key: cord-0915437-9e467aql
authors: Weaver, Kimberly N; Zhang, Xian; Dai, Xiangfeng; Watkins, Runa; Adler, Jeremy; Dubinsky, Marla C; Kastl, Arthur; Bousvaros, Athos; Strople, Jennifer A; Cross, Raymond K; Higgins, Peter D R; Ungaro, Ryan C; Bewtra, Meenakshi; Bellaguarda, Emanuelle; Farraye, Francis A; Boccieri, Margie E; Firestine, Ann; Kappelman, Michael D; Long, Millie D
title: Impact of SARS-CoV-2 Vaccination on Inflammatory Bowel Disease Activity and Development of Vaccine-Related Adverse Events: Results From PREVENT-COVID
date: 2021-12-06
journal: Inflamm Bowel Dis
DOI: 10.1093/ibd/izab302
sha: f8b013a87b47ba0e35b5ae28ab9ed0cc9ff35f8f
doc_id: 915437
cord_uid: 9e467aql

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 vaccination is recommended for all individuals with inflammatory bowel disease (IBD), including those on immunosuppressive therapies; however, little is known about vaccine safety and efficacy in these patients or the impact of vaccination on IBD disease course. METHODS: We evaluated coronavirus disease 2019 (COVID-19) vaccine–related adverse events (AEs) and the effect of vaccination on IBD disease course among participants in the PREVENT-COVID (Partnership to Report Effectiveness of Vaccination in populations Excluded from iNitial Trials of COVID) study, a prospective, observational cohort study. Localized and systemic reactions were assessed via questionnaire. Disease flare was defined by worsening IBD symptoms and change in IBD medications. Outcomes were stratified by vaccine type and IBD medication classes. RESULTS: A total of 3316 individuals with IBD received at least 1 COVID-19 vaccine. Injection site tenderness (68%) and fatigue (46% dose 1, 68% dose 2) were the most commonly reported localized and systemic AEs after vaccination. Severe localized and systemic vaccine-related AEs were rare. The mRNA-1273 vaccine was associated with significantly greater severe AEs at dose 2 (localized 4% vs 2%, systemic 15% vs 10%; P < .001 for both). Prior COVID-19 infection, female sex, and vaccine type were associated with severe systemic reactions to dose 1, while age <50 years, female sex, vaccine type, and antitumor necrosis factor and vedolizumab use were associated with severe systemic reactions to dose 2. Overall rates (2%) of IBD flare were low following vaccination. CONCLUSIONS: Our findings provide reassurance that the severe acute respiratory syndrome coronavirus 2 vaccine is safe and well tolerated among individuals with IBD, which may help to combat vaccine hesitancy and increase vaccine confidence.

The clinical trials that led to emergency use authorization (EUA) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines showed low rates of serious adverse events (AEs) among participants but did not include individuals with Crohn's disease (CD) or ulcerative colitis (UC). [1] [2] [3] Thus, little is known about the safety and the efficacy of these vaccines in patients with inflammatory bowel disease (IBD), many of whom are treated with immunosuppressive medications. A recent survey of patients with IBD indicated that although a vast majority of individuals felt that the coronavirus disease 2019 (COVID-19) vaccine was important for their health and the health of others, many participants had concerns about the unknown safety of the vaccine, preferred to see how others tolerated the vaccine first, and desired specific data regarding vaccine safety and effectiveness in IBD patients. 4 There is no evidence to date that other vaccinations trigger flares of IBD. Prior studies of IBD patients who received the 23-valent polysaccharide pneumococcal, H1N1 influenza, trivalent influenza vaccines, or recombinant zoster vaccine did not show increased risk of serious AEs, and there were no significant changes in IBD clinical activity scores postimmunization. [5] [6] [7] [8] [9] Additionally, a small study of IBD patients (n = 246) suggested that individuals with IBD experience similar frequencies of AEs after SARS-CoV-2 vaccination compared with the healthy participants studied in the initial vaccine clinical trials. 10 Despite this early reassuring data, larger real-world studies are needed to evaluate COVID-19 vaccine safety and tolerability in IBD patients. This study aimed to evaluate SARS-CoV-2 vaccine-related AEs in patients with IBD and the effects of vaccination on IBD disease activity.

Partnership to Report Effectiveness of Vaccination in populations Excluded from iNitial Trials of COVID (PREVENT-COVID) is a prospective, observational, cohort study of patients with IBD in the United States who have received any COVID-19 vaccine granted EUA including BNT162b2 (Pfizer-BioNTech), mRNA-1273 (NIH-Moderna), and Ad26. COV2.S (Johnson & Johnson). Eligibility criteria have previously been described and include (1) diagnosis of IBD, (2) receipt of 1 or more doses of any COVID-19 vaccine approved under the EUA within the prior 90 days, (3) age 12 years or older, (4) residence in the United States, (5) access to the internet and ability to complete surveys in English, and (6) willingness to remain in this study for 18 months. 11 Participants were recruited through education, social media, and other outreach efforts in collaboration with the Crohn's & Colitis Foundation and by referral at selected clinical sites and will be followed through Internet surveys for up to 18 months to ascertain outcomes of COVID-19 infection and safety events. Baseline surveys assessed type of immunization, date and lot numbers of immunization(s), patient demographics and IBD characteristics, and detailed data regarding IBD medication use around the time of vaccination. IBD disease activity was measured via the Manitoba index. 12 The 30-day follow-up survey collected data on the second immunization, including the specific timing of this vaccination in relation to the first, and ascertained whether participants developed COVID-19, the method of diagnosis, and the severity of infection. Both surveys collected data on vaccine AEs and clinical course of IBD following vaccination. Vaccine AEs were classified as injection site (localized) or systemic reactions. Adverse localized reactions included pain, redness, itching, swelling, tenderness, or warmth at the injection site. Systemic adverse reactions included fever, chills, fatigue, headache, joint pain, muscle aches, nausea, allergic reaction, rash, or other. If individuals reported an adverse reaction to the SARS-CoV-2 vaccine, they were asked to rate the severity of reaction as mild (did not interfere with daily activity), moderate (interfered with daily activity), severe (prevented daily activity, required medications), or requiring emergency room visit or hospitalization. Participants were also assessed for flare of IBD, which was defined as (1) worsening of at least 1 of the symptoms of abdominal pain, bowel frequency, rectal bleeding, and extraintestinal manifestation after vaccine 1 or 2; and (2) a need to add or change IBD medication due to symptoms within 1 month of vaccination.

This analysis included all participants who completed baseline and 30-day post-enrollment surveys prior to July 8, 2021. We used descriptive statistics to characterize the study population, vaccine-related AEs, IBD disease activity, and development of COVID-19 infection after vaccination. Outcomes were stratified by vaccine type and by IBD medication classes. We used bivariate analyses to identify factors associated with severe localized or systemic AEs to SARS-CoV-2 vaccination.

All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA). P values <.05 were considered statistically significant. The study protocol was approved by the Institutional Review Board at the University of North Carolina at Chapel Hill.

A total of 3316 participants with IBD (71.7% female, mean age 43.7 years, 54.6% Crohn's disease) completed the baseline survey and were included in the study population as of July 8, 2021. A total of 160 (4.8%) participants reported a history of COVID-19 infection before SARS-CoV-2 immunization. Vaccine distribution included 1908 (57.5%) BNT162b2 (Pfizer-BioNTech), 1247 (37.6%) mRNA-1273 (NIH-Moderna), and 161 (4.9%) Ad26.COV2.S (Johnson & Johnson). A majority of participants were taking biologic or small molecule therapies at baseline. Full details regarding medication distribution, demographics, and IBD clinical characteristics are presented in Table 1 . 

Participants were asked to report localized and systemic AEs within 7 days after receiving SARS-CoV-2 vaccine dose 1 (D1) and vaccine dose 2 (D2). When considering localized reaction to D1, 13.0% reported no reaction, 69.7% reported mild reaction, 15.8% reported moderate reaction, and 1.1% reported severe reaction (Table 2 ). For D2, 13.2% reported no reaction, 64.0% reported a mild reaction, 19.7% reported a moderate reaction, and 2.8% reported a severe reaction (Table  3) . Systemic reactions were more commonly seen after D2, with 21.5% reporting no reaction, 28.0% reporting a mild reaction, 37.8% reporting a moderate reaction, and 11.6% reporting a severe reaction to D2 compared with 41.7% reporting no reaction, 36.5% reporting a mild reaction, 17.9% reporting a moderate reaction, and 2.9% reporting a severe reaction to D1. There were 10 (0.3%) participants after D1 and 6 participants after D2 who required a visit to emergency room or hospitalization due to vaccine-related adverse effects (Tables 2 and 3 ).

The most common injection site reactions included tenderness (68% D1, 68% D2) or pain (66% D1, 65% D2). Fatigue (46% D1, 68% D2), headache (32% D1, 51% D2), and myalgias (20% D1, 43% D2) were the most frequently reported systemic reactions. Allergic reactions including anaphylaxis were rare, occurring in 0.7% after D1 and 0.5% after D2 (Tables 2 and 3) .

Prior COVID-19 infection was positively associated with severe localized and systemic AEs to D1, but this same trend was not seen for D2. Female sex and vaccine type were also found to be positively associated with severe systemic reactions at D1. Treatment with ustekinumab was negatively associated with severe localized reaction at D1, while antitumor necrosis factor (TNF) therapy was positively associated with severe systemic reaction at D1 (Table 4) .

Vaccine type was positively associated with severe injection site reaction to D2 with more localized reactions occurring with mRNA-1273 compared with BNT162b2. Age <50 years, female sex, mRNA-1273 vaccine, anti-TNF use, and vedolizumab use were all positively associated with severe systemic reactions to D2 (Table 4) .

When asked about IBD activity in the 6 months leading up to COVID-19 vaccination, 32.5% described IBD in remission, 16 .8% described IBD as rarely active, 15.9% described IBD as occasionally active, 18.2% described IBD as sometimes active, 11.0% described IBD as often active, and 5.7% described IBD as constantly active ( 

A total of 456 (13.8%) participants reported changing the timing of their IBD therapy due to receiving SARS-CoV-2 D1 or D2. The medication with greatest proportion of users reporting a change in timing of dosing surrounding vaccination was methotrexate, with 32% adjusting timing of administration at D1 or D2, holding methotrexate for a median of 7 days before and after each immunization (Table 5 ). In comparison, only 8% and 4% of those on small molecules tofacitinib and thiopurines, respectively, reported change in timing of these medications around the time of SARS-CoV-2 vaccination. Of the biologics, the largest proportion of individuals on certolizumab changed medication timing surrounding COVID-19 vaccination, with 22% of participants on certolizumab altering medication timing followed by adalimumab (20%), ustekinumab (14%), infliximab (10%), vedolizumab (9%), and golimumab (9%). Additional details regarding median length of time medications were held preand postvaccination are found in Table 5 . 

Our study evaluated the development of COVID-19 vaccinerelated AEs and the effect of SARS-CoV-2 vaccination on IBD disease course in a large, geographically diverse U.S. cohort of individuals with IBD. Overall, severe vaccine-related AEs were rare. Importantly, very few patients reported clinically significant IBD exacerbations following immunization. We observed that prior COVID-19 infection was associated with severe local and systemic AEs to D1; female sex and vaccine type were associated with systemic reactions to D1 and D2; and age <50 years, anti-TNF use, and vedolizumab use were associated with severe systemic reactions to D2. Overall, our findings of a more severe reaction to D1 in those with prior COVID-19 is consistent with studies in the general population in which high reactogenicity was observed after a single dose of messenger RNA (mRNA) vaccine among individuals previously infected with SARS-CoV-2. 13, 14 Our main finding of relatively low vaccine-related AEs is also consistent with a prior small study of IBD patients that indicated similar 

Age <50 AE frequency to that of the general population. 10 Our findings differ from this prior study in that they found AEs to be less common in those on biologic therapies, whereas we found both vedolizumab and anti-TNF therapies to be positively associated with severe systemic reactions to D2. 10 Such differences may be explained by their smaller sample size of participants on biologic therapies; however, there is no consistent pattern that would warrant change in immunization recommendations in subgroups of IBD patients. Very few participants in our study described worsening IBD disease activity requiring either a change or addition of medication following SARS-CoV-2 vaccination. This extends the findings of with Hadi et al, 15 who found no difference in new steroid prescriptions 1 month following SARS-CoV-2 vaccination in a matched cohort of vaccinated IBD and nonvaccinated IBD patients. Rates of IBD flare reported in our cohort are similar to those previously reported in prior studies evaluating the effect of influenza, pneumococcal, and shingles vaccination on IBD disease course. 5, [7] [8] [9] When examining patterns of IBD medication use surrounding SARS-CoV-2 vaccination, we found that a higher proportion of individuals taking methotrexate changed the timing of medication dosing in comparison with other small molecules or biologics. This may have been driven by the rheumatology literature in which expert opinion recommended holding methotrexate for 1 week after each of the 2 mRNA vaccine doses and 2 weeks following Ad26.COV2.S vaccination. 16 This is in comparison with guidance from the International Organization for Study of Inflammatory Bowel Disease in which it was recommended that the best time for patients to receive SARS-CoV-2 vaccination was the earliest opportunity to do so with no specific recommendations to hold or delay IBD medications around the time of immunization. 17 COVID-19 infection after SARS-CoV-2 vaccination was rare in our cohort, occurring in <0.5% of participants, with a majority of these cases occurring before receipt of second dose of mRNA vaccine or within weeks of completing the vaccine series. A recent study that used electronic health record data to evaluate the efficacy of SARS-CoV-2 vaccination in IBD patients (n = 5561) found a similar incidence of breakthrough COVID-19 infection at 0.4% with a majority of cases occurring within 1 month of first immunization. 15 Longerterm follow-up is ongoing within our PREVENT-COVID cohort to estimate the true rate of breakthrough COVID-19 infections in the IBD population. In particular, as the delta variant becomes more prevalent across the United States, the PREVENT-COVID study will continue to have longitudinal follow-up, with the ability to capture additional vaccinations and to assess COVID-19 infection outcomes.

Our study has several limitations including lack of racialethnic diversity, a convenience sample that may impact external validity, and reliance on self-report owing to directto-patient recruitment. Additionally, the relatively infrequent occurrence of serious AEs precluded multivariable modeling, and we did not adjust for multiple comparisons. Hence, associations between clinical and treatment-related characteristics and serious vaccine-related AEs must be considered exploratory and may be subject to confounding or false discovery. Despite these limitations, our study provides highly anticipated data regarding the safety and tolerability of the SARS-CoV-2 vaccination in an IBD-specific population, which was a key area of interest among patients with IBD who were surveyed about their intent and perceptions regarding SARS-CoV-2 vaccination. 4 Strengths of this study include the geographic diversity as well as the size of our cohort, the largest sample to date reporting on IBD patient-reported outcomes following SARS-CoV-2 vaccination. Although safety outcomes after SARS-CoV-2 vaccination in the IBD population were previously reported by Hadi et al, 15 these focused on immediate AEs within 1 day of vaccination and AEs of special interest per the Centers for Disease Control and Prevention. Our study uses the same categories of localized and systemic AEs that were described in the initial SARS-CoV-2 vaccine clinical trials, which contributes to the generalizability of this study. [1] [2] [3] Our findings provide reassurance that the SARS-CoV-2 vaccine is safe and well tolerated among individuals with IBD, including those on immune-suppressing therapies. Although longer-term follow-up is ongoing, these data may help to combat vaccine hesitancy and increase vaccine confidence in those with IBD. 

This study was supported by the Leona M. and Harry B. Helmsley Charitable Trust.

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X.Z., X.D., R.W., A.K., J.A.S., M.E.B., and A.F. have no conflicts of interest. K.N.W. has consulted for AbbVie. J.A. has consulted for Janssen, and has received research support from the Gary R.C.U. has served as an advisory board member or consultant for AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, and Takeda; has received research support from AbbVie, Boehringer Ingelheim, and Pfizer; and is funded by an National Institutes of Health Career Development Award (K23KD111995-01A1). M.B. discloses research funding from Janssen, GlaxoSmithKline, and Takeda; having served as a consultant for Janssen, AbbVie, BMS, and Pfizer; and having received honorarium for participation in a continuing medical education program sponsored by AbbVie. E.B. has consulted for AbbVie, Pfizer, and Bristol Myers Squibb. F.A.F. is a consultant for Arena, BMS, Braintree Labs, Gilead, GI Reviewers, Innovation Pharmaceuticals, Iterative Scopes, Janssen, Pfizer, and Sebela; and sits on a Data Safety Monitoring Board for Lilly and Theravance. M.D.K. has consulted for AbbVie, Janssen, Pfizer, and Takeda; is a shareholder in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, and Arena Pharmaceuticals. M.D.L. has received research/grants from Pfizer and has consulted for AbbVie, Bristol Myers Squibb, Calibr, Eli Lilly and Company, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Pfizer, Roche, Takeda Pharmaceuticals, TARGET PharmaSolutions, and Theravance Biopharma.