From the AGA Journals

IBD patients have limited protection against Omicron with third vaccine dose

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Unanswered question remains

Understanding how inflammatory bowel disease (IBD) impacts COVID-19 infection risk and how IBD medications influence this risk remains an ever-evolving discussion, particularly with the emergence of new SARS-CoV-2 variants and booster vaccines. In this study, Liu et al. further shape this conversation: They show that a third mRNA COVID-19 vaccine dose increases neutralizing antibody levels against the Omicron variant in IBD patients compared to the level following a second vaccine dose, but that infliximab and tofacitinib significantly attenuate this response. They additionally suggest that IBD patients achieve lower neutralizing antibody levels after a third COVID-19 vaccine and may have a higher breakthrough infection risk compared to healthy controls without IBD.

Dr. Erica J. Brenner MD, MSCR, Assistant Professor, Department of Pediatrics, Division of Pediatric Gastroenterology, University of North Carolina University of North Carolina

Dr. Erica J. Brenner

Given the myriad health benefits of adequately controlling active IBD, few would argue that these results call for IBD patients to switch off infliximab or tofacitinib. Rather, the findings underscore the importance of multiple COVID-19 booster vaccinations for IBD patients, especially as most breakthrough COVID-19 infections take a mild course, even in the setting of immunosuppression.

Whether to change booster vaccination recommendations specifically for IBD patients on tofacitinib or infliximab, however, remains an unanswered question. The small sample of patients on tofacitinib precludes definitive conclusions regarding tofacitinib’s impact on vaccine response. Moreover, this humoral antibody-based study tells only half the story: We need analyses of the cell-mediated booster vaccine response to truly understand vaccine efficacy during immunosuppressant use. Lastly, future studies including the bivalent booster will provide the most up-to-date information on protecting our IBD patients from the Omicron variant.

Dr. Erica J. Brenner MD, MSCR is an Assistant Professor, Department of Pediatrics, Division of Pediatric Gastroenterology, University of North Carolina School of Medicine; and a cofounder of the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) Registry. She has no relevant financial conflicts of interest.



For people with inflammatory bowel disease (IBD) taking immunosuppressive medication, a third dose of a COVID-19 mRNA vaccine significantly increases neutralizing antibodies against the original SARS-CoV-2 strain, but the picture is more complicated for protection against the Omicron variant, according to a research letter published in Gastroenterology.

Though IBD patients do mount a response against Omicron, the response is substantially lower for those taking tofacitinib or infliximab, particularly infliximab monotherapy.

“As further mutations in the viral genome accumulate over time, with the attendant risk of immune evasion, it remains important to continue to reappraise vaccination strategy, including the implementation of personalized approaches for some patients, such as those treated with anti-TNF drugs and JAK inhibitors,” wrote Zhigang Liu, PhD, a research associate in the department of metabolism, digestion, and reproduction at Imperial College London, and his colleagues. “Preferential use of bivalent vaccines may be especially valuable in IBD patients taking anti-TNF agents or JAK inhibitors,” they wrote. Their study did not assess neutralizing antibodies resulting from use of the bivalent vaccine, however.

The researchers tracked 268 participants, including 49 healthy participants serving as controls, from May 2021 through March 2022. The other participants had IBD and included 51 patients taking thiopurines, 36 patients taking infliximab, 39 taking both infliximab and thiopurines, 39 taking ustekinumab, 38 taking vedolizumab, and 16 taking tofacitinib. The IBD patients were all enrolled in the SARS-CoV-2 Vaccination Immunogenicity in Immunosuppressed Inflammatory Bowel Disease Patients (VIP) cohort.

None of the participants had evidence of a SARS-CoV-2 infection at baseline. All had received two doses of an mRNA COVID-19 vaccine (all received Pfizer, except two controls who received Moderna) or two doses of the AstraZeneca vaccine as their primary vaccination. All received an mRNA vaccine for their third dose. Among the IBD patients, 137 received the AstraZeneca in their primary two-dose series, and 82 received Pfizer.

First the researchers assessed the participants’ humoral response to the vaccine against the original SARS-CoV-2 strain and against the Omicron BA.1 variant. Neutralizing antibody titers rose significantly against both strains after the third vaccine dose for all participants.

“However, 50% neutralization titer (NT50) values were significantly lower against Omicron than against the ancestral strain in all study groups, irrespective of the immunosuppressive treatment regimen,” the authors reported. NT50 values are a measure that reflect a vaccine-induced humoral immunity against SARS-CoV-2 after vaccination.

Compared to the healthy controls, individuals receiving infliximab, tofacitinib, or infliximab/thiopurine combination therapy showed significantly lower responses after the second and third vaccine doses. Thirteen patients did not generate NT50 against Omicron after the second vaccine dose, and 7 of them were on infliximab monotherapy. They represented nearly 20% of all infliximab monotherapy participants.

Next the researchers assessed the risk of a breakthrough infection according to neutralizing titer thresholds. Individuals with an NT50 less than 500 had 1.6 times greater odds of a breakthrough infection than those with an NT50 above 500, they noted. After two vaccine doses, 46% of participants with IBD had an NT50 above 500 for the ancestral strain, which rose to 85% of those with IBD after a third dose.

In the healthy control group, 35% had an NT50 under 500 after two doses, and 14% of them had a breakthrough infection, all of which were mild and none of which required hospitalization. The NT50 in healthy controls, however, was not significantly associated with risk of breakthrough infection.

“In this study, neutralizing titers elicited against the omicron variant were generally poor for all individuals and were substantially lower in recipients of infliximab, infliximab/thiopurine combination, or tofacitinib therapy,” the authors concluded. “This raises concerns about whether currently available vaccines will be sufficient to protect against continually evolving SARS-CoV-2 variants, especially in patients established on certain immunosuppressive drugs.”

The small population sizes for each subgroup based on medication was one of the study’s limitations. Another was the fact that it was underpowered to conclusively determine whether an increased risk of breakthrough infection exists in IBD patients who have lower titers of neutralizing antibodies. A limitation for generalization to U.S. patients is that just 64% of the IBD patients received the AstraZeneca vaccine, which is not offered in the United States, for their first two doses before receiving the third mRNA (Pfizer) dose.

The study was funded by Pfizer in an independent research grant and by the NIHR Biomedical Research Centres in Imperial College London and Imperial College Healthcare NHS Trust and Cambridge, and the NIHR Clinical Research Facility Cambridge.

Dr. Liu and one other author had no disclosures. The other 18 authors have a range of disclosures related to various pharmaceutical companies, including Pfizer.

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