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. 2024 Apr 1;15(4):e00688.
doi: 10.14309/ctg.0000000000000688.

Higher and Sustained Cell-Mediated Immune Responses After 3 Doses of mRNA COVID-19 Vaccine in Patients With Inflammatory Bowel Disease on Anti-Tumor Necrosis Factor Therapy

Freddy Caldera  1 , Stacey Rolak  2 , Francis A Farraye  3 , Brian M Necela  4 , Davitte Cogen  4 , Emily E Zona  5 , Trevor L Schell  6 , Oscar Ramirez Ramirez  6 , Mazen Almasry  6 , Kelly Chun  7 , Mary S Hayney  8 , Keith L Knutson  4
Affiliations

Higher and Sustained Cell-Mediated Immune Responses After 3 Doses of mRNA COVID-19 Vaccine in Patients With Inflammatory Bowel Disease on Anti-Tumor Necrosis Factor Therapy

Freddy Caldera et al. Clin Transl Gastroenterol. .

Abstract

Introduction: Studies suggest that the generation of durable T-cell immunity following coronavirus disease 2019 (COVID-19) vaccination protects against severe disease. The aim of this study was to measure cell-mediated immune response (CMIR) 1-2 months and 6 months after a third dose of a COVID-19 mRNA vaccine.

Methods: This prospective study (HumoRal and CellULar initial and Sustained immunogenicity in patients with inflammatory bowel disease [IBD]) evaluated CMIR at 28-65 days (t 1 ) after dose 2, 28-65 days (t 2 ) (n = 183) and 6 months (±45 days) (t 3 ) (n = 167) after a third dose of an mRNA COVID-19 vaccine. A small cohort had blood sample available 28-65 days (t 4 ) (n = 55) after a fourth dose. Primary outcomes were CMIR at (t 2 ) and (t 3 ). Secondary outcomes included the effect of immunosuppressing IBD medications on CMIR and response at (t 4 ).

Results: All patients had measurable CMIR at all time points. CMIR increased at t 2 compared with that at t 1 (median 1,467 responding cells per million (interquartile range [IQR] 410-5,971) vs 313 (94-960) P < 0.001). There was no significant waning in t 2 vs t 3 or significant boosting at t 4 . Those on anti-tumor necrosis factor monotherapy had a higher CMIR compared with those not on this therapy at t 2 (4,132 [IQR 1,136-8,795] vs 869 [IQR 343-3,221] P < 0.001) and t 3 (2,843 [IQR 596-6,459] vs 654 [IQR 143-2,067] P < 0.001). In univariable analysis, anti-tumor necrosis factor monotherapy was associated with a higher CMIR at t 2 ( P < 0.001) and t 3 ( P < 0.001) and confirmed in a multivariable model ( P < 0.001).

Discussion: A third dose of a COVID-19 vaccine boosts CMIR, and the response is sustained in patients with IBD.

Keywords: Crohn's disease; immune response; immunology; ulcerative colitis.

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Conflict of interest statement

Guarantor of the article: Freddy Caldera, DO, MS.

Specific author contributions: F.C.: study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of manuscript; S.R.: drafting of manuscript, critical revision of manuscript; F.A.F.: critical revision of manuscript; B.M.N.: acquisition of data and drafting of manuscript; D.C.: acquisition of data; E.E.Z.: critical revision of manuscript; T.L.S.: acquisition of data and critical revision of manuscript; O.R.R: acquisition of data, critical revision of manuscript; M.A.: acquisition of data, critical revision of manuscript; K.C.: acquisition of data, critical revision of manuscript, analysis and interpretation of data; M.S.H.: study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of manuscript; K.L.K.: acquisition of data, analysis and interpretation of data, drafting of manuscript, and critical revision of manuscript.

Financial support: Takeda Pharmaceuticals, American College of Gastroenterology, and Mayo Clinic.

Potential competing interests: F.C. has received research support from Takeda Pharmaceuticals, Janssen, and Novavax. He has been a consultant for Takeda, Arena Pharmaceuticals, GSK, and Celgene. F.A.F. is a consultant for Abbvie Avalo Therapeutics, BMS, Braintree Labs, Fresenius Kabi, GI Reviewers, GSK, IBD Educational Group, Iterative Health, Janssen, Pharmacosmos, Pfizer, Sandoz Immunology, and Sebela. He sits on a DSMB for Lilly Pharmaceuticals. M.S.H. is a consultant for GSK Vaccines and Seqirus and has received research support from Takeda Pharmaceuticals and Dynavax. Dr. Chun is an employee of LabCorp. Dr. Swift has received research support from Pfizer. K.L.K. is the Andrew A. and Mary S. Sugg Professor of Cancer Research and reports consulting fees from Leidos, Antigen Express, and Affyimmune; grant and other funding to Mayo Clinic from Marker Therapeutics, Macrogenics, Bolt Therapeutics and Tallac; royalties from Marker Therapeutics; and stocks from Kiromic, Inc.

Figures

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Graphical abstract
Figure 1.
Figure 1.
Flowchart of study participants in HERCULES study. Flowchart of participants in the HERCULES study at the different time points t1-t4. Blood draw timings: (a) (t1) 28–35 days after 2 dose mRNA vaccine series; (b) (t2) 28–65 days after a third dose; (c) (t3) approximately 6 months (±45 days) after a third dose of an mRNA COVID-19 vaccine; (d) (t4) 28–65 days after a fourth dose of an mRNA vaccine. HERCULES, HumoRal and CellULar initial and Sustained immunogenicity in patients with inflammatory bowel disease.
Figure 2.
Figure 2.
Cell-mediated immune response (CMIR) following COVID-19 mRNA vaccines. (a) CMIR increased after the 3rd vaccine dose (n = 161; median 1,444 responding cells/million (interquartile range [IQR] 421–6,011) compared with after 2 vaccine doses (n = 120; median 313 responding cells/million; IQR 94–960) P < 0.001. The CMIR approximately 6 months after the 3rd dose was not statistically significantly different from 1 month after dose 3 (median 1,241 responding cells/million (IQR 301–4,609) Wilcoxon signed rank P = 0.071). The CMIR did not boost following the 4th dose of vaccine (n = 55; median 1,387 responding cells/million [IQR 203–3,843] P = 0.88). (b) Patients with IBD treated with TNF agents (n = 69) had higher CMIR compared with those not treated with TNF agents (n = 92) at both 28–65 days after 3rd dose (median 3,927 responding cells/million [IQR 1,094–8,619] vs median 853 responding cells/million [IQR 343–2,984] P < 0.001) and at approximately 6 months post 3rd dose (median 2,876 responding cells/million [IQR 614–7,094] vs median 671 responding cells/million [IQR 161–2,191] P < 0.001). In addition, neither group showed statistically significant waning of CMIR over 6 months. (c) History of COVID-19 infection had no statistically significant effect on CMIR at 6 months after dose 3 (no COVID-19 infection median 1,024 responding cells/million; IQR 228–4,609 vs COVID-19 infection history median 1,690 responding cells/million; IQR 311–3,913; P = 0.098). (d) No statistically significant correlation was found between CMIR and SARS CoV spike antibody (Ab) concentrations (Spearman correlation coefficient 0.077; P = 0.12). This graph shows data points from all time points post vaccines. CMIR-antibody correlations for each time point are included in the Supplementary Digital Content (see Supplementary Figure 1, http://links.lww.com/CTG/B89). TNF, tumor necrosis factor.
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