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ORIGINAL CONTRIBUTIONS

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Immunosuppression Impairs Response to Pneumococcal Polysaccharide Vaccination in Patients With Inflammatory Bowel Disease Gil Y. Melmed, MD, MS1, Nik Agarwal, MD1, Robert W. Frenck, MD2, Andrew F. Ippoliti, MD1, Patricio Ibanez, MD1, Konstantinos A. Papadakis, MD1, Peter Simpson, MD1, Cristina Barolet-Garcia1, Joel Ward, MD2, Stephan R. Targan, MD1 and Eric A. Vasiliauskas, MD1

OBJECTIVES:

The treatment of inflammatory bowel disease (IBD) often includes immunosuppressive medications, which may increase the risk of vaccine-preventable illnesses. We aimed to assess the impact of immunosuppression on immune responses to pneumococcal vaccination in patients with IBD.

METHODS:

The study design consists of a prospective controlled clinical trial. This study was carried out at a tertiary-care IBD clinic. The subjects for the study belonged to one of the following three groups: adult patients with IBD on combination TNF-blockers and immunomodulators (Group A), those without immunosuppressive therapy (Group B), and age-matched healthy controls (Group C). The treatment consisted of immunization with 23-valent pneumococcal polysaccharide vaccines (PSVs). The main outcome was immune response for five serotypes defined as a twofold or greater increase from pre-vaccination titers and ⭓ 1 μg post-vaccination titer.

RESULTS:

Sixty-four subjects participated in the study: 20 in Group A, 25 in Group B, and 19 in Group C. Pre-vaccination titers were similar among the three groups. Vaccine responses were lower in Group A than in Group B (P ≤ 0.01 for four out of five antigens) and Group C (P < 0.01 for all five antigens). Overall vaccine response was seen in 45, 80, and 85% of Groups A, B, and C (P = 0.01), respectively.

CONCLUSIONS: Immune response to PSV-23 is impaired in Crohn’s disease (CD) patients on combination

immunosuppressive therapy but is normal among non-immunosuppressed patients. Given the unpredictable likelihood for immunosuppressive therapy, newly diagnosed patients with IBD should undergo vaccination before the initiation of immunosuppressive therapy. Am J Gastroenterol 2010; 105:148–154; doi:10.1038/ajg.2009.523; published online 15 September 2009

INTRODUCTION Inflammatory bowel diseases (IBD) are characterized by immune dysregulation of the gastrointestinal tract that may be classified as Crohn’s disease (CD) or ulcerative colitis (UC). Treatment of IBD often requires use of immune-suppressive medications such as steroids, immunomodulators (such as 6-mercaptopurine, methotrexate, or azathioprine), and/or targeted ‘biological’ therapy (including infliximab, adalimumab, certolizumab, or natalizumab) that likely increase patient risk for various infections (1,2). As a result, patients with IBD

may be at a higher risk for certain infections than the general population and the outcomes of these infections may be more severe or fatal (3,4). Although the incidence of vaccine-preventable infections among patients with IBD is not known, there are several published case reports of fulminant and/or fatal infections with Streptococcus pneumoniae, varicella, and hepatitis B (5–8). The 23-valent pneumococcal polysaccharide vaccine (PSV) reduces the morbidity associated with invasive pneumococcal disease in adults (9). At present, the PSV vaccine is

1

Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, University of California, Los Angeles, Los Angeles, California, USA; 2UCLA Center for Vaccine Research, LABioMed, Harbor-UCLA Medical Center, University of California, Los Angeles, Torrance, California, USA. Correspondence: Gil Y. Melmed, MD, MS, Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, University of California, Los Angeles, 8635 West 3rd Street, Suite 960-W, Los Angeles, California 90048, USA. E-mail: [email protected] Received 25 March 2009; accepted 3 August 2009 The American Journal of GASTROENTEROLOGY

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METHODS Study population

The study population included adult patients who received care at Cedars-Sinai Medical Center’s Inflammatory Bowel Disease Center between December 2005 and September 2007. Inclusion criteria included adults (at least 18 years of age) with IBD of greater than 1-month duration diagnosed by standard clinical, radiographic, endoscopic, and histopathological criteria. Subjects were enrolled and stratified into three groups: Group A included patients with IBD who were receiving combination treatment with anti-TNF therapy (either infliximab or adalimumab) and concomitant immunomodulator therapy. These patients were required to be on either 6-mercaptopurine (6-MP) at a dose of at least 1 mg/kg (or with therapeutic 6-thioguanine (6TG) metabolite levels) for a minimum of 3 months, or azathioprine at a dose of at least 2 mg/kg (or with therapeutic 6TG metabolite levels) for a minimum of 3 months, or methrotrexate (MTX) at a dose of at least 15 mg subcutaneously weekly for a minimum of 8 weeks. Subjects in Group A had to receive at least 1 dose of infliximab (5 mg/kg) or adalimumab (160 mg) before vaccination. Group B included patients with IBD who were not receiving any immunosuppressive therapy, not even oral or topical corticosteroids. These patients may have been taking oral or topical 5-aminosalicylates products, antibiotics, or probiotics. The control group, Group C, was independently recruited and was comprised of healthy volunteers, agematched to Group A. Inclusion in this group required that subjects had no chronic illness, and were not on any immunosuppressive agents, not even inhaled corticosteroids. © 2010 by the American College of Gastroenterology

Enrollment and clinical evaluations

Patients with IBD who presented to the outpatient CedarsSinai Medical Center IBD Center for clinic visits were invited to participate. Healthy control subjects included non-blood related family members of patients with IBD who accompanied them to clinic visits, and volunteers who responded to an institutional email invitation. At the baseline and at the 1-month follow-up visit, patients with IBD had a comprehensive medical history, physical exam, and disease activity assessment with the modified Harvey–Bradshaw Index for CD, or the modified Ulcerative Colitis Disease Activity Index for UC. Serum was obtained at baseline and 1 month for pneumococcal titers and C-reactive protein levels. Healthy control subjects had a brief medical history to ensure that subjects were eligible for participation. The study was approved by the Cedars-Sinai Medical Center institutional review board (#8823); all patients provided written informed consent before participation. Vaccination and follow-up

Pneumococcal vaccination was carried out with the PSV23 (Pneumovax, Merck, Whitehouse Station, NJ). The vaccine includes 23 purified capsular polysaccharide antigens of S. pneumoniae (serotypes 1, 2, 3, 4, 5,6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 20, 22F, 23F, and 33F). These antigens comprise at least 90% of the serotypes that cause invasive pneumococcal infection amongst children and adults in the United States of America. Subjects returned at 4 weeks for serum collection and assessment of adverse events, including worsening disease activity. Serological evaluation

Serum was collected at baseline (pre-vaccination) and 4 weeks after vaccination. These paired sera were tested for five antigens (6B, 9V, 14, 19F, and 23F) at the UCLA Center for Vaccine Research (Los Angeles Biomedical Research Institute, Torrance, CA, USA) using a third generation enzyme-linked immunosorbent assay as follows: briefly, 96-well microtiter plates were coated with serotype-specific polysaccharide in phosphate-buffered saline and incubated at 37 °C, then washed with phosphate-buffered saline-Tween 20. Reference sera or patient specimens were then mixed with 5 μg/ml pneumococcal C-polysaccharide and 10 μg/ml capsular polysaccharide for 30 min before being added to the plates. The plates were then incubated at room temperature, washed, and alkaline phosphatase-conjugated goat anti-human immunoglobulin G was added. After another incubation and washing, substrate (pnitrophenyl phosphate tab in Diethanolamine buffer pH 9.8) was added to the plates. After a final incubation, the reaction was stopped. Anti-pneumococcal antibody levels were then determined in each specimen by analysis of linear regression plots compared with the United States Food and Drug Administration reference serum (89SF-1) (prepared by the World Health Organization Pneumococcal Serology Reference Laboratories at the Institute of Child Health, University College London, London, England and the Department of Pathology The American Journal of GASTROENTEROLOGY

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recommended for adults with “chronic medical conditions,” including those receiving immunosuppressive medications (10). Patients with IBD meet at least one criterion (chronic medical condition), and often two (immunosuppression) for receipt of pneumococcal vaccination. Furthermore, some patients meet additional criteria for vaccination including co-morbid conditions or age ⭓ 65 years. Guidelines specific to the IBD population published in 2004 recommend that relevant vaccine guidelines should be followed, with the caveat that those vaccinated while immunosuppressed should be assessed for vaccine response whenever possible (11). However, despite these recommendations, pneumococcal immunization rates for patients with IBD may be less than 10%, as reported in a tertiary care setting (12). Few have evaluated immune responses to this or other vaccines in patients with IBD. In pediatric populations, immunosuppression is associated with lower responses to influenza vaccination (13,14). The objective of this study is to investigate the immune response to pneumococcal vaccination in patients with IBD with or without receipt of combination of anti-tumor necrosis factor-alpha (TNFα) therapy and immunosuppressive agents, relative to healthy, age-matched controls.

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at the University of Alabama at Birmingham, Birmingham, Alabama, USA) and expressed as μg immunoglobulin G antibody/ml. In addition, pre-vaccination serum was assayed for C-reactive protein as a marker of disease activity. Statistics

Immune responses to selected pneumococcal antigens were assessed qualitatively and quantitatively. Student’s t-test was used to assess for differences in mean antibody levels. Qualitative primary outcome measures included the proportion having twofold increase in geometric mean titer (GMT) for each of the five antibodies (6B, 9V, 14, 19F, and 23F), and the proportion achieving an absolute GMT ⭓ 1 μg/ml for each of the five antibodies. The primary analysis was determined a priori to compare Group A with Group B. Overall the primary vaccine response was defined as achieving both a twofold increase in GMT and a ⭓ 1 μg/ml post-vaccination GMT in the majority (three or more) of antibodies. Values below the level of detection (0.15 μg/ml) were assigned a value equal to half the limit of detection (0.08 μg/ml). To assess differential responses based on the level of the baseline titer, log by log plots of pre to post immunization antibody levels were constructed and evaluated. Reverse cumulative distribution curves were used to characterize the distribution of responses between the different study groups in pre and post immunization assessments. Based on estimates in the rheumatology literature for patients receiving combination methotrexate and TNF inhibitors (15,16), overall vaccine response was expected in 75, 70, and 35% for healthy controls, IBD subjects not on immunosuppressive therapy, and IBD subjects receiving immunosuppressive therapy, respectively. To achieve 80% power with a one-sided alpha of 0.05 for this pilot study, 20 patients per group were required. We expected a dropout rate of 20%, and therefore aimed to recruit 25 patients per group. The primary analysis was to compare response rates in IBD immunosuppressed (Group A) with healthy controls (Group C). A logistic regression model was performed to compare the IBD Groups A and B, accounting for potential confounders (age, sex, disease duration, and baseline C-reactive protein (CRP)).

RESULTS A total of 64 subjects participated in the study, including 45 patients with IBD and 19 healthy controls. In all, 20 patients with IBD in Group A were on anti-TNF therapy (infliximab (n = 18) or adalimumab (n = 2)), and on immunomodulator therapy (6-MP or azathioprine (n = 17), or MTX (n = 3)). All were on either infliximab 5 mg/kg every 8 weeks or adalimumab 40 mg every other week, except for three patients who were receiving infliximab at 10 mg/kg every 8 weeks. Group B consisted of 24 patients treated with oral or topical mesalamine and 1 patient treated with metronidazole. Demographic and clinical characteristics of patients and healthy volunteers are summarized in Table 1. The American Journal of GASTROENTEROLOGY

Table 1. Baseline characteristics Group A: IBD TNF/IM (n =20)

Group B: IBD ASA only (n =25)

Group C: healthy controls (n =19)

36.5 (22– 68)

40 (24 – 65)

37 (23 – 64)

75

56

53

Crohn’s

17 (85%)

13 (52%)

UC

2 (10%)

12 (48%)

IC

1 (5%)

0 (0%)

10 (1– 40)

10 (1– 38)

HBI (Crohn’s)

4 (0 –12)

4 (0 –14)

UCDAI (UC)

4 (3 – 5)

3 (1– 8)

C-reactive protein (g/100 ml)

0.18 (0.01–3.86)

0.34 (0.01–7.65)

0.15 (0.01–5.3)

Medications

IFX + 6-MP (n =16)

Mesalamine (n = 24)

N/A





Median age, years (range) Gender (% male)

Disease Type: n (%)

Disease duration in yrs (range)



Disease Severity

IFX + MTX (n =2) ADA + 6-MP (n =1) ADA + MTX (n =1) 6-MP dose, mg (range)

50 (25 –125)

6-MP duration, m (range)

21 (5 –168)

α-TNF duration, m (range)

12 (1–161)

ADA, adalimumab; ASA, aminosalicylates (no immunosuppression); CRP, C-reactive protein; HBI, Harvey–Bradshaw Index; IC, indeterminate colitis; IFX, infliximab; m, months; 6-MP, 6-mercaptopurine; MTX, methotrexate; TNF/IM = immunosuppressed with both a tumor necrosis factor-alpha blocker and immunomodulator; UC, ulcerative colitis; UCDAI, Ulcerative colitis disease activity index.

Age was similar in all groups, but Group A had a higher proportion of male subjects. In addition, Group A had a higher CD prevalence (85%) compared with Group B (52%) (P = 0.01). Groups A and B were similar in disease duration and baseline disease severity, estimated by Harvey Bradshaw Index for CD and Ulcerative Colitis Disease Activity Index for UC. Antibody titers to each of the five antigens (6B, 9V, 14, 19F, and 23F) were not different between the three groups before vaccination (not shown). Post-vaccination titers are shown in Figure 1. The combined pre-immunization titers are shown in Figure 2 for comparison. Post-vaccination titers were significantly lower in Group A as compared with Group B (P ≤ 0.01 for four out of five antigens) or Group C, (P ≤ 0.01 for all five antigens). There was no evidence for a differential response based VOLUME 105 | JANUARY 2010 www.amjgastro.com

2.5

2.5

2.0

2.0

1.5

1.5

1.0

1.0

0.5

0.5

0.0

0.0

–0.5

– 0.5

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–1.5 A

B

A

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–1.5

–1.5 A

B

C

14F

–1.5 A

C

B

A

C

B

19F

9V

C

23F

Figure 1. Distribution of post-vaccination pneumococcal antibody responses for each of five serotypes, by study group. Group A = inflammatory bowel disease (IBD), on combination tumor necrosis factor (TNF) blockers and immunomodulator; Group B = IBD, no immunosuppression; Group C = healthy, age-matched controls; y axis = log post-vaccination titers.

Proportion

Reverse cumulative distribution Black = baseline Red = IBD with IS Blue = IBD no IS Green = healthy controls

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Proportion

Pneumovax response titers

0

10

20

30

40

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

50

2

4

0

50

100

150

14F antibody titer

200

250

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

20

40

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80

100 120 140 160

19F antibody titer

6

8

10

12

14

16

18

9V antibody titer

Proportion

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Proportion

Proportion

6B antibody titer 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

10

20

30

40

50

60

23F antibody titer

Figure 2. Reverse cumulative distribution curves showing responses as the proportion of patients with a given post-vaccination titer for each serotype. Black = Pre-immunization titers for all three groups (no difference by group); red = Group A, inflammatory bowel disease (IBD) on tumor necrosis factor blockers and immunomodulator; blue = Group B, IBD not immunosuppressed; green = Group C, healthy controls; y axis = proportion of patients; x axis = post-vaccination titers.

upon pre-existing antibody levels (not shown). The immune response is best shown in the reverse distribution curves for each of the three groups and each serotype (Figure 2). For antigens 6B and 23F, there is overlap in the distributions of response between the IBD populations (Groups A and B) and the differences between Group A and Group C were most pronounced only for the highest levels of response. In contrast, across the distribution of antibody responses to 9V, 14F, and 19F, the titers were lowest in Group A as compared with both Groups B and C. © 2010 by the American College of Gastroenterology

Relative to Groups B and C for all endpoints and for each serotype, Group A had the lowest responses. This included lower GMTs, lower proportions of patients achieving ⭓ twofold increase in GMT (not shown), and lower proportions achieving a GMT ⭓ 1 mcg/ml (Figure 3). There were no significant or near-significant differences in responses between Group B and Group C for any of the five antigens. Among subjects with IBD, Group A subjects were least likely to achieve a GMT ⭓ 1 mcg/ ml for four out of the five antigens (6B, 9V, 14, 19F; P < 0.02 for each antigen) relative to Group B. The proportion of The American Journal of GASTROENTEROLOGY

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IBD TNF/IM

Proportion

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∗∗ 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0



IBD ASA ∗∗

∗Ptwofold increase and GMT ⭓ 1 mcg/ml (overall vaccine response), was also lower than Groups B and C for each of the five antigens (Figure 4). Logistic regression was used to assess response while adjusting for potential confounders (age, gender, disease duration, and baseline CRP). The odds of overall vaccine response were 4.6 times higher in Group B than Group A (odds ratio 4.6, 95% confidence interval 1.1–23.4). However, when disease type (UC or CD) was added as a covariate to the regression model, the odds of response were not significantly different between Groups A and B. Differences in vaccine response were also assessed by baseline Harvey Bradshaw Index, Ulcerative Colitis Disease Activity Index, and C-reactive protein scores; no significant differences in vaccine responses were identified based on baseline disease activity (data not shown).

DISCUSSION We demonstrate that patients with CD who receive antiTNF therapy and an immunomodulator have diminished pneumococcal antibody responses as compared with nonimmunosuppressed subjects with IBD and healthy controls. This difference was greatest for serotypes 6B, 9V, 14F, and 19F. Those with IBD, but not receiving immunosuppressive therapy, had responses similar to healthy control subjects. Furthermore, subjects with IBD on anti-TNF therapy and an immunomodulator had an overall vaccine response rate of The American Journal of GASTROENTEROLOGY

only 45%, compared with IBD patients not on immunosuppression (80%) and healthy controls (84%). Even after adjusting for age, sex, disease duration, and baseline disease activity, the odds of response were significantly impaired in those with IBD on combination immunosuppression as compared with those who were not. These findings need to be understood in the context of studies of response to PSV-23 in patients with rheumatological conditions who receive anti-TNF therapy and methotrexate (15–19). In a randomized placebo-controlled trial, Kaine et al. (19) showed that those treated with adalimumab monotherapy had response rates to PSV-23 similar to those treated with placebo. In another placebo-controlled trial, no difference was found in the infliximab plus MTX vs. the placebo plus MTX groups, but both groups had lower than normal responses (16). These studies taken together suggest that MTX alone or in combination with a TNF blocker impairs response to PSV-23, but monotherapy with a TNF blocker may not diminish the response. However, we are unable to determine from our study whether diminished responses are because of the anti-TNF agent, the immunomodulator, or the combination thereof. In children with IBD receiving anti-TNF therapy, diminished responses are seen after immunization with the influenza vaccine (13,14). Mamula et al. (13) compared 51 children with IBD and 29 healthy controls in the 2002–2004 influenza seasons, and found that responses were less effective for one out of three antigens among those with IBD as compared with controls, and those on anti-TNF medications in combination with immunomodulators showed impaired responses to two out of three antigens. In an uncontrolled study, Lu et al. (14) assessed response rates in 146 consecutive children with IBD in the 2007 influenza season, and found that vaccination responses were similar among all those with IBD, regardless of immunosuppressive status. However, sub-analysis revealed impaired seroprotection against strain B specifically in those receiving anti-TNF medications. Neither study was powered to address the question as to whether impaired responses were due to anti-TNF therapy specifically or only when combined with an immunomodulator. Thus, it is unclear whether the impaired effects seen in anti-TNF-treated patients are due to individual drugs or drug classes, or the combined effects of immunosuppression in these children. Several questions remain unanswered. We do not know the long-term antibody response rates to pneumococcal vaccination in IBD patients; titers have been shown to wane over time in other immunosuppressed populations, such as renal transplant recipients (20). Guidelines for immunization in the immunosuppressed IBD population suggest checking for titers if possible when patients are vaccinated; it is unclear, though, which of the 23 antigens should be assessed, what levels of titers are to be considered protective, and whether and when to revaccinate patients with low titers. Our data also suggest that there may be differences in response between serotypes. We assessed only 5 out of 23 serotypes, but these 5 serotypes are included among the 7 most common serotypes responsible for about 80% of invasive pneumococcal disease in several United States pediatric VOLUME 105 | JANUARY 2010 www.amjgastro.com

populations (21,22). In addition to serotypes 9V and 19F (pediatric types), our study identified serotype 14 (more commonly an adult type), as having impaired responses among immunosuppressed subjects. Serotype 14, in particular, caused 29–42% of all invasive pneumococcal infections in two United States pediatric cohorts (21,23). Our finding that serotype 14 exhibited large differences in response among immunosuppressed subjects suggests a need to study more effective immunization strategies for these patients, including consideration for the 7-valent conjugate vaccine which may show improved responses in adults who failed to mount a response to the PSV-23 (24). Our study has several limitations. We had relatively small study group sizes; however we still found significant differences. The “combination therapy” group was defined by medication classes, not individual drugs, thereby obviating the ability to discriminate differences between different TNF blockers, or between 6-MP and MTX. Finally, subjects included those with either CD or UC, which likely have different underlying immune defects. When disease type was added to the logistic regression model, the differences in response between Groups A and B were not significant. This reflects the fact that TNF blockers were not yet approved for use in UC during most of the study duration, and therefore 85% of Group A had CD, whereas Group B was comprised of approximately equal numbers of CD and UC patients. However, the finding that disease type influenced the multivariate model may limit the generalizability of our study to CD alone, as only CD patients showed diminished response rates, whereas UC patients did not. Future studies might therefore focus on one specific disease or phenotype to eliminate this potential confounding effect. Despite these limitations, we have demonstrated sub-optimal response to pneumococcal vaccination in patients with IBD, who are on combination immunosuppressive therapy. Current guidelines for IBD patients recommend pneumococcal vaccination in adult patients according to CDC recommendations for immunosuppressed individuals (11). Given the high but unpredictable likelihood of immunosuppression in patients with IBD, patients should be evaluated for immunization status and consideration of vaccinations where appropriate before starting immunosuppressive medications (1). In particular, pneumococcal vaccination should be considered given the potential for impaired response once immunosuppression is initiated. ACKNOWLEDGMENTS

The authors are grateful to Swei-Jiu Chang for laboratory support and Susan Partridge for regulatory support. CONFLICT OF INTEREST

Guarantor of the article: Gil Y. Melmed, MD, MS. Specific author contributions: Study design: Gil Y. Melmed, Robert W. Frenck, Andrew F. Ippoliti, Konstantinos A. Papadakis, Joel Ward, Stephan R. Targan, and Eric A. Vasiliauskas; procured funding: Gil Y. Melmed, Robert W. Frenck, and © 2010 by the American College of Gastroenterology

Eric A. Vasiliauskas; subject recruitment, vaccination and study procedures: Gil Y. Melmed, Patricio Ibanez, Peter Simpson, and Cristina Barolet-Garcia; data analysis: Gil Y. Melmed, Nik Agarwal, Robert W. Frenck, Andrew F. Ippoliti, Konstantinos A. Papadakis, Joel Ward, Stephan R. Targan, and Eric A. Vasiliauskas; manuscript preparation: Gil Y. Melmed, Nik Agarwal, and Robert W. Frenck; manuscript review: all authors. Financial support: Received from the Jackson Foundation and the Marcled Foundation. Potential competing interests: Gil Y Melmed, MD, MS: Speakers’ Bureau (Abbott Labs, Abbott Park, IL), Advisory Board (UCB), research support (Centocor, Horsham, PA); these companies produce anti-TNF medications. ClinicalTrials.gov identifier: NCT00829595.

Study Highlights WHAT IS CURRENT KNOWLEDGE Patients with inflammatory bowel disease are often prescribed immunosuppressive medications. Vaccination against pneumococcal disease is indicated in people on immunosuppressive medications. Vaccine response to influenza immunization may be impaired in children with inflammatory bowel disease (IBD) on immunosuppressive therapy. WHAT IS NEW HERE Patients with IBD not on immunosuppressive therapy have normal response to pneumococcal vaccination. Patients with inflammatory bowel disease on combination anti-tumor necrosis factor and immunomodulator therapy have impaired response to pneumococcal vaccination.

3 3 3 3 3

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