key: cord-0772902-aespogh7 authors: Bhurwal, Abhishek; Mutneja, Hemant; Bansal, Vikas; Goel, Akshay; Arora, Shilpa; Attar, Bashar; Minacapelli, Carlos D.; Kochhar, Gursimran; Chen, Lea Ann; Brant, Steve; Seril, Darren title: Effectiveness and safety of SARS‐CoV‐2 vaccine in Inflammatory Bowel Disease patients: a systematic review, meta‐analysis and meta‐regression date: 2022-03-30 journal: Aliment Pharmacol Ther DOI: 10.1111/apt.16913 sha: 9e801096dd2999d283c0942c27d7abd77f0a3424 doc_id: 772902 cord_uid: aespogh7 INTRODUCTION: There are concerns regarding the effectiveness and safety of SARS‐CoV‐2 vaccine in inflammatory Bowel Disease (IBD) patients. This systematic review and meta‐analysis comprehensively summarises the available literature regarding the safety and effectiveness of SARS‐CoV‐2 vaccine in IBD. METHODS: Three independent reviewers performed a comprehensive review of all original articles describing the response of SARS‐CoV‐2 vaccines in patients with IBD. Primary outcomes were (1) pooled seroconversion rate SARS‐CoV‐2 vaccination in IBD patients (2) comparison of breakthrough COVID‐19 infection rate SARS‐CoV‐2 vaccination in IBD patients with control cohort and (3) pooled adverse event rate of SARS‐CoV‐2 vaccine. All outcomes were evaluated for one and two doses of SARS‐CoV‐2 vaccine. Meta‐regression was performed. Probability of publication bias was assessed using funnel plots and with Egger’s test. RESULTS: Twenty‐one studies yielded a pooled seroconversion rate of 73.7% and 96.8% in IBD patients after one and two doses of SARS‐CoV‐2 vaccine respectively. Sub‐group analysis revealed non‐statistically significant differences between different immunosuppressive regimens for seroconversion. Meta‐regression revealed that the vaccine type and study location independently influenced seroconversion rates. There was no statistically significant difference in breakthrough infection in IBD patients as compared to control after vaccination. CONCLUSION: In summary, the systematic review and meta‐analysis suggest that SARS‐CoV‐2 vaccine is safe and effective in IBD patients. Corona Virus Disease 19 , caused by Severe Acute Respiratory Syndrome-COronaVirus-2 (SARS-CoV-2), has been associated with greater than 2 million deaths worldwide as well as significant economic and social upheaval. 1 One of the most significant efforts to reduce SARS-CoV-2 infections and COVID -19 morbidity has been the development of SARS-CoV-2 vaccines. Pharmaceutical companies and academic institutes have rapidly generated several vaccine candidates after sequencing the SARS-CoV-2 virus. 2, 3 In December 2020, two messenger RNA (mRNA) vaccines (BNT 162b2 and mRNA-1273) and one adenovirus vector vaccine (JNJ-78436735) were approved for use in the United States and multiple other countries. The safety and efficacy of ChAdOx1 nCoV-19 vaccine, based on replication-incompetent chimpanzee adenovirus vector expressing the spike protein, was first described in 2020. 4 Since then, there are indications that these vaccines could play a substantial role in curbing the SARS-CoV-2 pandemic, and decrease morbidity and mortality among those with breakthrough infections. Inflammatory Bowel Disease (IBD), chronic inflammatory diseases of the intestinal tract with two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), is increasing in incidence and prevalence worldwide. 5 IBD can significantly impact the quality of life of those affected, and also have marked effects on societies and healthcare systems as a whole. 6, 7 Immunosuppressive therapies are commonly used in the management of IBD and promote an increased risk of infections. 8 Despite this, current evidence demonstrates that patients with IBD do not have an increased risk of developing SARS-CoV-2 infection. [9] [10] [11] However, a significant proportion of the IBD patients have comorbidities (eg pulmonary, cardiovascular and thromboembolic diseases) that can increase the risk of adverse outcomes from COVID-19. 11 Therefore, current professional society guidelines recommend that patients with IBD should receive two doses of SARS-CoV-2 vaccination along with an additional booster dose regardless of immune-modifying therapy. [12] [13] [14] The efficacy of the SARS-CoV-2 vaccines has been demonstrated in several clinical trials; however, patients with IBD or those treated with immunosuppressive medications were excluded from these studies. 15 Therefore, multiple questions regarding the effectiveness of the SARS-CoV-2 vaccination in IBD have emerged. For example, it is unknown if the underlying immune dysregulation characteristic of IBD, or the immunosuppressive therapies used in IBD management, cause an attenuated response to the SARS-CoV-2 vaccination. 16 While several studies have reported the effectiveness of the SARS-CoV-2 vaccine in IBD patients, [17] [18] [19] [20] [21] the majority of the studies had a small sample size and are underpowered to accurately predict outcomes. This systematic review and meta-analysis summarises the available evidence regarding the effectiveness of SARS-CoV-2 vaccination in patients with IBD to fill this knowledge gap. A subgroup analysis was also performed to evaluate the impact of immunosuppressive medications on the effectiveness of the twodose SARS-CoV-2 vaccination schedule. The study has been performed in accordance with the Preferred Reporting Items for systematic reviews and meta-analyses statement (PRISMA statement). 22 The PRISMA Checklist has been added as a supplementary file. The protocol was not registered publicly. The search strategy was designed and conducted by the authors Figure S1 . All titles and abstracts were identified by the authors and screened to accrue potentially eligible studies. A manual search of the references of the included studies was also performed to supplement the electronic search. Then, the same reviewers independently assessed all selected full-text manuscripts for eligibility. Disagreements between two reviewers were resolved through consensus and after input from the third reviewer and the principal investigator. The specific inclusion criteria for the systematic review and metaanalysis were as follows: (1) all randomised control trials (RCTs) or prospective studies or retrospective studies of patients with IBD undergoing SARS-CoV-2 vaccination; (2) studies describing the seroconversion after SARS-CoV-2 vaccination (one and two doses) in IBD patients; (3) all studies with information available to evaluate the incidence of seroconversion and SARS-CoV-2 breakthrough infection after vaccination; (4) full-text articles available in English language and (5) studies with at least 10 IBD patients to avoid bias from small sample size. Only peer reviewed and published data from the studies were utilised for analysis. The data analysed were publicly available and therefore exempt from institutional review board (IRB). Non-randomised studies were evaluated using the preferred ROBINS-I tool. 23 For each non-randomised study, we assessed the study and ascertained the risk of bias due to confounding, selection of participants, classification of interventions, bias due to missing data measurement of outcomes, bias in reported results and overall risk of bias. The NIH study quality assessment Tool was used for measuring the risk of bias in case control studies and cohort studies. 24 Appraisal of individual study quality was based on tailored quality assessment tools developed jointly by methodologists from NHLBI and Research All the studies describing the effectiveness and safety of SARS-CoV-2 vaccine in IBD patients were evaluated. Primary outcomes were (1) Four reviewers (A.B., H.R.M., V.B., A.G.) independently reviewed and abstracted data on seroconversion rate, breakthrough infection and adverse event rate for each eligible study. The authors attempted to obtain an adjusted hazard ratio when feasible and adjusted ratios were considered to be equivalent to the unadjusted ratios, and therefore were pooled together. If there were multiple reports stemming from a specific study database, data from the most robust study were extracted with other studies contributing only towards the bibliography. The reviewers sorted the data separately in all stages of study collection, data extraction and quality assessment. All discrepancies found between the three reviewers were resolved with consensus and inputs from other authors. All outcomes were analysed by the Comprehensive Meta-Analysis software package (Biostat, Englewood, NJ, USA). 25 The final pooled risk estimates were obtained using random effects models. No transformation was necessary for random effects model. Inverse variance method was utilised for pooled ratios. To explore differences between studies that might be expected to influence the effect size on seroconversion after two doses of SARS-CoV-2 vaccines, we performed random effects (maximum likelihood method) univariate and multivariate meta-regression analyses. The potential sources of variability defined a priori included vaccine type and study location. Covariates were selected for further modelling if they significantly (p < 0.05) influenced the outcomes. Subsequently, preselected covariates were included in a manual backward and stepwise multiple meta-regression analysis with p = 0.05 as a cutoff point for removal. Sensitivity analysis was performed on the basis of study design (retrospective vs prospective study vs survey-based design). The Cochrane Q and the I 2 statistics were calculated to assess heterogeneity between studies. p < 0.10 for chi-square test and I 2 > 30% were interpreted as significant heterogeneity. 26 The probability of publication bias was assessed using funnel plots and with Egger's test. The initial library search identified 278 potentially relevant citations from PubMed MEDLINE, CINAHL and Cochrane CENTRAL. Subsequently, 27 duplicates were removed. Two hundred and twenty-six articles were excluded after title and abstract reviews, including articles that did not report the outcomes of seroconversion or breakthrough COVID-19 infection after SARS-CoV-2 vaccination, review articles, opinions, editorials and all articles not in the English language. The remaining 25 manuscripts were scrutinised further and an additional four studies were excluded because they did not meet inclusion criteria. Thus, 21 studies were included in their entirety as shown in Table 1 . These included 11 prospective studies, seven retrospective studies and three survey-based studies. [16] [17] [18] [19] [20] [21] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] The PRISMA Flow chart is shown in Figure 1 . The study details are shown in Table 1 . A summary of the studies reporting on seroconversion after SARS-CoV-2 vaccination is shown in Figure 2B , there was significant heterogeneity in the analysis (I 2 = 78%). There was a statistically significant difference between seroconversion rate after one dose and two doses of all SARS- There was no statistical difference between seroconversion rate after two doses of mRNA-1273 and BNT162b2 vaccines (p = 0.34). The seroconversion rates stratified by vaccine type and dose are shown in Figure 2C . The meta-regression revealed that the vaccine type and location of the study explained 90% of the between-study heterogeneity in the seroconversion rate after two doses of SARS-CoV-2 vaccination. Twelve studies were included in the meta-regression model. BNT162b2 vaccine was the reference group for the vaccine type. The study location was coded with four codes in meta-regression Additional subgroup analysis compared the seroconversion rates in patients on immunosuppression combination therapy vs those on immunosuppression monotherapy, as shown in Figure 3B . Anti-TNFα monotherapy was noticed to have a similar seroconversion rate as compared to anti-TNFα combination therapy (98.3% vs 95%, p = 0.25). There was no significant heterogeneity (I 2 = 28%). Four studies reported breakthrough infection after SARS-CoV-2 vaccination in IBD patients. [27] [28] [29] 39 This yielded a total of 29 breakthrough infections in 6765 IBD patients after one dose. Figure 4 ). There was significant heterogeneity in the analysis (I 2 = 71%). A summary of the studies is shown in Table 3 . Seven studies reported adverse events after SARS-CoV-2 vaccination in IBD patients, as shown in Table 4 . 18, 19, 21, 28, 37, 38 The pooled severe adverse advent rate after one dose of SARS-CoV-2 vaccination was 2.2% (95% CI 1.4-3.6). The pooled severe adverse event rate after the second dose of COVID-19 vaccine was 0.09% (95% CI 0.01-0.091)(see Figure 5A ). There was significant heterogeneity (I 2 = 95.52%). There was no significant difference in pooled severe adverse rates between one and two doses (p = 0.47). Mild adverse events after one and second vaccine doses were analysed individually. The pooled rate of injection site reactions after one and two SARS-CoV-2 vaccine doses was 52.6% (95% CI 38.2-66.6) and 50.2% (95% CI 35.7-64.6) respectively with high heterogeneity (I 2 = 96.14%) (see Figure 5B ). Pooled headache rate after one and two SARS-CoV-2 vaccine doses were 15.6% (95% CI 7.1-30.9) and 25.2% (95% CI 11-47.8), respectively, with high heterogeneity (I 2 = 98.45%). There was no significant difference in pooled headache rates between one and two doses (p = 0.37) (see Figure 5C ). Pooled fatigue rate after one and two SARS-CoV-2 vaccine doses were 24.5% (95% CI 10.8-46.6) and 36.1% (95% CI 13.2-67.7), respectively, with high heterogeneity (I 2 = 98.81%). There was no significant difference in the pooled fatigue rates between one and two doses (p = 0.50) (see Figure 5D ). Pooled febrile episode rate after one and two SARS-CoV-2 vaccine doses were 5.5% (95% CI 3.6-8.4) and 14.5% (95% CI 9.2-22), respectively, with high heterogeneity (I 2 = 97.97%). There was a significant difference in the pooled febrile rate rates between one and two doses (p < 0.0001) (see Figure 5E ). Pooled arthralgia rate after one and two SARS-CoV-2 vaccine doses were 9.9% (95% CI 6.5-14.7) and 9.1% (95% CI 3.3-22.8) with high heterogeneity (I 2 = 97.12%) (see Figure 5F ). There was no significant difference in pooled arthralgia rates between one and two doses (p = 0.87). Pooled myalgia rate after one and two SARS-CoV-2 vaccine doses were 15.9% (95% CI 9.9-24.4) and 20.5% (95% CI 8.8-40.8) with high heterogeneity (I 2 = 98.3%). There was no significant difference in pooled myalgia rates between one and two doses (p = 0.34) (see Figure 5G ). The quality of the non-randomised studies was assessed using ROBINS-I tool and NIH Quality assessment. Selection bias in surveybased studies included in the analysis. The homogeneous IBD patient cohort in the study by Khan et al (Veterans Affairs Cohort) may have introduced a baseline confounding effect. 29 These results are shown in Figures S4-S5 and Table S1. Sensitivity analysis was performed on the basis of study design Visual inspection of the standard error plots for the severity analysis also suggests symmetry without an underrepresentation of studies of any precision. However, in Egger's regression test the null hypothesis of no small study effects was rejected at p < 0.05 (estimated bias coefficient = 1.56 ± 1.03SE). The funnel plot is shown in Figure S7 . Therefore, further studies are necessary to evaluate the influence of the country site with the seroconversion rate. The meta-analysis revealed that the most common adverse event after the first and second dose of COVID-19 vaccine was injection site reaction occurring in more than 50% of patients. Injection site reaction has been reported in approximately 70% and 75.2% after one and two doses respectively. 49 Fatigue and myalgia were also frequently reported in the IBD patients after the second dose of COVID-19 vaccine. Prior study has reported fatigue rate of 30.9% and 53.9% after one and two doses of SARS-CoV-2 vaccination. 49 Similarly, myalgia rate of 19.4% and 44% after one and two doses of SARS-CoV-2 vaccination. 49 The overall pooled severe adverse event rate was around 2%. However, it is likely that this is an over-estimate due to suspected reporting bias as the majority of the studies evaluating adverse events were survey-based studies. Therefore, the current data indicate that the COVID-19 vaccine is safe in the IBD population, lending support to the current gastroenterological society recommendations noted above. The strength of this study is the large number of patients included in the meta-analysis across a high number of prospective, welldesigned studies. In addition, the subgroup analysis and sensitivity, and meta-regression, also added to the robust statistical design. There are also limitations to this meta-analysis. The heterogeneity in regard to immunosuppressive therapies and vaccine type indicates that certain outcomes could not be evaluated with certainty. We attempted to minimise the heterogeneity with regard to the immunosuppressive therapies and were able to explain 90% of the between-study heterogeneity. However, minimising heterogeneity in the evaluation of the adverse events was not feasible. This was due in part to the fact that survey-based studies, which were included for the evaluation of adverse events, have inherent limitations. 50 Additionally, there is a lack of randomised control group to evaluate the serious adverse events accurately in IBD population. It is also important to recognise that the studies utilised different assays to assess for the antibodies against SARS-CoV-2 which could also influence the outcomes. Even though, some of the assays are comparable, 51 further studies are necessary to compare the seroconversion rate between different assays for SARS-CoV-2 antibody measurement. The impact of booster dose and the seroconversion rate against SARS-CoV-2 variants (such as Omicron) also needs to be evaluated in patients with IBD. Additionally, it is important to note that breakthrough infections could still occur despite seroconversion after vaccination due to behavioural risk factors. 52 Therefore, further studies are necessary to accurately ascertain the adverse event rate, breakthrough infection and seroconversion rate with SARS-CoV-2 vaccine in IBD. In summary, this systematic review and meta-analysis shows that the overall seroconversion rate after COVID-19 vaccination in IBD patients is high and improves with a second dose, with no statistical differences in antibody response associated with different im- use, as well as the impact of the third 'booster' dose of the mRNA vaccines specifically in IBD patients, would be of great value. We certify that we have no financial affiliation/interest (eg employment, stock holdings, consultant arrangements, honoraria in the subject matter, materials or products mentioned in this manuscript). The manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work Abhishek Bhurwal: Conceptualization (lead); data curation (lead); formal analysis (lead); investigation (lead); software (lead); writing -origi- Declaration of funding interests: Dr. Bhurwal was supported by educational grant from Takeda. The data that support the findings of this study are available from the corresponding author upon reasonable request. Abhishek Bhurwal https://orcid.org/0000-0002-3886-7537 Hemant Mutneja https://orcid.org/0000-0001-9950-5161 Gursimran Kochhar https://orcid.org/0000-0002-0597-2760 Lea Ann Chen https://orcid.org/0000-0003-4675-9453 Engineering at Johns Hopkins. COVID-19 Map -Johns Hopkins Coronavirus Resource SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial The four epidemiological stages in the global evolution of inflammatory bowel disease Impact of inflammatory bowel disease on quality of life: results of the European Federation of Crohn's and ulcerative colitis associations (EFCCA) patient survey Family caregivers' burden in inflammatory bowel diseases: an integrative review Risk factors for opportunistic infections in patients with inflammatory bowel disease AGA clinical practice update on Management of Inflammatory Bowel Disease during the COVID-19 pandemic: expert commentary Secure-IBD Database Systematic review on inflammatory bowel disease patients with coronavirus disease 2019: it is time to take stock SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: recommendations from an international consensus meeting SARS-CoV-2 vaccination for patients with inflammatory bowel disease: a British Society of Gastroenterology Inflammatory Bowel Disease section and IBD clinical research group position statement The advisory committee on immunization Practices' interim recommendations for additional primary and booster doses of COVID-19 vaccines -United States Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD Humoral immune response to messenger RNA COVID-19 vaccines among patients with inflammatory bowel disease Serologic response to messenger RNA coronavirus disease 2019 vaccines in inflammatory bowel disease patients receiving biologic therapies Antibody response to SARS-CoV-2 vaccination in patients with inflammatory bowel disease -results of a single-center cohort study in a tertiary hospital in Germany Humoral immunogenicity of mRNA COVID-19 vaccines among patients with inflammatory bowel disease and healthy controls Impact of SARS-CoV-2 vaccination on inflammatory bowel disease activity and development of vaccine-related adverse events: results from PREVENT-COVID Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions Study Quality Assessment Tools Comprehensive Meta-analysis Version 3 Updated guidance for trusted systematic reviews: a new edition of the Cochrane handbook for systematic reviews of interventions BNT162b2 messenger RNA COVID-19 vaccine effectiveness in patients with inflammatory bowel disease: preliminary realworld data during mass vaccination campaign COVID-19 vaccination is safe and effective in patients with inflammatory bowel disease: analysis of a large multi-institutional research network in the United States Effectiveness of SARS-CoV-2 vaccination in a veterans affairs cohort of patients with inflammatory bowel disease with diverse exposure to immunosuppressive medications Decreased antibody responses to Ad26.COV2.S relative to SARS-CoV-2 mRNA vaccines in patients with inflammatory bowel disease Seroconversion following SARS-CoV-2 infection or vaccination in pediatric IBD patients Immunogenicity of BNT162b2 vaccine in patients with inflammatory bowel disease on infliximab combination therapy: a multicenter prospective study Impact of inflammatory bowel disease therapies on durability of humoral response to SARS-CoV-2 vaccination Antibody responses after SARS-CoV-2 mRNA vaccination in adults with inflammatory bowel disease Anti-SARS-CoV-2 vaccination and antibody response in patients with inflammatory bowel disease on immune-modifying therapy: prospective single-tertiary study T cell response after SARS-CoV-2 vaccination in immunocompromised patients with inflammatory bowel disease Risk of adverse events and reported clinical relapse after COVID-19 vaccination in patients with IBD Safety of COVID-19 vaccination in inflammatory bowel disease patients on biologic therapy COVID-19 vaccine is effective in inflammatory bowel disease patients and is not associated with disease exacerbation Lower serologic response to COVID-19 mRNA vaccine in patients with inflammatory bowel diseases treated with anti-TNFalpha COVID-19 vaccination and inflammatory bowel disease: desired antibody responses, future directions, and a note of caution Response to SARS-CoV-2 vaccination in immune mediated inflammatory diseases: systematic review and meta-analysis An mRNA vaccine against SARS-CoV-2 -preliminary report Interim results of a phase 1-2a trial of Ad26.COV2.S Covid-19 vaccine Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity Comparative effectiveness of BNT162b2 and mRNA-1273 vaccines in U.S Veterans Differences in IgG antibody responses following BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines Reactogenicity following receipt of mRNA-based COVID-19 vaccines The limitations of online surveys Characteristics of three different chemiluminescence assays for testing for SARS-CoV-2 antibodies Behavioral risk factors and adherence to preventive measures: evidence from the early stages of the COVID-19 pandemic Additional supporting information will be found online in the Supporting Information section.