Immunogenicity of COVID-19 Vaccine in Patients With Inflammatory Bowel Disease

The overall objective of this proposal is to evaluate the safety and immunogenicity of a COVID-19 vaccine in patients with Inflammatory Bowel Disease (IBD). This will help determine if immunosuppressive regimens impact COVID-19 vaccine response. The investigators will determine if certain groups may need more doses of a vaccine, with future adjuvanted vaccines or require a booster to maintain immunity. 260 participants with IBD and scheduled to get a COVID-19 vaccine will be recruited and can expect to be on study for 18 months.

Study Overview

• Status: Completed
• Conditions: IBD; Covid19 Vaccine
• Intervention / Treatment: Diagnostic test: Serological Assay for SARS-CoV-2

Detailed Description

COVID-19 has a variable spectrum of illness with the majority of infection resulting in asymptomatic or mild disease. However certain healthy adults and immunosuppressed populations can develop severe or critical symptoms that require hospitalization or intensive care stay. Emerging evidence suggest that certain immunosuppressive medications used to treat patients with IBD such as anti-tumor necrosis factor (TNF) do not appear to confer an increased risk for severe COVID-19, but the risk appears to be higher for other agents such as corticosteroids. The efficacy of a candidate COVID-19 may be lower in immunosuppressed patients with IBD, since these patient populations may have lower responses to vaccines. Multiple studies have shown that patients with IBD have variability in their vaccine responses compared to healthy individuals. While many patients have a normal vaccine response, those treated with TNF agents or combination therapy (TNF inhibitors and immunomodulators) are more likely to mount a poor immune response. Furthermore, preliminary data suggest some novel regimens (such as vedolizumab) may not impact the immune response but there is insufficient data to know their impact on vaccine response. Thus, there is a critical need to determine whether patients with IBD will mount normal immune responses to a COVID-19 vaccine.

This is a single center cross sectional clinical study of 260 patients with IBD who are receiving the COVID-19 vaccine as standard of care. After obtaining informed consent, individuals who meet the inclusion criteria and none of the exclusion criteria will be invited to participate in the study.

Aim 1. Determine the immunogenicity and safety of a COVID-19 vaccine in patients with IBD. To achieve this aim, the investigators will perform a prospective study evaluating the immunogenicity of a COVID-19 vaccine in 260 patients with IBD.

• Hypothesis: Systemic immunosuppressive regimens such as Anti-TNF in combination with an immunomodulator, associated with the lowest vaccine response, or other systemic immunosuppressive regimens will blunt the immunogenicity of a COVID-19 vaccine while other agents such as vedolizumab or aminosalicylates will not affect the vaccine response.

Aim 2. Determine the impact of systemic immunosuppression on sustained antibody COVID-19 concentrations in patients with IBD who received the COVID-19 vaccine. To achieve this aim, the investigators will evaluate sustained antibody concentrations using a quantitative assay from LabCorp that is currently being used by the Centers for Disease Control and Prevention (CDC) to evaluate seroprevalence and study immunity at 1, 6, 12, and 18 months after completion of vaccination. Labcorp activities are provided as a fee for service. Follow up In-Person visit 1 (one month visit) will be optional and participants can enter the study at the six months study visit (Follow up In-Person visit 2) or at approximately 1-2 month post third dose of the COVID-19 vaccine which has been approved for patients with IBD. The 12 month visit (Follow up In-Person visit 3) may be replaced by a 6 month post 3rd dose vaccine if participants received one booster, or1-2 months post a 4th dose vaccine if participants received a second booster. The 18 month visit (Follow up In-Person visit 4) may substitute for a 12, 6, or 1-2 months post vaccine, depending on when and how many boosters the participant received.

• Hypothesis: Vaccine-induced antibody concentrations will wane over the 12 month interval faster than the published rate in healthcare workers.

At the completion of the proposed research, the safety and immunogenicity of a COVID-19 vaccine in immunosuppressed patients with IBD will be determined.

Protocol Amendment Approved 2/24/2022 changes time points of data collection to 18 months post-2nd dose, 9 month post-3rd dose, or 3-4 months post-4th dose.

Protocol Amendment Approved 4/19/2022 changes time points of data collection to 18 months post-2nd dose, 12 month post-3rd dose, or 6 months post-4th dose.

Protocol Amendment Approved 6/21/2022 indicates that follow up In-Person Visit 4 (will occur from July-October 2022 prior to a Fall 2022 COVID-19 booster. This blood draw can occur at any time after completion of any doses of a COVID-19 vaccine series). For participants who have not completed Visit 3 prior to July 2022, Visit 3 will be their last blood draw, which can occur from July-October 2022 prior to a Fall 2022 COVID-19 booster. This blood draw can occur at any time after completion of any doses of a COVID-19 vaccine series).

• Study Type: Observational
• Enrollment (Actual): 222

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Participants with IBD and scheduled to receive a COVID-19 vaccine will be recruited from the University of Wisconsin Hospital and Clinics if they meet the inclusion and exclusion criteria.

• Group A IBD patients on non-systemic immunosuppressive therapy: no therapy or aminosalicylates or vedolizumab therapy
• Group B IBD patients on systemic immunosuppression

Patients in both groups will have been on stable treatment for IBD for at least two months.

Description

Inclusion Criteria:

For mRNA cohort:

• Participant has a history of ulcerative colitis (UC) or Crohn's disease diagnosed by standard clinical, radiographic, endoscopic, and histopathologic criteria.

• On one of the following treatment regimens:

  • Group A: Non-systemic immunosuppressive Group at least 75 participants

    • Mesalamine monotherapy or no therapy for IBD
    • Vedolizumab Therapy Group: on either vedolizumab monotherapy or combination therapy with methotrexate or azathioprine

  • Group B: Systemic immunosuppressive Group at least 75 participants

    • Thiopurine Therapy Group: on azathioprine at least 2.0mg/kg or 6MP 1.0mg/kg
    • Anti-TNF Therapy Group: on maintenance therapy infliximab (at least 8 every 8 weeks), golimumab (at least monthly), adalimumab (at least every 2 weeks), or certolizumab (at least monthly)
    • Anti-TNF Combination Therapy Group: on anti-TNF therapy as described above along with either 15mg of methotrexate or azathioprine at least 1.0mg/kg or 6MP 0.5mg/kg
    • Ustekinumab Therapy Group: on either ustekinumab monotherapy or combination therapy with methotrexate or azathioprine.
    • Tofacitinib Therapy Group: on tofacitinib at least 5mg PO BID
    • Corticosteroid Therapy Group: on any one of the systemic immunosuppressive groups and any dose of corticosteroids
• Participant has been on the same IBD treatment for at least two months.
• Participant is receiving an mRNA COVID-19 vaccine per standard of care recommended by their clinical provider or has started the COVID-19 series or finished the mRNA COVID-19 vaccine series within the past six months and would qualify for six month study visits or has received a third dose of the vaccine as standard of care.
• Participants entering in the study at the six month study visit must have been on same treatment at their time of immunization.

For Viral vector cohort:

• Participant has a history of ulcerative colitis (UC) or Crohn's disease diagnosed by standard clinical, radiographic, endoscopic, and histopathologic criteria.

• On one of the following treatment regimens:

  • Group A: Non-systemic immunosuppressive Group at least 15 participants

    • Mesalamine monotherapy or no therapy for IBD
    • Vedolizumab Therapy Group: on vedolizumab monotherapy

  • Group B: Systemic immunosuppressive Group at least 15 participants

    • Thiopurine Therapy Group: on azathioprine at least 2.0mg/kg or 6MP 1.0mg/kg
    • Anti-TNF Therapy Group: on maintenance therapy infliximab (at least 8 every 8 weeks), golimumab (at least monthly), adalimumab (at least every 2 weeks), or certolizumab (at least monthly)
    • Anti-TNF Combination Therapy Group: on anti-TNF therapy as described above along with either 15mg of methotrexate or azathioprine at least 1.0mg/kg or 6MP 0.5mg/kg
    • Ustekinumab Therapy Group: on either ustekinumab monotherapy or combination therapy with methotrexate or azathioprine.
    • Tofacitinib Therapy Group: on tofacitinib at least 5mg PO BID
    • Corticosteroid Therapy Group: on any one of the systemic immunosuppressive groups and any dose of corticosteroids
• Participant has been on the same IBD treatment for at least two months.
• Participant is receiving a viral vector COVID-19 vaccine per standard of care or has started or finished the viral vector series within the past 6 months. If participant entering at six months and would qualify for six month study visits and has received an additional one or two dose of viral vector of mRNA for a total of two -three COVID vaccines as standard of care.
• Participants entering in the study at the six month study visit must have been on same treatment at their time of immunization.

Exclusion Criteria:

For mRNA cohort:

• Allergy to COVID-19 vaccine or a component of it
• Participant cannot or will not provide written informed consent
• Unable to provide appropriate informed consent due to being illiterate or impairment in decision-making capacity

For Viral vector cohort:

• Allergy to COVID-19 vaccine or a component of it
• Participant cannot or will not provide written informed consent.
• Unable to provide appropriate informed consent due to being illiterate or impairment in decision-making capacity.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
IBD and Non-Immunosuppressive Group; Clinical diagnosis of IBD, non-systemic immunosuppressive therapies, and scheduled to take an mRNA vaccine for COVID-19	Diagnostic test: Serological Assay for SARS-CoV-2; LabCorp's Cov2Quant IgG™ assay which uses immunoassay that uses electrochemiluminescent technology (ECL) for quantitative determination of anti-receptor binding domain (RBD) IgG antibodies specific to SARS-CoV-2.
IBD and Immunosuppressive Group; Clinical diagnosis of IBD, treated with systemic immunosuppressive therapies, and scheduled to take an mRNA vaccine for COVID-19	Diagnostic test: Serological Assay for SARS-CoV-2; LabCorp's Cov2Quant IgG™ assay which uses immunoassay that uses electrochemiluminescent technology (ECL) for quantitative determination of anti-receptor binding domain (RBD) IgG antibodies specific to SARS-CoV-2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Geometric Mean Titers (GMT) of SARS-CoV-2 Antibody Concentrations following mRNA COVID-19 vaccine series	The primary endpoint will be evaluating the change in humoral immunity between the immunosuppressive and non-immunosuppressive IBD treatment regimens following the recommended doses mRNA COVID-19 vaccine series.	baseline to 18 months post-2nd dose, 12 months post-3rd dose, or 6 months post-4th dose
Sustained antibody concentrations of mRNA COVID-19 vaccines	The investigators will evaluate sustained antibody concentrations of mRNA COVID-19 vaccines by using a quantitative assay from LabCorp that is currently being used by the CDC to evaluate seroprevalence.	18 months post-2nd dose
Sustained antibody concentrations of mRNA COVID-19 vaccines	The investigators will evaluate sustained antibody concentrations of mRNA COVID-19 vaccines by using a quantitative assay from LabCorp that is currently being used by the CDC to evaluate seroprevalence.	12 months post-3rd dose
Sustained antibody concentrations of mRNA COVID-19 vaccines	The investigators will evaluate sustained antibody concentrations of mRNA COVID-19 vaccines by using a quantitative assay from LabCorp that is currently being used by the CDC to evaluate seroprevalence.	6 months post-4th dose
Change in level of T-cell response after mRNA COVID-19 vaccine	Investigators will evaluate sustained cell mediated immunity against Covid-spike proteins after completing the vaccine schedule of a mRNA COVID-19 vaccine.	18 months post-2nd dose, 12 months post-3rd dose, or 6 months post-4th dose
Percentage of participants with detectable level of T-cell response after mRNA COVID-19 vaccine	For each patient, peripheral blood monocytes (PBMCs) will be isolated. IFN-ϒ ELISpot, which detects both CD4 and CD8 T cell effectors, will be used to detect T-cell immunity to the Covid-spike protein or peptides. The plates will be read on an AID ELISpot reader (Cell Technology, Inc., Columbia MD, reader software v.3.1.1.). A positive response to antigen will be defined as a frequency that was significantly (p < 0.05, two-tailed t test) greater than the mean of control no-antigen wells and detectable (i.e., >1:100,000). T cell responses will be correlated to Covid-19 neutralizing antibody responses.	18 months post-2nd dose, 12 months post-3rd dose, or 6 months post-4th dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events	Safety will be assessed by the incidence of adverse events (AEs and SAEs) related to the vaccine.	up to 1 month post final immunization
Patient reported outcome 3 (PRO3) score	Safety will be assessed by monitoring the PRO3 scores at baseline and 1 month post-vaccination. PRO-3 is a measure of overall well-being as well as specific symptoms and complications of CD, such as stool frequency, abdominal pain and general well being. Greater PRO3 scores indicate more severe CD symptoms.	baseline, 18 months post-2nd dose, 12 months post-3rd dose, or 6 months post-4th dose
Simple Colitis Activity Index (SCAI) Questionnaire Score	For participants with Ulcerative Colitis (UC), safety will be assessed by monitoring the SCAI score at baseline and 1 month post-vaccination. SCAI is a measure of overall well-being as well as specific symptoms and complications of UC, such as stool frequency and abdominal pain. The total possible range of scores is 0-21, with higher scores indicative of increased symptoms.	baseline, 18 months post-2nd dose, 12 months post-3rd dose, or 6 months post-4th dose
Seroconversion: assessed by percentages of participants with ≥4-fold rise in antibody titer	Percentages (and 2-sided 95% CIs) of participants with ≥4-fold rise will be assessed for the COVID-19 vaccine within each group.	1 month post-immunization
Change in Geometric Mean Titers (GMT) of SARS-CoV-2 Antibody Concentrations following two doses of viral vector COVID-19 vaccine series	The primary endpoint will be evaluating the change in humoral immunity between the immunosuppressive and non-immunosuppressive IBD treatment regimens following the two doses viral vector COVID-19 vaccine series.	baseline,18 months post-2nd dose, 12 months post-3rd dose, or 6 months post-4th dose
Sustained antibody concentration of viral vector COVID-19 vaccines	The investigators will evaluate sustained antibody concentrations of viral vector COVID-19 vaccines by using a quantitative assay from LabCorp that is currently being used by the CDC to evaluate seroprevalence.	18 months post-2nd dose, 12 months post-3rd dose, or 6 months post-4th dose
Percentage of participants with detectable level of T-cell response after viral vector COVID-19 vaccine	For each patient, peripheral blood monocytes (PBMCs) will be isolated. IFN-ϒ ELISpot, which detects both CD4 and CD8 T cell effectors, will be used to detect T-cell immunity to the Covid-spike protein or peptides. The plates will be read on an AID ELISpot reader (Cell Technology, Inc., Columbia MD, reader software v.3.1.1.). A positive response to antigen will be defined as a frequency that was significantly (p < 0.05, two-tailed t test) greater than the mean of control no-antigen wells and detectable (i.e., >1:100,000). T cell responses will be correlated to Covid-19 neutralizing antibody responses.	18 months post-2nd dose, 12 months post-3rd dose, or 6 months post-4th dose
Change in level of T-cell response after viral vector COVID-19 vaccine	Investigators will evaluate sustained cell mediated immunity against Covid-spike protein after completing the vaccine schedule of a viral vectors vaccine.	18 months post-2nd dose, 12 months post-3rd dose, or 6 months post-4th dose
Presence of SARS-CoV2 anti-nucleocapside antibody : Yes/No	To evaluate the rate of asymptomatic COVID-19 infections in patients with IBD, investigators will evaluate the presence for anti-nucleocapside antibody in participants at baseline and/or 1 month visit after immunization to evaluate the rate of asymptomatic infection in our cohort. A SARS-CoV2 anti-nucleocapside antibody is not induced by vaccine so it's presence means there was a presence of a previous infection.	baseline, 18 months post-2nd dose, 12 months post-3rd dose, or 6 months post-4th dose

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Investigators: Principal Investigator: Freddy Caldera, DO, MS, UW School of Medicine and Public Health

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2021
• Primary Completion (Actual): November 11, 2022
• Study Completion (Actual): November 11, 2022

Study Registration Dates

• First Submitted: March 25, 2021
• First Submitted That Met QC Criteria: March 25, 2021
• First Posted (Actual): March 26, 2021

Study Record Updates

• Last Update Posted (Estimate): December 7, 2022
• Last Update Submitted That Met QC Criteria: December 5, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; COVID-19; Inflammatory Bowel Diseases
• Other Study ID Numbers: 2021-0043; SMPH/MEDICINE/GASTROENT (Other Identifier: UW Madison); A534250 (Other Identifier: UW Madison); Protocol Version 6/6/2022 (Other Identifier: UW Madison); MSN252947 (Other Grant/Funding Number: AMERICAN COLLEGE OF GASTROENTEROLOGY); MSN253788 (Other Grant/Funding Number: TAKEDA PHARMACEUTICALS USA INC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No