Introduction

Pneumococcal vaccination is essential in IBD patients. However, its efficacy in patients on immunosuppressive or anti-TNF therapy is much lower than in the normal population (45% vs 80%). Vaccine regimen recommendations vary according to the degree of immunodepression. The aim of our study was to identify an optimal vaccination strategy for immunocompromised IBD patients treated with anti-TNF, vedolizumab and/or IS.

Aims & Methods

This is a prospective, multicenter, randomized study comparing two vaccine regimens: intensified vaccine strategy (Prevenar13®/Prevenar13®/PSV-23® (or Pneumovax as a replacement for PSV-23) vs. normal strategy (Prevenar13®/PSV-23® (or Pneumovax as a replacement for PSV-23), (randomization 1: 1) on vaccine immunogenicity measured by antibody titer against at least 9 of the 13 pneumococcal serotypes contained in Prevenar13®. Any patient with confirmed IBD under biotherapy (anti TNF with or without immunosuppressive drugs or Vedolizumab) and in clinical remission (HBI <4 for CD and partial Mayo Score <3 for UC) was included. Vaccination and vaccine monitoring were carried out by the vaccination center of each center, with adverse events reported at each visit (8 for 36 months of follow-up), and ELISA and OPA serotype assays systematically collected and clinical activity was reported by the gastroenterologist at the same time. Correlate of protection in adults using serology testing was classically defined as at least 9 out of 13. Serotypes > 1µg/mL. For functional testing of antibodies using the Opsonophagocytic assays, we apply the well-defined 4 times increase of titer between pre and post-vaccination against at least 70% of serotypes. ClinicalTrials.gov Identifier: NCT02255227

Results

51 patients in the normal vaccination arm and 53 in the intensified vaccination arm were included (mean age: 42.9 years, male: 63%, CD: 68%, active smoking: 21%, duration of IBD: 10.2 years, 98% IBD inactive). Around 88% of patients were under anti-TNF monotherapy (28% on combotherapy) and 12% under vedolizumab. Serology criteria for good responders at M5 were 57.5% for the intensified regimen vs 25.6% for the standard regimen (RR: 2.25 (1.26;4.00), p = 0.003). For OPA correlate of protection, vaccine response was significantly greater in the intensified arm at all-time points: M5 (96% vs. 89%), M12 (76 vs. 58%) and M36 (68% vs. 36.8%). In multivariate analysis, two factors reduced vaccine response: anti-TNF use (RR: 6.84; CI95: 1.01-46.1; p=0.048) and CD type (RR: 9.48; CI95: 2.74-32.8; p:0.0004). The tolerability of the vaccine regimens was comparable throughout follow-up. In terms of IBD activity, percentage of clinical relapse was similar during follow-up (16.8% under the intensified regimen versus 25% under the normal regimen (p:NS).

Conclusion

In IBD on biotherapy and/or IS, the intensified pneumococcal vaccine regimen (2 injections of Prevenar followed by one of Pneumo 23) is significantly more immunogenic than a standard regimen, especially when using functional correlate of protection. The duration of the response is also greater in this intensified arm.

Introduction

Treatment goals in inflammatory bowel disease (IBD) have evolved beyond symptom control to include mucosal healing, prevention of disease-related complications, improvement of health-related quality of life, and reduction of long-term disability, as outlined by the STRIDE II initiative¹. Despite significant progress in the development of advanced therapies (ADTs), up to 50% of IBD patients fail to respond to currently available treatments, underscoring the urgent need for new therapies, which are investigated in randomized clinical trials (RCTs). However, stringent eligibility criteria in RCTs limit the inclusion of real-world IBD patients, potentially compromising the generalizability of trial findings to daily clinical practice.

Aims & Methods

The aim of this study was to evaluate the proportion of real-life IBD patients who would be eligible for ongoing RCTs and to assess the representativeness of this population. Moreover, we aimed to identify the most frequently unmet eligibility criteria leading to patient exclusion and to characterize the clinical profiles that differentiate eligible from ineligible patients.
This prospective, observational, multicenter study was conducted between October 2023 and October 2024 at 2 tertiary IBD referral centers: the Fondazione Policlinico Universitario “A. Gemelli” in Rome, Italy, and the Crohn’s & Colitis Center at the University of Miami, USA. Consecutive patients with IBD indicated for a new ADT were enrolled. Each patient was systematically screened for inclusion and exclusion criteria across all actively recruiting phase 2b and 3 RCTs available at each center at the time of evaluation (6 RCTs in Rome: 4 UC and 2 CD; 5 RCTs in Miami: 3 UC and 2 CD).

Results

A total of 166 IBD patients (69 UC and 97 CD) were enrolled, with 129 patients from the Italian cohort and 37 from the American cohort. Among UC patients, only 16 (23.2%) met the eligibility criteria for at least 1 RCT, whereas 53 (76.8%) were deemed ineligible (p<0.001). In the CD group, just 10 patients (10.3%) were eligible for at least 1 RCT, compared to 87 (89.7%) who were not (p<0.001). The most common reasons for ineligibility among UC patients included: Modified Mayo score not within the required range of 5–9 (50.7%), absence of bowel urgency (63.8%), Mayo Endoscopic Subscore <2 (39.1%), failure to comply with ADT washout requirements (56.5%), insufficient number of prior ADT failures (39.0%), and recent use of topical 5-ASA or steroids within 4 weeks prior to screening (62.3%).
In CD patients, the most frequently unmet criterion was a CDAI between 220 and 450 (92.8%), followed by insufficiently liquid stool frequency (≥4 very soft or liquid stools/day; 75.3%), SES-CD<6 (39.2%), and the presence of CD-related complications such as strictures or fistulas (13.1%).

Conclusion

The majority of real-life IBD patients, particularly those with CD, are ineligible for participation in current RCTs—primarily due to relatively mild disease activity or ongoing need for concomitant therapies that are not permitted by trial protocols. Importantly, many real-world CD patients initiate new ADTs based on radiologic signs of disease activity, the presence of disease complications, or as prophylaxis for post-surgical recurrence, rather than clinical activity scores alone. Similarly, UC patients may require ADTs even in the context of corticosteroid dependence and low-grade disease activity. These findings underscore the need to revisit and broaden eligibility criteria in future RCTs to ensure greater external validity and alignment with the heterogeneity of real-life IBD population.

References

1. Turner D, Ricciuto A, Lewis A, D'Amico F, Dhaliwal J, Griffiths AM, Bettenworth D, Sandborn WJ, Sands BE, Reinisch W, Schölmerich J, Bemelman W, Danese S, Mary JY, Rubin D, Colombel JF, Peyrin-Biroulet L, Dotan I, Abreu MT, Dignass A; International Organization for the Study of IBD. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology. 2021 Apr;160(5):1570-1583. doi: 10.1053/j.gastro.2020.12.031. Epub 2021 Feb 19. PMID: 33359090.