Three highly effective coronavirus disease 2019 (COVID-19) vaccines are currently available under an US Food and Drug Administration (FDA) emergency use authorization for all adults to help reduce the morbidity and mortality from COVID-19 disease (1). Whether these vaccines are equally effective for patients with inflammatory bowel disease (IBD), who are commonly on immune-modifying therapy that may blunt the immune response of certain vaccines, has been a concern since the vaccines were made available (2). Studies of solid organ transplant recipients have shown suboptimal humoral immune responses after immunization with either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) COVID-19 (mRNA) vaccine series. In a study of 658 transplant recipients, only 54% of patients developed antispike antibodies evaluated through a commercial assay (3).
By contrast, preliminary results among patients with IBD suggest that most of the patients with IBD produce antibodies after completing the mRNA COVID-19 vaccine series. Initial analysis of the PREVENT-COVID and CORALE-IBD studies showed that 95% and 100% of patients with IBD, respectively, had a humoral antibody response (4,5). Despite the reassurance in these studies that patients with IBD respond to the vaccine by generating antispike antibodies, control groups were not included, making it difficult to determine whether responses were generally normal or suboptimal. Thus, we assessed humoral immunogenicity among patients with IBD and healthy controls (HCs) after COVID-19 vaccination at time points similar to the initial COVID-19 vaccine trials (6).
This nonblinded multicenter study (HERCULES) evaluated the humoral immunogenicity of mRNA COVID-19 vaccines among patients with IBD seen at University of Wisconsin-Madison and HCs from Labcorp. Eligibility criteria for patients with IBD were as follows: a diagnosis of IBD, ages 18–85 years, on stable doses of maintenance therapy for at least 2 months (see supplementary methods), and completion of an mRNA vaccines series confirmed using the Wisconsin Immunization Registry. HCs were eligible if they were not on immunosuppressive therapy and had documentation that they completed an mRNA vaccine series. All participants had no clinical history of COVID-19 infection, and those with serological evidence of asymptomatic infection were not eligible.
Nucleocapsid and spike protein S1 receptor-binding domain–specific IgG antibodies were measured in sera at 28–35 days postcompletion of the 2-dose mRNA series in patients with IBD and at approximately 30 days in HCs similarly to COVID-19 immunogenicity clinical trials (see Supplementary methods for full details, Supplementary Digital Content 1, https://links.lww.com/AJG/C322) (6). The study received IRB approval at University of Wisconsin and Labcorp.
One hundred twenty-two patients with IBD and 60 HCs were enrolled. Characteristics of the groups were similar, except for the distribution of the mRNA vaccine preparations (Table 1).
The HC group had higher antibody concentrations (median 118 [interquartile range [IQR] 87–189 μg/mL) at 1 month after completing the mRNA vaccine series compared with the patients with IBD (median 31 [IQR 16–63] μg/mL; P < 0.001) (Figure 1). However, only 4 of the 122 (3%) patients with IBD, all of whom were on immunosuppressing therapies, failed to mount a measurable antibody response. All HCs had an antibody response. Among the patients with IBD, those who received the Moderna COVID-19 mRNA vaccine series (median 38; IQR 24–75 vs μg/mL) had higher antibody concentrations compared with those who received the Pfizer-BNT mRNA vaccine series (median 22; IQR 11–42 μg/mL; P < 0.001). Patients who were immunosuppressed (defined as treated with thiopurines, antitumor necrosis factor agent, ustekinumab, tofacitinib, or corticosteroids) (median 26; IQR 13–50 μg/mL) had lower antibody concentrations compared with those who were on no treatment, aminosalicylates, or vedolizumab (median 59; IQR 31–75 μg/mL; P = 0.003) (see Supplementary Figure 1, Supplementary Digital Content 2, https://links.lww.com/AJG/C321).
In our study, almost all patients with IBD developed a humoral immune response after completing their mRNA vaccine series similar to HCs. This, along with other studies, supports the finding that patients with IBD despite being on immune-modifying therapy still mount a humoral immune response and are able to achieve seropositivity after completing a 2-dose mRNA series. However, we found that patients with IBD had lower antibody concentrations compared with HC at approximately 1 month after the second vaccination. Lower neutralizing antibody concentrations were associated with asymptomatic or mild breakthrough infections with SARS-CoV2 in 30 fully vaccinated health care workers (7).
Not surprisingly, patients with IBD who are treated with immunosuppressing medications have lower vaccine-induced antibody concentrations than HCs (8). However, a lower antibody concentration does not necessarily mean lower protection or lack of immunity because a correlate of protection for COVID-19 vaccines has yet to be determined. Thus, until a correlate of protection for COVID-19 vaccines is identified, the Advisory Committee on Immunization Practice will continue to use the best evidence available to advise clinicians on additional COVID-19 doses and boosters.
The FDA recently expanded the emergency use authorization to allow patients who have the equivalent immunosuppression as solid organ transplant recipients to receive an additional dose of an mRNA vaccine. Accumulated data on patients with IBD, thus, far indicate that this group of immunosuppressed individuals do not require an additional mRNA dose to achieve seropositivity at 1 month because 97% of our patients and (95%–100%) of patients in PREVENT-IBD and CORALE-IBD studies achieved seropositivity. We were not able to compare the antibody concentrations of our patients with those of patients with IBD or HCs in other studies because antibody concentrations were measured with different assays and collected at different time points after immunization across the studies. We found that patients with IBD who received the mRNA-1273 (Moderna) COVID-19 series had higher antibody concentrations compared with those who received BNT162b2 (Pfizer-BioNTech) series. The importance of this finding needs to be evaluated in larger IBD cohorts and other immunosuppressed populations because the mRNA-1273 was found to have higher vaccine effectiveness against COVID-19 hospitalization and induce higher postvaccination antireceptor-binding domain antibody levels than BNT162b2 in healthy volunteers in a recent report from the Centers for Disease Control and Prevention (9).
The FDA and Advisory Committee on Immunization Practices now recommends a booster with BNT162b2 for all adults 65 years and older, and adults 50–64 years with underlying medical conditions. In addition, clinicians may offer a booster dose to 18- to 48-year-olds with underlying medical conditions or to adults 18–64 years who are at increased risk of COVID-19 exposure and transmission because of occupational or institutional setting (10). This booster should be given at least 6 months after completing the initial vaccine series. It is anticipated that boosters for m-RNA-1273 will also be recommended in the future. Whether patients with IBD, especially those on immunosuppressive medications, will need more than 3 doses of an mRNA series to prevent severe disease and/or breakthrough infection is not known because most of the studies have only evaluated antibody concentrations up to 2 months after completion of the primary series. However, because their vaccine-induced antibody concentrations are lower compared with those of healthy individuals, investigations into the need for and timing of additional booster doses should be a high priority. A recent report showed that antibodies wane after the second dose of BNT162b2 in HCs (11). Thus, it will be important to determine whether antibodies wane faster in individuals on immune-modifying therapy, especially if it is determined that neutralizing antibodies are deemed predictive of immune protection against severe disease or breakthrough infections (12).
Our study has several strengths. We evaluated humoral immunogenicity at 1 month after the COVID-19 vaccine series completion, similar to the immunogenicity clinical trials, in patients on stable treatment regimens and compared our results with HCs (13). Our study is limited by its sample size and small representation of certain treatment regimens.
In conclusion, most of the patients with IBD achieved seropositivity after completing the mRNA vaccine series. Further studies are needed in evaluating initial cell-mediated immunogenicity and long-term studies evaluating sustained antibody concentrations, cell-mediated immunity, and incidence of breakthrough infections to determine the need for and timing of booster doses in patients with IBD.
CONFLICTS OF INTEREST
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. K.L.K.—analysis and interpretation of data and critical revision of manuscript. S.S.—critical revision of manuscript. A.W.—critical revision of manuscript. H.S.P.—acquisition of data and critical revision of manuscript. K.C.—acquisition of data and critical revision of manuscript. I.G.—critical revision of manuscript. M.L.—critical revision of manuscript. M.S.H.—study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of manuscript. F.A.F.—analysis and interpretation of data and critical revision of manuscript.
Financial support: Takeda Pharmaceuticals and American College of Gastroenterology.
Potential competing interests: F.C. has received research support from Takeda Pharmaceuticals and Sanofi. He has been a consultant for Takeda, Arena Pharmaceuticals, GSK, and Celgene. F.A.F. is a consultant for Arena, BMS, Braintree Labs, Gilead, GSK, Innovation Pharmaceuticals, Iterative Scopes, Janssen, Pfizer, and Sebela. He sits on a DSMB for Lilly and Theravance. M.S.H. is a consultant for GSK Vaccines and Seqirus and has received research support from Takeda Pharmaceuticals, Dynavax, and Sanofi. K.C. is an employee of Labcorp.
The authors thank all the subjects who participated in the study, the specialty pharmacists at UW-Health for their help, and all the staff at the Office of Clinical Trials at University of Wisconsin-Madison for all their work in the completion of the study.
1. Rolak S, Hayney MS, Farraye FA, et al. What gastroenterologists should know about COVID-19 vaccines. Clin Gastroenterol Hepatol 2021;19:657–61.
2. Caldera F, Hayney MS, Farraye FA. Vaccination in patients with inflammatory bowel disease. Am J Gastroenterol 2020;115:1356–61.
3. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA 2021;325:2204–6.
4. Pozdnyakova V, Botwin GJ, Sobhani K, et al. Decreased antibody responses to Ad26.COV2.S relative to SARS-CoV-2 mRNA vaccines in patients with inflammatory bowel disease. Gastroenterology. [Epub ahead of print August 12, 2021.] doi: 10.1053/j.gastro.2021.08.014.
5. Kappelman MD, Weaver KN, Boccieri M, et al. Humoral immune response to messenger RNA COVID-19 vaccines among patients with inflammatory bowel disease. Gastroenterology 2021;161:1340–3.
6. Walsh EE, Frenck RW, Falsey AR, et al. Safety and immunogenicity of two RNA-based covid-19 vaccine candidates. New Engl J Med 2020;383:2439–50.
7. Bergwerk M, Gonen T, Lustig Y, et al. Covid-19 breakthrough infections in vaccinated health care workers. New Engl J Med 2021;385:1474–84.
8. Caldera F, Hillman L, Saha S, et al. Immunogenicity of high dose influenza vaccine for patients with inflammatory bowel disease on anti-TNF monotherapy: A randomized clinical trial. Inflamm Bowel Dis 2020;26:593–602.
9. Self WH, Tenforde MW, Rhoads JP, et al. Comparative effectiveness of Moderna, pfizer-BioNTech, and Janssen (Johnson & Johnson) vaccines in preventing COVID-19 hospitalizations among adults without immunocompromising conditions—United States, March–August 2021. MMWR Morb Mortal Wkly Rep 2021;70:1337–43.
11. Shrotri M, Navaratnam AMD, Nguyen V, et al. Spike-antibody waning after second dose of BNT162b2 or ChAdOx1. Lancet (London, England) 2021;398:385–7.
12. Krammer F. A correlate of protection for SARS-CoV-2 vaccines is urgently needed. Nat Med 2021;27:1147–8.
13. Anderson EJ, Rouphael NG, Widge AT, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med 2020;383:2427–38.