Streptococcus pneumoniae is a leading cause of morbidity and mortality worldwide, both in children and adults, with approximately 14.5 million episodes of serious pneumococcal disease and 826,000 deaths annually in young children globally.1 The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) into routine infant immunization programs has led to near eradication of vaccine-serotype invasive pneumococcal disease (IPD) in vaccinated children as well as in older children and adults, through herd effect.2 – 10
The large declines in PCV7 serotype infections have been offset to some extent by increased infections with a limited number of nonvaccine serotypes.5,7,11 – 14 It is estimated that a 13-valent PCV (PCV13) could prevent 64% of the remaining cases of IPD in the United States in children <5 years old, mostly attributed to serotype 19A (42%).2 It could also prevent IPD caused by serotype 5, which has recently emerged in Western Canada, and continues to be an important serotype worldwide.15 – 17 Pneumococcal empyema would be better covered, given that 48% of isolates in a Canadian study were PCV7 serotypes, whereas the remainder were contained with PCV13.18 Furthermore, the serotypes in PCV13 are the most common serotypes causing IPD globally, accounting for 75% of IPD in children <5 years of age worldwide.17
Five clinical trials (United States,2 United Kingdom, Germany, and Italy) have reported on the immunogenicity and safety of PCV13 in comparison to PCV7.19 – 23 Those trials used different schedules and different concomitant vaccines.19 – 23
The objectives of this study were to evaluate the immune responses to concomitant routine childhood vaccines when given with PCV13, compared with PCV7. The safety and tolerability of PCV13 were evaluated. Serotype-specific responses to PCV13 were also measured.
MATERIALS AND METHODS
This was a phase III, parallel-group, double-blind, multicenter trial conducted at 11 centers across Canada (Appendix I). Approval was obtained from an independent ethics committee and/or each institutional review board at each study site. Written informed consent was obtained from the parent/guardian of each subject prior to enrollment. The study was conducted between June 2007 and May 2009.
Two-month-old (day 42–98 at enrollment) healthy infants were eligible to participate. Exclusion criteria are detailed in Figure 1. A medical history was obtained, and physical examination performed at enrollment and reviewed before each vaccination.
Subjects were randomized 1:1 to receive either PCV13 or PCV7 at 2, 4, and 6 months (primary infant series) followed by a toddler booster at 12 months.
The routine concomitant vaccines given were diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b (Pentacel, Sanofi Pasteur Ltd.) at 2, 4, and 6 months; meningococcal C conjugate (NeisVac-C, GlaxoSmithKline Inc., Mississauga, Ontario, Canada) at 2, 6, and 12 months; and measles, mumps, and rubella (MMR II, Merck Frosst, Kirkland, Quebec, Canada) and varicella vaccines (Varivax III, Merck Frosst) at 12 months of age. Blood draws were performed at 7 and 13 months.
PCV7 used in this trial was identical to the licensed product Prevnar (with the exception of the blinded package labeling) containing saccharides from 7 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), covalently conjugated to CRM197, a nontoxic variant of diphtheria toxin. The adjuvant used was aluminum phosphate, containing 0.125 mg of aluminum. PCV13 additionally contained saccharides from pneumococcal serotypes 1, 3, 5, 6A, 7F, and 19A. PCV13 contained 2.2 μg of each saccharide, except for 4.4 μg of 6B.
A 3 to 5 mL venous blood sample was obtained at each blood draw. Sera were stored at −20°C to −70°C until testing was performed.
Both blood samples obtained from the subjects receiving PCV13 were tested by an enzyme-linked immunosorbent assay to measure the concentration of serotype-specific polysaccharide (PS)-binding antibodies.
Antibody responses to Hib polyribosylribitol phosphate (PRP) were measured in blood samples collected at 7 months of age, as were immunoglobulin G (IgG) responses to the pertussis antigens (pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3). Group C meningococcal antibody titers were measured in both blood samples.
The primary immunologic comparisons were the concomitant vaccine antigen immune responses in subjects receiving PCV13 or PCV7 measured 1 month after the infant series. The primary end point for each concomitant vaccine antigen was the proportion of subjects achieving a serum antibody concentration ≥ the predefined concentration, as follows: meningococcal C serum bactericidal assay titer ≥1:8; pertussis toxoid and pertactin ≥5 enzyme-linked immunosorbent assay units (EU)/mL; and filamentous hemagglutinin ≥7.82 EU/mL, fimbrial agglutinogens (types 2 and 3) ≥2.2 EU/mL, and Hib anti-PRP ≥0.15 μg/mL.
The secondary end point for the concomitant vaccine antigens was the proportion of subjects achieving a meningococcal C serum bactericidal assay ≥1:8 measured 1 month after the toddler dose. An additional end point for Hib was the proportion of subjects achieving an anti-PRP level ≥1.0 μg/mL measured 1 month after the infant series.
The immunogenicity end points for each of the pneumococcal serotypes were the proportions of subjects in the 13vPnC group achieving a serotype-specific IgG concentration ≥0.35 μg/mL, the reference concentration for assessment of vaccine efficacy against IPD defined by the World Health Organization.24 The IgG geometric mean concentrations (GMC) were calculated for each serotype at both sampling points.
Safety assessments were based on data from the daily monitoring and recording of local reactions and systemic events by the parent(s)/guardian(s) in an e-diary for 4 days after each vaccination (days 1–4) and adverse event (AE) monitoring through 1 month following the third infant immunization and from the toddler dose to the 1-month follow-up visit. Local reactions included redness, swelling, and tenderness at the site of pneumococcal conjugate injection. Redness and swelling were categorized as mild (0.5–2.0 cm), moderate (2.5–7.0 cm), or severe (>7.0 cm). Tenderness was recorded as none, present, or interfered with limb movement. Solicited systemic events included fever, decreased appetite, irritability, increased sleep, and decreased sleep. Axillary temperature was documented daily at bedtime for 4 days and at any time during those days if fever was suspected. The highest temperature was to be recorded in the e-diary. Temperature was measured and recorded to 1 decimal place and then categorized according to the following terms and scale: absent, <38.0°C (100.4°F); mild, ≥38.0°C (100.4°F) to ≤39.0°C (102.2°F); moderate, >39.0°C (102.2°F) to ≤40.0°C (104.0°F); and severe >40.0°C (104.0°F). The use of antipyretic medication was also documented. All subjects were monitored for 30 minutes following each vaccination.
A serious adverse event (SAE) was defined as an AE that resulted in death, was life-threatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity, resulted in cancer, or important medical events not resulting in the above as determined by investigator. SAEs and newly diagnosed chronic medical conditions were monitored from enrollment through 6 months following the toddler dose.
Within each vaccine group and for each concomitant vaccine antigen separately, the proportion of subjects achieving at least the predefined antibody concentration was computed. For all concomitant vaccine antigens, noninferiority was declared if the lower limit of the 2-sided, 95% confidence interval (CI) for the difference in proportions was greater than −0.10.
For subjects in the 13vPnC group, the proportion of subjects achieving an antibody concentration ≥0.35 μg/mL for each of the pneumococcal serotypes was computed along with an exact, 2-sided, 95% CI for the proportion. The serotype-specific pneumococcal IgG concentrations were logarithmically transformed for analysis. For each serotype separately, geometric means of the antibody concentrations from each of the blood draws were calculated. Two-sided 95% CIs were constructed by back transformation of the CIs for the mean of the logarithmically transformed assay results computed using the Student t distribution.
The evaluable concomitant vaccine infant immunogenicity population was the primary analysis population and included those randomly assigned subjects who met all inclusion criteria, had at least 1 valid and determinate assay result for the proposed analysis, and had no major protocol violations.
The safety population included all subjects who received at least 1 dose of the study vaccine. The safety end points were rates of local reactions, systemic events including fever, and use of antipyretic medications to treat or prevent symptoms. Rates of local reactions, systemic events, and AEs after administration of each dose of study vaccine in the PCV13 group and PCV7 group were compared with the 2-sided Fisher exact test.
A sample size of 240 evaluable subjects per group was calculated to provide at least 92% overall power to declare noninferiority for all concomitant vaccine antigens using a noninferiority criterion of −0.10 and a 2-sided, type I error rate of 0.05. Assuming a maximal drop-out rate of 15%, 570 subjects overall (285 subjects per group) were to be enrolled.
A total of 603 children were enrolled, 300 were randomized to the PCV13 vaccine group and 303 to the PCV7 group (Fig. 1). The baseline characteristics for the subjects vaccinated were 51% male, 83.7% white, 3.3% Asian, 3.0% black, and 10% other race. In all, 3.2% were of Hispanic or Latino ethnicity. There were no significant differences between treatment groups with respect to sex, race, ethnicity, age, weight, or protocol.
Response to Concomitant Vaccines
The primary end point of noninferiority of PCV13 compared with PCV7 was met for each of the concomitant vaccine antigens (Table 1). The proportions of subjects exceeding predefined levels of antibodies to concomitant vaccine antigens after the infant series and toddler dose were not significantly different between the PCV13 and PCV7 groups except for a 2.4% lower proportion of subjects achieving the predefined antibody levels to meningococcal C antigen in the PCV13 infant group (Table 1).
The proportion of subjects achieving serotype-specific pneumococcal IgG concentrations ≥0.35 μg/mL following the infant series and toddler dose are shown in Table 2. Following the infant series serotype-specific pneumococcal IgG concentrations of ≥0.35 μg/mL were achieved for most serotypes in >90% of infants with the exception of serotype 3 (79.6%) and 5 (87.0%). Following the toddler dose, serotype-specific pneumococcal IgG concentrations of ≥0.35 μg/mL were achieved in >98% of the toddler's with the exception of serotype 3 (84.8%).
Complete safety data were available for 569 subjects (94.4%) (Fig. 1). There were no severe local reactions after any dose. In the PCV13 group, tenderness at the injection site following immunization was observed in 44.5% (dose 1), 37.5% (dose 2), 27.3% (dose 3), and 25% (dose 4). Tenderness interfered with limb use in 4.4% (dose 1), 3.6% (dose 2), 3.8% (dose 3), and 2.5% (dose 4). Mild induration (0.5–2.0 cm) at the injection site occurred in 5.6% (dose 1), 10.4% (dose 2), 11.1% (dose 3), and 10.6% (dose 4). Induration was moderate (2.5–7.0 cm) in 0.7% (dose 1), 0.8% (dose 2), 0.8% (dose 3), and 1.0% (dose 4). Mild erythema (0.5–2.0 cm) at the injection site occurred in 10.7% (dose 1), 16.8% (dose 2), 16.4% (dose 3), and 18.8% (dose 4). Erythema was moderate (2.5–7.0 cm) in 0.4% (dose 1), 2.0% (dose 2), 0.4% (dose 3), and 2.5% (dose 4).There were no significant differences between the 2 vaccine groups with respect to local tenderness, swelling, or redness.
The incidence of fever did not differ significantly between the 2 vaccine groups. Fever ≥38°C but ≤39°C was observed in 8.9% (dose 1), 8.0% (dose 2), 8.9% (dose 3), and 13.3% (dose 4). Fever >39°C but ≤40°C was observed in 0.7% (dose 1), 0.4% (dose 2), 0.4% (dose 3), and 2.0% (dose 4). Fever >40°C was observed in 1 PCV7 subject and was not observed in PCV13 subjects. Rates, if other systemic AEs, were similar between groups with the exception of irritability following the fourth dose being more common in the PCV13 group (68.8% vs. 58.5%) (Table 3). Antipyretic medications were commonly administered for fever prophylaxis and treatment (Table 3).
There were no deaths or life-threatening AEs reported in the infant portion of the study, although 76.3% of subjects receiving PCV13 and 75.9% of subjects receiving PCV7 experienced at least 1 AE. A mild infection (most commonly upper respiratory tract infection) was noted in 54.0% and 50.8% of the PCV13 and PCV7 groups, respectively. There were no significant differences between the 2 groups with respect to other AEs reported, majority of them being benign childhood illnesses. Ten subjects had SAEs, most commonly bronchiolitis or gastroenteritis, with no significant difference between the 2 groups.
One PCV7 subject was withdrawn during the infant series for mild urticaria that occurred 2 days following dose 3. Four subjects were withdrawn after the infant series (4 PCV7 group, 0 PCV13 group) for febrile neutropenia (1), convulsion (1), febrile convulsion (1), and movement disorder (1).
There were no deaths or life-threatening AEs reported during the month after the toddler dose. Overall, 38.8% of subjects receiving PCV13 and 38.9% of subjects receiving PCV7 experienced at least 1 AE during the toddler portion of the study, with 13 SAEs, considered unrelated to vaccine product by the local investigator. There were no significant differences between the 2 groups with respect to AEs reported, most of them being benign childhood illnesses. A 6-month follow-up telephone contact revealed a total of 10 subjects who had vaccine-unrelated SAEs.
When given concomitantly with routine childhood vaccines in Canada, we found that PCV13 was noninferior to PCV7 with respect to the immunogenicity of concomitant vaccines (antigens contained within Pentacel and NeisVac-C). No significant safety and tolerability concerns were detected in this study.
In addition, the number of subjects achieving predefined antibody response thresholds for concomitantly administered vaccines was not significantly different (Table 1) following the infant series. Similarly, antibody threshold levels for meningococcal C antigen following the toddler dose were achieved by all subjects in both groups. No evidence of interference between vaccines was seen in this trial of PCV13, similar to other studies with different concomitant childhood vaccines.19 – 23
The proportions of subjects achieving serotype-specific pneumococcal IgG concentration ≥0.35 μg/mL, the level considered protective by the World Health Organization working group,24 in the PCV13 group were >90% for the shared PCV7 serotypes and between 80% and 98% for the additional 6 serotypes in PCV13 after the infant series. Serotypes 3 (80%) and 5 (87%) had the lowest immunogenicity in the infant series. Following the toddler dose (12 months), the proportion of responders for all PCV13 serotype was >90%, with the continued exception of serotype 3 at 84.8% similar to the United Kingdom 2-dose study,23 but the GMC of serotype 3-specific IgG was not significantly lower (data not shown) than the other reported serotypes in another study.19 This differs from other comparative studies that found serotype 6B to be the least immunogenic after the infant series.19,20,22 In this study, opsonophagocytic assays were not performed, but in the other study where the proportion of subjects achieving protective serotype 3-specific IgG responses was similar to the present study, the opsonophagocytic assay responses were robust (95%–100%) following the infant and toddler doses.23
After the toddler dose GMCs of the serotype-specific IgG in the PCV13 group increased approximately 2-fold (data not shown), compared with after the infant series, for all serotypes except serotype 3 which increased from 0.63 to 0.74 μg/mL. Overall, the immune response generated by PCV13 was similar compared with reported immune responses to PCV7.19 – 23,25
The safety profile of PCV13 was similar to PCV7 in both this trial and previously reported trials.19 – 23 No severe injection site reactions, severe or life-threatening AEs, or deaths were reported in this trial. The number and types of solicited AEs were similar between groups. Unsolicited AEs were consistent with normal childhood events. The only difference between the treatment groups was a 10% increase in irritability in the PCV13 group following the toddler dose (Table 3). However, this was not demonstrated in other trials,19,20,22,23 although 1 study noted the same difference at the first dose in the infant series.21 The rates of antipyretic medication use as prevention or treatment were similar in both groups.
A recent study demonstrated interference by antipyretic use on immunogenicity of a conjugate vaccine.26 The effect of antipyretics on the immunogenicity and reactogenicity of PCV7 or PCV13 is unknown and will require further study. It is unclear why parents considered antipyretics necessary in both the PCV7 and PCV13 populations (Table 3).
Overall, this double-blind, randomized, controlled trial demonstrated no differences between PCV7 and PCV13 on immune responses elicited by selected routine childhood vaccines concomitantly administered in the standard Canadian program (Pentacel and NeisVac-C). Immune responses to concomitantly administered measles, mumps, and rubella and varicella vaccines were not assessed. Immune responses to the pneumococcal serotypes, both those contained in PCV7 and the additional serotypes included in PCV13 were satisfactory. The safety profile of PCV13 was similar to PCV7 with adverse reactions generally being mild and self-limited. PCV13 has the potential to significantly affect the remaining IPD, including the Western Canadian outbreak strain, serotype 5, and the emerging serotype 19A. The additional serotypes in PCV13 have the potential to prevent a large burden of disease worldwide.
The Canadian PCV13 Study Group consists of Dr. David Scheifele (Site PI), Dr. Simon Dobson (Vaccine Evaluation Centre, Vancouver, BC); Dr. Paul Zickler (Site PI) (TASC Research Services Inc., Surrey, BC); Dr. William Meekison (Site PI) (WestCoast Clinical Research, Coquitlam, BC); Dr. James D. Kellner (Site PI), Dr. Otto G. Vanderkooi (Alberta Children's Hospital, Calgary, AB); Dr. Gerald Predy (Site PI) (Alberta Health, Edmonton, AB); Dr. Ethan Rubinstein (Site PI) (Manitoba Institute of Child Health, Winnipeg, MN); Dr. Marc Dionne (Site PI) (Unité de recherche en santé publique, Quebec, QC); Dr. Bruce Tapiero (Site PI) (CHU Sainte Justine, Montreal, QC); Dr. Jane MacDonald (Site PI) (MUHC-Vaccine Study Centre, Montreal, QC); Dr. Scott Halperin (Site PI), Joanne M. Langley, Shelly McNeil (Canadian Center for Vaccinology, Dalhouse University and the IWK Health Centre, Halifax, NS), Michael Pride (Pfizer Inc., Pearl River, NY).
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