Booster doses of mRNA vaccines improve humoral immunogenicity in patients with inflammatory bowel disease

In response to the ongoing coronavirus disease 2019 (COVID-19) pandemic, regulatory bodies provided emergency approvals for three safe and effective COVID-19 vaccines for mass vaccination programs. Neither patients with inflammatory bowel disease (IBD) nor immunosuppressed patients were included in the initial phase III clinical trials performed to prove the efficacy of the vaccine.

Study: Humoral immunogenicity of three COVID-19 mRNA vaccine doses in patients with inflammatory bowel disease.  Image credit: Lana Leon / ShutterstockExamination: Humoral immunogenicity of three COVID-19 mRNA vaccine doses in patients with inflammatory bowel disease. Image credit: Lana Leon / Shutterstock

Studies performed later with IBD patients have shown a humoral immune response rate of 95-99% after vaccination with a double dose of different mRNA vaccines. The results also showed that patients in certain immunomodifying treatments, such as anti-tumor necrosis factor (anti-TNF) therapy in combination with an immune modulator or on systemic corticosteroids, showed a relatively diminished humoral immune response. They also underwent a relative reduction in serum antibody concentrations over time.

The Advisory Committee on Immunization Practice (ACIP) recommends a series of primary three-dose mRNA vaccines for patients who are moderately or severely immunocompromised, with the reduced antibody titers in mind.

Researchers have recently published a study in the preprint server medRxiv* where they evaluated the humoral immunogenicity of a third COVID-19 mRNA vaccine dose in patients with IBD. They further hypothesized that patients would have a significant humoral immune response and that patients in certain immunomodulatory therapies, such as systemic corticosteroids or combination therapy, may have lower antibody concentrations.

Study details

The study was a multicenter, prospective, non-randomized study, known as the “HumoRal and CellULar initial and Sustained immunogenicity in IBD” (HERCULES) study. Participants with IBD were enrolled at the University of Wisconsin-Madison (Madison, Wisconsin) and the Mayo Clinic (Jacksonville, Florida), while rapid controls (HC) were employed by LabCorp.

Eligibility criteria for patients included a diagnosis of IBD, age 18-85 years, stable doses of maintenance therapy (≥ 2 months), vaccination with a double-dose mRNA vaccine, as confirmed by interview, review of medical records and possibly , Review of the Wisconsin Immunization Registry. The eligibility criteria for the controls (HC) included the absence of immunosuppressive therapy and documented evidence of a double-dose mRNA vaccination. A third dose of COVID-19 mRNA vaccine was available only to patients with IBD. The primary study result was total serum SARS-CoV-2 anti-spike IgG antibody concentrations after a third dose compared to antibody concentrations after the conventional double dose series in the IBD cohort.

Serum IgG antibodies specific for nucleocapsid and spike protein S1 receptor binding domain (RDB) were reported in mcg / ml. In patients with IBD, antibody concentrations were measured between 28 and 35 days (t1) after completion of the dual dose series and between 28 and 65 days (t2) after the third dose. Only patients with IBD who received a third dose had antibody concentrations measured at t2, and not all subjects who received antibody concentrations measured at t2 had them measured at t1 due to the time of enrollment. In the control group, antibody concentrations were measured 30 days (t1) and 180 days (t2) after completion of the dual dose series.

The study included 139 patients with IBD who had competed with the double-dose regimen and had antibody concentrations measured at t1, and 85 patients who received a third dose and had antibody concentrations measured at t2. 46 HC completed the double-dose regimen and had antibody concentrations measured at both time points. In the IBD cohort, 48.2% and 51.8% received double doses of the Moderna and Pfizer series, respectively, compared with 93.5% and 6.5% in HC.

135 patients with IBD (97.1%) had detectable antibody concentrations at t1, while all 85 (100%) had detectable antibody concentrations at t2. Of the 2 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 in immunosuppressive therapy and non-immunosuppressive therapy (median 69 vs 66). Additional subgroup analysis revealed that those receiving systemic corticosteroids or anti-TNF combination therapy had significantly lower antibody concentrations at t2 than patients not on these treatments (median 29 vs. 7).

When added to the former group on anti-TNF monotherapy, the difference in median antibody concentrations was reduced but remained statistically significant (median 38 vs. 73). Serum antibodies were significantly higher at t2 for patients with IBD who received three doses of the Moderna vaccine compared to those who received the same in Pfizer (median 94 vs. 62).

Although the control group had higher antibody concentrations compared to IBD subjects at t1 (median 120 vs. 31), their antibody concentrations decreased significantly below the IBD cohort at t2 (median 17 vs. 68).


All patients were seropositive and had higher antibody concentrations after the third dose than at the end of the primary two-dose series. This adds to the growing body of evidence regarding booster doses of vaccines. This will also help lead to more studies of different populations of immunocompromised patients, as well as help politicians define their booster dosing criteria for the general public.

*Important message

medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered as crucial, guide clinical practice / health-related behavior or be treated as established information.


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