Vaccine Reports
Pneumococcal Conjugate Vaccine-elicited Antibody Persistence and Immunogenicity and Safety of 13-Valent Pneumococcal Conjugate Vaccine in Children Previously Vaccinated with 4 Doses of Either 7-Valent or 13-Valent Pneumococcal Conjugate Vaccine Béatrice Quinet, MD,* France Laudat, MD,† Alejandra Gurtman, MD,‡ Scott Patterson, PhD,‡ Mohinder Sidhu, PhD,§ William C. Gruber, MD,§ and Daniel A. Scott, MD§ Background: Pneumococcal conjugate vaccine (PCV) antibody persistence and immunologic memory responses may be indicative of protection in previously vaccinated children. In children vaccinated in a previous study with an infant/toddler regimen of 4 doses of PCV7, 4 doses of PCV13, or 3 doses of PCV7 (infant series) and a dose of PCV13 (toddler dose), this follow-on study evaluated antibody persistence ≥24 months after the toddler dose, and immunogenicity and safety of a follow-on dose of PCV13. Methods: Children ≥3 years of age who had completed the initial study received 1 dose of PCV13 in this phase 3, open-label follow-on study in France. Serotype-specific anticapsular immunoglobulin G (IgG) and functional opsonophagocytic activity (OPA) were compared across the previous study vaccination groups, before, 4–7 days (IgG only), and 1 month after follow-on vaccination. Safety was assessed. Results: Before follow-on vaccination, IgG and OPA levels for the PCV7 serotypes were comparable across vaccination groups, but were generally higher for the 6 additional serotypes in children who received PCV13 in the previous study. At both time points after the follow-on vaccination, IgG and OPA values for all 13 serotypes increased, those for the PCV7 serotypes were similar across vaccination groups, but concentrations for the additional serotypes were higher in children who had received PCV13 in the previous study. PCV13 was well-tolerated. Conclusions: Antibody persistence and rapid responses after a follow-on dose of PCV13 suggest that even a single toddler dose of PCV13 is likely to provide protection against the 6 additional PCV13 serotypes. Key Words: 13-valent, pneumococcal conjugate vaccine, immunogenicity, safety, antibody persistence (Pediatr Infect Dis J 2014;33:1065–1076)
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treptococcus pneumoniae causes pneumonia, meningitis, sepsis and bacteremia and is the leading cause of vaccine-preventable death in children 7.0 cm). Injection site pain was categorized as mild (does not interfere with activity), moderate (interferes with activity) or severe (prevents daily activity). Systemic events (fever, vomiting, diarrhea and fatigue) and the use of antipyretic medication were also recorded in the e-diary by the parents/legal guardian for 7 days after vaccination. Temperature was measured at bedtime daily for 7 days after vaccination and at any time fever was suspected. Fever severity was categorized as mild (≥38.0°C to ≤39.0°C), moderate (>39.0°C to ≤40.0°C) and severe (>40.0°C). Severity of other systemic events was categorized as follows: vomiting, mild (1–2 times in 24 hours), moderate (>2 times in 24 hours) and severe (requires intravenous hydration); diarrhea, mild (2–3 loose stools in 24 hours), moderate (4–5 loose stools in 24 hours) and severe (≥6 loose stools in 24 hours); and fatigue, mild (does not interfere with activity), moderate (some interference with activity) and severe (prevents daily routine activity). The use of antipyretic medications to prevent or treat symptoms was recorded daily during the 7 days after vaccination. Other adverse events (AEs) and serious AEs (SAEs) were also collected from the signing of the consent form to 1 month after follow-on vaccination.
Statistical Analysis The evaluable immunogenicity population included eligible subjects who had blood drawn within required time frames, had ≥1 valid and determinate assay result for the proposed analysis, received no prohibited vaccines and had no major protocol violations. Pneumococcal serotype-specific IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) were calculated using logarithmically transformed assay results. Two-sided 95% confidence intervals (CIs) were constructed by back transformation of the CIs for the mean of the logarithmically transformed assay results computed using the Student t distribution. IgG GMCs and OPA GMTs were compared pairwise among the 3 groups at each time point using geometric mean ratios and 95% CIs. Differences between groups were considered statistically significant if the 95% CIs of IgG GMCs or OPA GMTs were non overlapping; if the lower 95% CI of the GMC or GMT ratio was >1; or if the upper 95% CI of the GMC or GMT ratio was 56 days after vaccination (n=3) No valid or determinate assay result (n=3) Blood draw within >7 days prior to vaccination (n=2) Prevaccination blood draw >Day 1 of vaccination (n=2)
Evaluable immunogenicity population (n=120)
At prevaccination, post-toddler dose levels of antibodies for the 6 additional serotypes had decreased in PCV13/13/13
PCV7/7/13 Consented, enrolled, vaccinated (n=65) Withdrawn from study (n=1) Lost to follow-up (n=1) Completed study (n=64) Excluded from all-available immunogenicity population (n=2) Did not receive the 4 assigned doses in Study 008 (n=1) No original ICF (n=1) All-available immunogenicity population (n=63)
Excluded from evaluable immunogenicity population (n=8)* Did not receive the 4 assigned doses in Study 008 (n=1) No valid or determinate assay result (n=1) Not in all-available immunogenicity population (n=2) Blood draw within >7 days prior to vaccination (n=2) Did not receive the 4 assigned doses in Study 008 (n=1) Not eligible for the study (n=3) Received prohibited vaccines or medications (n=3) Blood draw 56 days after vaccination (n=3) No valid or determinate assay result (n=1) Not in all-available immunogenicity population (n=3) Blood draw within >7 days prior to vaccination (n=1) Did not receive the 4 assigned doses in Study 008 (n=3) Blood draw 1 or an upper 95% CI of the ratio that was 1 or an upper 95% CI of the ratio that was 40°C. At least 1 AE was reported for 13.1%, 9.4% and 7.8% of subjects in PCV13/13/13, PCV7/7/13 and PCV7/13/13, respectively. AEs were consistent with childhood illnesses; the most frequently reported AE in all 3 groups was “infections and infestations”. Nasopharyngitis was the only AE reported by >2% of subjects in any group (2.3% of subjects in PCV13/13/13). The incidence of AEs did not differ significantly among the groups overall or for any individual AE. The only treatment-related AE was injection site erythema in 1 subject in PCV13/13/13. No deaths occurred, no SAEs were reported, and no subject withdrew due to AEs during the course of the study.
DISCUSSION Subjects in this follow-on study had previously received a 4-dose schedule of PCV at 2, 3, 4 and 12 months in 3 different regimens (either 4 doses of PCV7, or 4 doses of PCV13, or 3 doses of PCV7 and 1 toddler dose of PCV13) in the previous study.16 This allowed the present study to assess antibody persistence
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approximately 24 months after the toddler dose of PCV, both for the PCV7 serotypes as well as for the 6 additional serotypes. In addition, the response to the follow-on dose of PCV13 given as part of this study approximately 24 months after the last toddler dose of PCV7 allowed the assessment of immunological memory to the PCV serotypes, as well as the safety of a fifth dose of PCV administered in young children. For the 7 common serotypes, IgG GMCs and OPA GMTs prior to and following the follow-on dose of PCV13 were generally comparable in the 3 study groups at all 3 time points, with the exception of serotype 18C, which showed lower IgG GMC and OPA GMT levels prevaccination and 1-month postvaccination in PCV13/13/13 compared with PCV7/7/13; serotype 6B, which showed lower IgG GMC levels 1-month postvaccination in PCV13/13/13 compared with PCV7/7/13; and serotype 4, which showed lower OPA GMTs 1-month postvaccination in PCV13/13/13 compared with the other groups. In previous phase 3 studies, PCV13 elicited immune responses to the 7 common serotypes that were comparable or slightly lower in comparison with PCV7, whether administered as 3 infant doses followed by a toddler dose,10,11,22,23 2 infant doses followed by a toddler dose24,25 or as a toddler dose following 3 infant doses of PCV7.16 The generally similar levels of response in the 3 vaccine groups in this study suggest that the slightly lower IgG GMCs observed with PCV13 compared with PCV7 in the previous studies did not impact antibody persistence or establishment of memory. In contrast, in previous phase 3 studies, PCV13 elicited higher immune responses for the 6 additional serotypes compared with PCV7.10,11,16,22–25 In this study, for the 6 additional serotypes, immune responses at each time point were generally higher in the 2 groups previously vaccinated with ≥1 dose of PCV13. The generally higher pre-follow-on vaccination IgG GMCs for the 6 additional serotypes in these groups compared with PCV7/7/13 demonstrate antibody persistence. In addition, the rapid response at 4–7 days post-follow-on vaccination, as well as the higher IgG levels and OPA activity at 1-month postvaccination compared with PCV7/7/13, are suggestive of a memory response. Of note, OPA GMTs for serotype 3 at 1-month postvaccination were higher in PCV13/13/13 and PCV7/13/13 compared with PCV7/7/13, even © 2014 Lippincott Williams & Wilkins
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FIGURE 2. Serotype-specific IgG GMCs: (A) the 7 common serotypes and (B) the 6 additional serotypes.
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Figure 2. (Continued) though the IgG response to serotype 3 was similar in all 3 groups. The greater serotype 3 OPA responses to the PCV13 follow-on dose in subjects previously vaccinated with PCV13 suggest that these responses may represent memory responses following a potential maturation of the response to serotype 3. Previous studies have demonstrated that OPA responses to serotype 3 elicited by PCV13 have increased from postinfant series to post-toddler dose,11,24,25 which may also reflect the maturation of the response to serotype 3. The immune responses to serotype 3 following vaccination with PCV13 have generally been lower compared with responses to the other additional PCV13 serotypes,24–26 and the immune responses to serotype 3 in this study are also consistent with previous observations reported in PCV13 studies conducted in either infants and toddlers,24–26 or in children previously vaccinated with PCV7.27 In this study, serotype 3 OPA GMTs increased by at least 10-fold from prevaccination in all 3 study groups, demonstrating a functional immune response for this serotype. The impact of PCV13 against
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serotype 3 disease, including impact on nasopharyngeal carriage, requires further monitoring of emerging surveillance data from multiple countries. Overall, an acceptable safety profile was demonstrated for the follow-on dose of PCV13, supporting the safety of a fifth dose of PCV in children in this age group. The data from this study are consistent with those from a previous study in the United States,26 and confirm that the safety profile of a fifth dose of PCV administered at approximately 3.4 years of age in previously vaccinated children is acceptable. Early effectiveness studies have demonstrated reductions in prevalence of IPD caused by PCV13 serotypes following introduction of PCV13 into routine immunization programs. A study in the UK reported 73% effectiveness (95% CI, 29–90) for the PCV13 serotypes and serotype 6C in children who had received 1 dose of PCV13 at ≥12 months of age.13 These children may have previously received infant doses of PCV7, which was a routine pediatric © 2014 Lippincott Williams & Wilkins
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FIGURE 3. Serotype-specific OPA GMTs: (A) the 7 common serotypes and (B) the 6 additional serotypes.
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Figure 3. (Continued) vaccine prior to introduction of PCV13 in the UK, and thus the UK study may support the benefits of a catch-up or follow-on dose of PCV13 in children previously vaccinated with PCV7. In a study in 8 children’s hospitals in the United States, the incidence of IPD decreased significantly in the 3 years (2009–2011) following introduction of PCV13 in 2009, compared with 2007–2009; the proportion of cases caused by PCV13 serotypes declined by 57%.12 Similarly, in Alaska, in a population of Native Alaskan children with high (>90%) rates of vaccine uptake, the incidence of PCV13-serotype IPD declined significantly following introduction of PCV13 in 2009; of note, the incidence of nonvaccine serotype IPD also declined during the study period.28 In France, nasopharyngeal carriage of PCV13 serotypes and serotype 6C was significantly reduced in children with acute otitis media who had been vaccinated with PCV13 compared with a similar cohort who had
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been vaccinated with PCV7.29 Finally, in a study in the autonomous region of Madrid, Spain, incidence rates of IPD in children after introduction of PCV13 in 2010 declined significantly in 2010–2011 compared with 2007–2009, with significant declines in IPD caused by all PCV13 serotypes combined, and by serotypes 5 and 19A.14 These early effectiveness studies demonstrate that PCV13 is effective in reducing the incidence of PCV13-serotype IPD and nasopharyngeal carriage, whether administered as a catch-up vaccination or as an infant series followed by a toddler dose. A possible limitation of this study was that 23-valent pneumococcal polysaccharide vaccine (PPSV23) was not used to evaluate memory responses. However, PPSV23 was not used in this study, both because PPSV23 may be only be used in this age group for supplemental vaccination of children at high risk for pneumococcal disease, and because results from the studies which used PPSV23 © 2014 Lippincott Williams & Wilkins
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TABLE 5. Local Reactions Within 7 Days Postvaccination Vaccine Group PCV13/13/13 Local Reaction Pain Any Mild§ Moderate§ Severe§ Swelling Any Mild¶ Moderate¶ Severe¶ Redness Any Mild¶ Moderate¶ Severe¶ Any of the above
PCV7/7/13
PCV7/13/13
N*
n†
%
N*
n†
%
N*
n†
%
P-value‡
112 109 95 90
62 55 17 1
55.4 50.5 17.9 1.1
52 51 47 43
29 25 12 1
55.8 49.0 25.5 2.3
53 51 48 45
34 29 10 1
64.2 56.9 20.8 2.2
>0.99, 0.429, 0.314 >0.99, 0.552, 0.499 0.376, 0.633, 0.658 0.544, >0.99, >0.99
101 96 97 90
40 27 24 0
39.6 28.1 24.7 0.0
48 48 44 43
20 17 9 1
41.7 35.4 20.5 2.3
47 47 46 45
13 11 5 0
27.7 23.4 10.9 0.0
0.859, 0.197, 0.198 0.443, 0.261, 0.687 0.671, 0.253, 0.074 0.323, 0.489, NE
105 101 95 90 117
51 39 21 0 82
48.6 38.6 22.1 0.0 70.1
50 49 45 43 54
27 20 14 1 36
54.0 40.8 31.1 2.3 66.7
50 48 47 45 54
23 18 8 0 39
46.0 37.5 17.0 0.0 72.2
0.607, 0.549, 0.864 0.859, 0.836, >0.99 0.297, 0.145, 0.517 0.323, 0.489, NE 0.723, 0.676, 0.857
*Number of subjects reporting “yes” for ≥1 day or no for all days. †Number of subjects reporting the specific reaction. ‡Fisher exact test, 2-sided. Pairwise comparison [(PCV13/PCV13/PCV13 vs. PCV7/PCV7/PCV13); (PCV7/PCV13/PCV13 vs. PCV7/PCV7/PCV13) and (PCV13/PCV13/PCV13 vs. PCV7/PCV13/PCV13)]. §Mild, does not interfere with activity; moderate, interferes with activity and severe, prevents daily activity. ¶Mild, 0.5–2.0 cm; moderate, 2.5–7.0 cm and severe, >7.0 cm. NE, not estimable.
TABLE 6. Systemic Events and Antipyretic Medication Use Within 7 Days Postvaccination Vaccine Group PCV13/13/13
PCV7/7/13
PCV7/13/13
Systemic Event
N*
n†
%
N*
n†
%
N*
n†
%
P-value‡
Fever ≥38°C but ≤39°C Fever >39°C but ≤40°C Fever >40°C Vomiting Diarrhea Fatigue Use of antipyretic medications Any systemic event§
93 92 90 91 90 103 96 103
14 2 0 3 8 42 19 52
15.1 2.2 0.0 3.3 8.9 40.8 19.8 50.5
49 43 43 44 45 54 52 56
14 2 0 4 8 28 23 33
28.6 4.7 0.0 9.1 17.8 51.9 44.2 58.9
46 46 45 45 47 48 47 49
9 1 1 3 4 15 10 21
19.6 2.2 2.2 6.7 8.5 31.3 21.3 42.9
0.075, 0.345, 0.628 0.592, 0.608, >0.99 NE, >0.99, 0.333 0.215, 0.714, 0.397 0.161, 0.226, >0.99 0.237, 0.045, 0.285 0.002, 0.019, 0.828 0.323, 0.120, 0.392
*Number of subjects reporting “yes” for ≥1 day or no for all days. †Number of subjects reporting the event. ‡Fisher exact test 2-sided. Pairwise comparison [(PCV13/PCV13/PCV13 vs. PCV7/PCV7/PCV13); (PCV7/PCV13/PCV13 vs. PCV7/PCV7/PCV13) and (PCV13/PCV13/PCV13 vs. PCV7/PCV13/PCV13)]. §Includes fever ≥38°C, vomiting, diarrhea and fatigue. NE, not estimable.
as a booster dose suggest possible hyporesponsiveness following the use of PPSV23 in this age group.30,31 Another limitation is that this study relied on the participation of study sites and enrollment of subjects who had previously participated in and completed the previous study, which could have introduced bias, particularly if there were differences in enrollment ratios between the treatment groups in this study. However, although both the number of study sites and number of study subjects in this study were lower than those in the previous study, the ratio of subjects in each of the 3 study groups in this study was similar to the initial randomization ratio that had been set for the previous study, suggesting that bias because of differential enrollment is unlikely to be a factor in this study. In conclusion, at ≥2 years after a toddler dose of PCV7 or PCV13, antibody persistence for the 7 common serotypes was generally comparable whether subjects received a vaccination regimen © 2014 Lippincott Williams & Wilkins
of PCV7 alone, PCV13 alone or PCV7 with PCV13. Groups previously administered PCV13 had generally higher antibody levels for the 6 additional serotypes compared with the group previously vaccinated with PCV7 alone. The rapid increase in pneumococcal immunogenicity response observed at 4–7 days after vaccination is suggestive of a memory response induced by previous PCV13 vaccination. The follow-on dose of PCV13 was immunogenic and had an acceptable safety profile regardless of previous PCV vaccination regimen.
ACKNOWLEDGMENTS The authors thank all members of the 3021 Study Group. Medical writing support was provided by Vicki Schwartz, PhD, at Excerpta Medica and was funded by Pfizer Inc. www.pidj.com | 1075
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REFERENCES 1. Centers for Disease Control and Prevention. Vaccine preventable deaths and the Global Immunization Vision and Strategy, 2006–2015. MMWR Morb Mortal Wkly Rep. 2006;55:511–515. 2. World Health Organization. Pneumococcal conjugate vaccine for childhood immunization--WHO position paper. Wkly Epidemiol Rec. 2007;82:93–104. 3. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J. 2000;19:187–195. 4. O’Brien KL, Moulton LH, Reid R, et al. Efficacy and safety of seven-valent conjugate pneumococcal vaccine in American Indian children: group randomised trial. Lancet. 2003;362:355–361. 5. Black S, Shinefield H, Baxter R, et al. Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J. 2004;23:485–489. 6. Black SB, Shinefield HR, Hansen J, et al. Postlicensure evaluation of the effectiveness of seven valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2001;20:1105–1107. 7. Centers for Disease Control and Prevention. Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease--United States, 1998– 2003. MMWR Morb Mortal Wkly Rep. 2005;54:893–897. 8. Grall N, Hurmic O, Al Nakib M, et al; ORP Ile de France Ouest. Epidemiology of Streptococcus pneumoniae in France before introduction of the PCV-13 vaccine. Eur J Clin Microbiol Infect Dis. 2011;30: 1511–1519. 9. European Medicines Agency. Prevenar 13. Available at: http://www.emea. europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001104/ human_med_001220.jsp. Accessed August 27, 2013. 10. Kieninger DM, Kueper K, Steul K, et al; 006 study group. Safety, tolerability, and immunologic noninferiority of a 13-valent pneumococcal conjugate vaccine compared to a 7-valent pneumococcal conjugate vaccine given with routine pediatric vaccinations in Germany. Vaccine. 2010;28:4192–4203. 11. Yeh SH, Gurtman A, Hurley DC, et al; 004 Study Group. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in infants and toddlers. Pediatrics. 2010;126:e493–e505. 12. Kaplan SL, Barson WJ, Lin PL, et al. Early trends for invasive pneumococcal infections in children after the introduction of the 13-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2013;32:203–207. 13. Miller E, Andrews NJ, Waight PA, et al. Effectiveness of the new serotypes in the 13-valent pneumococcal conjugate vaccine. Vaccine. 2011;29: 9127–9131. 14. Picazo J, Ruiz-Contreras J, Casado-Flores J, et al; Heracles Study Group. Impact of introduction of conjugate vaccines in the vaccination schedule on the incidence of pediatric invasive pneumococcal disease requiring hospitalization in Madrid 2007 to 2011. Pediatr Infect Dis J. 2013;32:656–661. 15. Levy C, Varon E, Bingen E, et al; Bacterial Meningitis Study Group. Pneumococcal meningitis in French children before and after the introduction of pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2011;30:168–170. 16. Grimprel E, Laudat F, Patterson S, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine (PCV13) when given as a toddler dose to children immunized with PCV7 as infants. Vaccine. 2011;29: 9675–9683.
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17. Quataert SA, Rittenhouse-Olson K, Kirch CS, et al. Assignment of weightbased antibody units for 13 serotypes to a human antipneumococcal standard reference serum, lot 89-S(f). Clin Diagn Lab Immunol. 2004;11: 1064–1069. 18. Siber GR, Chang I, Baker S, et al. Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine. 2007;25:3816–3826. 19. Wernette CM, Frasch CE, Madore D, et al. Enzyme-linked immunosorbent assay for quantitation of human antibodies to pneumococcal polysaccharides. Clin Diagn Lab Immunol. 2003;10:514–519. 20. Cooper D, Yu X, Sidhu M, et al. The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A. Vaccine. 2011;29:7207–7211. 21. Romero-Steiner S, Libutti D, Pais LB, et al. Standardization of an opsonophagocytic assay for the measurement of functional antibody activity against Streptococcus pneumoniae using differentiated HL-60 cells. Clin Diagn Lab Immunol. 1997;4:415–422. 22. Bryant KA, Block SL, Baker SA, et al; PCV13 Infant Study Group. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine. Pediatrics. 2010;125:866–875. 23. Vanderkooi OG, Scheifele DW, Girgenti D, et al; Canadian PCV13 Study Group. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine in healthy infants and toddlers given with routine pediatric vaccinations in Canada. Pediatr Infect Dis J. 2012;31:72–77. 24. Esposito S, Tansey S, Thompson A, et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine compared to those of a 7-valent pneumococcal conjugate vaccine given as a three-dose series with routine vaccines in healthy infants and toddlers. Clin Vaccine Immunol. 2010;17:1017–1026. 25. Snape MD, Klinger CL, Daniels ED, et al. 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. Pediatr Infect Dis J. 2010;29:e80–e90. 26. Frenck R Jr, Thompson A, Yeh SH, et al; 3011 Study Group. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in children previously immunized with 7-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2011;30:1086–1091. 27. Frenck R Jr, Thompson A, Senders S, et al. 13-Valent pneumococcal conjugate vaccine in older children and adolescents either previously immunized with or naïve to 7-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2014;33:183–189. 28. Singleton R, Wenger J, Klejka JA, et al. The 13-valent pneumococcal conjugate vaccine for invasive pneumococcal disease in Alaska native children: results of a clinical trial. Pediatr Infect Dis J. 2013;32:257–263. 29. Cohen R, Levy C, Bingen E, et al. Impact of 13-valent pneumococcal conjugate vaccine on pneumococcal nasopharyngeal carriage in children with acute otitis media. Pediatr Infect Dis J. 2012;31:297–301. 30. Knuf M, Pankow-Culot H, Grunert D, et al. Induction of immunologic memory following primary vaccination with the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine in infants. Pediatr Infect Dis J. 2012;31:e31–e36. 31. Sigurdardottir ST, Center KJ, Davidsdottir K, et al. Number of infant PCV doses and type of booster may affect immune responses to Prevenar13 in childhood [Poster No. 218]. Available at: http://www2.kenes.com/ISPPD/ Scientific/Documents/FinalAbstractbook.pdf. Accessed August 27, 2013.
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Pneumococcal Conjugate Vaccine-elicited Antibody Persistence and Immunogenicity and Safety of 13-Valent Pneumococcal Conjugate Vaccine in Children Previously Vaccinated with 4 Doses of Either 7-Valent or 13-Valent Pneumococcal Conjugate Vaccine Béatrice Quinet, MD,* France Laudat, MD,† Alejandra Gurtman, MD,‡ Scott Patterson, PhD,‡ Mohinder Sidhu, PhD,§ William C. Gruber, MD,§ and Daniel A. Scott, MD§ Background: Pneumococcal conjugate vaccine (PCV) antibody persistence and immunologic memory responses may be indicative of protection in previously vaccinated children. In children vaccinated in a previous study with an infant/toddler regimen of 4 doses of PCV7, 4 doses of PCV13, or 3 doses of PCV7 (infant series) and a dose of PCV13 (toddler dose), this follow-on study evaluated antibody persistence ≥24 months after the toddler dose, and immunogenicity and safety of a follow-on dose of PCV13. Methods: Children ≥3 years of age who had completed the initial study received 1 dose of PCV13 in this phase 3, open-label follow-on study in France. Serotype-specific anticapsular immunoglobulin G (IgG) and functional opsonophagocytic activity (OPA) were compared across the previous study vaccination groups, before, 4–7 days (IgG only), and 1 month after follow-on vaccination. Safety was assessed. Results: Before follow-on vaccination, IgG and OPA levels for the PCV7 serotypes were comparable across vaccination groups, but were generally higher for the 6 additional serotypes in children who received PCV13 in the previous study. At both time points after the follow-on vaccination, IgG and OPA values for all 13 serotypes increased, those for the PCV7 serotypes were similar across vaccination groups, but concentrations for the additional serotypes were higher in children who had received PCV13 in the previous study. PCV13 was well-tolerated. Conclusions: Antibody persistence and rapid responses after a follow-on dose of PCV13 suggest that even a single toddler dose of PCV13 is likely to provide protection against the 6 additional PCV13 serotypes. Key Words: 13-valent, pneumococcal conjugate vaccine, immunogenicity, safety, antibody persistence (Pediatr Infect Dis J 2014;33:1065–1076)
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treptococcus pneumoniae causes pneumonia, meningitis, sepsis and bacteremia and is the leading cause of vaccine-preventable death in children 7.0 cm). Injection site pain was categorized as mild (does not interfere with activity), moderate (interferes with activity) or severe (prevents daily activity). Systemic events (fever, vomiting, diarrhea and fatigue) and the use of antipyretic medication were also recorded in the e-diary by the parents/legal guardian for 7 days after vaccination. Temperature was measured at bedtime daily for 7 days after vaccination and at any time fever was suspected. Fever severity was categorized as mild (≥38.0°C to ≤39.0°C), moderate (>39.0°C to ≤40.0°C) and severe (>40.0°C). Severity of other systemic events was categorized as follows: vomiting, mild (1–2 times in 24 hours), moderate (>2 times in 24 hours) and severe (requires intravenous hydration); diarrhea, mild (2–3 loose stools in 24 hours), moderate (4–5 loose stools in 24 hours) and severe (≥6 loose stools in 24 hours); and fatigue, mild (does not interfere with activity), moderate (some interference with activity) and severe (prevents daily routine activity). The use of antipyretic medications to prevent or treat symptoms was recorded daily during the 7 days after vaccination. Other adverse events (AEs) and serious AEs (SAEs) were also collected from the signing of the consent form to 1 month after follow-on vaccination.
Statistical Analysis The evaluable immunogenicity population included eligible subjects who had blood drawn within required time frames, had ≥1 valid and determinate assay result for the proposed analysis, received no prohibited vaccines and had no major protocol violations. Pneumococcal serotype-specific IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) were calculated using logarithmically transformed assay results. Two-sided 95% confidence intervals (CIs) were constructed by back transformation of the CIs for the mean of the logarithmically transformed assay results computed using the Student t distribution. IgG GMCs and OPA GMTs were compared pairwise among the 3 groups at each time point using geometric mean ratios and 95% CIs. Differences between groups were considered statistically significant if the 95% CIs of IgG GMCs or OPA GMTs were non overlapping; if the lower 95% CI of the GMC or GMT ratio was >1; or if the upper 95% CI of the GMC or GMT ratio was 56 days after vaccination (n=3) No valid or determinate assay result (n=3) Blood draw within >7 days prior to vaccination (n=2) Prevaccination blood draw >Day 1 of vaccination (n=2)
Evaluable immunogenicity population (n=120)
At prevaccination, post-toddler dose levels of antibodies for the 6 additional serotypes had decreased in PCV13/13/13
PCV7/7/13 Consented, enrolled, vaccinated (n=65) Withdrawn from study (n=1) Lost to follow-up (n=1) Completed study (n=64) Excluded from all-available immunogenicity population (n=2) Did not receive the 4 assigned doses in Study 008 (n=1) No original ICF (n=1) All-available immunogenicity population (n=63)
Excluded from evaluable immunogenicity population (n=8)* Did not receive the 4 assigned doses in Study 008 (n=1) No valid or determinate assay result (n=1) Not in all-available immunogenicity population (n=2) Blood draw within >7 days prior to vaccination (n=2) Did not receive the 4 assigned doses in Study 008 (n=1) Not eligible for the study (n=3) Received prohibited vaccines or medications (n=3) Blood draw 56 days after vaccination (n=3) No valid or determinate assay result (n=1) Not in all-available immunogenicity population (n=3) Blood draw within >7 days prior to vaccination (n=1) Did not receive the 4 assigned doses in Study 008 (n=3) Blood draw 1 or an upper 95% CI of the ratio that was 1 or an upper 95% CI of the ratio that was 40°C. At least 1 AE was reported for 13.1%, 9.4% and 7.8% of subjects in PCV13/13/13, PCV7/7/13 and PCV7/13/13, respectively. AEs were consistent with childhood illnesses; the most frequently reported AE in all 3 groups was “infections and infestations”. Nasopharyngitis was the only AE reported by >2% of subjects in any group (2.3% of subjects in PCV13/13/13). The incidence of AEs did not differ significantly among the groups overall or for any individual AE. The only treatment-related AE was injection site erythema in 1 subject in PCV13/13/13. No deaths occurred, no SAEs were reported, and no subject withdrew due to AEs during the course of the study.
DISCUSSION Subjects in this follow-on study had previously received a 4-dose schedule of PCV at 2, 3, 4 and 12 months in 3 different regimens (either 4 doses of PCV7, or 4 doses of PCV13, or 3 doses of PCV7 and 1 toddler dose of PCV13) in the previous study.16 This allowed the present study to assess antibody persistence
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approximately 24 months after the toddler dose of PCV, both for the PCV7 serotypes as well as for the 6 additional serotypes. In addition, the response to the follow-on dose of PCV13 given as part of this study approximately 24 months after the last toddler dose of PCV7 allowed the assessment of immunological memory to the PCV serotypes, as well as the safety of a fifth dose of PCV administered in young children. For the 7 common serotypes, IgG GMCs and OPA GMTs prior to and following the follow-on dose of PCV13 were generally comparable in the 3 study groups at all 3 time points, with the exception of serotype 18C, which showed lower IgG GMC and OPA GMT levels prevaccination and 1-month postvaccination in PCV13/13/13 compared with PCV7/7/13; serotype 6B, which showed lower IgG GMC levels 1-month postvaccination in PCV13/13/13 compared with PCV7/7/13; and serotype 4, which showed lower OPA GMTs 1-month postvaccination in PCV13/13/13 compared with the other groups. In previous phase 3 studies, PCV13 elicited immune responses to the 7 common serotypes that were comparable or slightly lower in comparison with PCV7, whether administered as 3 infant doses followed by a toddler dose,10,11,22,23 2 infant doses followed by a toddler dose24,25 or as a toddler dose following 3 infant doses of PCV7.16 The generally similar levels of response in the 3 vaccine groups in this study suggest that the slightly lower IgG GMCs observed with PCV13 compared with PCV7 in the previous studies did not impact antibody persistence or establishment of memory. In contrast, in previous phase 3 studies, PCV13 elicited higher immune responses for the 6 additional serotypes compared with PCV7.10,11,16,22–25 In this study, for the 6 additional serotypes, immune responses at each time point were generally higher in the 2 groups previously vaccinated with ≥1 dose of PCV13. The generally higher pre-follow-on vaccination IgG GMCs for the 6 additional serotypes in these groups compared with PCV7/7/13 demonstrate antibody persistence. In addition, the rapid response at 4–7 days post-follow-on vaccination, as well as the higher IgG levels and OPA activity at 1-month postvaccination compared with PCV7/7/13, are suggestive of a memory response. Of note, OPA GMTs for serotype 3 at 1-month postvaccination were higher in PCV13/13/13 and PCV7/13/13 compared with PCV7/7/13, even © 2014 Lippincott Williams & Wilkins
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FIGURE 2. Serotype-specific IgG GMCs: (A) the 7 common serotypes and (B) the 6 additional serotypes.
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Figure 2. (Continued) though the IgG response to serotype 3 was similar in all 3 groups. The greater serotype 3 OPA responses to the PCV13 follow-on dose in subjects previously vaccinated with PCV13 suggest that these responses may represent memory responses following a potential maturation of the response to serotype 3. Previous studies have demonstrated that OPA responses to serotype 3 elicited by PCV13 have increased from postinfant series to post-toddler dose,11,24,25 which may also reflect the maturation of the response to serotype 3. The immune responses to serotype 3 following vaccination with PCV13 have generally been lower compared with responses to the other additional PCV13 serotypes,24–26 and the immune responses to serotype 3 in this study are also consistent with previous observations reported in PCV13 studies conducted in either infants and toddlers,24–26 or in children previously vaccinated with PCV7.27 In this study, serotype 3 OPA GMTs increased by at least 10-fold from prevaccination in all 3 study groups, demonstrating a functional immune response for this serotype. The impact of PCV13 against
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serotype 3 disease, including impact on nasopharyngeal carriage, requires further monitoring of emerging surveillance data from multiple countries. Overall, an acceptable safety profile was demonstrated for the follow-on dose of PCV13, supporting the safety of a fifth dose of PCV in children in this age group. The data from this study are consistent with those from a previous study in the United States,26 and confirm that the safety profile of a fifth dose of PCV administered at approximately 3.4 years of age in previously vaccinated children is acceptable. Early effectiveness studies have demonstrated reductions in prevalence of IPD caused by PCV13 serotypes following introduction of PCV13 into routine immunization programs. A study in the UK reported 73% effectiveness (95% CI, 29–90) for the PCV13 serotypes and serotype 6C in children who had received 1 dose of PCV13 at ≥12 months of age.13 These children may have previously received infant doses of PCV7, which was a routine pediatric © 2014 Lippincott Williams & Wilkins
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FIGURE 3. Serotype-specific OPA GMTs: (A) the 7 common serotypes and (B) the 6 additional serotypes.
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Figure 3. (Continued) vaccine prior to introduction of PCV13 in the UK, and thus the UK study may support the benefits of a catch-up or follow-on dose of PCV13 in children previously vaccinated with PCV7. In a study in 8 children’s hospitals in the United States, the incidence of IPD decreased significantly in the 3 years (2009–2011) following introduction of PCV13 in 2009, compared with 2007–2009; the proportion of cases caused by PCV13 serotypes declined by 57%.12 Similarly, in Alaska, in a population of Native Alaskan children with high (>90%) rates of vaccine uptake, the incidence of PCV13-serotype IPD declined significantly following introduction of PCV13 in 2009; of note, the incidence of nonvaccine serotype IPD also declined during the study period.28 In France, nasopharyngeal carriage of PCV13 serotypes and serotype 6C was significantly reduced in children with acute otitis media who had been vaccinated with PCV13 compared with a similar cohort who had
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been vaccinated with PCV7.29 Finally, in a study in the autonomous region of Madrid, Spain, incidence rates of IPD in children after introduction of PCV13 in 2010 declined significantly in 2010–2011 compared with 2007–2009, with significant declines in IPD caused by all PCV13 serotypes combined, and by serotypes 5 and 19A.14 These early effectiveness studies demonstrate that PCV13 is effective in reducing the incidence of PCV13-serotype IPD and nasopharyngeal carriage, whether administered as a catch-up vaccination or as an infant series followed by a toddler dose. A possible limitation of this study was that 23-valent pneumococcal polysaccharide vaccine (PPSV23) was not used to evaluate memory responses. However, PPSV23 was not used in this study, both because PPSV23 may be only be used in this age group for supplemental vaccination of children at high risk for pneumococcal disease, and because results from the studies which used PPSV23 © 2014 Lippincott Williams & Wilkins
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TABLE 5. Local Reactions Within 7 Days Postvaccination Vaccine Group PCV13/13/13 Local Reaction Pain Any Mild§ Moderate§ Severe§ Swelling Any Mild¶ Moderate¶ Severe¶ Redness Any Mild¶ Moderate¶ Severe¶ Any of the above
PCV7/7/13
PCV7/13/13
N*
n†
%
N*
n†
%
N*
n†
%
P-value‡
112 109 95 90
62 55 17 1
55.4 50.5 17.9 1.1
52 51 47 43
29 25 12 1
55.8 49.0 25.5 2.3
53 51 48 45
34 29 10 1
64.2 56.9 20.8 2.2
>0.99, 0.429, 0.314 >0.99, 0.552, 0.499 0.376, 0.633, 0.658 0.544, >0.99, >0.99
101 96 97 90
40 27 24 0
39.6 28.1 24.7 0.0
48 48 44 43
20 17 9 1
41.7 35.4 20.5 2.3
47 47 46 45
13 11 5 0
27.7 23.4 10.9 0.0
0.859, 0.197, 0.198 0.443, 0.261, 0.687 0.671, 0.253, 0.074 0.323, 0.489, NE
105 101 95 90 117
51 39 21 0 82
48.6 38.6 22.1 0.0 70.1
50 49 45 43 54
27 20 14 1 36
54.0 40.8 31.1 2.3 66.7
50 48 47 45 54
23 18 8 0 39
46.0 37.5 17.0 0.0 72.2
0.607, 0.549, 0.864 0.859, 0.836, >0.99 0.297, 0.145, 0.517 0.323, 0.489, NE 0.723, 0.676, 0.857
*Number of subjects reporting “yes” for ≥1 day or no for all days. †Number of subjects reporting the specific reaction. ‡Fisher exact test, 2-sided. Pairwise comparison [(PCV13/PCV13/PCV13 vs. PCV7/PCV7/PCV13); (PCV7/PCV13/PCV13 vs. PCV7/PCV7/PCV13) and (PCV13/PCV13/PCV13 vs. PCV7/PCV13/PCV13)]. §Mild, does not interfere with activity; moderate, interferes with activity and severe, prevents daily activity. ¶Mild, 0.5–2.0 cm; moderate, 2.5–7.0 cm and severe, >7.0 cm. NE, not estimable.
TABLE 6. Systemic Events and Antipyretic Medication Use Within 7 Days Postvaccination Vaccine Group PCV13/13/13
PCV7/7/13
PCV7/13/13
Systemic Event
N*
n†
%
N*
n†
%
N*
n†
%
P-value‡
Fever ≥38°C but ≤39°C Fever >39°C but ≤40°C Fever >40°C Vomiting Diarrhea Fatigue Use of antipyretic medications Any systemic event§
93 92 90 91 90 103 96 103
14 2 0 3 8 42 19 52
15.1 2.2 0.0 3.3 8.9 40.8 19.8 50.5
49 43 43 44 45 54 52 56
14 2 0 4 8 28 23 33
28.6 4.7 0.0 9.1 17.8 51.9 44.2 58.9
46 46 45 45 47 48 47 49
9 1 1 3 4 15 10 21
19.6 2.2 2.2 6.7 8.5 31.3 21.3 42.9
0.075, 0.345, 0.628 0.592, 0.608, >0.99 NE, >0.99, 0.333 0.215, 0.714, 0.397 0.161, 0.226, >0.99 0.237, 0.045, 0.285 0.002, 0.019, 0.828 0.323, 0.120, 0.392
*Number of subjects reporting “yes” for ≥1 day or no for all days. †Number of subjects reporting the event. ‡Fisher exact test 2-sided. Pairwise comparison [(PCV13/PCV13/PCV13 vs. PCV7/PCV7/PCV13); (PCV7/PCV13/PCV13 vs. PCV7/PCV7/PCV13) and (PCV13/PCV13/PCV13 vs. PCV7/PCV13/PCV13)]. §Includes fever ≥38°C, vomiting, diarrhea and fatigue. NE, not estimable.
as a booster dose suggest possible hyporesponsiveness following the use of PPSV23 in this age group.30,31 Another limitation is that this study relied on the participation of study sites and enrollment of subjects who had previously participated in and completed the previous study, which could have introduced bias, particularly if there were differences in enrollment ratios between the treatment groups in this study. However, although both the number of study sites and number of study subjects in this study were lower than those in the previous study, the ratio of subjects in each of the 3 study groups in this study was similar to the initial randomization ratio that had been set for the previous study, suggesting that bias because of differential enrollment is unlikely to be a factor in this study. In conclusion, at ≥2 years after a toddler dose of PCV7 or PCV13, antibody persistence for the 7 common serotypes was generally comparable whether subjects received a vaccination regimen © 2014 Lippincott Williams & Wilkins
of PCV7 alone, PCV13 alone or PCV7 with PCV13. Groups previously administered PCV13 had generally higher antibody levels for the 6 additional serotypes compared with the group previously vaccinated with PCV7 alone. The rapid increase in pneumococcal immunogenicity response observed at 4–7 days after vaccination is suggestive of a memory response induced by previous PCV13 vaccination. The follow-on dose of PCV13 was immunogenic and had an acceptable safety profile regardless of previous PCV vaccination regimen.
ACKNOWLEDGMENTS The authors thank all members of the 3021 Study Group. Medical writing support was provided by Vicki Schwartz, PhD, at Excerpta Medica and was funded by Pfizer Inc. www.pidj.com | 1075
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REFERENCES 1. Centers for Disease Control and Prevention. Vaccine preventable deaths and the Global Immunization Vision and Strategy, 2006–2015. MMWR Morb Mortal Wkly Rep. 2006;55:511–515. 2. World Health Organization. Pneumococcal conjugate vaccine for childhood immunization--WHO position paper. Wkly Epidemiol Rec. 2007;82:93–104. 3. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J. 2000;19:187–195. 4. O’Brien KL, Moulton LH, Reid R, et al. Efficacy and safety of seven-valent conjugate pneumococcal vaccine in American Indian children: group randomised trial. Lancet. 2003;362:355–361. 5. Black S, Shinefield H, Baxter R, et al. Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J. 2004;23:485–489. 6. Black SB, Shinefield HR, Hansen J, et al. Postlicensure evaluation of the effectiveness of seven valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2001;20:1105–1107. 7. Centers for Disease Control and Prevention. Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease--United States, 1998– 2003. MMWR Morb Mortal Wkly Rep. 2005;54:893–897. 8. Grall N, Hurmic O, Al Nakib M, et al; ORP Ile de France Ouest. Epidemiology of Streptococcus pneumoniae in France before introduction of the PCV-13 vaccine. Eur J Clin Microbiol Infect Dis. 2011;30: 1511–1519. 9. European Medicines Agency. Prevenar 13. Available at: http://www.emea. europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001104/ human_med_001220.jsp. Accessed August 27, 2013. 10. Kieninger DM, Kueper K, Steul K, et al; 006 study group. Safety, tolerability, and immunologic noninferiority of a 13-valent pneumococcal conjugate vaccine compared to a 7-valent pneumococcal conjugate vaccine given with routine pediatric vaccinations in Germany. Vaccine. 2010;28:4192–4203. 11. Yeh SH, Gurtman A, Hurley DC, et al; 004 Study Group. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in infants and toddlers. Pediatrics. 2010;126:e493–e505. 12. Kaplan SL, Barson WJ, Lin PL, et al. Early trends for invasive pneumococcal infections in children after the introduction of the 13-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2013;32:203–207. 13. Miller E, Andrews NJ, Waight PA, et al. Effectiveness of the new serotypes in the 13-valent pneumococcal conjugate vaccine. Vaccine. 2011;29: 9127–9131. 14. Picazo J, Ruiz-Contreras J, Casado-Flores J, et al; Heracles Study Group. Impact of introduction of conjugate vaccines in the vaccination schedule on the incidence of pediatric invasive pneumococcal disease requiring hospitalization in Madrid 2007 to 2011. Pediatr Infect Dis J. 2013;32:656–661. 15. Levy C, Varon E, Bingen E, et al; Bacterial Meningitis Study Group. Pneumococcal meningitis in French children before and after the introduction of pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2011;30:168–170. 16. Grimprel E, Laudat F, Patterson S, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine (PCV13) when given as a toddler dose to children immunized with PCV7 as infants. Vaccine. 2011;29: 9675–9683.
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17. Quataert SA, Rittenhouse-Olson K, Kirch CS, et al. Assignment of weightbased antibody units for 13 serotypes to a human antipneumococcal standard reference serum, lot 89-S(f). Clin Diagn Lab Immunol. 2004;11: 1064–1069. 18. Siber GR, Chang I, Baker S, et al. Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine. 2007;25:3816–3826. 19. Wernette CM, Frasch CE, Madore D, et al. Enzyme-linked immunosorbent assay for quantitation of human antibodies to pneumococcal polysaccharides. Clin Diagn Lab Immunol. 2003;10:514–519. 20. Cooper D, Yu X, Sidhu M, et al. The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A. Vaccine. 2011;29:7207–7211. 21. Romero-Steiner S, Libutti D, Pais LB, et al. Standardization of an opsonophagocytic assay for the measurement of functional antibody activity against Streptococcus pneumoniae using differentiated HL-60 cells. Clin Diagn Lab Immunol. 1997;4:415–422. 22. Bryant KA, Block SL, Baker SA, et al; PCV13 Infant Study Group. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine. Pediatrics. 2010;125:866–875. 23. Vanderkooi OG, Scheifele DW, Girgenti D, et al; Canadian PCV13 Study Group. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine in healthy infants and toddlers given with routine pediatric vaccinations in Canada. Pediatr Infect Dis J. 2012;31:72–77. 24. Esposito S, Tansey S, Thompson A, et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine compared to those of a 7-valent pneumococcal conjugate vaccine given as a three-dose series with routine vaccines in healthy infants and toddlers. Clin Vaccine Immunol. 2010;17:1017–1026. 25. Snape MD, Klinger CL, Daniels ED, et al. 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. Pediatr Infect Dis J. 2010;29:e80–e90. 26. Frenck R Jr, Thompson A, Yeh SH, et al; 3011 Study Group. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in children previously immunized with 7-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2011;30:1086–1091. 27. Frenck R Jr, Thompson A, Senders S, et al. 13-Valent pneumococcal conjugate vaccine in older children and adolescents either previously immunized with or naïve to 7-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2014;33:183–189. 28. Singleton R, Wenger J, Klejka JA, et al. The 13-valent pneumococcal conjugate vaccine for invasive pneumococcal disease in Alaska native children: results of a clinical trial. Pediatr Infect Dis J. 2013;32:257–263. 29. Cohen R, Levy C, Bingen E, et al. Impact of 13-valent pneumococcal conjugate vaccine on pneumococcal nasopharyngeal carriage in children with acute otitis media. Pediatr Infect Dis J. 2012;31:297–301. 30. Knuf M, Pankow-Culot H, Grunert D, et al. Induction of immunologic memory following primary vaccination with the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine in infants. Pediatr Infect Dis J. 2012;31:e31–e36. 31. Sigurdardottir ST, Center KJ, Davidsdottir K, et al. Number of infant PCV doses and type of booster may affect immune responses to Prevenar13 in childhood [Poster No. 218]. Available at: http://www2.kenes.com/ISPPD/ Scientific/Documents/FinalAbstractbook.pdf. Accessed August 27, 2013.
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