key: cord-0295321-cz57n5ol authors: Edelman-Klapper, H.; Zittan, E.; Bar-Gil Shitrit, A.; Rabinowitz, K. M.; Goren, I.; Avni-Biron, I.; Ollech, J. E. O. E.; Lichtenstein, L.; Banai-Eran, H.; Yanai, H.; Snir, Y.; Pauker, M. H.; Friedenberg, A.; Levy-Barda, A.; Segal, A.; Broitman, Y.; Maoz, E.; Ovadia, B.; Aharoni Golan, M. A. G.; Shachar, E.; Ben-Horin, S.; Perets, T.-T.; Eliakim, R.; Goren, S.; Navon, M.; Krugliak, N.; Werbner, M.; Alter, J.; Dessau, M.; Gal-Tanamy, M.; Freund, N. M.; Cohen, D.; Dotan, I. title: Decreased Immune Response to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases Treated with Anti TNFα date: 2021-08-28 journal: nan DOI: 10.1101/2021.08.22.21262263 sha: 528ec55375e0970124975b5e1ece2d39dc5c980f doc_id: 295321 cord_uid: cz57n5ol Background: Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF) biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear. Aim: to assess immune responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC). Methods: Prospective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike (S) antibodies levels and functional activity, anti-TNF levels and adverse events (AEs) were detected longitudinaly. Results: Overall 258 subjects: 185 IBD (67 treated with anti-TNF), and 73 HC. After the first vaccine dose all HC were seropositive, while some patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-S levels were significantly lower in anti-TNF treated compared to untreated patients, and HC (p<0.001; p<0.001, respectively). Neutralizing and inhibitory functions were both lower in anti-TNF treated compared to untreated patients, and HC (p<0.03; p<0.0001, respectively). Anti-TNF drug levels and vaccine responses did not affect anti-S levels. Infection rate (~2%) and AEs were comparable in all groups. IBD activity did not change in response to BNT162b2. Conclusions: In this prospective study in patients with IBD stratified according to treatment all patients mounted an immune response to two doses of BNT162b2. However, its magnitude was significantly lower in patients treated with anti-TNF, regardless of administration timing and drug levels. Vaccine was safe. As vaccine immune response longevity in this group may be limited, vaccine booster dose should be considered. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) resulted in a worldwide pandemic 1 . To face the immense morbidity and mortality burden, accelerated vaccine development programs and mass vaccination campaigns were conducted. Vaccine studies included healthy adults or those with stable chronic diseases 2,3 . Patients with inflammatory bowel diseases (IBD), both Crohn's disease (CD) and ulcerative colitis (UC) were excluded. These patients are often treated with immunomodulators and/or biologic therapy such as anti-tumor necrosis factor (TNF) α, potentially associated with an increased risk of infection 4-6 . While guidelines recommend vaccination per standard immunization schedules 4,7,8 , patients' ability to mount an adequate immune response to certain vaccines or infections is doubted 6, [9] [10] [11] [12] [13] [14] [15] [16] [17] . This was even less clear for the new mRNA-based vaccines against SARS-CoV-2. Concerns regarding adverse events (AEs), including IBD exacerbation, further underscored the need for vaccine responses assessment in these patients. A massive vaccination campaign against COVID-19 started in Israel on December 19, 2020, with mRNA-based COVID-19 vaccine (BNT162b2, Pfizer/BioNTech), administered in two doses three weeks apart 18 . We conducted a prospective multi-center Israeli study to assess immune responses to BNT162b2 in patients with IBD stratified according to therapy, compared to healthy controls (HC). . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. A prospective, observational, multi-center study was conducted to assess immune responses to the mRNA-based COVID-19 vaccine BNT162b2, their dynamics, predictors of response and safety, in patients with IBD compared to HC. A call for patient referral was distributed to all Israeli gastroenterologists and patients with IBD on December 28, 2020. Patients aged≥18 years were recruited. IBD diagnosis was defined by accepted criteria. HC group included volunteers (healthcare professionals and their relatives) without known gastrointestinal diseases. Patients with past COVID-19 infection proved by SARS-CoV-2 polymerase-chain-reaction test and pregnant women were excluded. Patients with IBD were stratified at baseline into those treated with anti-TNFα, or those with any other IBD treatment or untreated. All participants received two 30µg BNT162b2 vaccine doses intramuscularly, administered 21-28 days apart, as per manufacturers' recommendations. MOH number: 2020-12-30_009617. All participants signed an informed consent form before any study procedure. Eligible participants were evaluated at 4-time points: (i) before the first vaccine dose -V1, (ii) 14-21 days after the first and before the second vaccine dose -V2, (iii) phone call a week after the second vaccine dose to report adverse events (AEs) and (iv) 21-35 days after the second vaccine dose -V3, (see Figure 1A ). At enrolment, patients were assessed for baseline demographic and IBD characteristics. Specifically, medical treatment, duration and dose were registered, including date of biologics injections/infusions as well as interval between biologics administration and vaccination. Each visit clinical evaluation was . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.22.21262263 doi: medRxiv preprint 10 performed using IBD specific questionnaires -Harvey-Bradshaw Index (HBI) 19 , Simple Clinical Colitis Activity Index (SCCAI) 20 and Pouch Disease Activity Index (PDAI) 21 for CD, UC and patients with an ileal pouch, respectively. Post-vaccination AEs 22 were evaluated by standard questionnaires , specifically referring to pain or swelling at injection site, fever, headache, shivering, nausea, dizziness, fatigue, muscle soreness, joints pain, allergic reaction, other AEs 2,22 , and severe AEs (SAEs, anaphylactic reaction, hospitalization, death). Safety measures also included assessment of IBD clinical activity as well as inflammatory biomarkers. Laboratory tests were performed at V1, V2 and V3 including complete blood count, Creactive protein (CRP), COVID-19 serology and functional neutralization and inhibition assays. Anti-TNFα drug levels and anti-TNFα antibodies were measured. Serum was separated from collected blood, aliquoted and stored at -80°C until further analyses. The primary endpoint was seropositivity rate and magnitude of the immune response (levels of binding IgG antibodies to SARS-CoV-2 spike (S) antigen and neutralizing and inhibitory antibodies functionality) following BNT162b2 in patients with IBD with or without anti-TNFα treatment, or HC, at V3. Secondary endpoints were immune response dynamics induced after the first and second vaccine doses; and AEs, specifically local and systemic reactions and IBD exacerbation. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. Anti-TNFα drug and anti-drug antibody levels were assessed for adalimumab (ADA and ADA-Abs) and infliximab (IFX and IFX-Abs) using Lisa-Tracker ELISA in accordance with manufacturer's instructions (Theradiag, Beaubourg, France). Range for drug levels: 0.3-20 µg/mL. Range for Abs levels: 10-160 ng/mL and 10-200 ng/mL for ADA-Abs and IFX-Abs, respectively. was performed as described 25 using RBD-serum mix incubated with ACE2 coated plates. Inhibition percentage was calculated for each well by the formula: ) × 100. Negative results, indicating no inhibition, were set as 0% inhibition. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; 12 polyethylenimine (PEI). Twenty-four hours post-transfection, the cells were infected with Gcomplemented VSV GFP ∆G (*G-VSV GFP ∆G) at a multiplicity of infection (MOI) of 3. Following 6 hours incubation to allow internalization, cells were extensively washed 4 times with fresh medium to eliminate excess of *G-VSV GFP ∆G. After additional 30 hours of incubation the culture's supernatant containing pseudotyped VSV (S∆19-VSV GFP ∆G) was centrifuged (300×g, 5 min, 4 °C) to avoid cell debris, filtered on 0.2 µm filter cup, and stored in 1 mL aliquots at −80 °C until use. Titers were between 0.5×10 6 to 1.5×10 6 pseudovirus/mL. HEK-293 cells stably expressing human ACE2 were cultured in DMEM (Biological Industries, Beit Haemek, Israel) supplemented in 10% FBS, 1% L-glutamine, and 1% penicillin streptavidin. These cells were seeded into 100 μg/mL poly-D-lysine-coated 96-well plates (Greiner-Bio-one, Kremsmünster, Austria) at an initial density of 0.5×10 5 cells per well. The following day concentrated pseudo-particles were incubated with sera samples at dilution of 1:200 for 1 hour at 37°C and then added to the 96-well pre-seeded plates. After 24 h, medium was replaced with fresh DMEM excluding phenol red and plates were imaged by the IncuCyte ZOOM system (Essen BioScience, Michigan, USA). Cells were imaged with a 10X objective using the default IncuCyte software settings, which were used to calculate number of GFP-positive cells from four 488 nm-channel images in each well (data were collected in triplicate). The number of GFP-positive cells was normalized and converted to a neutralization percentage in each sample, compared to the average of control samples. Data were collected in secured web-based platform (REDCap) and analyzed using SPSS version 27 (IBM, New York, United States). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.22.21262263 doi: medRxiv preprint 13 All tests were two tailed and p<0.05 was considered significant. Anti-S antibody concentrations are expressed as geometric mean concentrations (GMCs) with 95% confidence intervals (CI). Other continuous data are reported as median and IQR unless otherwise stated. Counts and percentages were employed for categorical variables. Univariate analyses, using independent samples t-test, one-way analysis of variance (ANOVA) with Bonferroni multiple-comparison correction or Kruskal-Wallis nonparametric test of ln-transformed anti-S antibody concentration and Spearman's rank correlation coefficients, were used to identify demographic, disease, vaccine, and treatment-related factors associated with anti-S levels. We used multivariate stepwise linear regression models to identify factors independently associated with ln anti-S levels. Standardized Beta coefficients were obtained from linear regression. Subjects were recruited in IBD centers located in central (Rabin); Northern (Emek); Eastern and Jerusalem (Shaare Zedek); and Southern (Soroka) Israel, between December 29 th , 2020, and May 5 th , 2021. Participants' baseline characteristics are presented in Table 1 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. Table 1 ). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.22.21262263 doi: medRxiv preprint 15 (no subject< 50 AU/mL), 14 patients with IBD were still seronegative, of whom 6 were treated and 8 untreated with anti-TNFα ( Figure 2D ). We next assessed neutralizing antibodies, considered critical for patients survival and virus control 26 . Using competitive ELISA we show that while at V1 inhibition activity was low and comparable between the groups (Figure 3 , A-C, Supplementary Table 3) , at V2 the anti-TNFα treated group had significantly lower ability to inhibit RBD:ACE2 binding compared to HC (p<0.05). This was even more prominent at V3 (p<0.001). Notably, significant differences in inhibition activity were apparent between patients with IBD, regardless of treatment regimen, and HC ( Figure 3C ). We observed a positive correlation between anti-S titers and inhibition activity in V2, which increased even further in V3, suggesting that after two vaccine doses the proportion of anti-S IgG antibodies with inhibitory function increases Finally, we assessed vaccine functional activity using SARS-CoV-2 spike pseudoparticles neutralization assays. Serum from patients in all groups did not neutralize infection in V1, and was used for normalizing neutralization at V2 and V3. At V2 HC serum had a 65% neutralization capability, contrasting with significantly reduced activity in the anti-TNFα group (51%, p<0.05; Supplementary Table 4) . Furthermore, at V3 serum from the HC and the non-anti-TNFα treated groups had significantly higher neutralization activity compared to serum from patients in the anti-TNFα group (97%, 96%, and 79%, respectively, p<0.0001; is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; Importantly, non-anti-TNFα IBD therapies did not significantly modify seroconversion or magnitude of response. Specifically, in patients treated with vedolizumab (n=27, 51.8% UC) or 5-ASA (n=35, 76.9% UC), vaccine responses were comparable to those of HC (p=0.288, 0.191, respectively). Anti-N, reflecting infection with COVID-19 was positive after the second vaccine dose in <2% of study participants and comparable between the groups. Specifically, anti-N Abs were detected in 2 HC, 2 non-anti-TNFα and 1 anti-TNFα treated patients. These subjects were not excluded from analysis given the equal distribution between the groups and the comparable to not-infected patients anti-S titers. In univariate analysis (Supplementary Table 5 ) factors such as older age, male gender and WBC were also associated with a lower serologic response after the first vaccine dose (male gender and WBC value) and after both vaccine doses (older age). In multivariate linear regression model only anti-TNFα treatment and older age maintained a significant distinct association with lower IgG anti-S response (Supplementary Table 6 ). The inverse correlation between older age and lower IgG anti-S antibodies levels in the three study groups after the first and second vaccine doses is displayed in Supplementary Figure 1 , while Supplementary Table 7 shows the consistently lower GMCs in subjects 40 years and above compared with younger ones in all study groups after the first and second vaccine doses. . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; We next asked whether anti-TNFα drug levels mediated lower vaccine immune responses in this group. Importantly, anti-TNFα drug level measurement was not assessed at trough (i.e., immediately prior to anti-TNFα drug administration), but at the time of serologic assessment at V1, V2 and V3. No correlation between drug levels and immune responses was observed (Supplementary Table 8 ). We further asked whether lower responses in patients treated with anti-TNFα were affected by the interval between anti-TNFα drug administration and vaccination. Importantly, no such correlation was observed neither when anti-TNFα drugs were administered before the first or second vaccine doses (Supplementary Figure 2) . Finally, only two patients had anti-IFX and two anti-ADA drug antibodies. Those did not correlate with vaccine immune responses (Supplementary Table 9 ). Immediate and short-term AEs were detected using phone call and accepted questionnaires, respectively. We further evaluated IBD exacerbation using clinical and laboratory variables. To this end, no SAEs were registered. The most common AEs were local pain and headache, with more AEs after the second compared to first vaccine dose (Supplementary Table 10 ). AEs were not in excess or more prominent in patients treated with anti-TNFα who had higher drug levels during vaccination. Finally, baseline IBD activity was comparable in patients treated with anti-TNFα or not and remained comparable after the first and second vaccine doses (Supplementary Table 11 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.22.21262263 doi: medRxiv preprint 19 vaccination for this patient subpopulation, as already considered for severely immunocompromised patients such as those with certain cancers and chemotherapy 36,37 . The prospective nature of our study enabled evaluation of immune responses dynamics. Importantly, about 10% of patients treated with anti-TNFα were still seronegative after the first vaccine dose, and additional 18% had a low level (50-150 AU) of anti-S antibodies. This supports maintainance of thorough COVID-19 precautions for them and their household members until after the second vaccine dose. Notably, after the first vaccine dose there were also 8 (7%) seronegative patients in the non-anti-TNFα treated group pointing to additional patient factors that may modify seronegativity. In this regard, we found that age was an independent predictor of lower vaccine immune responses, regardless of IBD treatment. While our patients were mostly young (~37 years), a continuous decline in serology with age was noticed. As older age is also a risk factor for severe COVID-19 38,39 these patients should be at highest priority for booster vaccine doses. A recent report from US Veteran Affairs data base demonstrating only 80.4% vaccine effectiveness in a patient population with a median age of 68 supports our finding 40 . Our study, the first specifically designed to adress vaccine timing relative to anti-TNFα drug administration did not demonstrate such correlation. Moreover, in 14 patients vaccinated during anti-TNFα induction, responses were comparable to those vaccinated during maintenance. Anti-TNFα drug levels during vaccination, were unrelated to impaired responses. Altogether, these findings lend evidence to the empiric recommendation to vaccinate patients with IBD regardless of anti-TNFα administration timing 30 . Importantly, no SAEs were reported in the week following vaccination. While our study included only 10 subjects< 21 years, it is reassuring that no cardiac AEs, specifically . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.22.21262263 doi: medRxiv preprint 20 myocarditis 38 were detected. AEs were similar in all subjects-mainly local pain, and resolved within a few days. No IBD exacerbation was observed, regardless of disease activity during vaccination. This is specifically reassuring as approximately a third of patients were not in remission. There are several strengths to our study. This is the first prospective multi-center study Our study, including 67 patients treated with anti-TNFα was powered to demonstrate significant differences, which indeed were apparent, between them and untreated patients. Limitations include difference in gender ratio between IBD and HC groups at baseline, the relatively young age of participants (although this reflects typical IBD populations) and the use of only one vaccine type. Evaluation of vaccine efficacy is limited, as infection rate in Israel during the study period was low. Finally, observation was limited to 4 weeks after the second vaccine. To conclude, our study provides prospective, controlled evidence for the efficacy and safety of the COVID-19 BNT162b2 vaccine in patients with IBD stratified according to therapy. We is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. Patients were enrolled at visit 1 (V1), before the first vaccine dose. Second visit (V2) was 14-21 days after the first but before the second vaccine dose. A week after the second vaccine dose a phone call was made to evaluate adverse events (AEs), and a third visit (V3) was 4 weeks after the second vaccine dose. In each visit laboratory tests were performed, and questionnaires regarding disease severity and AEs were filled. B. Patients disposition. The diagram represents all enrolled participants who were recruited before vaccination. *28 subjects were recruited at the second visit (after first vaccine dose but before the second one), mainly due to logistic reasons. Most of them (22) were healthy controls (HC). Number of subjects at each visit is detailed in the table below the diagram. Abbreviations: HC=healthy controls, Vacc=vaccine dose. (A-C) Ability of serum from healthy controls (HC, shown in green), patients with IBD receiving non-anti-TNFα treatment (non-anti-TNFα, shown in blue) and patients with IBD receiving anti-TNFα treatment (anti-TNFα, shown in red) to inhibit SARS-CoV-2 RBD binding to ACE2 receptor. Values measured by ELISA are presented as % inhibition (y axis), following vaccination. Visit 1 (V1) -before vaccination, visit 2 (V2) and visit 3 (V3), after first and second vaccine doses, respectively. Zero inhibition was set as the value of RBD without added sera. Statistical analysis was carried out using independent-samples Kruskal-Wallis test *** -p< 0.0005, **** -p<0.0001. At least three repetitions for every sample. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.22.21262263 doi: medRxiv preprint panels represent V2 and V3 timepoints, respectively. The lower panels are zoom-in view for each of the black frame-surrounded portions from the upper panel. Correlation was calculated by Pearson correlation analysis. Abbreviations: RBD= receptor-binding domain, ACE2= angiotensin converting enzyme-2 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint , high blood pressure (5) and celiac (2) . The rest were fatty liver disease, hypothyroidism, ankylosing spondylitis, and prostate cancer. b Disease activity was quantified clinically by validated questionnaires. c Including 6-mercatopurine, azathioprine, methotrexate. Abbreviations: HC=healthy controls, BMI=body mass index, CD=Crohn's disease, UC=ulcerative colitis, IBD-U=IBD-unclassified, IPAA=ileal pouch anal-anastomosis, IFX=infliximab, ADA=adalimumab, 5-ASA= 5-aminosalicylic acid. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; Non-anti-TNFα (n) HC (n) V1 65 114 51 V2 60 112 72 Phone call 66 115 71 V3 65 114 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. x < 5 0 It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. 3 9 x < 1 0 1 0 < x < 4 5 4 5 < x < 8 0 x < 8 0 3 9 5 3 x < 1 0 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.22.21262263 doi: medRxiv preprint Supplementary Table 7 : levels of IgG anti-S (GMC and 95% CI) by treatment group and age (40 years of age as cutoff) before (V1) and after first (V2) and second (V3) vaccine doses. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.22.21262263 doi: medRxiv preprint Correlation between older age and lower levels of IgG anti-S antibodies in the three study groups after first (A) and second (B) vaccine doses. Anti-TNFα in red, non-anti-TNFα in blue, healthy controls (HC) in green circles. P<0.001 in both V2 and V3 by Pearson's correlation The bars describe the intervals in days grouped into < 3 days (black), < 10 days (dark grey), and > 10 days (light grey). Y axis: anti-S IgG antibodies after first (V2) and second (V3) vaccine doses. Error bars denote SD. n o n -a n ti-T N F  a n ti-T N F  n o n -a n ti-T N F  a n ti-T N F  C D U C Activity was measured by validated questionnaires. Bars represent the average score of either HBI for CD or SCCAI for UC, stratified according to treatment (with and without anti- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.22.21262263 doi: medRxiv preprint TNFα), before the first vaccine dose (V1, black), and before and after the second vaccine dose (V2, dark grey; V3, light grey, respectively). Error bars denote SD. Abbreviations: HBI= Harvey-Bradshaw Index; SCCAI= Simple Clinical Colitis Activity Index, UC=Ulcerative colitis, CD=Crohn's disease . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.22.21262263 doi: medRxiv preprint World Health Organization. Laboratory testing for 2019 novel coronavirus (2019-nCoV) in suspected human cases. WHO -Interim Guid Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine An mRNA Vaccine against SARS-CoV-2 -Preliminary Report Δ dose 1 -dose