Review Article

Vaccination for Patients With Inflammatory Bowel Disease During the COVID-19 Pandemic

Jayne Doherty; Sean Fennessy; Roisin Stack; Neil O' Morain; Garret Cullen; Elizabeth J. Ryan; Cillian De Gascun; Glen A. Doherty


Aliment Pharmacol Ther. 2021;54(9):1110-1123. 

In This Article

Do Patients With IBD Have Suboptimal Responses to Vaccination?

IBD is characterised by chronic inflammation arising from an abnormal host immune response to dietary and microbial antigens. The pathogenesis of both Crohn's disease (CD) and ulcerative colitis (UC) is complex and is thought to be secondary to the interplay between genetic susceptibility, environmental factors and an altered gut microbiota leading to aberrant innate and adaptive immune responses.[7,8] Multiple immune pathways are dysregulated in both CD and UC.[7,8] There have been several reports suggesting IBD may arise from a fundamentally inadequate rather than excessive gut immune response with one study showing a defective neutrophil recruitment and bacterial clearance in patients with CD.[9]

There is a body of evidence highlighting immune-system dysfunction in patients with IBD. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are pathogen recognition receptors (PRRs) that alert the innate immune system to the presence of microbes by detecting conserved molecular patterns (eg bacterial lipopolysaccharide or viral nucleic acids). Ligation of TLRs/NLRs triggers innate immune responses and pro-inflammatory cytokine production that drives the subsequent adaptive immune response. PRRs play a critical role in maintaining gut homeostasis, controlling immune responses along with shaping the microbiota. Patients with IBD exhibit differential expression of TLRs in comparison to healthy controls.[10] Mutations in NLRs have been identified in CD, with NOD2 mutations the most common mutation.[11] Vaccine formulations contain adjuvants that activate innate immunity via PRRs resulting in local inflammation at the injection site. Antigen-presenting cells (APCs) traffic to the site of injection in response to these inflammatory signals and are enabled to process and present antigens and prime both the humoral and cellular arms of the adaptive immune response (Figure 1). Thus, the inherent defects in microbial sensing that underpin IBD pathogenesis may also impact a patient's response to vaccination.

Figure 1.

Impact of having IBD and IBD medications on the immune response to COVID-19 vaccines. A, Innate immune priming: IBD is associated with SNPs in genes regulating the innate immune response (eg innate immune sensors such as TLRs), therefore tissue resident antigen presenting cells (eg DCs) in patients with IBD may respond differently to the vaccines. Inflammatory cytokines produced in response to the vaccines may be blunted by anti-inflammatory medications (eg corticosteroids or biologic agents such as anti-TNF). B, Antigen presentation: Mature DC migrate to the local LN where they present antigen to naïve CD4/CD8+ T and B lymphocytes, providing co-stimulation and driving polarisation by secreting cytokines. IBD medications can limit antigen presentation. C, T cell proliferation and polarisation: Patients with CD tend to have immune responses polarised towards inflammatory Th1/Th17 cells, while patients with UC have a bias towards Th2 cells. D, CD4+ T cell: B cell interaction: Antigen specific CD4+ T cells interact with B cells providing co-stimulation via CD40:CD40L interaction to drive B cell proliferation, affinity maturation and class switch recombination. T cell-derived cytokines (eg IL-4) are key to determining the antibody isotype and function. E, Immune Memory: Antigen-specific T and B cell clones expanded due to vaccination should give rise to long-lived memory cells. Patients with IBD frequently display an exhausted T cell phenotype (due to constant immune activation) and this may impact the phenotype and function of immune memory cells. Image created by

Dendritic cells (DC) are an important population of APCs expressing high levels of PRRs. They respond to microbial signals, traffic to local lymph nodes where they process and present antigens to naïve T-cells. Once in the lymph node, they upregulate co-stimulatory molecules such as CD40/CD80/CD86 and secrete cytokines such as IL-12 that are required for T-cell polarisation. The plasmacytoid DC subset plays an important role in anti-viral immunity as they are a potent source of type I Interferon (IFN).[12] Thus, DCs are key mediators of response to vaccination. Patients with IBD have significantly lower levels of circulating DC during disease flares compared to healthy controls.[11] Even patients with the inactive disease have shown reduced frequencies of circulating DC.[13] A significantly higher frequency of plasmacytoid DC in the inflamed colonic mucosa and mesenteric lymph nodes of IBD patients compared to healthy controls has also been reported.[14] It appears that in IBD especially when the disease is active, DC migrate from the bloodstream to the gut.

Macrophages are another population of APCs critical in the initiation of vaccine-induced immunity and protection against viral infection. Macrophages have the ability to destroy virally infected cells and produce IFN. However, these effects are evident only if the virus is destroyed or contained by macrophages. If a virus replicates in macrophages, the infected macrophages may aid viral transmission. The permissiveness of macrophages for viral replication depends on factors including the age and host genetics.[15] In CD, macrophages are compromised and produce subnormal amounts of pro-inflammatory cytokines.[16] Whether these defects in DC, macrophages and PRRs in patients with IBD could impact systemic immunogenicity and aspects such as a patient's response to vaccination is still unknown. One recent review of 14 590 patients with IBD reported an elevated risk of opportunistic infections (OI) but no increased risk was evident for patients on biologic therapy.[17] This observation supports the hypothesis that an immune-system dysfunction in these patients may contribute to poorer vaccine response. Despite the indirect evidence outlined above, it remains the case that there is little direct evidence that patients with IBD, even if experiencing active disease, should be considered significantly immunosuppressed and therefore less likely to respond to vaccination. The statement from the ECCO guidelines on OI in IBD still, therefore, remains broadly true when it states "Patients with IBD should not be routinely considered to have altered immunocompetence."[5] This topic should, however, remain a focus for investigation and efforts made to evaluate whether patients with IBD, not receiving systemic immunosuppressive therapies show any difference in the degree in initial response and durability of response to COVID-19 vaccination.