key: cord-0324267-2iul5pxa
authors: Schell, T. L.; Knutson, K. L.; Saha, S.; Wald, A.; Phan, H. S.; Almasry, M.; Chun, K.; Grimes, I.; Lutz, M.; Hayney, M. S.; Farraye, F. A.; Caldera, F.
title: Humoral Immunogenicity of Three COVID-19 mRNA Vaccine Doses in Patients with Inflammatory Bowel Disease
date: 2021-12-27
journal: nan
DOI: 10.1101/2021.12.22.21268217
sha: 1a9dc52b7aa690d1de620c22894a21bebb3d82b8
doc_id: 324267
cord_uid: 2iul5pxa

Summary: Herein, we evaluated the humoral immunogenicity of a third COVID-19 mRNA vaccine dose in patients with IBD. All patients were seropositive and had higher antibody concentrations after the third dose than after completion of the two-dose primary series.

Dr. Freddy Caldera has received research support from Takeda Pharmaceuticals. He has been a consultant for Takeda, Arena Pharmaceuticals, GSK, and Celgene. Dr. Farraye is a consultant for Arena, BMS, Braintree Labs, GSK, Innovation Pharmaceuticals, Iterative Scopes, Janssen, Pfizer and Sebela. He sits on a DSMB for Lilly and Theravance. Dr. Hayney is a consultant for GSK Vaccines and Seqirus and has received research support from Takeda Pharmaceuticals, Dynavax, and Sanofi. Dr. Chun is an employee of LabCorp.

Herein, we evaluated the humoral immunogenicity of a third COVID-19 mRNA vaccine dose in patients with IBD. All patients were seropositive and had higher antibody concentrations after the third dose than after completion of the two-dose primary series.

Inflammatory bowel disease: Crohn's disease: Ulcerative colitis: COVID-19 vaccine

Three safe and effective COVID-19 vaccines were authorized by the Food and Drug Administration in response to the COVID-19 pandemic. Neither patients with inflammatory bowel disease (IBD) nor immunosuppressed patients were included in the original Phase III clinical trials. Studies have since demonstrated a humoral immune response rate of 95-99% following vaccination with a two-dose mRNA vaccine series in patients with IBD. 1, 2 Results show that those on certain immune-modifying therapies, such as anti-tumor necrosis factor (anti-TNF) therapy in combination with an immunomodulator or the use of systemic corticosteroids, exhibit a relatively diminished humoral immune response and a relative decrease in serum antibody concentrations over time. [1] [2] [3] For those who are moderately-to-severely immunocompromised, the Advisory Committee on Immunization Practice (ACIP) recommends a three-dose primary mRNA vaccine series. The aim of this study was to evaluate the humoral immunogenicity of a third COVID-19 mRNA vaccine dose in patients with IBD. We hypothesized that they would mount a significant humoral immune response, and that those on certain immune-modifying therapy, such as systemic corticosteroids or combination therapy, may have lower antibody concentrations.

This was a multicenter, prospective, non-randomized study comprised of patients with IBD and healthy controls (HC) in the "HumoRal and CellULar initial and Sustained immunogenicity in patients with IBD" (HERCULES) cohort. 2 Participants with IBD were enrolled at the University of Wisconsin-Madison (Madison, Wisconsin) and Mayo Clinic (Jacksonville, Florida), while HC were employees of LabCorp. Patient eligibility criteria included a diagnosis of IBD, age 18-85 years, stable doses of maintenance therapy (≥ 2 months), completion of a two-dose mRNA vaccine series confirmed by interview, review of medical records, and if applicable, review of the Wisconsin Immunization Registry. HC eligibility criteria included absence of immunosuppressive therapy and documented completion of a two-dose mRNA vaccine series. A third COVID-19 mRNA vaccine dose was available to patients with IBD but not HC. No participants had clinical history of COVID-19 infection, and those with laboratory evidence of prior infection, as demonstrated by presence of SARS-CoV-2 nucleocapsid antibodies, were excluded.

The primary outcome was total serum SARS-CoV-2 anti-spike IgG antibody concentrations following a third dose compared to antibody concentrations following the two-dose series in the IBD cohort. Secondary outcomes included antibody concentrations following a third dose in patients with IBD compared to antibody concentrations 180 days after the two-dose series in HC. The effects of vaccine manufacturer and immunosuppressive therapy on antibody concentrations following a third dose in patients with IBD were also evaluated. Specific antibodies measured in sera were nucleocapsid and spike protein S1 receptor-binding domain (RDB)-specific IgG antibodies reported as mcg/ml as previously described. 2 In patients with IBD, we measured antibody concentrations 28-35 days (t1) after completion of the two-dose series and 28-65 days (t2) after the third dose. Only patients with IBD who received a third dose had antibody concentrations measured at t2, and not every subject who had antibody concentrations measured at t2 had them measured at t1 due to timing of enrollment. In HC, we measured antibody concentrations 30 days (t1) and 180 days (t2) after completion of the two-dose series.

IBD treatment groups were defined as subjects on stable doses of maintenance therapy as previously described. 2 Non-immunosuppressive therapy was defined as absence of IBD therapy, mesalamine monotherapy, or vedolizumab monotherapy. Immunosuppressive therapy was defined as thiopurine monotherapy (i.e., azathioprine, 6-mercaptopurine), anti-TNF monotherapy, anti-TNF combination therapy (i.e., plus antimetabolite), ustekinumab monotherapy or combination therapy, tofacitinib, or systemic corticosteroid therapy (i.e., any of the aforementioned groups plus systemic corticosteroids). Antibody concentrations between groups were compared using Mann-Whitney U tests. The study received IRB approval at the University of Wisconsin, Mayo Clinic, and LabCorp.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint 

One hundred thirty-nine patients with IBD completed the two-dose series and had antibody concentrations measured at t1, and 85 received a third dose and had antibody concentrations measured at t2 (Table 1) . Forty-six HC completed the two-dose series and had antibody concentrations measured at both timepoints. In the IBD cohort, 48.2% and 51.8% received the two-dose Moderna and Pfizer series, respectively, compared to 93.5% and 6.5% in HC (p<0.001). Two patients with IBD switched from the Moderna two-dose series to the Pfizer third dose. The median age of patients with IBD was significantly lower than that of HC (median 38 (IQR 30-49) vs 42 (IQR 35-58), p=0.033). The age of patients with IBD who received a third dose was significantly greater than that of those who completed only the two-dose series (median 48 (IQR 38-60) vs 41 (IQR 34-52), p=0.003). The characteristics of the groups were otherwise similar.

In patients with IBD, antibody concentrations were significantly higher following a third dose in comparison to the two-dose series (median 68 (IQR 32-147) vs 31 (IQR 16-61), p<0.001) ( Figure 1A ). One hundred thirty-five patients with IBD (97.1%) had detectable antibody concentrations at t1, while all 85 (100%) had detectable antibody concentrations at t2 (p=0.12). Of the two patients with IBD who were seronegative at t1 and received a third dose, each had detectable antibody concentrations (mean 6.25 µg/mL, SD 2.1) at t2; one subject was on anti-TNF monotherapy and the other was on tofacitinib.

At t2, antibody concentrations were similar between patients with IBD on immunosuppressive therapy and non-immunosuppressive therapy (median 69 (IQR 46-159) vs 66 (IQR 28-147), p=0.27) ( Figure 1B) . Further subgroup analysis revealed that those on systemic corticosteroids or anti-TNF combination therapy had significantly lower antibody concentrations at t2 than patients that were not (median 29 (IQR 10-39) vs 72 (IQR 37-164), p<0.001). When adding those on anti-TNF monotherapy to the former group, the difference in median antibody concentrations was reduced but remained statistically significant (median 38 (IQR 20-120) vs 73 (IQR 58-167), p=0.015). Serum antibodies were significantly higher at t2 for patients with IBD who received three Moderna doses compared to those who received three Pfizer doses (median 94 (IQR 38-170) vs 62 (IQR 31-96), p=0.047).

Although HC had higher antibody concentrations compared to IBD subjects at t1 (median 120 (IQR 88-190) vs 31 (IQR 16-61), p<0.001), HC had lower antibody concentrations than IBD subjects at t2 (median 17 (IQR 11-22) vs 68 (IQR 32-147), p<0.001).

All patients with IBD who received a third COVID-19 mRNA vaccine dose were seropositive. Median antibody concentrations were higher following a third dose than after the two-dose series. Patients on corticosteroids and patients on anti-TNF monotherapy or combination therapy had relatively lower antibody concentrations than patients who were not, suggesting that such therapy may blunt the humoral immune response to the vaccine. These findings are similar to those reported in other immunosuppressed patient populations with autoimmune disease, but are distinct from solid organ transplant since all patients seroconverted following three COVID-19 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 27, 2021. ; https://doi.org/10.1101/2021.12.22.21268217 doi: medRxiv preprint mRNA vaccine doses. 4,5 Furthermore, those who completed a three-dose Moderna series had higher antibody concentrations than those who completed a three-dose Pfizer series, which is similar to previously reported findings regarding the two-dose series. 2 There is evidence of waning humoral immunity in the general population following COVID-19 vaccination, especially in those who are immunosuppressed or older than 65 years. 6 We observed this phenomenon in our HC cohort, none of whom received a third dose. A high incidence of breakthrough infection among vaccinated healthcare workers and the general population has also been described. 7, 8 As such, the ACIP recommended a booster mRNA vaccine dose six months following completion of the original two-dose vaccine series for all adults. Booster doses have reduced incidence of infection and severity of illness. 9,10 Those with moderate-to-severe immunosuppression who completed a three-dose mRNA vaccine primary series may be eligible for a fourth, booster dose 6 months after the most recent dose. Our data indicate that certain patients with IBD on immune-modifying therapy may benefit from a fourth COVID-19 mRNA vaccine dose. Whether patients with IBD would benefit from a mix-and-match strategy or should continue with their original series when receiving their third or fourth doses of COVID-19 mRNA vaccines is unknown.

Our study has several strengths. We evaluated humoral immunogenicity in patients on stable medication regimens (median 39 months in those who received a third dose), which permitted us to assess the effect of medications on the immune response to vaccination. We also included a HC reference population that received the two-dose primary series but did not receive a third dose. Our study is limited in its sample size, small representation of certain treatment regimens, and the absence of a reference HC population that received a third dose.

In conclusion, all patients with IBD exhibited a humoral immune response following a third COVID-19 mRNA vaccine dose, and this response may be blunted by certain immunemodifying therapy. The role of serum antibody concentrations as a correlate of immunity has not been definitively established. Further studies are needed to investigate the durability of humoral immunity in addition to other aspects of the adaptive immune response following COVID-19 vaccination in the IBD population.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 27, 2021. ; https://doi.org/10.1101/2021.12.22.21268217 doi: medRxiv preprint

Antibody Responses After SARS-CoV-2 mRNA Vaccination in Adults With Inflammatory Bowel Disease

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

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

Booster-dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series

Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients

Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months

Covid-19 Breakthrough Infections in Vaccinated Health Care Workers

Correlation of SARS-CoV-2-breakthrough infections to time-from-vaccine

Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel

Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study

The authors thank all the subjects who participated in the study, the specialty pharmacists at UW-Health for their help, and the staff at the Office of Clinical Trials at University of Wisconsin-Madison for all their work.