Vaccine Reports
Pneumococcal Conjugate Vaccine Administration During Therapy for Pediatric Leukemia Nigel W. Crawford, MB BS, MPH, PhD, FRACP,*†‡ Anne Balloch, BSc, MSc,§ Leena Tikkanen, BSc, MSc,§ Francoise Merchinaud, MD,¶ Peter Downie, MB BS, FRACP,¶‖ and Jim P. Buttery, BMMS, MD, FRACP*,**†† Background: Pediatric leukemia patients are at high risk of invasive pneumococcal disease. The study aim was to determine the antibody response to a 10-valent pneumococcal conjugate vaccine (PCV10) administered during chemotherapy. Methods: An open-label study in pediatric leukemia patients: Group 1 had completed a primary 7-valent (PCV7) course and received a single PCV10 dose. Group 2 were PCV immunization naïve and received 3 doses of PCV10, administered 2 months apart. Serum samples were taken at baseline and 1 month post each PCV10 dose. Antipneumococcal serotype-specific IgG to 10 serotypes were measured by enzyme-linked immunosorbent assay and the functional response to 4 serotypes (1, 6B, 19F and 23F) was measured using opsonophagocytic assays. Results: Thirty-nine participants were recruited between May 2010 and January 2011; group 1 (n = 27) and group 2 (n = 12). The diagnosis was acute lymphoblastic leukemia (38) and acute myeloid leukemia (1). Median age was 6.2 years (1.7–17.2 years) with 62% male. The median time from diagnosis to baseline serology was 7.4 months (1.6–36.8 months). At baseline, protective geometric mean concentration above the threshold (>0.35 μg/mL) ranged from 5.3% (serotype 4) to 71% (serotype 19F). More than 60% of participants in both groups were above threshold postimmunization for 7 of the 10 PCV serotypes. Opsonophagocytic assay correlated with enzyme-linked immunosorbent assay for 3 of the 4 serotypes and r ranged from 0.51 to 0.84. An injection-site reaction was reported in 73% (27/37). Conclusions: It is safe to administer PCV10 vaccine during therapy for pediatric leukemia. It provided a satisfactory serum immune response for the majority of vaccine serotypes. Key Words: childhood cancer, invasive pneumococcal disease, vaccination (Pediatr Infect Dis J 2015;34:e9–e15)
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p olysaccharide vaccine (23-valent pneumococcal polysaccharide vaccine) and pneumococcal conjugate vaccine (PCV) available.2 The 23-valent pneumococcal polysaccharide vaccine is not efficacious in children 2-fold rise for those positive at baseline was considered a significant immunogenic response to the PCV10 vaccine. A serologic response above this protective threshold in >60% of participants to 5 of the 10 serotypes in the PCV10 vaccine was considered protective. The secondary endpoints included the following: (1) functional OPA response to 4 serotypes (1, 6A, 19F, 23F), with assay titers ≥1:8 considered significant; (2) immunogenicity sensitivity analysis of serotype-specific ELISA titers ≥0.20 μg/mL was used to compare study results to published immunogenicity data for PCV10 in infants11,18 and (3) safety of the vaccine, with a particular focus on febrile responses and tolerability in those aged ≥6 years in whom the PCV10 vaccine was not licensed at the time of the study.
Statistical Considerations In Australia, approximately 700 children and adolescents aged 0–18 years are diagnosed each year with cancer.19 One-third of these patients have leukemia (ALL or AML). In Victoria, approximately 80 children with leukemia are treated annually, managed at the 2 study sites. A recruitment rate of 60%, over a 12-month time frame, produced a study target of 50 participants, which is comparable with other vaccine immunogenicity studies in oncology cohorts.20,21 The ELISA serotype-specific antibody concentrations and OPA titers were log(e) transformed for statistical analysis to
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approximate normal distributions. The ELISA GMCs were determined by taking the antilogarithm of the means of the log-transformed values. The paired t test was used to compare the mean at postimmunization to preimmunization, with a P value 0.35 μg/mL) ranged from 5.3% for serotype 4 to 71% for serotype 19F. Following immunization, there was a significant increase in GMC from baseline for all serotypes (P < 0.01). Following a single dose of PCV10, the percentage of all participants with protective GMC above the protective threshold ranged from 33.3% for serotype 4 to 81.1% for serotype 14. The primary study endpoint of >60% of participants above the protective threshold following a single PCV10 dose was achieved in 5 of the 10 PCV serotypes (6B, 9V, 14, 19F, 23F; Fig. 2). In those participants who were seropositive at baseline, the percentage who had a >2-fold rise in GMC ranged from 0% to 63.6%. A sensitivity analysis for the combined results (groups 1 and 2) post a single PCV10 dose using the GSK 0.20 μg/ mL protective threshold cutoff,11 compared with infant historical data, was undertaken (data not shown). Using this lower threshold © 2014 Lippincott Williams & Wilkins
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128 patients eligible • 80 declined • 9 language barrier
39 participants recruited • 33 RCH • 6 MMC Group 1 • 2 participants had baseline serology only • one withdrew (needle phobia) • one unsatisfactory immunogenicity sample
Received PCV10 vaccine (N = 37) Group 1 = 25 Group 2 = 12
Group 2 • 1 participant received single dose • 2 participants received two doses
Functional Antibody (OPA) (N = 15) Group 1 = 13 Group 2 = 2
FIGURE 1. PCV10 study flow diagram. RCH indicates Royal Children’s Hospital; International Classification of Diseases 10th Edition. TABLE 1. Ten-valent Pneumococcal Conjugate Vaccine Baseline Clinical Characteristics Group 1 Number of 27 participants Male (%) 63 Median age (yr) 4.9 (1.7–9.6) (range) Time on 5.5 (1.6–36.8) chemotherapy (mo) (range) Chemotherapy stage at baseline Intensification 3 Consolidation 3 Interim 3 maintenance Delayed 4 intensification AML 1 Total on 14 intensive therapy Maintenance 13*
Group 2
Overall
12
39
58 12 (4.5–17.2)
62 6.2 (1.7–17.2)
16.1 (2.8–35.5) 7.4 (1.6–36.8)
1 1 2
4 4 5
0
4
0 4
1 18
8
21
*n = 11 received a PCV10 dose.
(0.20 μg/mL) for our oncology cohort, 8 of the PCV10 serotypes had 60% or more participants above this cutoff. A subgroup analysis of immune response by subgroups of intensive early-phase chemotherapy and maintenance chemotherapy is detailed in Table 2. It identified that the maintenance chemotherapy subset in group 1 (single dose) was more likely to have a significant increase above baseline, with 9 of the 10 serotypes having a P value 0.35 μg/mL at baseline and post–dose-1 PCV10. had an increase above baseline in the intensive therapy subgroup. There was no statistical difference in the group 2 analysis by subgroup. The percentage of participants above the protective threshold (>0.35) for group 1 ranged from 45% to 82% (maintenance subgroup) and 38% to 86% (intensive). For group 2 (dose 1) it ranged from 45% to 82% (maintenance subgroup) and 38% to 86% (intensive chemotherapy subgroup). The overall immunogenicity data by group are detailed in Tables 3 and 4. The primary endpoint of >60% of participants above the threshold following a single PCV10 dose in group 1 was obtained in 7 of the 10 PCV serotypes (4, 6B, 9V, 14, 19F, 18C, 23F). These are all serotypes in the PCV7 vaccine, which by inclusion criteria had been received before diagnosis. In group 2 (Table 4) at baseline, the percentage with GMC above the protective threshold (>0.35 μg/mL) ranged from 9.1% for serotype 4 to 54.6% for serotype 19F. The GMC only increased significantly from baseline (P value 60% of participants being above the threshold following a PCV10 course (2 or 3 doses), was obtained in 7 of the 10 PCV serotypes (6B, 7F, 9V, 14, 19F, 18C, 23F). At baseline, the percentage above the OPA threshold titer (≥1:8) to 4 serotypes (1, 6b, 19F, 23F) ranged from 0% (serotype 1, a non-PCV7 serotype) to 40% for serotype 6B. Following a single dose of PCV10 vaccine this increased to 39.4% (serotype 1), 83.8% (serotype 6B), 86.5% (serotype 19F) and 70.3% (serotype 23F). ELISA and OPA showed good correlation for the serotypes in both the 7-valent and 10-valent PCVs (6B, 19F and 23F), with the Pearson coefficient (r) ranging from 0.81 to 0.84 (Fig. 3). It was lower for the non-PCV7 serotype 1, with r = 0.51. There was 1 participant with a diagnosis of AML (myeloid leukemia of Down syndrome), receiving intensive chemotherapy over 6 monthly cycles. The individual was 23 months of age at diagnosis and in group 1, having received 3 previous PCV7 doses at the routine 2, 4 and 6 months of age. At study baseline, 4.5 months since diagnosis, he was seropositive to 4 serotypes (6B, 9V, 19F, 23F). At 1 month post the vaccine, GMC ELISA antibody levels were seroprotective to 6 of the PCV10 serotypes (1, 5, 6B, 7F, 14, 23F). The majority of adverse events following immunization reported were tenderness at the injection site in 73% (27/37). Systemic symptoms were reported in 41% (15/37) overall, with diarrhea being the most common (4 participants). There was 1 reported fever >38°C in a non-neutropenic patient, who had some associated diarrhea and required hospital admission for 48 hours of intravenous fluids. These symptoms while temporally related to vaccine timing may have been chemotherapy-related side effects. www.pidj.com | e11
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TABLE 2. Geometric Mean Concentration by Group and Intensive or Maintenance Therapy (Following Dose-1 PCV10) Group 1 (N = 25) Intensive Therapy (n = 14) Serotype
Maintenance (n = 11) Percentage >0.35 μg/mL
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
GMC (μg/mL)
95% CI
1 4 5 6B 7F 9V 14 18C
0.26 0.43 0.38 1.37 0.47 0.44 3.03* 0.69
0.13–0.56 0.16–1.22 0.18–0.79 0.48–3.93 0.16–1.37 0.17–1.15 1.12–8.25 0.22–2.18
38 57 43 79 50 54 93 57
0.39 1.4* 0.33 1.2* 0.34* 1.81* 4.23* 1.71*
45 72 55 64 55 82 82 64
19F
3.05
0.95–9.77
86
4.84*
23F
0.62
0.25–1.56
64
0.95*
0.12–1.2 0.27–7.76 0.09–1.28 0.33–4.3 0.09–1.15 0.41–8.0 0.71–25.2 0.23– 12.80 0.94– 24.98 0.20–4.56
82 64
Group 2 (N = 12) Intensive Therapy (n = 4) Serotype
Maintenance (n = 8)
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
0.26 0.29 1.09 1.82 0.53 0.97 3.25 0.89 1.48. 2.55
0.11–0.59 0.03–2.80 0.03–40.18 0.16–21.06 0.08–3.48 0.12–7.64 0.04–235.8 0.21–3.74 0.17–12.79 0.28–23.34
25 50 50 100 75 75 100 75 75 100
0.20 0.14 0.16 0.29 0.21 0.14 0.72 0.15 0.87 0.65
0.09–0.43 0.04–0.51 0.08–0.34 0.07–1.13 0.09–0.48 0.05–0.38 0.17–3.02 0.07–0.32 0.19–4.04 0.14–1.78
13 25 13 25 25 38 50 25 63 50
1 4 5 6B 7F 9V 14 18C 19F 23F
Shaded rows are non-PCV7 serotypes. *P < 0.01 (comparison of GMC at baseline to post–dose-1 PCV10). CI indicates confidence interval.
TABLE 3. Pneumococcal GMC Pre-dose and Post-dose 1 (Group1 Only) Serotypes
1 4 5 6B 7F 9V 14 18C 19F 23F
Baseline (n = 27)
Post-dose 1 (n = 25)
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
0.13 0.10 0.15 0.31 0.09 0.15 0.42 0.13 0.74 0.21
0.10–0.17 0.08–0.14 0.11–0.21 0.19–0.52 0.06–0.14 0.10–0.24 0.30–0.58 0.09–0.20 0.42–1.28 0.14–0.34
3.7 3.7 11.1 30.8 14.8 14.8 59.3 18.5 77.8 29.6
0.31* 0.74* 0.36* 1.2* 0.41* 0.81* 3.5* 1.03* 3.7* 0.75*
0.17–0.58 0.30–1.81 0.19–0.69 0.61–2.73 0.19–0.86 0.35–1.88 1.45–8.51 0.37–2.85 1.52–9.18 0.34–1.66
40 64 48 72 52 64 88 60 84 64
Shaded rows are non-PCV7 serotypes. *P < 0.01 (comparison of GMC at baseline to post–dose-1 PCV10). CI indicates confidence interval.
Discussion This Australian study describes the serum immune response to PCV10 immunization in children and adolescents receiving chemotherapy for leukemia. The majority had received a previous PCV (PCV7) in infancy, but did not have protective antibody levels above the >0.35 μg/mL threshold at baseline, with 6 serotypes 60% of participants seroprotected. In group 1, the primary study endpoint was obtained in all of the PCV7 serotypes, indicating a satisfactory immunogenicity “booster” response. In the subgroup
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analysis by therapy intensity, those on maintenance therapy (n = 11) were more likely to have a significant increase in GMC from baseline in 9 of 10 serotypes. The primary endpoint in group 2, following a PCV10 course (2 or 3 doses), was obtained in 7 of the PCV10 serotypes. There was no difference in subgroup analysis by chemotherapy intensity following dose-1 PCV10 vaccine. The results of this study can be compared with that of a PCV7 immunogenicity study in a Hong Kong pediatric oncology cohort.22 Cheng et al22 reviewed the immunogenicity post 2 doses of PCV7 vaccine administered a month apart in 44 patients [29 © 2014 Lippincott Williams & Wilkins
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TABLE 4. Pneumococcal GMC Pre-dose 1 and Post-dose 1 (Group 2 Only) Serotypes
1 4 5 6B 7F 9V 14 18C 19F 23F
Baseline (n = 11)
Post-dose 1 (n = 12)
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
0.17 0.08 0.20 0.22 0.14 0.14 0.53 0.13 0.49 0.22
0.10–0.31 0.04–0.17 0.08–0.48 0.11–0.44 0.06–0.32 0.06–0.37 0.19–1.47 0.05–0.34 0.19–1.28 0.10–0.46
18.2 9.1 27.3 27.3 18.2 27.3 36.4 18.2 54.6 36.4
GMC (μg/mL) 0.21 0.18 0.31 0.53 0.28 0.27 1.20 0.27 1.04 1.02*
Post-dose 2 (n = 11)
95% CI
Percentage >0.35 μg/mL
GMC
95% CI
0.13–0.36 0.07–0.46 0.11–0.88 0.17–1.64 0.13–0.57 0.10–0.70 0.32–4.51 0.12–0.60 0.37–2.96 0.33–3.12
16.7 33.3 25 50 41.7 50 66.7 41.7 66.7 66.7
0.37 0.20 0.38 0.82* 0.46* 0.35 1.91* 0.55* 1.20 0.96*
0.12–1.02 0.08–0.53 0.12–1.13 0.29–2.27 0.20–1.06 0.14–0.87 0.49–7.44 0.28–1.07 0.41–3.46 0.35–2.66
Post-dose 3 (n = 9)
Percentage > 0.35 μg/mL GMC 36.4 36.4 36.4 63.6 63.6 63.6 81.8 54.6 81.8 72.7
0.31 0.23 0.34 0.40 0.45 0.33 1.73 0.69* 0.94 0.73*
Percentage >0.35 95% CI μg/mL 0.14–0.66 0.09–0.56 0.12–0.98 0.17–0.92 0.19–1.06 0.11–0.94 0.47–6.41 0.42–1.15 0.32–2.82 0.38–1.42
44.4 44.4 33.3 55.6 55.6 55.6 77.8 88.9 77.8 88.9
Shaded rows are non-PCV7 serotypes. *P < 0.01 (comparison of GMC at baseline to post–PCV10 dose 1, dose 2 and dose 3). CI indicates confidence interval.
hematological (25 ALL); 15 solid tumors]. Pneumococcal serology was taken at baseline and 1 month post the 2nd PCV7 dose. At the study endpoint, the protective antibody GMC above threshold to the PCV7 serotypes ranged from 86% to 100%. Directly correlating our
PCV10 study with the Hong Kong PCV7 data is difficult, as a large number of patients in the study by Cheng et al22 were completely off therapy (median 6 months; range 1–12 months). The high levels of baseline seropositive results may reflect pneumococcal carriage
FIGURE 3. Antipneumococcal antibody (ELISA GMC) correlation with functional antibody (OPA). © 2014 Lippincott Williams & Wilkins
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incidence and the levels of IPD in Hong Kong, calculated as 18.3 per 100,000 in children aged ≤2 years (1995–2004).23 A limitation of both this PCV10 study and the PCV7 study by Cheng et al22 is the small sample size. This was particularly in group 2 (12 participants), with recruitment hampered in adolescents when they were advised that 3 doses of PCV10 were required. The 2 participants who withdrew before the 3rd dose also affected the comparison between 2 and 3 doses in group 2. Both withdrawal participants had very robust responses to 2 doses, and it is encouraging that despite being PCV naïve, the study endpoint was obtained in 7 of the 10 PCV serotypes. It was also a limitation of subgroup analysis by intensive therapy, with only 4 participants in this group. This study also did not assess pneumococcal antibody status at the end of therapy, and these data would help in formulating the optimal guideline for long-term IPD protection. With only 1 AML participant, more data are required to determine the serum immune responses in this disease. A sensitivity analysis reviewed how the findings would vary depending on the serum immune response threshold. Using the lower threshold of 0.20 μg/mL, the number of serotypes that reached the primary study endpoint increased to 8 serotypes.11 This highlights a requirement to standardize threshold cutoffs for PCV studies, particularly those in immunocompromised hosts. As expected, the lowest immune response was in the non-PCV7 serotypes (1, 5 and 7F) indicating that more than 1 dose of PCV may be required to optimize protection for naïve pneumococcal serotypes. A satisfactory correlation between OPA and ELISA was obtained for 3 of the 4 serotypes. The lower correlation for serotype 1 most likely relates to it being a non-PCV7 serotype, so it was not a “booster” dose for the majority of group 1 participants. These findings are in keeping with the moderate correlation between IgG ELISA and OPA (r values, 0.41–0.70) found in a PCV7 study of children and young adults with sickle cell disease.24 The main solicited adverse event following immunization reported in the study was pain or tenderness at the injection site in 73% (27/37). Adolescents and older children often have higher reports of pain at the injection site, as seen with the 81% reporting rate following a quadrivalent human papillomavirus vaccine.25 It was reassuring that there were few systemic adverse events following immunization reported and no admissions for febrile neutropenia postimmunization, which reflected our strict protocol of delaying vaccine administration if neutropenic or any concerns from the participant or treating oncologist. This study overcame some of the logistical difficulties in administering vaccines to children and adolescents with cancer, highlighted in both Australia and the United Kingdom.26–28 Bate et al28 in a survey of principal treating pediatric oncologists found PCV was recommended post completion of chemotherapy by only 58%, reflecting the lack of specific guidelines in the United Kingdom regarding this vaccine in pediatric cancer patients. The administration of vaccine only at completion of therapy means that they are still vulnerable when most at risk of IPD, that is, when immunosuppressed during therapy.1 Post this study, in mid-2011, Australia’s National Immunisation Program decided to transition from the PCV7 vaccine to PCV13.29 This vaccine is made by the same manufacturer as PCV7 and has 6 additional serotypes (1, 3, 5, 6A, 7F, 19A). This includes 19A, identified as the most prevalent cause of IPD in most Australian states following PCV7 introduction.30 With this change in the Australian National Immunisation Program, PCV13 is now the funded “booster” vaccine for special-risk groups and recommended during chemotherapy, as well as a “booster” 6 months post completion of therapy.10 It remains crucial to have ongoing national IPD surveillance and capture medical risk factors, such as chemotherapy
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for pediatric oncology. This will help monitor disease prevalence in special-risk populations and formulation of strategies to administer additional doses required, both during and after therapy. In conclusion, this study identified that it is possible and safe to administer PCV10 vaccine during therapy for pediatric leukemia. It provided a satisfactory serum immune response for the majority of vaccine serotypes. A single-dose “booster” in those who had received PCV7 before diagnosis produced a significant increase in response, particularly in those participants on maintenance chemotherapy. Multiple doses may be required during therapy and for vaccine-naïve serotypes.
ACKNOWLEDGMENTS The authors thank the patients and families involved in the study and SAEFVIC research staff: Annette Alafaci, Ainsley Gillies, Thao Nguyen and Julie Quinn. N.W.C. acknowledges support from an NHMRC postgraduate PhD scholarship. The authors also thank the treating pediatric oncologists at the Children’s Cancer Centre Royal Children’s Hospital and Monash Children's Hospital (alphabetical: David Ashley, John Heath, Lisa Orme, Elizabeth Smibert, Leanne Super, Karin Tiedemann, Keith Waters). REFERENCES 1. Hjuler T, Wohlfahrt J, Staum Kaltoft M, et al. Risks of invasive pneumococcal disease in children with underlying chronic diseases. Pediatrics. 2008;122:e26–e32. 2. Rijkers GT, van Mens SP, van Velzen-Blad H. What do the next 100 years hold for pneumococcal vaccination? Expert Rev Vaccines. 2010;9:1241–1244. 3. Moberley S, Holden J, Tatham David P, et al. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev. 2013:CD000422. 4. Goldblatt D. Bacteria, polysaccharides, vaccines and boosting: measuring and maintaining population immunity. Arch Dis Child. 2008;93:646–647. 5. Spickermann D, Gause A, Pfreundschuh M, et al. Impaired antibody levels to tetanus toxoid and pneumococcal polysaccharides in acute leukemias. Leuk Lymphoma. 1994;16:89–96. 6. Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;61:816–819. 7. Orthopoulos GV, Theodoridou MC, Ladis VA, et al. The effect of 23-valent pneumococcal polysaccharide vaccine on immunological priming induced by 7-valent conjugate vaccine in asplenic subjects with [beta]-thalassemia. Vaccine. 2009;27:350–354. 8. Patel SR, Bate J, Borrow R, et al. Serotype-specific pneumococcal antibody concentrations in children treated for acute leukaemia. Arch Dis Child. 2010;97:46–48. 9. Lehrnbecher T, Schubert R, Behl M, et al. Impaired pneumococcal immunity in children after treatment for acute lymphoblastic leukaemia. Br J Haematol. 2009;147:700–705. 10. National Health and Medical Research Council. Australian Immunisation Handbook. 10th ed. Canberra, Australia: NHMRC, National Capital Press; 2009. Available at: http://www.immunise.health.gov.au/internet/immunise/ publishing.nsf/Content/Handbook10-home. Accessed April 4, 2013. 11. GSK. Product Information: Synflorix. 2010. Available at: http://www.gsk. com.au/products_vaccines_detail.aspx?view=171. Accessed March 20, 2011. 12. National Health and Medical Research Council. Australian Immunisation Handbook. 9th ed. Canberra, Australia: National Health and Medical Research Council, National Capital Press; 2008. Available at: http://www. health.gov.au/internet/immunise/publishing.nsf/Content/Handbook-home. Accessed March 20, 2011. 13. Balloch A, Licciardi PV, Leach A, et al. Results from an inter-laboratory comparison of pneumococcal serotype-specific IgG measurement and critical parameters that affect assay performance. Vaccine. 2010;28:1333–1340. 14. Russell FM, Carapetis JR, Burton RL, et al. Opsonophagocytic activity following a reduced dose 7-valent pneumococcal conjugate vaccine infant primary series and 23-valent pneumococcal polysaccharide vaccine at 12 months of age. Vaccine. 2011;29:535–544. 15. World Health Organization. Expert Committee on Biological Standardization. Pneumococcal Conjugate Vaccines: Recommendations
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for Production and Quality Control of Pneumococcal Conjugate Vaccines. Geneva, Switzerland: World Health Organization; 2003. Available at: http:// www.who.int/biologicals/publications/en/pneumococcal_conjugate_raccines_recomm_nov_2003.pdf. Accessed March 20, 2011. 16. Siber GR, Chang I, Baker S, et al. Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine. 2007;25:3816–3826. 17. Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol. 2010;17:1055–1065. 18. GlaxoSmithKline Vaccine HPV-007 Study Group, Romanowski B, de Borba PC, Naud PS, Roteli-Martins CM, De Carvalho NS, Teixeira JC, Aoki F, Ramjattan B, Shier RM, Somani R, Barbier S, Blatter MM, Chambers C, Ferris D, Gall SA, Guerra FA, Harper DM, Hedrick JA, Henry DC, Korn AP, Kroll R, Moscicki AB, Rosenfeld WD, Sullivan BJ, Thoming CS, Tyring SK, Wheeler CM, Dubin G, Schuind A, Zahaf T, Greenacre M, Sgriobhadair A. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebocontrolled trial up to 6·4 years. Lancet. 2009;374:1975–1985. 19. Australian Institute of Health and Welfare. Cancer in Australia 2010: An Overview. Available at: http://www.aihw.gov.au/publication-detail/?id=644 2472459&libID=6442472440. Accessed March 20, 2011. 20. Patel SR, Ortin M, Bernard JC, et al. Revaccination of children after completion of standard chemotherapy for acute leukaemia. Clin Infect Dis. 2007;44:635–642. 21. van Tilburg CM, Sanders EA, Rovers MM, et al. Loss of antibodies and response to (re-)vaccination in children after treatment for acute lymphocytic leukemia: a systematic review. Leukemia. 2006;20:1717–1722.
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22. Cheng FWT, Ip M, Chu YYL, et al. Humoral response to conjugate pneumococcal vaccine in paediatric oncology patients. Arch Dis Child. 2012;97:358–360. 23. Ho PL, Chiu SS, Cheung CH, et al. Invasive pneumococcal disease burden in Hong Kong children. Pediatr Infect Dis J. 2006;25:454–455. 24. Vernacchio L, Romero-Steiner S, Martinez JE, et al. Comparison of an opsonophagocytic assay and IgG ELISA to assess responses to pneumococcal polysaccharide and pneumococcal conjugate vaccines in children and young adults with sickle cell disease. J Infect Dis. 2000;181:1162–1166. 25. Block SL, Brown DR, Chatterjee A, et al. Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine. Pediatr Infect Dis J. 2010;29:95–101. 26. Crawford NW, Heath JA, Buttery JP. Immunisation practices of paediatric oncologists: an Australasian survey. J Paediatr Child Health. 2007;43: 593–596. 27. Crawford NW, Heath JA, Ashley D, et al. Survivors of childhood cancer: an Australian audit of vaccination status after treatment. Pediatr Blood Cancer. 2010;54:128–133. 28. Bate J, Patel SR, Chisholm J, et al. Immunisation practices of paediatric oncology and shared care oncology consultants: a United Kingdom survey. Pediatr Blood Cancer. 2010;54:941–946. 29. Pfizer. Prevenar13. Available at: http://www.prevnar13.com/. Accessed June 15, 2011. 30. Williams SR, Mernagh PJ, Lee MH, et al. Changing epidemiology of invasive pneumococcal disease in Australian children after introduction of a 7-valent pneumococcal conjugate vaccine. Med J Aust. 2011;194:116–120.
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Pneumococcal Conjugate Vaccine Administration During Therapy for Pediatric Leukemia Nigel W. Crawford, MB BS, MPH, PhD, FRACP,*†‡ Anne Balloch, BSc, MSc,§ Leena Tikkanen, BSc, MSc,§ Francoise Merchinaud, MD,¶ Peter Downie, MB BS, FRACP,¶‖ and Jim P. Buttery, BMMS, MD, FRACP*,**†† Background: Pediatric leukemia patients are at high risk of invasive pneumococcal disease. The study aim was to determine the antibody response to a 10-valent pneumococcal conjugate vaccine (PCV10) administered during chemotherapy. Methods: An open-label study in pediatric leukemia patients: Group 1 had completed a primary 7-valent (PCV7) course and received a single PCV10 dose. Group 2 were PCV immunization naïve and received 3 doses of PCV10, administered 2 months apart. Serum samples were taken at baseline and 1 month post each PCV10 dose. Antipneumococcal serotype-specific IgG to 10 serotypes were measured by enzyme-linked immunosorbent assay and the functional response to 4 serotypes (1, 6B, 19F and 23F) was measured using opsonophagocytic assays. Results: Thirty-nine participants were recruited between May 2010 and January 2011; group 1 (n = 27) and group 2 (n = 12). The diagnosis was acute lymphoblastic leukemia (38) and acute myeloid leukemia (1). Median age was 6.2 years (1.7–17.2 years) with 62% male. The median time from diagnosis to baseline serology was 7.4 months (1.6–36.8 months). At baseline, protective geometric mean concentration above the threshold (>0.35 μg/mL) ranged from 5.3% (serotype 4) to 71% (serotype 19F). More than 60% of participants in both groups were above threshold postimmunization for 7 of the 10 PCV serotypes. Opsonophagocytic assay correlated with enzyme-linked immunosorbent assay for 3 of the 4 serotypes and r ranged from 0.51 to 0.84. An injection-site reaction was reported in 73% (27/37). Conclusions: It is safe to administer PCV10 vaccine during therapy for pediatric leukemia. It provided a satisfactory serum immune response for the majority of vaccine serotypes. Key Words: childhood cancer, invasive pneumococcal disease, vaccination (Pediatr Infect Dis J 2015;34:e9–e15)
T
p olysaccharide vaccine (23-valent pneumococcal polysaccharide vaccine) and pneumococcal conjugate vaccine (PCV) available.2 The 23-valent pneumococcal polysaccharide vaccine is not efficacious in children 2-fold rise for those positive at baseline was considered a significant immunogenic response to the PCV10 vaccine. A serologic response above this protective threshold in >60% of participants to 5 of the 10 serotypes in the PCV10 vaccine was considered protective. The secondary endpoints included the following: (1) functional OPA response to 4 serotypes (1, 6A, 19F, 23F), with assay titers ≥1:8 considered significant; (2) immunogenicity sensitivity analysis of serotype-specific ELISA titers ≥0.20 μg/mL was used to compare study results to published immunogenicity data for PCV10 in infants11,18 and (3) safety of the vaccine, with a particular focus on febrile responses and tolerability in those aged ≥6 years in whom the PCV10 vaccine was not licensed at the time of the study.
Statistical Considerations In Australia, approximately 700 children and adolescents aged 0–18 years are diagnosed each year with cancer.19 One-third of these patients have leukemia (ALL or AML). In Victoria, approximately 80 children with leukemia are treated annually, managed at the 2 study sites. A recruitment rate of 60%, over a 12-month time frame, produced a study target of 50 participants, which is comparable with other vaccine immunogenicity studies in oncology cohorts.20,21 The ELISA serotype-specific antibody concentrations and OPA titers were log(e) transformed for statistical analysis to
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approximate normal distributions. The ELISA GMCs were determined by taking the antilogarithm of the means of the log-transformed values. The paired t test was used to compare the mean at postimmunization to preimmunization, with a P value 0.35 μg/mL) ranged from 5.3% for serotype 4 to 71% for serotype 19F. Following immunization, there was a significant increase in GMC from baseline for all serotypes (P < 0.01). Following a single dose of PCV10, the percentage of all participants with protective GMC above the protective threshold ranged from 33.3% for serotype 4 to 81.1% for serotype 14. The primary study endpoint of >60% of participants above the protective threshold following a single PCV10 dose was achieved in 5 of the 10 PCV serotypes (6B, 9V, 14, 19F, 23F; Fig. 2). In those participants who were seropositive at baseline, the percentage who had a >2-fold rise in GMC ranged from 0% to 63.6%. A sensitivity analysis for the combined results (groups 1 and 2) post a single PCV10 dose using the GSK 0.20 μg/ mL protective threshold cutoff,11 compared with infant historical data, was undertaken (data not shown). Using this lower threshold © 2014 Lippincott Williams & Wilkins
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128 patients eligible • 80 declined • 9 language barrier
39 participants recruited • 33 RCH • 6 MMC Group 1 • 2 participants had baseline serology only • one withdrew (needle phobia) • one unsatisfactory immunogenicity sample
Received PCV10 vaccine (N = 37) Group 1 = 25 Group 2 = 12
Group 2 • 1 participant received single dose • 2 participants received two doses
Functional Antibody (OPA) (N = 15) Group 1 = 13 Group 2 = 2
FIGURE 1. PCV10 study flow diagram. RCH indicates Royal Children’s Hospital; International Classification of Diseases 10th Edition. TABLE 1. Ten-valent Pneumococcal Conjugate Vaccine Baseline Clinical Characteristics Group 1 Number of 27 participants Male (%) 63 Median age (yr) 4.9 (1.7–9.6) (range) Time on 5.5 (1.6–36.8) chemotherapy (mo) (range) Chemotherapy stage at baseline Intensification 3 Consolidation 3 Interim 3 maintenance Delayed 4 intensification AML 1 Total on 14 intensive therapy Maintenance 13*
Group 2
Overall
12
39
58 12 (4.5–17.2)
62 6.2 (1.7–17.2)
16.1 (2.8–35.5) 7.4 (1.6–36.8)
1 1 2
4 4 5
0
4
0 4
1 18
8
21
*n = 11 received a PCV10 dose.
(0.20 μg/mL) for our oncology cohort, 8 of the PCV10 serotypes had 60% or more participants above this cutoff. A subgroup analysis of immune response by subgroups of intensive early-phase chemotherapy and maintenance chemotherapy is detailed in Table 2. It identified that the maintenance chemotherapy subset in group 1 (single dose) was more likely to have a significant increase above baseline, with 9 of the 10 serotypes having a P value 0.35 μg/mL at baseline and post–dose-1 PCV10. had an increase above baseline in the intensive therapy subgroup. There was no statistical difference in the group 2 analysis by subgroup. The percentage of participants above the protective threshold (>0.35) for group 1 ranged from 45% to 82% (maintenance subgroup) and 38% to 86% (intensive). For group 2 (dose 1) it ranged from 45% to 82% (maintenance subgroup) and 38% to 86% (intensive chemotherapy subgroup). The overall immunogenicity data by group are detailed in Tables 3 and 4. The primary endpoint of >60% of participants above the threshold following a single PCV10 dose in group 1 was obtained in 7 of the 10 PCV serotypes (4, 6B, 9V, 14, 19F, 18C, 23F). These are all serotypes in the PCV7 vaccine, which by inclusion criteria had been received before diagnosis. In group 2 (Table 4) at baseline, the percentage with GMC above the protective threshold (>0.35 μg/mL) ranged from 9.1% for serotype 4 to 54.6% for serotype 19F. The GMC only increased significantly from baseline (P value 60% of participants being above the threshold following a PCV10 course (2 or 3 doses), was obtained in 7 of the 10 PCV serotypes (6B, 7F, 9V, 14, 19F, 18C, 23F). At baseline, the percentage above the OPA threshold titer (≥1:8) to 4 serotypes (1, 6b, 19F, 23F) ranged from 0% (serotype 1, a non-PCV7 serotype) to 40% for serotype 6B. Following a single dose of PCV10 vaccine this increased to 39.4% (serotype 1), 83.8% (serotype 6B), 86.5% (serotype 19F) and 70.3% (serotype 23F). ELISA and OPA showed good correlation for the serotypes in both the 7-valent and 10-valent PCVs (6B, 19F and 23F), with the Pearson coefficient (r) ranging from 0.81 to 0.84 (Fig. 3). It was lower for the non-PCV7 serotype 1, with r = 0.51. There was 1 participant with a diagnosis of AML (myeloid leukemia of Down syndrome), receiving intensive chemotherapy over 6 monthly cycles. The individual was 23 months of age at diagnosis and in group 1, having received 3 previous PCV7 doses at the routine 2, 4 and 6 months of age. At study baseline, 4.5 months since diagnosis, he was seropositive to 4 serotypes (6B, 9V, 19F, 23F). At 1 month post the vaccine, GMC ELISA antibody levels were seroprotective to 6 of the PCV10 serotypes (1, 5, 6B, 7F, 14, 23F). The majority of adverse events following immunization reported were tenderness at the injection site in 73% (27/37). Systemic symptoms were reported in 41% (15/37) overall, with diarrhea being the most common (4 participants). There was 1 reported fever >38°C in a non-neutropenic patient, who had some associated diarrhea and required hospital admission for 48 hours of intravenous fluids. These symptoms while temporally related to vaccine timing may have been chemotherapy-related side effects. www.pidj.com | e11
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TABLE 2. Geometric Mean Concentration by Group and Intensive or Maintenance Therapy (Following Dose-1 PCV10) Group 1 (N = 25) Intensive Therapy (n = 14) Serotype
Maintenance (n = 11) Percentage >0.35 μg/mL
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
GMC (μg/mL)
95% CI
1 4 5 6B 7F 9V 14 18C
0.26 0.43 0.38 1.37 0.47 0.44 3.03* 0.69
0.13–0.56 0.16–1.22 0.18–0.79 0.48–3.93 0.16–1.37 0.17–1.15 1.12–8.25 0.22–2.18
38 57 43 79 50 54 93 57
0.39 1.4* 0.33 1.2* 0.34* 1.81* 4.23* 1.71*
45 72 55 64 55 82 82 64
19F
3.05
0.95–9.77
86
4.84*
23F
0.62
0.25–1.56
64
0.95*
0.12–1.2 0.27–7.76 0.09–1.28 0.33–4.3 0.09–1.15 0.41–8.0 0.71–25.2 0.23– 12.80 0.94– 24.98 0.20–4.56
82 64
Group 2 (N = 12) Intensive Therapy (n = 4) Serotype
Maintenance (n = 8)
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
0.26 0.29 1.09 1.82 0.53 0.97 3.25 0.89 1.48. 2.55
0.11–0.59 0.03–2.80 0.03–40.18 0.16–21.06 0.08–3.48 0.12–7.64 0.04–235.8 0.21–3.74 0.17–12.79 0.28–23.34
25 50 50 100 75 75 100 75 75 100
0.20 0.14 0.16 0.29 0.21 0.14 0.72 0.15 0.87 0.65
0.09–0.43 0.04–0.51 0.08–0.34 0.07–1.13 0.09–0.48 0.05–0.38 0.17–3.02 0.07–0.32 0.19–4.04 0.14–1.78
13 25 13 25 25 38 50 25 63 50
1 4 5 6B 7F 9V 14 18C 19F 23F
Shaded rows are non-PCV7 serotypes. *P < 0.01 (comparison of GMC at baseline to post–dose-1 PCV10). CI indicates confidence interval.
TABLE 3. Pneumococcal GMC Pre-dose and Post-dose 1 (Group1 Only) Serotypes
1 4 5 6B 7F 9V 14 18C 19F 23F
Baseline (n = 27)
Post-dose 1 (n = 25)
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
0.13 0.10 0.15 0.31 0.09 0.15 0.42 0.13 0.74 0.21
0.10–0.17 0.08–0.14 0.11–0.21 0.19–0.52 0.06–0.14 0.10–0.24 0.30–0.58 0.09–0.20 0.42–1.28 0.14–0.34
3.7 3.7 11.1 30.8 14.8 14.8 59.3 18.5 77.8 29.6
0.31* 0.74* 0.36* 1.2* 0.41* 0.81* 3.5* 1.03* 3.7* 0.75*
0.17–0.58 0.30–1.81 0.19–0.69 0.61–2.73 0.19–0.86 0.35–1.88 1.45–8.51 0.37–2.85 1.52–9.18 0.34–1.66
40 64 48 72 52 64 88 60 84 64
Shaded rows are non-PCV7 serotypes. *P < 0.01 (comparison of GMC at baseline to post–dose-1 PCV10). CI indicates confidence interval.
Discussion This Australian study describes the serum immune response to PCV10 immunization in children and adolescents receiving chemotherapy for leukemia. The majority had received a previous PCV (PCV7) in infancy, but did not have protective antibody levels above the >0.35 μg/mL threshold at baseline, with 6 serotypes 60% of participants seroprotected. In group 1, the primary study endpoint was obtained in all of the PCV7 serotypes, indicating a satisfactory immunogenicity “booster” response. In the subgroup
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analysis by therapy intensity, those on maintenance therapy (n = 11) were more likely to have a significant increase in GMC from baseline in 9 of 10 serotypes. The primary endpoint in group 2, following a PCV10 course (2 or 3 doses), was obtained in 7 of the PCV10 serotypes. There was no difference in subgroup analysis by chemotherapy intensity following dose-1 PCV10 vaccine. The results of this study can be compared with that of a PCV7 immunogenicity study in a Hong Kong pediatric oncology cohort.22 Cheng et al22 reviewed the immunogenicity post 2 doses of PCV7 vaccine administered a month apart in 44 patients [29 © 2014 Lippincott Williams & Wilkins
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TABLE 4. Pneumococcal GMC Pre-dose 1 and Post-dose 1 (Group 2 Only) Serotypes
1 4 5 6B 7F 9V 14 18C 19F 23F
Baseline (n = 11)
Post-dose 1 (n = 12)
GMC (μg/mL)
95% CI
Percentage >0.35 μg/mL
0.17 0.08 0.20 0.22 0.14 0.14 0.53 0.13 0.49 0.22
0.10–0.31 0.04–0.17 0.08–0.48 0.11–0.44 0.06–0.32 0.06–0.37 0.19–1.47 0.05–0.34 0.19–1.28 0.10–0.46
18.2 9.1 27.3 27.3 18.2 27.3 36.4 18.2 54.6 36.4
GMC (μg/mL) 0.21 0.18 0.31 0.53 0.28 0.27 1.20 0.27 1.04 1.02*
Post-dose 2 (n = 11)
95% CI
Percentage >0.35 μg/mL
GMC
95% CI
0.13–0.36 0.07–0.46 0.11–0.88 0.17–1.64 0.13–0.57 0.10–0.70 0.32–4.51 0.12–0.60 0.37–2.96 0.33–3.12
16.7 33.3 25 50 41.7 50 66.7 41.7 66.7 66.7
0.37 0.20 0.38 0.82* 0.46* 0.35 1.91* 0.55* 1.20 0.96*
0.12–1.02 0.08–0.53 0.12–1.13 0.29–2.27 0.20–1.06 0.14–0.87 0.49–7.44 0.28–1.07 0.41–3.46 0.35–2.66
Post-dose 3 (n = 9)
Percentage > 0.35 μg/mL GMC 36.4 36.4 36.4 63.6 63.6 63.6 81.8 54.6 81.8 72.7
0.31 0.23 0.34 0.40 0.45 0.33 1.73 0.69* 0.94 0.73*
Percentage >0.35 95% CI μg/mL 0.14–0.66 0.09–0.56 0.12–0.98 0.17–0.92 0.19–1.06 0.11–0.94 0.47–6.41 0.42–1.15 0.32–2.82 0.38–1.42
44.4 44.4 33.3 55.6 55.6 55.6 77.8 88.9 77.8 88.9
Shaded rows are non-PCV7 serotypes. *P < 0.01 (comparison of GMC at baseline to post–PCV10 dose 1, dose 2 and dose 3). CI indicates confidence interval.
hematological (25 ALL); 15 solid tumors]. Pneumococcal serology was taken at baseline and 1 month post the 2nd PCV7 dose. At the study endpoint, the protective antibody GMC above threshold to the PCV7 serotypes ranged from 86% to 100%. Directly correlating our
PCV10 study with the Hong Kong PCV7 data is difficult, as a large number of patients in the study by Cheng et al22 were completely off therapy (median 6 months; range 1–12 months). The high levels of baseline seropositive results may reflect pneumococcal carriage
FIGURE 3. Antipneumococcal antibody (ELISA GMC) correlation with functional antibody (OPA). © 2014 Lippincott Williams & Wilkins
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incidence and the levels of IPD in Hong Kong, calculated as 18.3 per 100,000 in children aged ≤2 years (1995–2004).23 A limitation of both this PCV10 study and the PCV7 study by Cheng et al22 is the small sample size. This was particularly in group 2 (12 participants), with recruitment hampered in adolescents when they were advised that 3 doses of PCV10 were required. The 2 participants who withdrew before the 3rd dose also affected the comparison between 2 and 3 doses in group 2. Both withdrawal participants had very robust responses to 2 doses, and it is encouraging that despite being PCV naïve, the study endpoint was obtained in 7 of the 10 PCV serotypes. It was also a limitation of subgroup analysis by intensive therapy, with only 4 participants in this group. This study also did not assess pneumococcal antibody status at the end of therapy, and these data would help in formulating the optimal guideline for long-term IPD protection. With only 1 AML participant, more data are required to determine the serum immune responses in this disease. A sensitivity analysis reviewed how the findings would vary depending on the serum immune response threshold. Using the lower threshold of 0.20 μg/mL, the number of serotypes that reached the primary study endpoint increased to 8 serotypes.11 This highlights a requirement to standardize threshold cutoffs for PCV studies, particularly those in immunocompromised hosts. As expected, the lowest immune response was in the non-PCV7 serotypes (1, 5 and 7F) indicating that more than 1 dose of PCV may be required to optimize protection for naïve pneumococcal serotypes. A satisfactory correlation between OPA and ELISA was obtained for 3 of the 4 serotypes. The lower correlation for serotype 1 most likely relates to it being a non-PCV7 serotype, so it was not a “booster” dose for the majority of group 1 participants. These findings are in keeping with the moderate correlation between IgG ELISA and OPA (r values, 0.41–0.70) found in a PCV7 study of children and young adults with sickle cell disease.24 The main solicited adverse event following immunization reported in the study was pain or tenderness at the injection site in 73% (27/37). Adolescents and older children often have higher reports of pain at the injection site, as seen with the 81% reporting rate following a quadrivalent human papillomavirus vaccine.25 It was reassuring that there were few systemic adverse events following immunization reported and no admissions for febrile neutropenia postimmunization, which reflected our strict protocol of delaying vaccine administration if neutropenic or any concerns from the participant or treating oncologist. This study overcame some of the logistical difficulties in administering vaccines to children and adolescents with cancer, highlighted in both Australia and the United Kingdom.26–28 Bate et al28 in a survey of principal treating pediatric oncologists found PCV was recommended post completion of chemotherapy by only 58%, reflecting the lack of specific guidelines in the United Kingdom regarding this vaccine in pediatric cancer patients. The administration of vaccine only at completion of therapy means that they are still vulnerable when most at risk of IPD, that is, when immunosuppressed during therapy.1 Post this study, in mid-2011, Australia’s National Immunisation Program decided to transition from the PCV7 vaccine to PCV13.29 This vaccine is made by the same manufacturer as PCV7 and has 6 additional serotypes (1, 3, 5, 6A, 7F, 19A). This includes 19A, identified as the most prevalent cause of IPD in most Australian states following PCV7 introduction.30 With this change in the Australian National Immunisation Program, PCV13 is now the funded “booster” vaccine for special-risk groups and recommended during chemotherapy, as well as a “booster” 6 months post completion of therapy.10 It remains crucial to have ongoing national IPD surveillance and capture medical risk factors, such as chemotherapy
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for pediatric oncology. This will help monitor disease prevalence in special-risk populations and formulation of strategies to administer additional doses required, both during and after therapy. In conclusion, this study identified that it is possible and safe to administer PCV10 vaccine during therapy for pediatric leukemia. It provided a satisfactory serum immune response for the majority of vaccine serotypes. A single-dose “booster” in those who had received PCV7 before diagnosis produced a significant increase in response, particularly in those participants on maintenance chemotherapy. Multiple doses may be required during therapy and for vaccine-naïve serotypes.
ACKNOWLEDGMENTS The authors thank the patients and families involved in the study and SAEFVIC research staff: Annette Alafaci, Ainsley Gillies, Thao Nguyen and Julie Quinn. N.W.C. acknowledges support from an NHMRC postgraduate PhD scholarship. The authors also thank the treating pediatric oncologists at the Children’s Cancer Centre Royal Children’s Hospital and Monash Children's Hospital (alphabetical: David Ashley, John Heath, Lisa Orme, Elizabeth Smibert, Leanne Super, Karin Tiedemann, Keith Waters). REFERENCES 1. Hjuler T, Wohlfahrt J, Staum Kaltoft M, et al. Risks of invasive pneumococcal disease in children with underlying chronic diseases. Pediatrics. 2008;122:e26–e32. 2. Rijkers GT, van Mens SP, van Velzen-Blad H. What do the next 100 years hold for pneumococcal vaccination? Expert Rev Vaccines. 2010;9:1241–1244. 3. Moberley S, Holden J, Tatham David P, et al. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev. 2013:CD000422. 4. Goldblatt D. Bacteria, polysaccharides, vaccines and boosting: measuring and maintaining population immunity. Arch Dis Child. 2008;93:646–647. 5. Spickermann D, Gause A, Pfreundschuh M, et al. Impaired antibody levels to tetanus toxoid and pneumococcal polysaccharides in acute leukemias. Leuk Lymphoma. 1994;16:89–96. 6. Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;61:816–819. 7. Orthopoulos GV, Theodoridou MC, Ladis VA, et al. The effect of 23-valent pneumococcal polysaccharide vaccine on immunological priming induced by 7-valent conjugate vaccine in asplenic subjects with [beta]-thalassemia. Vaccine. 2009;27:350–354. 8. Patel SR, Bate J, Borrow R, et al. Serotype-specific pneumococcal antibody concentrations in children treated for acute leukaemia. Arch Dis Child. 2010;97:46–48. 9. Lehrnbecher T, Schubert R, Behl M, et al. Impaired pneumococcal immunity in children after treatment for acute lymphoblastic leukaemia. Br J Haematol. 2009;147:700–705. 10. National Health and Medical Research Council. Australian Immunisation Handbook. 10th ed. Canberra, Australia: NHMRC, National Capital Press; 2009. Available at: http://www.immunise.health.gov.au/internet/immunise/ publishing.nsf/Content/Handbook10-home. Accessed April 4, 2013. 11. GSK. Product Information: Synflorix. 2010. Available at: http://www.gsk. com.au/products_vaccines_detail.aspx?view=171. Accessed March 20, 2011. 12. National Health and Medical Research Council. Australian Immunisation Handbook. 9th ed. Canberra, Australia: National Health and Medical Research Council, National Capital Press; 2008. Available at: http://www. health.gov.au/internet/immunise/publishing.nsf/Content/Handbook-home. Accessed March 20, 2011. 13. Balloch A, Licciardi PV, Leach A, et al. Results from an inter-laboratory comparison of pneumococcal serotype-specific IgG measurement and critical parameters that affect assay performance. Vaccine. 2010;28:1333–1340. 14. Russell FM, Carapetis JR, Burton RL, et al. Opsonophagocytic activity following a reduced dose 7-valent pneumococcal conjugate vaccine infant primary series and 23-valent pneumococcal polysaccharide vaccine at 12 months of age. Vaccine. 2011;29:535–544. 15. World Health Organization. Expert Committee on Biological Standardization. Pneumococcal Conjugate Vaccines: Recommendations
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for Production and Quality Control of Pneumococcal Conjugate Vaccines. Geneva, Switzerland: World Health Organization; 2003. Available at: http:// www.who.int/biologicals/publications/en/pneumococcal_conjugate_raccines_recomm_nov_2003.pdf. Accessed March 20, 2011. 16. Siber GR, Chang I, Baker S, et al. Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine. 2007;25:3816–3826. 17. Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol. 2010;17:1055–1065. 18. GlaxoSmithKline Vaccine HPV-007 Study Group, Romanowski B, de Borba PC, Naud PS, Roteli-Martins CM, De Carvalho NS, Teixeira JC, Aoki F, Ramjattan B, Shier RM, Somani R, Barbier S, Blatter MM, Chambers C, Ferris D, Gall SA, Guerra FA, Harper DM, Hedrick JA, Henry DC, Korn AP, Kroll R, Moscicki AB, Rosenfeld WD, Sullivan BJ, Thoming CS, Tyring SK, Wheeler CM, Dubin G, Schuind A, Zahaf T, Greenacre M, Sgriobhadair A. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebocontrolled trial up to 6·4 years. Lancet. 2009;374:1975–1985. 19. Australian Institute of Health and Welfare. Cancer in Australia 2010: An Overview. Available at: http://www.aihw.gov.au/publication-detail/?id=644 2472459&libID=6442472440. Accessed March 20, 2011. 20. Patel SR, Ortin M, Bernard JC, et al. Revaccination of children after completion of standard chemotherapy for acute leukaemia. Clin Infect Dis. 2007;44:635–642. 21. van Tilburg CM, Sanders EA, Rovers MM, et al. Loss of antibodies and response to (re-)vaccination in children after treatment for acute lymphocytic leukemia: a systematic review. Leukemia. 2006;20:1717–1722.
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Pneumococcal Vaccine and Leukemia
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