Serologic Response and Safety after Third Dose of the Covid-19 Bnt162b2 Vaccine in Patients with Inflammatory Bowel Diseases

ABSTRACT

Introduction: Vaccines are pivotal for control of the ongoing coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF)-alpha have significantly lower serologic response after two COVID-19 vaccine doses. Data regarding a 3rd vaccine are scarce. Aims & Methods: We conducted a prospective observational multi-center Israeli study aiming to assess immune responses to, and safety of mRNAbased COVID-19 vaccines in patients with IBD, stratified according to therapy, and compared to healthy controls (HC). Subjects were recruited before the 1st vaccine (BNT162b2, Pfizer) and were prospectively evaluated one and six months after the 2nd vaccine dose, as well as one month after the 3rd vaccine dose. Disease activity was assessed using accepted clinical scores and biomarkers. COVID-19 spike (S) and nucleocapsid (N) antibodies concentrations were analyzed using ELISA. Anti- TNFalpha drug levels were measured using ELISA. Adverse events (AE) were registered. Result(s) Of 198 subjects having the 3rd vaccine dose, 125 had IBD average age 39.1+/-14.8 years;40.8% females;82- Crohn's disease (CD), 33 ulcerative colitis (UC), 6 pouch, 3 IBD-U. There were 73 HC average age 39.4+/-12.5 years, 69.9% females. IBD treatment 51 (40.8%) patients were treated with anti-TNFalpha monotherapy 35, concomitant immunomodulators 7, 5ASA 5, steroids 3 and ustekinumab 1. In 74 non-TNFalpha treated patients 5ASA were received by 19, vedolizumab 18, ustekinumab 9, immunomodulators 2, steroids 2, tofacitinib 4, no medication 19 patients. The 3rd vaccine dose was administered 201 (187-216) (median [IQR]) days after the 2nddose and 267 (250-278) days after the 1st dose. A month after the 3rd vaccine dose IBD activity was comparable in all patients regardless of treatment, and no increase in C-reactive protein or white blood cells was observed. Higher but not significant AE rate was registered in all subjects after the 3rd compared to 2nd vaccine dose (81% vs. 76%, respectively). AE proportion in IBD and HC was comparable, mostly local pain. No serious AE detected. Significant increase in anti-S levels one month after compared to pre 3rd vaccine dose was observed in IBD and HC. Furthermore, increase was 2-3 folds higher than that observed one month after the 2nd dose. Importantly, patients treated with anti-TNFalpha compared to non-anti-TNFalpha treated had significantly lower responses 9219 (6347-13390) vs 16955 (13721- 20951) (GMC (95%CI)), p<0.05. Anti-N levels reflecting infection were positive in only 4 subjects- all with IBD, 2 treated with anti-TNFalpha, 1 ustekinumab, 1 untreated. Serologic response did not correlate with anti-TNFalpha drug levels, antibodies or interval between drug and vaccine administration (p=0.616, p=0.697 and p=0.6, respectively). Conclusion(s) In this prospective study we show that a 3rd dose of BNT162b2 vaccine is effective and safe in patients with IBD, however, patients treated with anti-TNFalpha had significantly lower serologic responses compared to anti-TNFalpha untreated ones. Lack of correlation between anti-TNFalpha drug levels and immune responses suggests there is no need to modify vaccination timing relatively to anti-TNFalpha administration. The significantly steeper increase in anti-S levels between 2nd and 3rd doses, suggests the 3rd dose is crucial in anti-TNFalpha treated patients. Their significantly lower anti-S levels compared to anti-TNFalpha untreated ones may suggest the advantage of a 4th vaccine dose.