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 IBD Therapies Reduce Vaccine Responses in Patients With IBD?

Immunosuppressive treatment is a significant driver of the increased susceptibility to infection observed in patients with IBD.[5] One recent study reported a threefold increase of serious systemic viral infections in patients with IBD compared to the general population. The main risk factors for contracting infection were clinically active IBD and exposure to thiopurines.[30] Data on rates of immunogenicity to vaccines against COVID-19 are limited in patients with IBD but we can extrapolate data from other vaccination programmes focusing mainly on vaccinations against viruses including influenza, HBV and Varicella-zoster.

Influenza Vaccine

Approximately 300 000–650 000 people die worldwide from influenza each year.[31] The risk of contracting influenza and requiring hospitalisation is significantly greater in the IBD population,[32] therefore, yearly influenza vaccination is recommended.[5,18,19] The influenza vaccine comes in two forms, an inactivated vaccine and a live vaccine. The live vaccine is not recommended for use in immunocompromised patients.[5,18,19] Guidelines do not advise whether immunocompromised patients should receive standard dosage (SD) or high dosage (HD) of the trivalent inactivated influenza vaccine. One systematic review highlighted the fact that patients who received a HD vaccination had increased rates of seroconversion compared to those who received the SD in both immunocompromised individuals and adults aged 50–64 years.[33]

The emergence of the novel influenza A (H1N1) virus in 2009 stimulated research activity in the field of influenza vaccination. In the general population, serological protection rates of greater than 85% were reported with the H1N1 influenza vaccine.[34,35] However, rates of serological protection to influenza in patients with IBD tend to differ depending on treatment strategies. One study found influenza vaccine yielded high seroprotection rates in patients with IBD, however, patients receiving anti-TNF treatment had lower rates of persistent seroprotection at 6 months post-vaccination.[36] Cullen et al found serological protection rates against the H1N1 influenza vaccine in the IBD community was much less than that of the general population at only 50%.[37] Levels of seroprotection were significantly lower in patients receiving immunosuppression (glucocorticoids, immunomodulators or biologic treatments) compared with patients not on these drugs (44% versus 64%).[37] A prospective randomised control trial (RCT) examined serologic response to the inactivated trivalent influenza vaccine in patients receiving infliximab (IFX) and found despite patients mounting an initial immune response to vaccination, response rates ranged between 25% and 40%.[38] Interestingly, vaccine administration at the time of infusion, or between infusions, did not impact response.[38] Furthermore, a 2018 Japanese study assessed the immunogenicity of the quadrivalent influenza vaccine for patients with IBD on immunosuppression and found patients receiving IFX had lower seroprotection rates than those on 5-ASA or azathioprine.[39]

The addition of a booster vaccine does not appear to improve response rates in patients with IBD.[39,40] However, the HD quadrivalent influenza vaccine seems to improve immunogenicity in patients on immunosuppressive therapy.[41,42] One RCT found patients with IBD on anti-TNF monotherapy receiving the HD influenza vaccine had significantly higher post-immunisation antibody levels compared with SD vaccine,[41] with similar results seen in patients with rheumatoid arthritis on immunosuppressants.[42]

Overall, the inactivated influenza vaccine is safe to administer to patients with IBD, including patients on immunosuppressants with no association with increased IBD activity.[43,44]

Patients on immunosuppressants have reduced seroconversion rates compared to the general population. The ideal time to vaccinate patients is prior to starting immunosuppressive therapy where possible, to improve response rates. It is unclear whether patients on immunosuppressants would have higher response rates and be better protected with the HD vaccination protocol and this could be an area for further research if similar response rates are seen with the COVID-19 vaccines.

Hepatitis B Vaccination

The prevalence of HBV infection varies throughout the world, with <1% of the population of Northern Europe being infected.[45] ECCO and BSG guidelines recommend all patients should be screened for HBV at diagnosis of IBD to help expedite necessary vaccinations and reduce delays initiating therapy.[5,18]

In the healthy, general population 10% of HBV vaccine recipients fail to mount an adequate antibody response.[46] Andrade et al[47] found patients receiving IFX, azathioprine or combination therapy had lower anti-HBsAg levels indicating an inadequate vaccine response. A 2017 meta-analysis found response rate to the HBV vaccine in patients with IBD, regardless of therapy was 61%[48] compared to 90% in the general population.[46] Younger patients and those vaccinated during remission had higher response rates. Use of immunosuppressive agents was associated with reduced rates of immunogenicity (Table 1).[48] Loras et al[49] found seroconversion rates against Hepatitis B were only 44% in adults with IBD on anti-TNF therapy (Table 1). A second metanalysis evaluated the efficacy of the HBV vaccine in patients with IBD and found patients with IBD were significantly less likely to respond to the HBV vaccination compared with healthy controls. Overall, the pooled proportion of adequate response to the Hepatitis B vaccine in patients with IBD was 61% and the odds ratio of HBV response in patients with IBD was 0.13 (95% confidence interval 0.05–0.33, P = 0.001).[50] Patients with IBD on immunosuppressants had significantly lower serological response rates to the HBV vaccine compared to the general population.[50]

The standard HBV vaccination of three doses is given at 0, 1 and 6 months with an accelerated schedule for "rapid protection" with dosing at 0, 1, 2 and 12 months.[51] A randomised prospective study found patients with IBD had a significantly higher response rate to the accelerated dosing schedule compared to standard dosing (75% vs 41%) (Table 2).[52] A recent RCT from Chaparro et al found a 4-dose schedule was more effective than a 3-dose regimen with significantly higher response rates for Hepatitis B vaccination in patients with IBD. As seen in other studies older age and treatment with immunomodulators or anti-TNFs impaired response to vaccination.[53]

ECCO guidelines recommend all IBD patients receive an accelerated vaccination schedule using a double-dose protocol, whilst the ACG guidelines recommend the standard vaccination schedule.[5,19] Once further data are available on response rates in patients with IBD to the COVID-19 vaccines the use of accelerated or double-dose vaccine schedules for sub-cohorts of patient with IBD that have impaired response to the vaccine may be an option.

Varicella Zoster Vaccine

Varicella-zoster virus (VZV) causes chickenpox and herpes zoster (shingles). In most European countries there is close to universal VZV seroconversion by late childhood.[54] Primary VZV infection is more severe in adults than children.[55] Patients with IBD on immunosuppression appear to be at increased risk of complications with primary varicella infection.[56,57] A retrospective review of 20 patients with IBD on immunosuppression found a 20% mortality from primary VZV infection, with three of these patients on corticosteroids at the time of infection.[58] A separate retrospective study found a strong association with the requirement of hospitalisation for primary VZV and IBD in a paediatric cohort.[59] Given the high risk of complications with primary varicella infection in patients with IBD, the ACG and ECCO recommend screening for prior exposure to varicella in all patients with IBD and vaccination if naïve.[5,19] The varicella vaccine is a live vaccine, therefore, cannot be given to patients receiving immunosuppressants. Both ECCO and the ACG recommends vaccination at least 3–4weeks prior to commencing immunosuppressants.[5,19] In a systematic review of 40 observational studies in patients with immune-mediated disorders (IBD n = 20 556) investigators found although seroconversion following the varicella vaccine was high, it was reduced by immunosuppressive therapies.[60]