigen Specific Antibody Geometric Mean Concentrations/Titers After Dose 2 of the Infant Series (5 Months of Age)—per Protocol Infant Immunogenicity Population

Following the 12-month dose of Hib-MenC-TT, the percentage of participants with anti-PRP IgG concentrations ≥0.15 μg/mL and ≥1.0 μg/mL was over 99% in both groups, while 100% of participants in both groups had MenC SBA titers ≥1:8 (Table 5).

TABLE 5
TABLE 5:
Comparison of Participants Achieving Prespecified Level for Concomitant Vaccine Antigens and Geometric Mean Concentrations/Titers After 12 Months Dose Hib-MenC-TT—per Protocol Immunogenicity Population

Reactogenicity and Safety

Fewer erythematous reactions were recorded following the first dose of PCV13 than PCV7, however, there were no statistically significant differences between the 2 groups for any other reactions (Tables 6, 7).

TABLE 6
TABLE 6:
Percentage of Participants Reporting Local Reactions Within 4 Days of Vaccination
TABLE 7
TABLE 7:
Percentage of Participants Reporting Systemic Events and Antipyretic Medication Use Within 4 Days of Vaccination

Seven serious adverse events were seen in each group. One PCV7 recipient was diagnosed at 6 months of age with cerebral palsy due to a cerebrovascular accident identified on imaging as being of antenatal origin. Other diagnoses were transient gastrointestinal, respiratory, or soft-tissue infections, trauma and a breath holding episode. None of the serious adverse events were judged by the study investigators to be related to vaccination or the conduct of the study.

DISCUSSION

In this study, we have shown that a 2-, 4-, and 12-month course of PCV13 is immunogenic, well tolerated and does not interfere with the immunogenicity of concomitantly administered routine immunizations. Immunogenicity was comparable for the 7 serotypes shared between PCV7 and PCV13 and, for the latter, excellent responses against an additional 6 serotypes were demonstrated. Furthermore, the antibodies induced by immunization with PCV13 were found to be functional in an opsonophagocytic assay. These data are directly relevant to countries such as the United Kingdom, which have adopted a 2-dose priming and single-dose booster regimen for pneumococcal conjugate vaccines, and suggest that a higher valency pneumococcal conjugate vaccine administered in such a schedule has the potential to extend protection against pneumococcal disease to a broader range of pneumococcal serotypes.

In the year to June 2008, 24% of the cases of pediatric IPD in England and Wales were caused by serotypes contained in PCV7, compared with 53% for the recently licensed 10-valent-pneumococcal conjugate vaccine29 and 74% for PCV13.5 Of particular note was the increased incidence of serotype 19A disease, as has been observed internationally.5,6,30 In this study, we have shown that the reduced dose schedule of PCV13 induced antibodies that displayed opsonophagocytic activity for serotype 19A, in contrast to the nonfunctional cross-reactive antipolysaccharide antibody produced following infant immunization with PCV7. Therefore, while all children receiving a 2-, 4-, and 12-month course of PCV7 or PCV13 had serotype 19A specific IgG concentrations ≥0.35 μg/mL, only 62.7% of those receiving this course of PCV7 developed OPA titers ≥1:8 for this serotype, compared with 98.7% after PCV13. Additionally, OPA GMTs were over 20-fold higher after a 2-, 4-, and 12-month course of PCV13 than PCV7, suggesting that, unlike PCV7, immunization with PCV13 has the potential to protect against this serotype.

Lower IgG response rates for serotypes 6B and 23F were observed following immunization with PCV13 at 2 and 4 months than that previously seen following a 2-, 4- and 6-month course of PCV13.9 Similar differences in serotype 6B and 23F response rates have also been observed following 2- versus 3-dose priming courses of PCV7.31 It is therefore notable that PCV13 given at 2 and 4 months induced serotype 6B and 23F-specific OPA titers of 1:8 or greater in over 88% of recipients. This, along with the considerable reduction in IPD due to these serotypes seen in England and Wales following the introduction of a reduced schedule of PCV7,5 suggests that a similar schedule of PCV13 could also prevent IPD due to serotypes 6B and 23F.

In this study, we have used the WHO criteria of a serotype-specific IgG concentration of 0.35 μg/mL as the threshold of response, although the above data for serotype 6F, 23F and 19A raise the possibility that this may not be appropriate for all serotypes.32 Similarly, it may be inappropriate to apply a single OPA titer threshold of 1:8 for all serotypes.32 In this study, almost all recipients of a full course of PCV7 had OPA titers of 1:8 or more against serotype 7F, yet pneumococcal surveillance data shows that PCV7 is ineffective against this serotype.5 This apparent discrepancy may reflect the need for a higher threshold of response for serotype 7F OPA, nonetheless it is notable that the OPA GMTs following 3 doses of PCV13 were approximately 20 times higher than after PCV7.

There are several potential limitations to our study. Due to slow recruitment the original sample size was decreased and the analysis modified to be descriptive. Despite this, as detailed, we have been able to draw firm conclusions that provide support for the use of PCV13 in a reduced dose schedule. Although we found no evidence of reduced immunogenicity of the MenC-tetanus toxoid conjugate vaccine when administered with PCV13 compared with PCV7, we did not evaluated the concomitant administration of PCV13 with either of the 2 licensed CRM197—conjugated MenC vaccines. This is currently under evaluation in another study.33 Also, we did not specifically assess the cross-protection afforded by PCV7 and PCV13 against the newly identified serotype 6C, however other studies have identified that unlike serotype 6B polysaccharide (which is present in both vaccines), infant immunization with serotype 6A polysaccharide (present in PCV13 alone) is able to induce opsonophagocytic activity against serotype 6C34 and it is to be hoped that this will be reflected by evidence of protection against this serotype in surveillance efficacy data for PCV13 immunization campaigns. Another limitation of the current study was the relatively high rates of exclusion from the per-protocol analysis for both immunogenicity and safety analysis (outlined in Fig. 1 and Tables 6, 7). These exclusions were primarily due to lack of available serum or electronic diary data entry at the relevant time points.

CONCLUSIONS

The data outlined here complement those of other recent studies of PCV13 administered in a variety of schedules, all of which show this vaccine to be well tolerated and immunogenic.9,35,36 The results from all these studies suggest that PCV13 has the potential to dramatically reduce the burden of pediatric IPD when employed in either a 3-dose or 2-dose infant immunization schedule. In the United Kingdom, PCV13 has recently replaced PCV7 in the routine immunization schedule,10 and the ongoing IPD enhanced surveillance and postmarketing safety surveillance programs in this country will allow the assessment of whether the promising results from our study will translate to the ultimate goal of safe and effective disease prevention.

ACKNOWLEDGMENTS

The authors thank the parents and children who participated in the trials and are grateful for the clinical and administrative assistance of Emma Godfrey. A.J.P. is a Jenner Institute Investigator. The contribution of the following investigators who enrolled subjects into the study is gratefully acknowledged: K. Young, T. Egerton, M. McCaughey, D. A. Weston, and T. Hall, as is that of J. Simpson (subinvestigator at Southampton). The contribution of the Wyeth Vaccines Research staff who provided logistical direction and support is also acknowledged; in particular Anita Moradoghli-Haftvani, Helen Smith, Stephen Black, Pascale Servais and Keri Clark. Accenture staff are thanked for performing the clinical data management tasks for the study. The authors are grateful for the clinical and administrative assistance of the staff of the Southampton Wellcome Trust Clinical Research Facility, Janet Freemantle at Southampton City PCT and the staff of the child health departments of Oxfordshire, Berkshire, Buckinghamshire, Wandsworth, and Croydon.

A.J.P., M.D.S., A.F., P.T.H., S.N.F. all act as chief and principle investigator for clinical trials conducted on behalf of their employing institutions and/or their associated NHS Trusts sponsored by vaccine manufacturers including Wyeth. All have participated in advisory participated in advisory boards for vaccine manufacturers including Wyeth but receive no personal payments for this work. M.S., S.N.F., P.T.H., and A.F. have received financial assistance from Wyeth to attend conferences. All grants and honoraria are paid into an educational/research fund held by their employing institutions or an independent charity. E.D.D., S.T., D.A.S., S.A.B., T.J., W.C.G., and E.A.E. were employees of Wyeth Pharmaceuticals at the time the study was carried out.

The first draft of this article was prepared by C.L.K. The article was subsequently revised by M.D.S. incorporating comments from A.J.P. (chief investigator and guarantor of the study), A.F., P.T.H., S.N.F., D.A.S., E.D.D., S.T., T.M.J., H.L., L.R., S.P., S.D., E.G., W.C.G., E.A.E., S.A.B., T.R.J., and L.M.Y. The study protocol was developed by S.T., D.A.S., S.A.B., and W.C.G. incorporating comments from A.J.P., T.M.J., and M.S., Data analysis was performed by S.A.B., and verified by L.M.Y., E.G., C.L.K., T.M.J., H.L., L.R., and S.D., were responsible for conduct of the study at their respective sites. E.D.D., and S.T., were medical monitors, S.A.B., developed the analysis plan and performed statistical analysis, T.R.J., was responsible for serology, D.A.S., W.C.G., and E.E., had overall responsibility for the clinical development of PCV13.

All authors had full access to all of the data in the study (including statistical reports and Tables). Statistical analysis of results was performed by Wyeth Pharmaceuticals and verified by LMY. Wyeth Pharmaceuticals reviewed the paper prior to submission for publication. The researchers at the Oxford Vaccine Group, Wellcome Trust Clinical Research Facility, University of Southampton, Bristol Children's Vaccine Centre, St George's Vaccine Institute and Centre for Statistics in Medicine are all independent from Pfizer Inc.

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Keywords:

clinical trial; pneumococcal conjugate vaccine

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