ORIGINAL ARTICLE
Immunogenicity of 13-Valent Pneumococcal Conjugate Vaccine in Pediatric Patients with Inflammatory Bowel Disease ska, MD, PhD,† Kinga Kowalska-Duplaga, MD, PhD,‡ Aleksandra Banaszkiewicz, MD, PhD,* Brygida Targon Katarzyna Karolewska-Bochenek, MD, PhD,* Agnieszka Sieczkowska, MD,§ ska, MD, PhD,* Urszula Grzybowska-Chlebowczyk, MD, PhD,jj Agnieszka Gawron Elz_ bieta Krzesiek, MD, PhD,¶ Izabella Łazowska-Przeorek, MD, PhD,* Maria Kotowska, MD, PhD,* Edyta Sienkiewicz, MD, PhD,* Jarosław Walkowiak, MD, PhD,† Hanna Gregorek, MD, PhD,** Andrzej Radzikowski, MD, PhD,* and Piotr Albrecht, MD, PhD*
Background: There are only a few studies on immune response to pneumococcal vaccines in patients with inflammatory bowel disease (IBD); all of them assessed polysaccharide vaccines only. The aim of the study was to evaluate the immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) in IBD pediatric patients compared with healthy controls.
Methods: This was a multicenter, prospective, and controlled study on children and adolescents aged 5 to 18 years with IBD with no history of pneumococcal immunization. The subjects for the study belonged to one of the following groups: patients with IBD on no immunosuppressive therapy (group A), those on tumor necrosis factor agents or immunomodulators (group B), and healthy controls (group C). The study population received 1 intramuscular injection of PCV13. The primary outcome measure was adequate vaccine response defined as postvaccination titer $0.35 mg/mL to all 13 serotypes. Geometric mean titers and geometric mean titer rises were measured for all serotypes. The evidence of local and systemic adverse effects for 5 days after the vaccine was registered. Results: A total of 178 subjects (122 patients and 56 controls) completed the study course. There was no significant difference in the rate of adequate vaccine response between patients with IBD and controls measured 4 to 8 weeks after vaccination (90.4% versus 96.5%, P ¼ 0.5281). Children in group A had higher geometric mean titer rises than children in group B (P ¼ 0.0369). There were no serious adverse events related to PCV13 during the study.
Conclusions: PCV13 is both immunogenic and safe in pediatric patients with IBD. (Inflamm Bowel Dis 2015;21:1607–1614) Key Words: Crohn’s disease, ulcerative colitis, PCV, immune response
P
neumococcal infections include serious invasive diseases such as meningitis, sepsis, and pneumonia with bacteremia, as well as milder but more common noninvasive illnesses such as sinusitis and otitis media. The causative agent, Streptococcus pneumoniae, Received for publication February 3, 2015; Accepted February 24, 2015. From the *Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw, Poland; †Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland; ‡ Department of Pediatrics, Gastroenterology and Nutrition, Polish-American Children’s Hospital, Jagiellonian University Medical College, Krakow, Poland; §Department of Pediatric Gastroenterology, Hepatology and Nutrition, Medical University of Gdansk, Gdansk, Poland; jjDepartment of Pediatrics, Medical University of Silesia, Katowice, Poland; ¶Department of Pediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw, Poland; and **Department of Microbiology and Clinical Immunology, The Children’s Memorial Health Institute, Warsaw, Poland. Supported by grant no. N404 077140 0771/B/P01/2011/40 from the Polish Ministry of Science and Higher Education. The project was approved in February 4, 2010. The authors have no conflicts of interest to disclose. Reprints: Aleksandra Banaszkiewicz, MD, PhD, Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Dzialdowska 1, 01-184 Warsaw, Poland (e-mail: [email protected]). Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000406 Published online 27 April 2015.
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frequently colonizes the human nasopharynx and is transmitted mainly through respiratory droplets. S. pneumoniae includes 91 distinct serotypes. Distribution of serotypes that cause disease varies with age, disease syndrome, disease severity, geographic region, and over time.1 In Europe and in the United States, S. pneumoniae is estimated to cause approximately 30% to 50% of communityacquired pneumonia requiring hospitalizations in adults.2,3 The incidence of hospitalized pneumonia (clinical findings and chest x-ray) in children at the age ,16 years was estimated as follows: in Norway, 14.7 per 10,0004; in the United Kingdom, 14.4 per 10,0005; in Germany, 30 per 10,000.6 Mixed pneumococcal and viral infections seem important and are found in 62% of pneumococcal pneumonias.7 Given that S. pneumoniae is a leading human pathogen with relatively high incidence affecting all age groups, and because of very expensive treatment, and a high mortality, prevention against pneumococcal infections seems to be of great clinical importance and World Health Organization priority.8 In patients with IBD, the risk of pneumococcal disease is increased and include chronic pulmonary involvement (approximately 40% www.ibdjournal.org |
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Banaszkiewicz et al
of IBD adults),9 frequent hospitalizations, and immunosuppressive treatment. Although data are limited, the increased risk of bacterial pneumonia was found in 2 big American cohorts of patients with IBD.10,11 Those studies found immunosuppressive therapy as an additional risk factor. For these reasons, immunization against pneumococcal disease is recommended for patients with IBD in all recognized guidelines.12–14 There are 2 different types of pneumococcal vaccine. One type is pneumococcal polysaccharide vaccine (PPV), which includes 23 S. pneumoniae serotypes (PPV23), that induces poor or absent anamnestic antibody response in children ,2 years of age and weak response in older people. The other type is conjugate vaccines that are based on chemical coupling of S. pneumoniae polysaccharides to an immunogenic protein carrier. The carrier enhances the antibody response and induces immune memory, rendering conjugate vaccines immunogenic also for children in age ,2 years. Originally, pneumococcal conjugate vaccines (PCV) were designated only for young children. Recently, the immunogenicity of PCV has been evidenced in adults15 and seemed to be higher than that found after PPV.16 Therefore currently, Advisory Committee on Immunization Practices and Infectious Diseases Society of America recommend using of both the PCV13 and PPV23 to protect immunocompromised individuals against pneumococcal disease including patients with IBD.13,17,18 In patients with IBD, the immunosuppressive character of both the disease and the treatment could compromise, to some extent, the natural immune response to infection and could have an impact on the efficacy and safety of vaccination. Therefore, a committee formed by the Crohn’s and Colitis Foundation of America in 2004 and by the European Crohn’s and Colitis Organization recommends the need of evaluation of the immune response to vaccines in patients with IBD.12,14 Until now, a few studies have assessed the immune response to PPV in adult patients with IBD.19–21 The aim of the study was to evaluate the immunogenicity of a PCV13 vaccine in pediatric patients with IBD and to compare their response with healthy controls. Additionally, the safety of the vaccine was assessed.
MATERIALS AND METHODS Study Design This multicenter, open, prospective, comparative trial was conducted in 6 University-affiliated hospitals for children in Poland (cities of Warsaw, Poznan, Wroclaw, Katowice, Gdansk and Krakow) between April 2013 and March 2014.
Patients and Controls The study population consisted of children and adolescents with IBD (Crohn’s disease [CD] and ulcerative colitis [UC]) between 5 and 18 years of age. Both hospitalized and ambulatory patients were invited to participate in the study. Patients were at different stages of the disease and treatment
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process. Diagnosis of CD and UC was based on clinical signs and symptoms, as well as endoscopic, histological, and radiological results according to the Porto criteria.22 Severity of the CD and UC was evaluated using the Pediatric Crohn’s Disease Activity Index and the Pediatric Ulcerative Colitis Activity Index, which include symptoms, physical examination findings, and laboratory test results; a Pediatric Crohn’s Disease Activity Index score #10 for CD and a Pediatric Ulcerative Colitis Activity Index score ,10 for UC were defined as remission. Patients were stratified into 3 groups. Group A included patients with IBD who were not receiving any immunosuppressive therapy. Group B included patients who were undergoing immunosuppressive treatment with steroids 2 mg/kg per day for 2 weeks or more, with azathioprine (AZA) 2.5 to 3 mg/kg per day or 6-mercaptopurine (6-MP) 1.5 mg/kg per day for 12 weeks or more, cyclosporine, infliximab or adalimumab. The control group, group C, consisted of healthy unvaccinated persons aged 5 to 18 years and was recruited concurrently. Inclusion in this group required that subjects had no chronic illness and were not on any immunosuppressive agents.
Pneumococcal Conjugate Vaccine 13 Pneumococcal 13-valent conjugate vaccine (Diphtheria CRM197 Protein) from Wyeth Pharmaceuticals Inc. was used. Each 0.5 mL dose of the vaccine contains the following: (1) ;2.2 mg of each saccharide from pneumococcal serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, and 23F, and 4.4 mg of serotype 6B individually conjugated to diphtheria cross-reacting material 197 (CRM197) carrier protein. The total concentration of CRM197 is ;34 mg; (2) 295 mg succinate buffer; (3) 125 mg aluminum as AlPO4 adjuvant; and (4) 100 mg polysorbate 80. PCV13 was administered intramuscularly in the left deltoid muscle. Vaccines were stored between 2 and 58C and were taken out immediately before use.
Intervention At screening, demographic data, medical history including pneumococcal infections, and physical examination were obtained. Patients and controls were screened for previous exposure to any pneumococcal vaccines. Patients with IBD had disease activity assessment with the Pediatric Ulcerative Colitis Activity Index for UC and Pediatric Crohn’s Disease Activity Index for CD. All included children were given 1 dose of PCV13. Peripheral blood samples were collected from each patient and controls immediately before and between 6 to 8 weeks after vaccination. Sera were stored at 2208C to 2708C until analysis was performed. Each serum sample was tested for serotype-specific antipneumococcal polysaccharide IgG antibodies to the thirteen polysaccharides in PCV13 (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) by a standardized enzyme-linked immunosorbent assay according to an adapted WHO protocol.23 The assay was performed with preabsorption of test sera by using pneumococcal C polysaccharide and pneumococcal polysaccharide from the nonvaccine
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Inflamm Bowel Dis Volume 21, Number 7, July 2015
22F serotype to enhance specificity of the assay for serotypespecific antibody.24,25 Patients and controls were observed by the investigators for immediate reactions for 30 minutes after injection. Parents or guardians of all patients received diary cards with the request to record any local or systematic symptoms for 5 days after each vaccination.
Outcomes The primary outcome measure was an adequate vaccine response defined as postvaccination titer $0.35 mg/mL to all 13 serotypes. The serotype-specific IgG antibody titers $0.35 mg/mL were considered as protective for invasive pneumococcal disease according to the WHO recommendation.26 The secondary outcome measures were as follows: (1) geometric mean titers (GMTs) for 13 pneumococcal serotypes, (2) geometric mean titer rise (GMTR) for 13 pneumococcal serotypes, and (3) the evidence of local and systemic adverse effects measured for 5 days after the vaccination. GMT was defined as the average titer of serotype-specific IgG antibody determined by enzyme-linked immunosorbent assay in a group of patients who have been immunized. The influence of treatment type in groups A and B on adequate vaccine response and GMTs was assessed.
Sample Size Sample size was calculated according to results of previous studies19–21 that reported approximately 83% serological response rates in patients with IBD treated with aminosalicylates and approximately 51% in patients with IBD treated with immunosuppressive drugs. To detect a difference of 32% between patients on aminosalicylates and immunosuppressive drugs, with a power of 80% and alpha of 0.05, 33 children were required in each group. With expected a dropout rate of 20%, 40 children in each group were required.
Statistical Analysis GMT of prevaccination and postvaccination antibodies level was used as the measure of central tendency. GMTR was used to describe the change in antibodies level after vaccination. Confidence intervals (CI) at 1 2 a ¼ 0.05 was computed (95% CI). The Sn statistic was computed as a measure of variability.27 Higher level reflects higher variability. Odds ratios and 95% CI were computed, and chi-square statistic (x2df) was used to test hypothesis for counts data in tables. T2—Hotelling and l—Pillai statistics were used to test differences in vaccination response between 2 and more groups. Standard box-and-whiskers plot were used to present the data.
Ethical Consideration This study was approved on January 26, 2010 by the Clinical Research Ethics Committee of the Medical University of Warsaw, Poland. All parents and children $16 years old signed the informed consent before participation in the study.
PCV13 in Pediatric Patients with IBD
RESULTS Study Demographics A total of 178 subjects participated in the study including 122 patients with IBD and 56 healthy controls. Age was similar in all groups. There were more boys in the IBD group than in the control group: 60% versus 48.2%, P ¼ 0.11. Groups A and B were similar in disease severity but different in therapy type (P ¼ 0.0018). The basic characteristics of the study participants are presented in Table 1.
Adequate Vaccine Response Adequate vaccine response was very high in all patients with CD, patients with UC, and controls, which is shown in Table 2. There was no significant difference in the rate of adequate vaccine response between patients with IBD and controls measured 4 to 8 weeks after vaccination (90.4% versus 96.5%, P ¼ 0.5281).
Serotype-specific GMTs GMTs and GMTRs for the pneumococcal serotypes included in PCV13 are shown in Table 3. All serotypes were immunogenic for the 3 study groups. In all study groups, there was a tendency for older children to have higher GMTs for all serotypes; however, the difference was not statistical significant (lPillai ¼ 0.125, P ¼ 0.6025). Gender was not associated with GMTs (lPillai ¼ 0.047, P ¼ 0.7768). GMTRs for all 13 serotypes were as follows: for patients with CD, 3.74 (95% CI, 3.22–4.35); for patients with UC, 5.81 (95% CI, 4.9–6.88); and for controls, 5.35 (95% CI, 4.49–6.38).
TABLE 1. Basic Characteristics of Study Groups
N Median age, yr Boys/girlsa Median PCDAI Median PUCAI Drugs, % 5-ASA Antibiotics Immunomodulators Azathioprine Cyclosporine TNF alpha agents Infliximab Adalimumab
CD
UC
CD + UC
Controls
72 15.08 44/28 5 —
50 15.16 30/20 — 5
122 15.08 74/48 — —
56 12.87 27/29 — —
70 (97.2) 5 (6.9) 57 (79.2) 57 — 10 (13.9) 8 (11.1) 2
47 (94) 2 (4) 25 (50) 23 (46) 2 (4) 2 (4) 2 (4) —
117 (95.9) 7 (5.7) 82 (67.2) 80 (65.6) 2 (1.6) 12 (9.8) 10 (8.2) 2 (1.6)
— — — — — — — —
Odds ratios ¼ 1.66; 95% CI, 0.88–3.14; x2df ¼ 1 ¼ 2.42; P ¼ 0.1198. PCDAI, Pediatric Crohn’s Disease Activity Index; PUCAI, Pediatric Ulcerative Colitis Activity Index.
a
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Banaszkiewicz et al
TABLE 2. Adequate Vaccine Response Response to Serotypes
N
%
9/13
10/13
11/13
12/13
13/13
S
9/13
10/13
11/13
12/13
13/13
S
0 1 1 0
0 0 0 0
0 1 1 1
3 2 5 0
37 29 66 28
40 33 73 29
0 3.03 1.37 0
0 0 0 0
0 3.03 1.37 3.45
7.5 6.06 6.85 0
92.5 87.88 90.41 96.55
100 100 100 100
CD UC CD + UC Controls
Bold values indicate adequate vaccine response. P ¼ 0.5281.
TABLE 3. Prevaccination and Postvaccination GMT and GMTRs for 13 Serotypes GMT (95% CI)
PCV13 Serotypes 1
Pre Post
3
Pre Post
4
Pre Post
5
Pre Post
6A
Pre Post
6B
Pre Post
7F
Pre Post
9V
Pre Post
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GMTR (95% CI)
CD
UC
Controls
CD
UC
Controls
0.91 0.71–1.17 2.65 2.12–3.32 1.30 0.99–1.70 1.85 1.40–2.44 0.56 0.45–0.69 2.98 2.36–3.75 1.29 1.06–1.55 4.57 3.47–6.00 2.52 2.03–3.13 8.98 7.01–11.49 2.10 1.70–2.59 8.56 6.50–11.27 1.94 1.40–2.67 6.66 5.27–8.35 1.37 1.07–1.75 4.98 3.98–6.24
0.67 0.52–0.84 3.08 2.18–4.35 0.67 0.51–0.87 1.15 0.88–1.51 0.51 0.39–0.69 3.63 2.56–5.16 1.03 0.83–1.27 5.13 3.41–7.70 2.07 1.66–2.56 11.01 7.78–15.52 1.96 1.48–2.59 12.10 8.51–17.32 0.72 0.55–0.95 4.05 2.92–5.65 1.21 0.91–1.61 5.92 4.17–8.41
0.79 0.60–1.02 4.08 3.26–5.11 1.28 1.00–1.63 2.18 1.75–2.72 0.58 0.45–0.75 6.10 4.49–8.26 1.35 1.09–1.67 6.03 4.40–8.30 2.52 1.93–3.26 11.05 7.94–15.42 2.46 1.82–3.31 14.99 10.30–21.80 0.93 0.65–1.32 7.11 5.37–9.43 1.60 1.24–2.05 6.03 4.67–7.78
2.76 2.3–3.3
4.6 3.4–6.2
5.16 4.0–6.7
1.42 1.3–1.6
1.73 1.4–2.1
1.7 1.4–2.0
5.26 4.1–6.8
6.99 5.1–9.6
10.45 7.6–14.4
3.54 2.8–4.5
4.96 3.6–6.8
4.45 3.4–5.9
3.56 2.8–4.5
5.32 3.9–7.3
4.39 3.3–5.8
4.07 3.1–5.3
6.15 4.4–8.6
6.08 4.5–8.2
3.42 2.7–4.4
5.58 4.0–7.7
7.6 5.3–10.8
3.63 2.9–4.6
4.87 3.5–6.7
3.75 2.9–4.8
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Inflamm Bowel Dis Volume 21, Number 7, July 2015
PCV13 in Pediatric Patients with IBD
TABLE 3 (Continued) GMT (95% CI)
PCV13 Serotypes 14
Pre Post
18C
Pre Post
19A
Pre Post
19F
Pre Post
23F
Pre Post
GMTR (95% CI)
CD
UC
Controls
CD
UC
Controls
4.11 3.08–5.49 22.03 15.60–31.10 1.83 1.33–2.53 10.71 8.26–13.90 4.74 3.77–5.96 14.76 11.64–18.69 3.14 2.27–4.24 14.90 10.40–21.32 1.91 1.44–2.54 11.36 8.49–15.18
3.52 2.42–5.11 36.46 24.81–53.53 1.06 0.78–1.43 9.26 6.78–12.67 3.63 2.79–4.70 21.78 15.78–30.03 1.85 1.37–2.50 18.08 10.60–30.82 1.09 0.77–1.53 12.19 7.82–18.99
3.79 2.64–5.43 30.48 20.80–44.66 0.96 0.70–1.32 7.97 5.86–10.85 5.51 4.03–7.54 18.10 13.46–24.31 5.71 3.50–9.33 30.22 19.73–46.25 1.29 0.95–1.75 10.62 7.24–15.56
5.35 4.0–7.2
10.35 7.1–15.0
8.03 5.3–12.2
5.83 4.3–7.8
8.72 6.4–11.8
8.24 5.8–11.7
3.11 2.4–4.0
6 4.6–7.8
3.28 2.5–4.2
4.74 3.4–6.5
9.75 5.8–16.3
5.28 3.4–8.3
5.93 4.5–7.9
11.18 7.6–16.4
8.2 5.3–12.6
In patients with UC, postvaccination of GMTRs was, on average, 1.55 times higher than in patients with CD (95% CI, 1.23–1.96). In controls, GMTRs was, on average, 1.43 times higher than in patients with CD (95% CI, 1.14–1.79). GMTRs according to treatment type are present in Tables 4 and 5. Children treated with 5-ASA and antibiotics exclusively had higher GMTRs than children treated with immunomodulators and biologicals (P ¼ 0.0369). In children treated with immunomodulators, GMTR was 1.49 higher than in children treated with immunomodulators and biologicals; however, the difference was not statistically significant (P ¼ 0.0792). There were no significant differences between GMTR and disease severity of CD and UC (lPillai ¼ 0.073, P ¼ 0.9659 and lPillai ¼ 0.31, P ¼ 0.2362, respectively) for all 13 serotypes. Figure 1 shows differences of mean GMTR between the study groups.
Adverse Effects There were no serious adverse events related to PCV13 during the study. Of the local side effects, the most frequently reported was soreness in 43.4% (53 of 122) of patients and 60.7% (34 of 56) of controls. No systemic side effects were observed in the 3 groups. Adverse events data comparing patients with IBD with controls are shown in Table 6. Additionally, in group A, nausea (1 person), muscle pain (1 person), shivers (1 person), and fatigue (1 person) were noted. In group
B, 1 person had diarrhea and 1 person had skin itching. In the control group, increased thirst (1 person) and dizziness (1 person) were observed. In patients with IBD, adverse events were not depended on therapy type.
DISCUSSION The results of this prospective trial indicate that PCV13 is both immunogenic and safe in children and adolescents with IBD. To the best of our knowledge, this is the first study assessing the immune response to PCV13 vaccine in patients with IBD. Our findings are in line with the results from previous pediatric studies assessing the immune response to PCV13 in a healthy pediatric population28 and in HIV-infected children.29 They are also in line with the results from sparse studies evaluating 7-valent PCV in autoimmune diseases, other than IBD, such as juvenile arthritis.30 The good response to the PCV13 is similar to results of other studies that assessed response rates in IBD adults vaccinated with polysaccharide vaccines.19–21 In these studies, adequate vaccine response was achieved in 78% to 88% of patients with IBD who did not receive immunosuppressive treatment and in 45% to 78% of those on immunosuppressive therapy.19–21 However, in those studies, in which subanalysis of immunosuppressive treatment was performed, vaccine response was the lowest in infliximab-treated only groups.20,21 The direct comparison www.ibdjournal.org |
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10.25 7.06 1.45 0.84–2.51 7.08 6.44 1.1 0.49–2.46 4.84 3.86 1.25 0.85–1.85
TABLE 5. GMTRs in Children Treated with Immunosuppressive Therapy Type of Treatment Immunomodulators Immunomodulators and biologicals Immunomodulators/Immunomodulators and biologicals Tdf
T212;42.5 ¼ 2.1; P ¼ 0.0369. A (non-IS), group A treated with nonimmunosuppressive therapy; B (IS), group B treated with immunosuppressive therapy.
A (non-IS) B (IS) A/B 95% CI
5.44 2.96 1.84 1.17–2.9
1.45 1.57 0.92 0.74–1.15
7.24 5.57 1.3 0.79–2.14
5.96 3.63 1.64 1.03–2.63
5.86 3.8 1.54 0.93–2.56
7.64 4.2 1.82 1.03–3.22
5.08 3.95 1.29 0.79–2.11
5.72 3.7 1.55 0.98–2.44
10.88 6.16 1.77 1.02–3.06
7.63 6.67 1.14 0.69–1.89
19F 7F 5 4 3 1 Groups
TABLE 4. GMTRs According to Treatment Type
6A
6B
Serotypes
9V
14b
18C
19A
23F
Banaszkiewicz et al
¼ 9.69
GMTRs
95% CI
4.13 2.77 1.49
3.53–4.83 1.78–4.32 0.94–2.34
¼ 1.9615; P ¼ 0.0792.
between our results and abovementioned studies is very difficult for some reasons. First of all, we assessed 13 serotypes, Melmed et al19 5 serotypes, and Fiorino et al20 and Lee et al21 23 serotypes. Second, different definitions of vaccine response were used. In this study, we defined the adequate vaccine response as postvaccination titers $0.35 mg/mL for all vaccine serotypes. In 2 of above-cited studies,20,21 2-fold increase of GMT was defined as serotype-specific response. In the study of Melmed et al,19 the value of $1 mg/mL for each serotype had to be fulfilled in addition to meet the definition of serotype-specific response. Third, the study populations (children versus adults) were different. Notwithstanding these differences, we would like to emphasize that serological response to PCV13 is probable better than to PPV23. This supposition is consistent with a preliminary study of Kantsø et al, presented as a poster at International Symposium on Pneumococci and Pneumococcal Diseases in 2014. In their randomized study, the authors assessed the specific antibody response to PCV13 and PPV23 and found higher postvaccination GMTs in patients with IBD receiving PCV13 than in those receiving PPV23. Our results strengthen the current Advisory Committee on Immunization Practices recommendation for routine use of PCV13 in immunocompromised children aged 6 to 18 years.17,18
FIGURE 1. GMTR of study groups.
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Inflamm Bowel Dis Volume 21, Number 7, July 2015
PCV13 in Pediatric Patients with IBD
TABLE 6. Adverse Events Adverse Events, % Induration Redness Sorenessa CD versus UC: x2df
a
¼ 1
CD
UC
CD + UC
Controls
6 (8.3) 9 (12.5) 25 (34.7)
8 (16) 10 (20) 28 (56)
14 (11.5) 19 (15.6) 53 (43.4)
12 (21.4) 15 (26.8) 34 (60.7)
¼ 5.45, P ¼ 0.0196; CD + UC versus controls: x2df
¼ 1
x2df
P
¼ 2
4.44 4.19 10.06
0.1086 0.1231 0.0065
¼ 4.61, P ¼ 0.0318.
The good response to the PCV13 correlates with results of other studies that assessed vaccine response rates in patients with IBD vaccinated with trivalent influenza vaccine,31,32 inactivated hepatitis A vaccine,33 and tetanus toxoid booster vaccine.34 In our study, disease activity both in CD and UC did not influence serotype-specific vaccine responses. Similar findings were observed in studies investigating the immunogenicity of PPV in adults with IBD.19–21 In our study, immunosuppressive treatment significantly reduced GMTRs. This is in agreement with the study of Melmed et al19 who showed diminished antibody response for 5 pneumococcal serotypes in patients who received anti-tumor necrosis factor alpha therapy and immunomodulators. The authors assessed only 5 from 23 vaccine serotypes; 4 of them are also included in PCV13. Two other studies assessed only overall PPV23 response without evaluation of GMT’ for particular vaccine serotypes.20,21 Results of a majority of studies that assessed other than pneumococcal vaccines in IBD patients, found immunosuppressive treatment as a risk factor for inadequate response to vaccination.31,32,35 Our results provide further support for the theory that the response to vaccination in this group of patients is diminished by immunosupressive drugs rather than by the disease itself. PCV13 seems to be a very safe vaccine. In the present study only local adverse events were reported. Soreness was the most common and occurred slightly more frequent in controls and UC patients than in CD patients (60.7% versus 56% versus 34.7%, respectively). The major advantage of our study is fact that we measured specific antipneumococcal antibodies to all serotypes included in PCV13 vaccine that has never been done in previous studies assessing PPV23 in IBD patients.19–21 We also decided to include the control group which allowed us to compare the GMTRs value of patients with healthy children. The impact of our study, although it was conducted in Poland, is global. The very good serological response to all vaccine serotypes common in the United States (such as 3 and 19A) and in Europe (such as serotype 1, 3, 4, 14, or 19F) was found.36 We achieved good response for serotypes 3, 7F, or 19A, which are associated with high case fatality rates worldwide; 19A serotype is also a multidrug resistant serotype.37,38 A shortcoming of the study is the fact that we did not perform subanalysis of patients treated with type B (immunomodulatory and
biological) therapy. We are unable to determine whether deficient response are because of anti-tumor necrosis factor alpha agents, the immunomodulator, or the combination thereof. Most of our patients take both immunomodulatory and biological drugs, so we were not able to gather big enough group of “the anti-tumor necrosis factor alpha only treated patients.” However, classifying patients on immunomodulators and biologicals to the same group was common practice in many previous studies that assessed the immunogenicity of vaccines in patients with IBD.19,31 Finally, according to Rahier et al,14 all patients with IBD on immunosuppression aged $2 years, who have not previously received PCV13 or PPV23, should receive a dose of PCV13 first, followed by a dose of PPV23 at least 8 weeks later. The second dose of PPV23 is recommended 5 years later. For those patients who have been previously vaccinated with PPV23, a PCV13 should be given $1 year after the last PPV23.
CONCLUSIONS In summary, results of our prospective study showed that PCV13 is highly immunogenic and safe in IBD children and adolescents. Immunosuppressive treatment diminished the serological response to PCV13; however, this response was still high. The most important task for future research is further longterm observational studies on clinical impact of pneumococcal vaccination (effectiveness) with PCV13 in patients with IBD, e.g., hospitalization rates and/or incidence of pneumonia in these individuals.
ACKNOWLEDGMENTS The authors thank Prof. Dr. David Goldblatt (Immunobiology Unit, Institute of Child Health, University College London, London, United Kingdom) for providing training opportunities and fruitful advices on ELISA analysis of serotype-specific antipneumococcal antibodies to the thirteen polysaccharides in PCV13.
REFERENCES 1. Centers for Disease Control and Prevention. Pneumococcal Disease Epidemiology and Prevention of Vaccine-preventable Diseases the Pink Book: Course Textbook. 12th Edition Second Printing. 2012;7. Available at: http://www.cdc.gov/vaccines/pubs/pinkbook/pneumo.html Accessed December 4, 2014. www.ibdjournal.org |
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2. File TM Jr. Streptococcus pneumoniae and community-acquired pneumonia: a cause for concern. Am J Med. 2004;117(suppl 3A):39S–50S. 3. Rozenbaum MH, Pechlivanoglou P, van der Werf TS, et al. The role of Streptococcus pneumoniae in community-acquired pneumonia among adults in Europe: a meta-analysis. Eur J Clin Microbiol Infect Dis. 2013;32:305–316. 4. Senstad AC, Suren P, Brauteset L, et al. Community-acquired pneumonia (CAP) in children in Oslo, Norway. Acta Paediatr. 2009;98:332–336. 5. Clark JE, Hammal D, Hampton F, et al. Epidemiology of communityacquired pneumonia in children seen in hospital. Epidemiol Infect. 2007; 135:262–269. 6. Weigl JA, Puppe W, Belke O, et al. Population-based incidence of severe pneumonia in children in Kiel, Germany. Klin Padiatr. 2005;217: 211–219. 7. Cevey-Macherel M, Galetto-Lacour A, Gervaix A, et al. Etiology of community-acquired pneumonia in hospitalised children based on WHO clinical guidelines. Eur J Pediatr. 2009;168:1429–1436. 8. Pneumococcal vaccines WHO position paper—2012. Weekly Epidemiol Rec. 2012;87:129–144. 9. Herrlinger KR, Noftz MK, Dalhoff K, et al. Alterations in pulmonary function in inflammatory bowel disease are frequent and persist during remission. Am J Gastroenterol. 2002;97:377–381. 10. Long MD, Martin C, Sandler RS, et al. Increased risk of pneumonia among patients with inflammatory bowel disease. Am J Gastroenterol. 2013;108:240–248. 11. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT™ registry. Am J Gastroenterol. 2012;107: 1409–1422. 12. Wasan SK, Baker SE, Skolnik PR, et al. A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol. 2010;105: 1231–1238. 13. Rubin LG, Levin MJ, Ljungman P, et al; Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58:309–318. 14. Rahier JF, Magro F, Abreu C, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8:443–468. 15. Jackson LA, Gurtman A, van Cleeff M, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults. Vaccine. 2013;31:3577–3584. 16. Moberley S, Holden J, Tatham DP, et al. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev. 2013;1: CD000422. 17. Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among children aged 6-18 years with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2013; 62:521–524. 18. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged $65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2014;63:822–825. 19. Melmed GY, Agarwal N, Frenck RW, et al. Immunosuppression impairs response to pneumococcal polysaccharide vaccination in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105:148–154. 20. Fiorino G, Peyrin-Biroulet L, Naccarato P, et al. Effects of immunosuppression on immune response to pneumococcal vaccine in inflammatory
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21.
22. 23. 24. 25.
26. 27. 28.
29. 30.
31. 32. 33. 34.
35. 36. 37. 38.
bowel disease: a prospective study. Inflamm Bowel Dis. 2012;18: 1042–1047. Lee CK, Kim HS, Ye BD, et al; Korean Association for the Study of Intestinal Diseases (KASID) Study. Patients with Crohn’s disease on antitumor necrosis factor therapy are at significant risk of inadequate response to the 23-valent pneumococcal polysaccharide vaccine. J Crohns Colitis. 2014;8:384–391. Levine A, Koletzko S, Turner D, et al. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr. 2014;58:795–806. World Health Organisation. Pneumococcal conjugate vaccines. Recommendations for the production and control of pneumococcal conjugate vaccines. WHO Tech Rep Ser. 2005;927:64–98. 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. Concepcion NF, Frasch CE. Pneumococcal type 22F polysaccharide absorption improves the specificity of a pneumococcal-polysaccharide enzyme-linked immunosorbent assay. Clin Diagn Lab Immunol. 2001;8: 266–272. Siber GR, Chang I, Baker S, et al. Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine. 2007; 25:3816–3826. Rousseeuw PJ, Croux C. Alternatives to the median absolute deviation. J Am Stat Assoc. 1993;88:1273–1283. 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. Bamford A, Kelleher P, Lyall H, et al. Serological response to 13-valent pneumococcal conjugate vaccine in children and adolescents with perinatally acquired HIV infection. AIDS. 2014;28:2033–2043. Farmaki E, Kanakoudi-Tsakalidou F, Spoulou V, et al. The effect of antiTNF treatment on the immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis. Vaccine. 2010;28:5109–5113. Lu Y, Jacobson DL, Ashworth LA, et al. Immune response to influenza vaccine in children with inflammatory bowel disease. Am J Gastroenterol. 2009;104:444–453. Mamula P, Markowitz JE, Piccoli DA, et al. Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5:851–856. Radzikowski A, Banaszkiewicz A, qazowska-Przeorek I, et al. Immunogenicity of hepatitis A vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:1117–1124. Nielsen HJ, Mortensen T, Holten-Andersen M, et al. Increased levels of specific leukocyte- and platelet-derived substances during normal antitetanus antibody synthesis in patients with inactive Crohn disease. Scand J Gastroenterol. 2001;36:265–269. Moses J, Alkhouri N, Shannon A, et al. Hepatitis B immunity and response to booster vaccination in children with inflammatory bowel disease treated with infliximab. Am J Gastroenterol. 2012;107:133–138. Richter SS, Heilmann KP, Dohrn CL, et al. Pneumococcal serotypes before and after introduction of conjugate vaccines, United States, 1999–2011. Emerg Infect Dis. 2013;19:1074–1083. Ruckinger S, von Kries R, Siedler A, et al. Association of serotype of Streptococcus pneumoniae with risk of severe and fatal outcome. Pediatr Infect Dis J. 2009;28:118–122. Song JH, Dagan R, Klugman KP, et al. The relationship between pneumococcal serotypes and antibiotic resistance. Vaccine. 2012;30: 2728–2737.
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Immunogenicity of 13-Valent Pneumococcal Conjugate Vaccine in Pediatric Patients with Inflammatory Bowel Disease ska, MD, PhD,† Kinga Kowalska-Duplaga, MD, PhD,‡ Aleksandra Banaszkiewicz, MD, PhD,* Brygida Targon Katarzyna Karolewska-Bochenek, MD, PhD,* Agnieszka Sieczkowska, MD,§ ska, MD, PhD,* Urszula Grzybowska-Chlebowczyk, MD, PhD,jj Agnieszka Gawron Elz_ bieta Krzesiek, MD, PhD,¶ Izabella Łazowska-Przeorek, MD, PhD,* Maria Kotowska, MD, PhD,* Edyta Sienkiewicz, MD, PhD,* Jarosław Walkowiak, MD, PhD,† Hanna Gregorek, MD, PhD,** Andrzej Radzikowski, MD, PhD,* and Piotr Albrecht, MD, PhD*
Background: There are only a few studies on immune response to pneumococcal vaccines in patients with inflammatory bowel disease (IBD); all of them assessed polysaccharide vaccines only. The aim of the study was to evaluate the immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) in IBD pediatric patients compared with healthy controls.
Methods: This was a multicenter, prospective, and controlled study on children and adolescents aged 5 to 18 years with IBD with no history of pneumococcal immunization. The subjects for the study belonged to one of the following groups: patients with IBD on no immunosuppressive therapy (group A), those on tumor necrosis factor agents or immunomodulators (group B), and healthy controls (group C). The study population received 1 intramuscular injection of PCV13. The primary outcome measure was adequate vaccine response defined as postvaccination titer $0.35 mg/mL to all 13 serotypes. Geometric mean titers and geometric mean titer rises were measured for all serotypes. The evidence of local and systemic adverse effects for 5 days after the vaccine was registered. Results: A total of 178 subjects (122 patients and 56 controls) completed the study course. There was no significant difference in the rate of adequate vaccine response between patients with IBD and controls measured 4 to 8 weeks after vaccination (90.4% versus 96.5%, P ¼ 0.5281). Children in group A had higher geometric mean titer rises than children in group B (P ¼ 0.0369). There were no serious adverse events related to PCV13 during the study.
Conclusions: PCV13 is both immunogenic and safe in pediatric patients with IBD. (Inflamm Bowel Dis 2015;21:1607–1614) Key Words: Crohn’s disease, ulcerative colitis, PCV, immune response
P
neumococcal infections include serious invasive diseases such as meningitis, sepsis, and pneumonia with bacteremia, as well as milder but more common noninvasive illnesses such as sinusitis and otitis media. The causative agent, Streptococcus pneumoniae, Received for publication February 3, 2015; Accepted February 24, 2015. From the *Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw, Poland; †Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland; ‡ Department of Pediatrics, Gastroenterology and Nutrition, Polish-American Children’s Hospital, Jagiellonian University Medical College, Krakow, Poland; §Department of Pediatric Gastroenterology, Hepatology and Nutrition, Medical University of Gdansk, Gdansk, Poland; jjDepartment of Pediatrics, Medical University of Silesia, Katowice, Poland; ¶Department of Pediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw, Poland; and **Department of Microbiology and Clinical Immunology, The Children’s Memorial Health Institute, Warsaw, Poland. Supported by grant no. N404 077140 0771/B/P01/2011/40 from the Polish Ministry of Science and Higher Education. The project was approved in February 4, 2010. The authors have no conflicts of interest to disclose. Reprints: Aleksandra Banaszkiewicz, MD, PhD, Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Dzialdowska 1, 01-184 Warsaw, Poland (e-mail: [email protected]). Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000406 Published online 27 April 2015.
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frequently colonizes the human nasopharynx and is transmitted mainly through respiratory droplets. S. pneumoniae includes 91 distinct serotypes. Distribution of serotypes that cause disease varies with age, disease syndrome, disease severity, geographic region, and over time.1 In Europe and in the United States, S. pneumoniae is estimated to cause approximately 30% to 50% of communityacquired pneumonia requiring hospitalizations in adults.2,3 The incidence of hospitalized pneumonia (clinical findings and chest x-ray) in children at the age ,16 years was estimated as follows: in Norway, 14.7 per 10,0004; in the United Kingdom, 14.4 per 10,0005; in Germany, 30 per 10,000.6 Mixed pneumococcal and viral infections seem important and are found in 62% of pneumococcal pneumonias.7 Given that S. pneumoniae is a leading human pathogen with relatively high incidence affecting all age groups, and because of very expensive treatment, and a high mortality, prevention against pneumococcal infections seems to be of great clinical importance and World Health Organization priority.8 In patients with IBD, the risk of pneumococcal disease is increased and include chronic pulmonary involvement (approximately 40% www.ibdjournal.org |
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of IBD adults),9 frequent hospitalizations, and immunosuppressive treatment. Although data are limited, the increased risk of bacterial pneumonia was found in 2 big American cohorts of patients with IBD.10,11 Those studies found immunosuppressive therapy as an additional risk factor. For these reasons, immunization against pneumococcal disease is recommended for patients with IBD in all recognized guidelines.12–14 There are 2 different types of pneumococcal vaccine. One type is pneumococcal polysaccharide vaccine (PPV), which includes 23 S. pneumoniae serotypes (PPV23), that induces poor or absent anamnestic antibody response in children ,2 years of age and weak response in older people. The other type is conjugate vaccines that are based on chemical coupling of S. pneumoniae polysaccharides to an immunogenic protein carrier. The carrier enhances the antibody response and induces immune memory, rendering conjugate vaccines immunogenic also for children in age ,2 years. Originally, pneumococcal conjugate vaccines (PCV) were designated only for young children. Recently, the immunogenicity of PCV has been evidenced in adults15 and seemed to be higher than that found after PPV.16 Therefore currently, Advisory Committee on Immunization Practices and Infectious Diseases Society of America recommend using of both the PCV13 and PPV23 to protect immunocompromised individuals against pneumococcal disease including patients with IBD.13,17,18 In patients with IBD, the immunosuppressive character of both the disease and the treatment could compromise, to some extent, the natural immune response to infection and could have an impact on the efficacy and safety of vaccination. Therefore, a committee formed by the Crohn’s and Colitis Foundation of America in 2004 and by the European Crohn’s and Colitis Organization recommends the need of evaluation of the immune response to vaccines in patients with IBD.12,14 Until now, a few studies have assessed the immune response to PPV in adult patients with IBD.19–21 The aim of the study was to evaluate the immunogenicity of a PCV13 vaccine in pediatric patients with IBD and to compare their response with healthy controls. Additionally, the safety of the vaccine was assessed.
MATERIALS AND METHODS Study Design This multicenter, open, prospective, comparative trial was conducted in 6 University-affiliated hospitals for children in Poland (cities of Warsaw, Poznan, Wroclaw, Katowice, Gdansk and Krakow) between April 2013 and March 2014.
Patients and Controls The study population consisted of children and adolescents with IBD (Crohn’s disease [CD] and ulcerative colitis [UC]) between 5 and 18 years of age. Both hospitalized and ambulatory patients were invited to participate in the study. Patients were at different stages of the disease and treatment
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process. Diagnosis of CD and UC was based on clinical signs and symptoms, as well as endoscopic, histological, and radiological results according to the Porto criteria.22 Severity of the CD and UC was evaluated using the Pediatric Crohn’s Disease Activity Index and the Pediatric Ulcerative Colitis Activity Index, which include symptoms, physical examination findings, and laboratory test results; a Pediatric Crohn’s Disease Activity Index score #10 for CD and a Pediatric Ulcerative Colitis Activity Index score ,10 for UC were defined as remission. Patients were stratified into 3 groups. Group A included patients with IBD who were not receiving any immunosuppressive therapy. Group B included patients who were undergoing immunosuppressive treatment with steroids 2 mg/kg per day for 2 weeks or more, with azathioprine (AZA) 2.5 to 3 mg/kg per day or 6-mercaptopurine (6-MP) 1.5 mg/kg per day for 12 weeks or more, cyclosporine, infliximab or adalimumab. The control group, group C, consisted of healthy unvaccinated persons aged 5 to 18 years and was recruited concurrently. Inclusion in this group required that subjects had no chronic illness and were not on any immunosuppressive agents.
Pneumococcal Conjugate Vaccine 13 Pneumococcal 13-valent conjugate vaccine (Diphtheria CRM197 Protein) from Wyeth Pharmaceuticals Inc. was used. Each 0.5 mL dose of the vaccine contains the following: (1) ;2.2 mg of each saccharide from pneumococcal serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, and 23F, and 4.4 mg of serotype 6B individually conjugated to diphtheria cross-reacting material 197 (CRM197) carrier protein. The total concentration of CRM197 is ;34 mg; (2) 295 mg succinate buffer; (3) 125 mg aluminum as AlPO4 adjuvant; and (4) 100 mg polysorbate 80. PCV13 was administered intramuscularly in the left deltoid muscle. Vaccines were stored between 2 and 58C and were taken out immediately before use.
Intervention At screening, demographic data, medical history including pneumococcal infections, and physical examination were obtained. Patients and controls were screened for previous exposure to any pneumococcal vaccines. Patients with IBD had disease activity assessment with the Pediatric Ulcerative Colitis Activity Index for UC and Pediatric Crohn’s Disease Activity Index for CD. All included children were given 1 dose of PCV13. Peripheral blood samples were collected from each patient and controls immediately before and between 6 to 8 weeks after vaccination. Sera were stored at 2208C to 2708C until analysis was performed. Each serum sample was tested for serotype-specific antipneumococcal polysaccharide IgG antibodies to the thirteen polysaccharides in PCV13 (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) by a standardized enzyme-linked immunosorbent assay according to an adapted WHO protocol.23 The assay was performed with preabsorption of test sera by using pneumococcal C polysaccharide and pneumococcal polysaccharide from the nonvaccine
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Inflamm Bowel Dis Volume 21, Number 7, July 2015
22F serotype to enhance specificity of the assay for serotypespecific antibody.24,25 Patients and controls were observed by the investigators for immediate reactions for 30 minutes after injection. Parents or guardians of all patients received diary cards with the request to record any local or systematic symptoms for 5 days after each vaccination.
Outcomes The primary outcome measure was an adequate vaccine response defined as postvaccination titer $0.35 mg/mL to all 13 serotypes. The serotype-specific IgG antibody titers $0.35 mg/mL were considered as protective for invasive pneumococcal disease according to the WHO recommendation.26 The secondary outcome measures were as follows: (1) geometric mean titers (GMTs) for 13 pneumococcal serotypes, (2) geometric mean titer rise (GMTR) for 13 pneumococcal serotypes, and (3) the evidence of local and systemic adverse effects measured for 5 days after the vaccination. GMT was defined as the average titer of serotype-specific IgG antibody determined by enzyme-linked immunosorbent assay in a group of patients who have been immunized. The influence of treatment type in groups A and B on adequate vaccine response and GMTs was assessed.
Sample Size Sample size was calculated according to results of previous studies19–21 that reported approximately 83% serological response rates in patients with IBD treated with aminosalicylates and approximately 51% in patients with IBD treated with immunosuppressive drugs. To detect a difference of 32% between patients on aminosalicylates and immunosuppressive drugs, with a power of 80% and alpha of 0.05, 33 children were required in each group. With expected a dropout rate of 20%, 40 children in each group were required.
Statistical Analysis GMT of prevaccination and postvaccination antibodies level was used as the measure of central tendency. GMTR was used to describe the change in antibodies level after vaccination. Confidence intervals (CI) at 1 2 a ¼ 0.05 was computed (95% CI). The Sn statistic was computed as a measure of variability.27 Higher level reflects higher variability. Odds ratios and 95% CI were computed, and chi-square statistic (x2df) was used to test hypothesis for counts data in tables. T2—Hotelling and l—Pillai statistics were used to test differences in vaccination response between 2 and more groups. Standard box-and-whiskers plot were used to present the data.
Ethical Consideration This study was approved on January 26, 2010 by the Clinical Research Ethics Committee of the Medical University of Warsaw, Poland. All parents and children $16 years old signed the informed consent before participation in the study.
PCV13 in Pediatric Patients with IBD
RESULTS Study Demographics A total of 178 subjects participated in the study including 122 patients with IBD and 56 healthy controls. Age was similar in all groups. There were more boys in the IBD group than in the control group: 60% versus 48.2%, P ¼ 0.11. Groups A and B were similar in disease severity but different in therapy type (P ¼ 0.0018). The basic characteristics of the study participants are presented in Table 1.
Adequate Vaccine Response Adequate vaccine response was very high in all patients with CD, patients with UC, and controls, which is shown in Table 2. There was no significant difference in the rate of adequate vaccine response between patients with IBD and controls measured 4 to 8 weeks after vaccination (90.4% versus 96.5%, P ¼ 0.5281).
Serotype-specific GMTs GMTs and GMTRs for the pneumococcal serotypes included in PCV13 are shown in Table 3. All serotypes were immunogenic for the 3 study groups. In all study groups, there was a tendency for older children to have higher GMTs for all serotypes; however, the difference was not statistical significant (lPillai ¼ 0.125, P ¼ 0.6025). Gender was not associated with GMTs (lPillai ¼ 0.047, P ¼ 0.7768). GMTRs for all 13 serotypes were as follows: for patients with CD, 3.74 (95% CI, 3.22–4.35); for patients with UC, 5.81 (95% CI, 4.9–6.88); and for controls, 5.35 (95% CI, 4.49–6.38).
TABLE 1. Basic Characteristics of Study Groups
N Median age, yr Boys/girlsa Median PCDAI Median PUCAI Drugs, % 5-ASA Antibiotics Immunomodulators Azathioprine Cyclosporine TNF alpha agents Infliximab Adalimumab
CD
UC
CD + UC
Controls
72 15.08 44/28 5 —
50 15.16 30/20 — 5
122 15.08 74/48 — —
56 12.87 27/29 — —
70 (97.2) 5 (6.9) 57 (79.2) 57 — 10 (13.9) 8 (11.1) 2
47 (94) 2 (4) 25 (50) 23 (46) 2 (4) 2 (4) 2 (4) —
117 (95.9) 7 (5.7) 82 (67.2) 80 (65.6) 2 (1.6) 12 (9.8) 10 (8.2) 2 (1.6)
— — — — — — — —
Odds ratios ¼ 1.66; 95% CI, 0.88–3.14; x2df ¼ 1 ¼ 2.42; P ¼ 0.1198. PCDAI, Pediatric Crohn’s Disease Activity Index; PUCAI, Pediatric Ulcerative Colitis Activity Index.
a
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TABLE 2. Adequate Vaccine Response Response to Serotypes
N
%
9/13
10/13
11/13
12/13
13/13
S
9/13
10/13
11/13
12/13
13/13
S
0 1 1 0
0 0 0 0
0 1 1 1
3 2 5 0
37 29 66 28
40 33 73 29
0 3.03 1.37 0
0 0 0 0
0 3.03 1.37 3.45
7.5 6.06 6.85 0
92.5 87.88 90.41 96.55
100 100 100 100
CD UC CD + UC Controls
Bold values indicate adequate vaccine response. P ¼ 0.5281.
TABLE 3. Prevaccination and Postvaccination GMT and GMTRs for 13 Serotypes GMT (95% CI)
PCV13 Serotypes 1
Pre Post
3
Pre Post
4
Pre Post
5
Pre Post
6A
Pre Post
6B
Pre Post
7F
Pre Post
9V
Pre Post
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GMTR (95% CI)
CD
UC
Controls
CD
UC
Controls
0.91 0.71–1.17 2.65 2.12–3.32 1.30 0.99–1.70 1.85 1.40–2.44 0.56 0.45–0.69 2.98 2.36–3.75 1.29 1.06–1.55 4.57 3.47–6.00 2.52 2.03–3.13 8.98 7.01–11.49 2.10 1.70–2.59 8.56 6.50–11.27 1.94 1.40–2.67 6.66 5.27–8.35 1.37 1.07–1.75 4.98 3.98–6.24
0.67 0.52–0.84 3.08 2.18–4.35 0.67 0.51–0.87 1.15 0.88–1.51 0.51 0.39–0.69 3.63 2.56–5.16 1.03 0.83–1.27 5.13 3.41–7.70 2.07 1.66–2.56 11.01 7.78–15.52 1.96 1.48–2.59 12.10 8.51–17.32 0.72 0.55–0.95 4.05 2.92–5.65 1.21 0.91–1.61 5.92 4.17–8.41
0.79 0.60–1.02 4.08 3.26–5.11 1.28 1.00–1.63 2.18 1.75–2.72 0.58 0.45–0.75 6.10 4.49–8.26 1.35 1.09–1.67 6.03 4.40–8.30 2.52 1.93–3.26 11.05 7.94–15.42 2.46 1.82–3.31 14.99 10.30–21.80 0.93 0.65–1.32 7.11 5.37–9.43 1.60 1.24–2.05 6.03 4.67–7.78
2.76 2.3–3.3
4.6 3.4–6.2
5.16 4.0–6.7
1.42 1.3–1.6
1.73 1.4–2.1
1.7 1.4–2.0
5.26 4.1–6.8
6.99 5.1–9.6
10.45 7.6–14.4
3.54 2.8–4.5
4.96 3.6–6.8
4.45 3.4–5.9
3.56 2.8–4.5
5.32 3.9–7.3
4.39 3.3–5.8
4.07 3.1–5.3
6.15 4.4–8.6
6.08 4.5–8.2
3.42 2.7–4.4
5.58 4.0–7.7
7.6 5.3–10.8
3.63 2.9–4.6
4.87 3.5–6.7
3.75 2.9–4.8
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PCV13 in Pediatric Patients with IBD
TABLE 3 (Continued) GMT (95% CI)
PCV13 Serotypes 14
Pre Post
18C
Pre Post
19A
Pre Post
19F
Pre Post
23F
Pre Post
GMTR (95% CI)
CD
UC
Controls
CD
UC
Controls
4.11 3.08–5.49 22.03 15.60–31.10 1.83 1.33–2.53 10.71 8.26–13.90 4.74 3.77–5.96 14.76 11.64–18.69 3.14 2.27–4.24 14.90 10.40–21.32 1.91 1.44–2.54 11.36 8.49–15.18
3.52 2.42–5.11 36.46 24.81–53.53 1.06 0.78–1.43 9.26 6.78–12.67 3.63 2.79–4.70 21.78 15.78–30.03 1.85 1.37–2.50 18.08 10.60–30.82 1.09 0.77–1.53 12.19 7.82–18.99
3.79 2.64–5.43 30.48 20.80–44.66 0.96 0.70–1.32 7.97 5.86–10.85 5.51 4.03–7.54 18.10 13.46–24.31 5.71 3.50–9.33 30.22 19.73–46.25 1.29 0.95–1.75 10.62 7.24–15.56
5.35 4.0–7.2
10.35 7.1–15.0
8.03 5.3–12.2
5.83 4.3–7.8
8.72 6.4–11.8
8.24 5.8–11.7
3.11 2.4–4.0
6 4.6–7.8
3.28 2.5–4.2
4.74 3.4–6.5
9.75 5.8–16.3
5.28 3.4–8.3
5.93 4.5–7.9
11.18 7.6–16.4
8.2 5.3–12.6
In patients with UC, postvaccination of GMTRs was, on average, 1.55 times higher than in patients with CD (95% CI, 1.23–1.96). In controls, GMTRs was, on average, 1.43 times higher than in patients with CD (95% CI, 1.14–1.79). GMTRs according to treatment type are present in Tables 4 and 5. Children treated with 5-ASA and antibiotics exclusively had higher GMTRs than children treated with immunomodulators and biologicals (P ¼ 0.0369). In children treated with immunomodulators, GMTR was 1.49 higher than in children treated with immunomodulators and biologicals; however, the difference was not statistically significant (P ¼ 0.0792). There were no significant differences between GMTR and disease severity of CD and UC (lPillai ¼ 0.073, P ¼ 0.9659 and lPillai ¼ 0.31, P ¼ 0.2362, respectively) for all 13 serotypes. Figure 1 shows differences of mean GMTR between the study groups.
Adverse Effects There were no serious adverse events related to PCV13 during the study. Of the local side effects, the most frequently reported was soreness in 43.4% (53 of 122) of patients and 60.7% (34 of 56) of controls. No systemic side effects were observed in the 3 groups. Adverse events data comparing patients with IBD with controls are shown in Table 6. Additionally, in group A, nausea (1 person), muscle pain (1 person), shivers (1 person), and fatigue (1 person) were noted. In group
B, 1 person had diarrhea and 1 person had skin itching. In the control group, increased thirst (1 person) and dizziness (1 person) were observed. In patients with IBD, adverse events were not depended on therapy type.
DISCUSSION The results of this prospective trial indicate that PCV13 is both immunogenic and safe in children and adolescents with IBD. To the best of our knowledge, this is the first study assessing the immune response to PCV13 vaccine in patients with IBD. Our findings are in line with the results from previous pediatric studies assessing the immune response to PCV13 in a healthy pediatric population28 and in HIV-infected children.29 They are also in line with the results from sparse studies evaluating 7-valent PCV in autoimmune diseases, other than IBD, such as juvenile arthritis.30 The good response to the PCV13 is similar to results of other studies that assessed response rates in IBD adults vaccinated with polysaccharide vaccines.19–21 In these studies, adequate vaccine response was achieved in 78% to 88% of patients with IBD who did not receive immunosuppressive treatment and in 45% to 78% of those on immunosuppressive therapy.19–21 However, in those studies, in which subanalysis of immunosuppressive treatment was performed, vaccine response was the lowest in infliximab-treated only groups.20,21 The direct comparison www.ibdjournal.org |
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10.25 7.06 1.45 0.84–2.51 7.08 6.44 1.1 0.49–2.46 4.84 3.86 1.25 0.85–1.85
TABLE 5. GMTRs in Children Treated with Immunosuppressive Therapy Type of Treatment Immunomodulators Immunomodulators and biologicals Immunomodulators/Immunomodulators and biologicals Tdf
T212;42.5 ¼ 2.1; P ¼ 0.0369. A (non-IS), group A treated with nonimmunosuppressive therapy; B (IS), group B treated with immunosuppressive therapy.
A (non-IS) B (IS) A/B 95% CI
5.44 2.96 1.84 1.17–2.9
1.45 1.57 0.92 0.74–1.15
7.24 5.57 1.3 0.79–2.14
5.96 3.63 1.64 1.03–2.63
5.86 3.8 1.54 0.93–2.56
7.64 4.2 1.82 1.03–3.22
5.08 3.95 1.29 0.79–2.11
5.72 3.7 1.55 0.98–2.44
10.88 6.16 1.77 1.02–3.06
7.63 6.67 1.14 0.69–1.89
19F 7F 5 4 3 1 Groups
TABLE 4. GMTRs According to Treatment Type
6A
6B
Serotypes
9V
14b
18C
19A
23F
Banaszkiewicz et al
¼ 9.69
GMTRs
95% CI
4.13 2.77 1.49
3.53–4.83 1.78–4.32 0.94–2.34
¼ 1.9615; P ¼ 0.0792.
between our results and abovementioned studies is very difficult for some reasons. First of all, we assessed 13 serotypes, Melmed et al19 5 serotypes, and Fiorino et al20 and Lee et al21 23 serotypes. Second, different definitions of vaccine response were used. In this study, we defined the adequate vaccine response as postvaccination titers $0.35 mg/mL for all vaccine serotypes. In 2 of above-cited studies,20,21 2-fold increase of GMT was defined as serotype-specific response. In the study of Melmed et al,19 the value of $1 mg/mL for each serotype had to be fulfilled in addition to meet the definition of serotype-specific response. Third, the study populations (children versus adults) were different. Notwithstanding these differences, we would like to emphasize that serological response to PCV13 is probable better than to PPV23. This supposition is consistent with a preliminary study of Kantsø et al, presented as a poster at International Symposium on Pneumococci and Pneumococcal Diseases in 2014. In their randomized study, the authors assessed the specific antibody response to PCV13 and PPV23 and found higher postvaccination GMTs in patients with IBD receiving PCV13 than in those receiving PPV23. Our results strengthen the current Advisory Committee on Immunization Practices recommendation for routine use of PCV13 in immunocompromised children aged 6 to 18 years.17,18
FIGURE 1. GMTR of study groups.
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Inflamm Bowel Dis Volume 21, Number 7, July 2015
PCV13 in Pediatric Patients with IBD
TABLE 6. Adverse Events Adverse Events, % Induration Redness Sorenessa CD versus UC: x2df
a
¼ 1
CD
UC
CD + UC
Controls
6 (8.3) 9 (12.5) 25 (34.7)
8 (16) 10 (20) 28 (56)
14 (11.5) 19 (15.6) 53 (43.4)
12 (21.4) 15 (26.8) 34 (60.7)
¼ 5.45, P ¼ 0.0196; CD + UC versus controls: x2df
¼ 1
x2df
P
¼ 2
4.44 4.19 10.06
0.1086 0.1231 0.0065
¼ 4.61, P ¼ 0.0318.
The good response to the PCV13 correlates with results of other studies that assessed vaccine response rates in patients with IBD vaccinated with trivalent influenza vaccine,31,32 inactivated hepatitis A vaccine,33 and tetanus toxoid booster vaccine.34 In our study, disease activity both in CD and UC did not influence serotype-specific vaccine responses. Similar findings were observed in studies investigating the immunogenicity of PPV in adults with IBD.19–21 In our study, immunosuppressive treatment significantly reduced GMTRs. This is in agreement with the study of Melmed et al19 who showed diminished antibody response for 5 pneumococcal serotypes in patients who received anti-tumor necrosis factor alpha therapy and immunomodulators. The authors assessed only 5 from 23 vaccine serotypes; 4 of them are also included in PCV13. Two other studies assessed only overall PPV23 response without evaluation of GMT’ for particular vaccine serotypes.20,21 Results of a majority of studies that assessed other than pneumococcal vaccines in IBD patients, found immunosuppressive treatment as a risk factor for inadequate response to vaccination.31,32,35 Our results provide further support for the theory that the response to vaccination in this group of patients is diminished by immunosupressive drugs rather than by the disease itself. PCV13 seems to be a very safe vaccine. In the present study only local adverse events were reported. Soreness was the most common and occurred slightly more frequent in controls and UC patients than in CD patients (60.7% versus 56% versus 34.7%, respectively). The major advantage of our study is fact that we measured specific antipneumococcal antibodies to all serotypes included in PCV13 vaccine that has never been done in previous studies assessing PPV23 in IBD patients.19–21 We also decided to include the control group which allowed us to compare the GMTRs value of patients with healthy children. The impact of our study, although it was conducted in Poland, is global. The very good serological response to all vaccine serotypes common in the United States (such as 3 and 19A) and in Europe (such as serotype 1, 3, 4, 14, or 19F) was found.36 We achieved good response for serotypes 3, 7F, or 19A, which are associated with high case fatality rates worldwide; 19A serotype is also a multidrug resistant serotype.37,38 A shortcoming of the study is the fact that we did not perform subanalysis of patients treated with type B (immunomodulatory and
biological) therapy. We are unable to determine whether deficient response are because of anti-tumor necrosis factor alpha agents, the immunomodulator, or the combination thereof. Most of our patients take both immunomodulatory and biological drugs, so we were not able to gather big enough group of “the anti-tumor necrosis factor alpha only treated patients.” However, classifying patients on immunomodulators and biologicals to the same group was common practice in many previous studies that assessed the immunogenicity of vaccines in patients with IBD.19,31 Finally, according to Rahier et al,14 all patients with IBD on immunosuppression aged $2 years, who have not previously received PCV13 or PPV23, should receive a dose of PCV13 first, followed by a dose of PPV23 at least 8 weeks later. The second dose of PPV23 is recommended 5 years later. For those patients who have been previously vaccinated with PPV23, a PCV13 should be given $1 year after the last PPV23.
CONCLUSIONS In summary, results of our prospective study showed that PCV13 is highly immunogenic and safe in IBD children and adolescents. Immunosuppressive treatment diminished the serological response to PCV13; however, this response was still high. The most important task for future research is further longterm observational studies on clinical impact of pneumococcal vaccination (effectiveness) with PCV13 in patients with IBD, e.g., hospitalization rates and/or incidence of pneumonia in these individuals.
ACKNOWLEDGMENTS The authors thank Prof. Dr. David Goldblatt (Immunobiology Unit, Institute of Child Health, University College London, London, United Kingdom) for providing training opportunities and fruitful advices on ELISA analysis of serotype-specific antipneumococcal antibodies to the thirteen polysaccharides in PCV13.
REFERENCES 1. Centers for Disease Control and Prevention. Pneumococcal Disease Epidemiology and Prevention of Vaccine-preventable Diseases the Pink Book: Course Textbook. 12th Edition Second Printing. 2012;7. Available at: http://www.cdc.gov/vaccines/pubs/pinkbook/pneumo.html Accessed December 4, 2014. www.ibdjournal.org |
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2. File TM Jr. Streptococcus pneumoniae and community-acquired pneumonia: a cause for concern. Am J Med. 2004;117(suppl 3A):39S–50S. 3. Rozenbaum MH, Pechlivanoglou P, van der Werf TS, et al. The role of Streptococcus pneumoniae in community-acquired pneumonia among adults in Europe: a meta-analysis. Eur J Clin Microbiol Infect Dis. 2013;32:305–316. 4. Senstad AC, Suren P, Brauteset L, et al. Community-acquired pneumonia (CAP) in children in Oslo, Norway. Acta Paediatr. 2009;98:332–336. 5. Clark JE, Hammal D, Hampton F, et al. Epidemiology of communityacquired pneumonia in children seen in hospital. Epidemiol Infect. 2007; 135:262–269. 6. Weigl JA, Puppe W, Belke O, et al. Population-based incidence of severe pneumonia in children in Kiel, Germany. Klin Padiatr. 2005;217: 211–219. 7. Cevey-Macherel M, Galetto-Lacour A, Gervaix A, et al. Etiology of community-acquired pneumonia in hospitalised children based on WHO clinical guidelines. Eur J Pediatr. 2009;168:1429–1436. 8. Pneumococcal vaccines WHO position paper—2012. Weekly Epidemiol Rec. 2012;87:129–144. 9. Herrlinger KR, Noftz MK, Dalhoff K, et al. Alterations in pulmonary function in inflammatory bowel disease are frequent and persist during remission. Am J Gastroenterol. 2002;97:377–381. 10. Long MD, Martin C, Sandler RS, et al. Increased risk of pneumonia among patients with inflammatory bowel disease. Am J Gastroenterol. 2013;108:240–248. 11. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT™ registry. Am J Gastroenterol. 2012;107: 1409–1422. 12. Wasan SK, Baker SE, Skolnik PR, et al. A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol. 2010;105: 1231–1238. 13. Rubin LG, Levin MJ, Ljungman P, et al; Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58:309–318. 14. Rahier JF, Magro F, Abreu C, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8:443–468. 15. Jackson LA, Gurtman A, van Cleeff M, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults. Vaccine. 2013;31:3577–3584. 16. Moberley S, Holden J, Tatham DP, et al. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev. 2013;1: CD000422. 17. Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among children aged 6-18 years with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2013; 62:521–524. 18. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged $65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2014;63:822–825. 19. Melmed GY, Agarwal N, Frenck RW, et al. Immunosuppression impairs response to pneumococcal polysaccharide vaccination in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105:148–154. 20. Fiorino G, Peyrin-Biroulet L, Naccarato P, et al. Effects of immunosuppression on immune response to pneumococcal vaccine in inflammatory
1614
21.
22. 23. 24. 25.
26. 27. 28.
29. 30.
31. 32. 33. 34.
35. 36. 37. 38.
bowel disease: a prospective study. Inflamm Bowel Dis. 2012;18: 1042–1047. Lee CK, Kim HS, Ye BD, et al; Korean Association for the Study of Intestinal Diseases (KASID) Study. Patients with Crohn’s disease on antitumor necrosis factor therapy are at significant risk of inadequate response to the 23-valent pneumococcal polysaccharide vaccine. J Crohns Colitis. 2014;8:384–391. Levine A, Koletzko S, Turner D, et al. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr. 2014;58:795–806. World Health Organisation. Pneumococcal conjugate vaccines. Recommendations for the production and control of pneumococcal conjugate vaccines. WHO Tech Rep Ser. 2005;927:64–98. 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. Concepcion NF, Frasch CE. Pneumococcal type 22F polysaccharide absorption improves the specificity of a pneumococcal-polysaccharide enzyme-linked immunosorbent assay. Clin Diagn Lab Immunol. 2001;8: 266–272. Siber GR, Chang I, Baker S, et al. Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine. 2007; 25:3816–3826. Rousseeuw PJ, Croux C. Alternatives to the median absolute deviation. J Am Stat Assoc. 1993;88:1273–1283. 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. Bamford A, Kelleher P, Lyall H, et al. Serological response to 13-valent pneumococcal conjugate vaccine in children and adolescents with perinatally acquired HIV infection. AIDS. 2014;28:2033–2043. Farmaki E, Kanakoudi-Tsakalidou F, Spoulou V, et al. The effect of antiTNF treatment on the immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis. Vaccine. 2010;28:5109–5113. Lu Y, Jacobson DL, Ashworth LA, et al. Immune response to influenza vaccine in children with inflammatory bowel disease. Am J Gastroenterol. 2009;104:444–453. Mamula P, Markowitz JE, Piccoli DA, et al. Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5:851–856. Radzikowski A, Banaszkiewicz A, qazowska-Przeorek I, et al. Immunogenicity of hepatitis A vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:1117–1124. Nielsen HJ, Mortensen T, Holten-Andersen M, et al. Increased levels of specific leukocyte- and platelet-derived substances during normal antitetanus antibody synthesis in patients with inactive Crohn disease. Scand J Gastroenterol. 2001;36:265–269. Moses J, Alkhouri N, Shannon A, et al. Hepatitis B immunity and response to booster vaccination in children with inflammatory bowel disease treated with infliximab. Am J Gastroenterol. 2012;107:133–138. Richter SS, Heilmann KP, Dohrn CL, et al. Pneumococcal serotypes before and after introduction of conjugate vaccines, United States, 1999–2011. Emerg Infect Dis. 2013;19:1074–1083. Ruckinger S, von Kries R, Siedler A, et al. Association of serotype of Streptococcus pneumoniae with risk of severe and fatal outcome. Pediatr Infect Dis J. 2009;28:118–122. Song JH, Dagan R, Klugman KP, et al. The relationship between pneumococcal serotypes and antibiotic resistance. Vaccine. 2012;30: 2728–2737.
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