ABSTRACT
Background: 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 lower serologic response after two COVID-19 vaccine doses. Data regarding a 3rd vaccine are scarce. Method(s): Aim: To assess immune responses to, and safety of 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 prospectively evaluated after the 2nd and 3rd vaccine doses. Evaluation included: Disease activity, anti-spike (S) and nucleocapsid (N), anti-TNFalpha drug levels and adverse events (AE) Results: 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. Among patients with IBD: 51 and 74 (40.8%, 59.2%)) were treated or not with anti-TNFalpha, respectively. 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 rate in IBD and HC was comparable. No serious AE detected. There was a significant increase in anti-S levels one month after compared to pre 3rd vaccine dose in all participants. 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. Serologic response did not correlate with anti-TNFalpha drug levels, antibodies or interval between drug and vaccine administration. During extended follow-up post 3rd dose, we found that lower serologic response predicts infection over time. Conclusion(s): This prospective study shows that a 3rd dose of BNT162b2 vaccine is effective and safe in patients with IBD. Furthermore, 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, specifically due to the fact that higher serologic response predicts better defense from infection.
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.
ABSTRACT
Background: While vaccines against COVID-19 are effective in healthy individuals, we reported significantly lower serologic responses to BNT162b2 in patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF) α agents. As this was apparent already 4 weeks post vaccination, vaccine longevity is concerning. Aim: to assess long-term serologic responses to BNT162b2 in patients with IBD stratified according to medical treatment. Methods: A prospective, observational multi-center Israeli study. Patients with IBD (anti-TNFα treated versus non-anti-TNFα treated) and healthy controls (HC) were followed from before the 1st BNT162b2 dose until 6 months after vaccination. COVID-19 spike (S) and nucleocapsid (N) antibodies (Abs) concentrations were analyzed by ELISA, followed by neutralization studies. Specific anti-receptor binding domain (RBD) memory Bcells response, serologic responses against variants of concern (VOCs), Beta, Gamma and Delta, immunoglobulin levels and lymphocyte cell subsets were evaluated as well. Safety was assessed using questionnaires, clinical and laboratory data. Results: Of 193 subjects, 130 had IBD (45 and 85 in the anti-TNFa and non-anti-TNFα groups, respectively), 63 HC. Serologic response assessed 176 (median) days (IQR 166-186) and compared to 4 weeks after 1st dose significantly declined in all three groups, but was lowest in the anti- TNFα group: 6 months anti-S Abs titer geometric means: 193 (95%CI: 128-292), 703 (520- 951), and 1253 (1023-1534) in anti-TNFα, non- anti-TNFα and HC groups, respectively, p<0.001, Figure 1. This was further supported by neutralization and inhibition studies. Importantly, significantly decreased memory B-cell response towards RBD was detected only in the anti-TNFα group, with the most significant reduction in response to Beta VOC (p<0.0008 and p<0.0001, vs. non-anti-TNFα and HC, respectively). Older age was an additional predictor of lower serologic response. Immunoglobulin levels and lymphocyte cell subsets were comparable between the study groups. Infection rate reflected by anti-N Abs was ~1% in all groups. Safety was comparable in all groups. Conclusion: The 6-months serologic response to BNT162b2 vaccine, evaluated prospectively, decreased in all subjects, most prominently in patients with IBD treated with anti-TNFα. Importantly, the latter also had the sharpest decline in serologies, the lowest functional activity and lowest RBD specific memory B-cells. Older age is an additional predictor of decreased serologic response. Altogether, waning of COVID-19 serologic and functional response over 6 months, specifically in patients with IBD treated with anti-TNFα, supports the need for an early third vaccine dose. (Figure Presented)
ABSTRACT
Background: While vaccines against COVID-19 are effective in healthy individuals, we reported significantly lower serologic responses to BNT162b2 in patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF) α agents. As this was apparent already, 4 weeks post vaccination, vaccine longevity is concerning. Aim: to assess long-term serologic responses to BNT162b2 in patients with IBD stratified according to medical treatment. Methods: A prospective, observational multi-center Israeli study. Patients with IBD (anti-TNFα treated versus non-anti-TNFα treated) and healthy controls (HC) were followed from before the, 1st BNT162b2 dose until, 6 months after vaccination. COVID-19 spike (S) and nucleocapsid (N) antibodies (Abs) concentrations were analyzed by ELISA, followed by neutralization studies. Specific anti-receptor binding domain (RBD) memory B-cells response, serologic responses against variants of concern (VOCs), Beta, Gamma and Delta, immunoglobulin levels and lymphocyte cell subsets were evaluated as well. Safety was assessed using questionnaires, clinical and laboratory data. Results: Of, 193 subjects, 130 had IBD (45 and, 85 in the anti-TNFα and non-anti-TNFα groups, respectively), 63 HC. Serologic response assessed, 176 (median) days (IQR, 166-186) and compared to, 4 weeks after, 1st dose significantly declined in all three groups, but was lowest in the anti- TNFα group:, 6 months anti-S Abs titer geometric means:, 193 (95%CI:, 128-292), 703 (520-951), and, 1253 (1023-1534) in anti-TNFα, nonanti- TNFα and HC groups, respectively, p<0.001, Figure, 1. This was further supported by neutralization and inhibition studies. Importantly, significantly decreased memory B-cell response towards RBD was detected only in the anti-TNFα group, with the most significant reduction in response to Beta VOC (p<0.0008 and p<0.0001, vs. non-anti-TNFα and HC, respectively). Older age was an additional predictor of lower serologic response. Immunoglobulin levels and lymphocyte cell subsets were comparable between the study groups. Infection rate reflected by anti-N Abs was ∼1% in all groups. Safety was comparable in all groups. Conclusion: The, 6-months serologic response to BNT162b2 vaccine, evaluated prospectively, decreased in all subjects, most prominently in patients with IBD treated with anti-TNFα. Importantly, the latter also had the sharpest decline in serologies, the lowest functional activity and lowest RBD specific memory B-cells. Older age is an additional predictor of decreased serologic response. Altogether, waning of COVID- 19 serologic and functional response over, 6 months, specifically in patients with IBD treated with anti-TNFα, supports the need for an early third vaccine dose. (Figure Presented).