Table 2 An overview of studies included in this systematic scoping review and their main findings

Botwin et al. [17]

Adverse Events After SARS-CoV-2 mRNA Vaccination Among Patients With Inflammatory Bowel Disease

To evaluate post-mRNA vaccination adverse events in vaccinated adults with IBD patients.

246 (67% CD, 33% indeterminate or UC)

Prospective web-based survey in a longitudinal vaccine registry

Sulfasalazine/mesalamine, budesonide, oral/parenteral Steroids, Mercaptopurine Azathioprine monotherapy, Methotrexate monotherapy, anti- Tumor necrosis factor (TNF) without Mercaptopurine/ Azathioprine/ methotrexate, anti-TNF + Mercaptopurine/ Azathioprine/ Methotrexate, anti-integrin, IL12/23 inhibitor Janus kinase (JAK) inhibitor, Mesalamine

Pfizer, Moderna

Similar to general population

More common among younger patients

More common in patients with prior Covid-19

Less common in patients receiving biologic therapy Age was associated with side effects after dose 1 (OR = 0.97, P = 0.015), suggesting reduced AE risk with each year of advancing age

Significant side effects associations after dose 2 included age (OR = 0.97, P = 0.018) and biologic status (OR = 0.32, P = 0.049), suggesting a reduced side effects risk among biologic recipients, independent of age

Injection-site symptoms, Fatigue/malaise, Headache/dizziness/lightheadedness, fever/chills, Muscle/bone/joint/nerve symptoms, Gastrointestinal symptoms (including nausea, vomiting, diarrhea), Sleep changes, Swollen lymph node, Skin/nail or face changes, Eye/ear/mouth/throat changes, cough, chest/breathing symptoms, memory/ mood changes

IBD and other immune-mediated inflammatory diseases on immunosuppressive and biologic therapies can be reassured that the adverse events risk is likely not increased, and may be reduced, while on biologics.

III

Caldera et al. [14]

Humoral Immunogenicity of mRNA Covid-19 Vaccines Among Patients With Inflammatory Bowel Disease and Healthy Controls

To evaluate humoral immunogenicity of mRNA coronavirus disease 2019 (Covid-19) vaccines among patients with IBD and healthy controls.

182 (122 in IBD group, 60 in control group)

Prospective study

Mesalamine monotherapy,

Vedolizumab monotherapy,

Thiopurine,

Anti-TNF therapy,

Anti-TNF combination,

Ustekinumab monotherapy

or combination,

Tofacitinib,

Corticosteroid therapy

Moderna, Pfizer

All control group and 97% of patients with IBD developed antibodies

Antibody concentrations were lower in patients with IBD

Those who received Moderna had higher antibody concentrations compared with those who received the Pfizer vaccine series

Patients on immunemodifying therapy had lower antibody concentrations compared with those who were on no treatment, aminosalicylates, or vedolizumab

Not reported

Almost all patients with IBD in our study mounted an antibody response.

II

Cerna et al. [28]

Anti-SARS-CoV-2 Vaccination and Antibody Response in Patients With Inflammatory Bowel Disease on Immune-modifying Therapy: Prospective Single-Tertiary Study

To evaluate the rate and magnitude of seroconversion, assess the effect of different immune-modifying treatment modalities on the magnitude of anti-SARS-CoV-2 IgG antibody levels, and analyze the impact of anti-SARS-CoV-2 vaccination on the inflammatory biomarkers of IBD.

770 (602 in IBD group, 168: control group)

Prospective study

Infliximab, Adalimumab, Vedolizumab, Ustekinumab, Tofacitinib, Thiopurines monotherapy,

5-ASA monotherapy

Pfizer, Moderna,

AstraZeneca

The post vaccine seropositivity rate among IBD patients and controls was 97.8% vs 100%

Median anti-Covid-19 IgG levels were lower among IBD recipients of AstraZeneca compared with 2 other vaccines and control AstraZeneca recipients

No correlation was found between serum trough levels and anti-Covid-19 IgG concentrations for any of the biological drugs used

The TNF-α inhibitors with concomitant immunosuppressive treatment but no other treatment modalities were associated with a lower postvaccination antibody response

The laboratory activity of IBD evaluated by C-reactive protein and fecal calprotectin levels, and no significant differences were found before the vaccination and 8 weeks after its completion

Not reported

It is necessary to particular attention to the anti-Covid-19 vaccination of IBD patients treated with TNF-α inhibitors with concomitant immunomodulators

IBD patients can continue their high-efficacy immune-modifying therapy even during the anti-SARS-CoV-2 vaccination

In limited access areas, patients with IBD should be encouraged to receive any readily available vaccine

mRNA vaccines are preferred for patients with IBD.

II

Classen et al. [18]

Anti-SARS-CoV-2 Vaccination and Antibody Response in Patients With Inflammatory Bowel Disease on Immune-modifying Therapy: Prospective Single-Tertiary Study

To investigate antibody response to SARS-CoV-2 vaccination in patients with IBD receiving immunomodulators or biologics compared to healthy controls.

144 (72 in IBD group: 55.6% CD and 44.4% UC, and 72 in control group)

Retrospective observational design

Steroids, Mesalazine, Azathioprine, Methothrexate, Calcineurin inhibitor, TNF blocker, Integrin inhibitor, JAK inhibitor, Ustekinumab

Pfizer, Moderna,

AstraZeneca

All patients with IBD developed an immune response after full vaccination

There was no significant difference in antibody levels between the 3 different vaccines received upon first vaccination

Compared to the healthy group, reduced antibody response could be detected

There was no vaccination failure in the IBD group after 2 vaccinations

There was a trend to a reduced immune response in elderly patients

Muscle pain, Fever, Joint pain, Local redness, Pain injection side, Fatigue, Nausea/vomiting, Diarrhea

A 100% antibody response to vaccination against Covid-19 in patients with IBD and immunomodulatory therapies after 2 vaccinations. Antibody response was high in IBD patients even after the first vaccination – however, antibody levels were lower in IBD patients compared to controls. Overall, vaccination was well tolerated and no further or new adverse events were detected in IBD patients compared to healthy controls.

III

Edelman-Klapper et al. [19]

Lower Serologic Response to Covid-19 mRNA Vaccine in Patients With Inflammatory Bowel Diseases Treated With Anti-TNFalpha

To assess serologic responses to BNT162b2 in patients with IBD stratified according to therapy, compared with healthy controls.

258 (185 in IBD group, 73 in control group)

Patients with

IBD were divided to 2 separate groups: anti-TNFa group (67) and non-anti-TNFa group (118)

Prospective controlled study

Infliximab, Adalimumab, Vedolizumab, Ustekinumab, 5-ASA, Corticosteroids, Immunomodulatorsc, JAK inhibitor

Pfizer

Covid- anti-S IgG antibodies in all control group were seropositive, whereas about 7% of patients with IBD, regardless of treatment, remained seronegative after dose 1, and it was positive in all patients after dose 2

Anti-TNFa treatment was associated with significantly lower antibody levels

Neutralizing and inhibitory functions were both lower in anti-TNFa treated

Anti-TNFa drug levels and vaccine responses did not affect anti-spike levels

IBD activity was unaffected by vaccination

Only anti-TNFa treatment and older age maintained a significant distinct association with lower IgG anti-S response

Local pain, Headache

All patients mounted serologic response to 2 doses of vaccination. Its magnitude was significantly lower in patients treated with anti-TNFa, 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.

II

Garrido et al. [20]

"Safety of Covid-19 vaccination in inflammatory bowel disease patients on biologic therapy"

To assess adverse events of Covid-19 vaccination among IBD patients.

239 (76.7% CD and 23.3% UC)

Cohort/ real-life survey: telephone questionnaire

TNF inhibitors, Ustekinumab, Vedolizumab

Pfizer, Moderna, Janssen and AstraZeneca

Not reported

Pain /redness/

Swelling

State of sleep/fatigue

Headache

Myalgia

Fever

Joint pain

Nausea/vomiting

Diarrhea

Abdominal pain

IBD exacerbation

A high acceptance rate and a good safety profile of Covid-19 vaccination in IBD patients treated with biologics

Adverse effects were common but overall mild and transitory.

IV

Hadi et al. [21]

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

To assess safety and efficacy of Covid-19

vaccination in patients with IBD in comparison

with the general population without IBD.

864,575,

(5562 patients

with prior diagnosis of IBD: 2933 UC, 2629 CD)

Retrospective study

Biologics/thiopurines

Pfizer, Moderna

Similar in adverse events of special interest and a new diagnosis of Covid-19 in two groups

Similar in the 30-day hospitalization after the Covid-19 vaccination, after matching

Similar in steroid prescription at the 1 month follow-up in vaccinated and unvaccinated patients with IBD in unmatched and matched analysis

Similar in 30-day adverse events of special interest after the vaccination between patients with IBD with and without biologic or immunomodulator use, and also between patients with CD and UC

Similar in steroid use after vaccination was found between patients with and without biologic or immunomodulator use, or both, and between patients with CD and UC

Special adverse events of interest include: acute myocardial infarction, anaphylaxis, facial nerve palsy, coagulopathy, deep vein thrombosis, pulmonary embolism, Guillain-Barré syndrome, transverse myelitis, immune thrombocytopenia, disseminated intravascular coagulation, myocarditis, pericarditis, hemorrhagic stroke, nonhemorrhagic stroke, appendicitis, narcolepsy, and encephalomyelitis

Incidence

of Covid-19 in patients with IBD after vaccination is

very low, including patients on immunosuppressive agents,

and is similar to population without IBD.

III

Kappelman et al. [22]

Humoral Immune Response to Messenger RNA Covid-19 Vaccines Among Patients With Inflammatory Bowel Disease

To assess serologic response after completion of the 2-part mRNA vaccination series in a geographically diverse US IBD population.

317

Prospective study

5ASA, Sulfasalazine, Budesonide, Vedolizumab

monotherapy Ustekinumab

monotherapy, Mercaptopurine, Azathioprine, Methotrexate, Anti-TNF monotherapy, Anti-TNF combination therapy

Pfizer, Moderna

Antibody response was decreased in IBD patients receiving systemic corticosteroids

The proportion of detectible antibodies was 85% among steroid users versus 95% among non-steroid users

Antibody response was generally similar across age group, vaccine type, and use of other classes of IBD medications

Not reported

Two doses of mRNA Covid-19 vaccine in a geographically diverse cohort of over 300 patients with IBD, most had detectable antibody responses after the second dose

Most patients mount detectable humoral immune response to mRNA vaccinations and support current recommendations to vaccinate patients regardless of immunosuppressive treatment.

IV

Kennedy et al. [23]

Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD

To investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single

dose of a Covid-19 vaccine.

1293 (Infliximab

:865,

Vedolizumab-treated

patients: 428)

Prospective study

Infliximab, Vedolizumab

Pfizer, AstraZeneca

The concentration of anti-Covid-19 antibody were lower in patients treated with infliximab than vedolizumab, following vaccination

Multivariable models showed that antibody concentrations were lower in patients on infliximab compared with vedolizumab

Age ≥ 60 years, immunomodulator use, Crohn’s disease and smoking were associated with lower anti-body concentration

Non-white ethnicity was associated with higher Covid-19 antibody concentrations

Seroconversion rates after a single dose of either vaccine were higher in patients with prior Covid-19 infection and after two doses of Pfizer vaccine

Not reported

Infliximab is associated with attenuated immunogenicity to a single dose of Covid-19 vaccines. Vaccination after Covid-19 infection, or a second dose of vaccine led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab.

IV

Lev-Tzion et al. [10]

Covid-19 Vaccine Is Effective in Inflammatory Bowel Disease Patients and Is Not Associated With Disease Exacerbation

To explore the effectiveness of Covid-19 vaccination in IBD and to assess its effect on disease outcomes.

4946

Prospective study

Mesalamine,

Corticosteroid,

Immunomodulator,

Anti-TNF,

Vedolizumab,

Ustekinumab,

Tofacitinib

Pfizer

Overall, 0.3% developed Covid-19 after vaccination (OR = 1)

Infection rates were slightly higher in the unvaccinated IBD patients

Patients on tumor necrosis factor (TNF) inhibitors and/or corticosteroids did not have a higher incidence of infection

No difference in disease outcome was seen during the first 40 days after the second vaccination, however time to flare was shorter in vaccinated compared with unvaccinated IBD patients

The risk of exacerbation was 29% in the vaccinated patients compared with 26% in unvaccinated patients, but it was similar statistically

Covid-19 vaccine effectiveness in IBD patients is comparable with that in non-IBD controls and is not influenced by treatment with TNF inhibitors or corticosteroids. The IBD exacerbation rate did not differ between vaccinated and unvaccinated patients.

III

Levine et al. [29]

COVID-19 Vaccination and Inflammatory Bowel Disease: Desired Antibody Responses, Future Directions, and a Note of Caution

To assess Covid-19 nucleocapsid and spike domain antibodies

using a commercially

available ELISA assay among consecutively

tested postvaccination patients with IBD on biologic or

immunomodulator therapy.

19 patients

Prospective study

Biologic therapies: Infliximab, Adalimumab, Golimumab, Ustekinumab, Vedolizumab, Tofacitinib, Methotrexate

Pfizer, Moderna

A 95% overall response rate were observed

In patients with elevated spike domain antibodies (a true vaccine response rather than prior undiagnosed infection), 89% (17/19) had the highest measurable levels, at > 250.00 U/mL, with assay reference ranges of 0.79 U/mL indicating negative and 0.80 U/mL (positive results)

Not reported

Time and vaccine availability will lead to the same approach with regard to Covid-19

patients.

IV

Pozdnyakova et al. [24]

Decreased Antibody Responses to Ad26.COV2.S Relative to SARS-CoV-2 mRNA Vaccines in Patients With Inflammatory Bowel Disease

To assess for differences in serologic responses among patients with IBD who received Ad26.CoV2.S relative to those receiving mRNA-1273 or BNT162b2.

353

Prospective study

Immune-modifying therapies

(IMTs), as defined by receipt of advanced therapies (biologics

or JAK inhibitors), Immunomodulators, and/or systemic Corticosteroids

Moderna, Pfizer,

Johnson & Johnson

Two weeks after vaccination, positive antibody levels were detected in more than 90% of IBD patients

At week 2, only vaccine type was associated with antibody levels, with both Moderna and Pfizer having significantly higher levels than Jahnson & Jahnson

At week 8, vaccine type remained independently associated with antibody levels

Lower titers were independently associated with both a longer duration between completion of vaccine regimen and blood sampling and IMT receiving

Not reported

Positive levels of IgG(S) were achieved in virtually all IBD vaccine recipients regardless of vaccine type and IMT use.

IV

Rodriguez-Martino et al. [25]

Early immunologic response to mRNA COVID-19 vaccine in patients receiving biologics and/or immunomodulators

To evaluate humoral and cellular response to Covid-19 vaccines in patients with IBD using biologic and/or immunomodulatory therapies.

19 (CD, 2 UC)

Prospective study

Biologic monotherapy, Azathioprine

Pfizer

Total IgG antibodies increased 21.13 times after dose 1 and 90 times after dose 2

VTN% increased 11.92 times after dose 1 and 53.79 times after dose 2

Total IgG antibodies and VTN% were lower in IBD patients after dose 2

IgG antibodies increased after dose 2, but remained lower than controls

VTN% were similar to controls after dose 2

CD4 and CD8 mean levels had an upward trend after vaccinationn

Not reported

Neutralizing capacity response to the vaccine in subjects was similar to a healthy cohort in spite of lower increases in total IgG antibodies. The CD4 and CD8 results observed may support the capacity to mount an effective cellular response in patients on biologics.

IV

Shehab et al. [26]

Serological Response to BNT162b2 and ChAdOx1 nCoV-19 Vaccines in Patients with Inflammatory Bowel Disease on Biologic Therapies

To measure the serological response to BNT162b2 and ChAdOx1 nCoV-19 vaccines in patients with IBD receiving different biologic therapies.

126 (71 CD, 29 UC)

Prospective study

Adalimumab,

Infliximab,

Vedolizumab,  Ustekinumab

Pfizer, AstraZeneca

In patients being treated with infliximab and adalimumab, the proportion of patients who achieved positive anti-Covid-19 IgG antibody levels after receiving two doses of the vaccine were 74.5% and 81.2%

In patients receiving ustekinumab and vedolizumab, the proportion of patients who achieved positive anti-Covid-19 IgG antibody levels after receiving two doses of the vaccine were 100% and 92.8%

In patients receiving infliximab and adalimumab, the proportion of patients who had positive anti-Covid-19 neutralizing antibody levels after two-dose vaccination were 67.7% and 87.5%

The proportion of patients who had positive anti-Covid-19 neutralizing antibody levels were 92.3% and 92.8% in patients receiving ustekinumab and vedolizumab

Not reported

The majority of patients with IBD who were on infliximab, adalimumab, and vedolizumab seroconverted after two doses of Covid-19 vaccination. All patients on ustekinumab seroconverted after two doses of Covid-19 vaccine. The vaccines are likely to be effective after two doses in patients with IBD on biologics.

IV

Wong et al. [27]

Serologic Response to Messenger RNA Coronavirus Disease 2019 Vaccines in Inflammatory Bowel Disease Patients Receiving Biologic Therapies

To evaluated

serologic responses to Covid-19 vaccination with Pfizer and

Moderna in patients with IBD.

91 (48 in IBD group: 23 CD, 25 UC, 43 in control group)

Prospective study

Infliximab monotherapy, Adalimumab monotherapy, Vedolizumab monotherapy, Vedolizumab plus immunomodulator, Ustekinumab, Tofacitinib, Biologic, anya, Corticosteroids, oralb, Immunomodulatorb, Mesalamineb

Moderna, Pfizer

Side effect was not different in vaccinated IBD patients compared vaccinated non-IBD

Anti-TNF were associated with lower anti-RBD total immunoglobulin

Vedolizumab was associated with lower anti-RBD total immunoglobulin, anti-RBD IgG, and anti-S IgG than in control group

Local arm pain/swelling/rash, Myalgia, Arthralgia, Fatigue, Headache, Fever/subjective fever, Chills, Gastrointestinal symptoms, Other rash

Results support the consensus recommendation for IBD patients to receive Covid-19 vaccines when available.

IV