key: cord-1040759-nxh1su1i
authors: Edelman-Klapper, Hadar; Zittan, Eran; Bar-Gil Shitrit, Ariella; Rabinowitz, Keren Masha; Goren, Idan; Avni-Biron, Irit; Ollech, Jacob E.; Lichtenstein, Lev; Banai-Eran, Hagar; Yanai, Henit; Snir, Yifat; Pauker, Maor H.; Friedenberg, Adi; Levy-Barda, Adva; Segal, Arie; Broitman, Yelena; Maoz, Eran; Ovadia, Baruch; Golan, Maya Aharoni; Shachar, Eyal; Ben-Horin, Shomron; Perets, Tsachi-Tsadok; Ben Zvi, Haim; Eliakim, Rami; Barkan, Revital; Goren, Sophy; Navon, Michal; Krugliak, Noy; Werbner, Michal; Alter, Joel; Dessau, Moshe; Gal-Tanamy, Meital; Freund, Natalia T.; Cohen, Dani; Dotan, Iris
title: Lower Serologic Response to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases Treated with Anti-TNFα
date: 2021-10-28
journal: Gastroenterology
DOI: 10.1053/j.gastro.2021.10.029
sha: 6881414093e8427bdc85cef157854a3bfb5200d2
doc_id: 1040759
cord_uid: nxh1su1i

Background Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor-necrosis-factor (TNF)α biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear. Aim To assess serologic 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 antibodies levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinaly. Results Overall 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HC. After the first vaccine dose all HC were seropositive, while ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared to non-anti-TNFα treated patients, and HC (both P<.001). Neutralizing and inhibitory functions were both lower in anti-TNFα treated compared to non-anti-TNFα treated patients, and HC (P<.03; P<.0001, respectively). Anti-TNFα drug levels and vaccine responses did not affect anti-spike levels. Infection rate (∼2%) and AEs were comparable in all groups. IBD activity was unaffected by BNT162b2. Conclusions In this prospective study in patients with IBD stratified according to treatment all patients mounted serologic response to two doses of BNT162b2. However, its magnitude was significantly lower in patients treated with anti-TNFα, regardless of administration timing and drug levels. Vaccine was safe. As vaccine serologic response longevity in this group may be limited, vaccine booster dose should be considered.

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 immune mediated diseases such as inflammatory bowel diseases (IBD), both Crohn's disease (CD) and ulcerative colitis (UC) were specifically excluded from trials 2,3 . 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] [5] [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 mRNAbased vaccines against SARS-CoV-2. Concerns regarding adverse events (AEs), including IBD exacerbation, further underscored the need for vaccine responses assessment in these patients, which may also be relevant to patients with other immune-mediated inflammatory disorders using similar medications.

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 serologic responses to BNT162b2 in patients with IBD stratified according to therapy, compared to healthy controls (HC).

Study design and participants A prospective, observational, multi-center study was conducted to assess serologic 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 not treated with anti-TNFα but by other IBD treatments i.e. 5-ASA, immunomodulators, steroids, ustekinumab and JAK inhibitors who were included in a "non-anti-TNFα" group together with patients who were completely "untreated", i.e., they were not treated with anti-TNFα or any other agent. All participants received two 30µg BNT162b2 vaccine doses intramuscularly, administered 21-28 days apart, as per manufacturers' recommendations. The study was approved by the local IRBs at the Rabin, Shaare Zedek, Emek and Soroka Medical Centers, (  20  -1072 -RMC,   0557-20-SZMC, 0247-20-EMC,  20 -0568 -SOR, respectively). MOH number: 2020-12-30_009617. All participants signed an informed consent form before any study procedure.

Eligible participants were evaluated at four time points: (i) visit 1-before the first vaccine dose (ii) visit 2 -14-21 days after the first and before the second vaccine dose, (iii) phone call a week after the second vaccine dose to report adverse events (AEs) and (iv) visit 3 -21-35 days after the second vaccine dose, (see Figure 1A ). At enrolment, patients were assessed J o u r n a l P r e -p r o o f 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 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 each visit including complete blood count, C-reactive 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 serologic 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 visit 3. Secondary endpoints were serologic response dynamics induced after the first and second vaccine doses; and AEs, specifically local and systemic reactions and IBD exacerbation. 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. 24 was performed as described 25 using RBD-serum mix incubated with ACE2 coated plates.

Inhibition percentage was calculated for each well by the formula: Table 1 ). Table 3) . We also assessed the geometric mean concentration fold rise (GMCFR) of anti-S antibodies in the individual sera of subjects in the three study groups from baseline (visit 1) to either visit 2 and 3, and between visit 2 to 3, demonstrating that similarly to anti-S levels, GMCFR is significantly lower in the anti-TNFα group.

We next assessed neutralizing antibodies, considered critical for patients survival and virus control 26 . Using competitive ELISA we show that while at visit 1 inhibition activity was low and comparable between the groups ( Figure 3 , A-C, Supplementary Table 4 ), at visit 2 the anti-TNFα treated group had significantly lower ability to inhibit RBD:ACE2 binding compared to HC (P<.05). This was even more prominent at visit 3 (P <.001). Notably, J o u r n a l P r e -p r o o f 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 visit 2, which increased even further in visit 3, suggesting that after two vaccine doses the proportion of anti-S IgG antibodies with inhibitory function increases (Supplementary Figure 1) .

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 visit 1, and was used for normalizing neutralization at visit 2 and visit 3. At visit 2 HC serum had a 65% neutralization capability, contrasting with significantly reduced activity in the anti-TNFα group (51%, P<.05; Supplementary Table 5) . Furthermore, at visit 3 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<.0001; (38) , and other IBD medications who were used by lower numbers of patients (steroids [7] , immunomodulators [8] , ustekinumab [5] and JAK inhibitors [3] , see Table 1 ). Measuring serologic and functional responses of the 5ASA, vedolizumab, no J o u r n a l P r e -p r o o f medical treatment and "other" groups, comparable responses were found, further supporting the decision to include them in the same group (Supplementary Figure 4) .

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 after vaccination in two HC, two non-anti-TNFα (one treated with vedolizumab and one untreated) and one anti-TNFα (infliximab) treated patients. Importantly, subjects were asymptomatic and were not aware of having been infected (Supplementary Table 6 ). In addition, there were six subjects who had a positive anti-N already at visit 1. Interestingly, baseline anti-S IgG levels were negative in four of them, and positive in two (Supplementary Table 6 ) potentially suggesting differences in the dynamics of serologic responses, although numbers are too small for further analysis. These subjects were not excluded from analysis given the equal distribution between the groups and the comparability to uninfected patients anti-S titers.

In univariate analysis (Supplementary Table 7 In multivariate linear regression model only anti-TNFα treatment and older age maintained a significant distinct association with lower IgG anti-S response (P<.001, Table 2 ).

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 J o u r n a l P r e -p r o o f Table 8 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.

We next asked whether anti-TNFα drug levels mediated lower vaccine serologic 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 each visit. No correlation between drug levels and serologic responses was observed, using Spearman's correlation (Supplementary Table 9 ).

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 Table   10 ).

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 J o u r n a l P r e -p r o o f pain (<70%) and headache (~30%), with more AEs after the second compared to first vaccine dose (Supplementary Table 11 ). AEs were not in excess or more prominent in patients treated with anti-TNFα who had higher drug levels during vaccination (P=.722 and P=.909

after first and second vaccine dose, respectively, using Pearson's correlation).

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 12 ,

. Neither CRP levels nor WBC count were increased following vaccination in both groups.

Patients with IBD treated with immunomodulators and/or anti-TNFα biologics are at an increased risk of vaccine preventable diseases, and vaccination programs are recommended. Patients with chronic diseases were more prone to COVID-19 complications and death [27] [28] [29] . Vaccination campaigns encouraged patients with IBD to vaccinate 30,31 , despite their exclusion from phase-3 trials 2,3 . Here, we aimed to prospectively evaluate serologic responses and safety of the BNT162b2 vaccine in patients with IBD.

Our results show that all subjects, regardless of medical treatment, seroconverted after the second vaccine dose, consistent with recent reports 32 In this regard, we found that age was an independent predictor of lower vaccine serologic responses, regardless of IBD treatment. While our patients were mostly young (~37 years), a J o u r n a l P r e -p r o o f continuous decline in serology with age was noticed. As older age is also a risk factor for severe COVID-19 44, 45 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 46 .

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 Our study, including 67 patients treated with anti-TNFα was powered to demonstrate significant differences, which indeed were apparent, between them and to patients without anti-TNFα treatment. As a non-anti-TNFα group was specifically designed to include multiple IBD therapies, we were able to address serologic response of these sugroups as well, demonstrating its comparability to HC (Supplementary Figure 4 ) although the small numbers of patients treated with steroids and immunomodulators limit findings in these specific subgroups 33 Patients were enrolled at visit 1, before the first vaccine dose. Visit 2 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 visit 3 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. (6), diabetes (5), 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. NEW FINDINGS: Seroconversion demonstrated after two, but not one BNT162b2 doses. Significantly lower serologic responses in patients treated with anti-tumor necrosis factor-α, irrespective of drug levels and drug-vaccine intervals. Vaccine was safe.

LIMITATIONS: Evaluation of one vaccine type (BNT162b2). Short follow-up (~4 weeks) after the second vaccine dose.

IMPACT: Two doses of BNT162b2 in patients with IBD are safe and effective, however patients treated with anti-tumor necrosis factor-α biologics had lower serologic response supporting specific vaccination schedules for this population. No requirement to coordinate timing of vaccination and drug administration.

Patients with inflammatory bowel diseases treated with anti-TNFα had lower serologic response to COVID-19 vaccine compared to those treated with other medications and healthy controls. Vaccine was safe. 

In supplemental material. To generate SARS-CoV-2 pseudo typed vesicular stomatitis virus (VSV) particles, human embryonic kidney (HEK)-293T cells were grown to 70% confluence in Dulbecco's modified eagle medium (DMEM) supplemented in 10% fetal bovine serum (FBS), 1% L-glutamine, and 1% penicillin streptavidin. Cells were transfected with pCMV3 plasmid encoding the SARS-CoV-2 S protein with Cterminal, 19 residues truncation (pCMV3-SARS-CoV-2-SΔ19) using polyethylenimine (PEI). Twenty-four hours post-transfection, the cells were infected with G-complemented 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 GFPpositive 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. Activity was measured by validated questionnaires (HBI for patients with CD, SCCAI for patients with UC). No difference in disease activity between groups or within groups after vaccination was noticed. Data are presented as mean±SD. Abbreviations: CD=Crohn's disease, UC=ulcerative colitis. 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 (visit 2) and second (visit 3) vaccine doses. Error bars denote SD. The difference between the groups was not significant using Independent-Samples Kruskal-Wallis Test 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- 

---- ----- ----- Δ dose 2 -V3 (days) ----- ----- ----- 241/246 Rho=-0.036 .582 Δ dose 1 -dose 2 ----- ----- ----- 241/246 Rho=0.024 .715 Δ dose 1 -last medication 87/244 Rho=0.039 .722 ----- ----- ----- Δ dose 2 -last medication ----- ----- -----

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CD=Crohn's disease, UC=ulcerative colitis, IBD-U=IBD-unclassified, IPAA=ileal pouch anal-anastomosis

Correlation between neutralization and IgG titer for visit 3 J o u r n a l P r e -p r o o f 16 Graphs show correlation between anti-S titer measured in Figure 2 A-C and sera neutralization (Figure 4 A, B) for all donors. Left and right panels represent visits2 and 3 timepoints, respectively. Each data point represents the subjects: 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. The lower panels are zoom-in view for each of the black frame-surrounded portions from the upper panel. Correlations were calculated by Pearson correlation analysis.

Graphs show correlation between sera inhibition measured in Figure 3 A-C and sera neutralization (Figure 4, A, B) for all donors. Left and right panels represent visits 2 and 3 timepoints, respectively. Each data point represents the subjects: 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. Correlations were calculated by Pearson correlation analysis.