Avoid common mistakes on your manuscript.
In the beginning of 2020, when the world woke up to the coronavirus disease - 19 (COVID-19) pandemic, we knew little about a hitherto unknown virus and its impact on a vulnerable group of patients, many of whom were on therapies, which reduced their immune responses and largely dependent on our limited experience during previous pandemics [1] and rather hurried guidance from professional societies based largely on expert consensus [2, 3]. As we enter 2023, patients with inflammatory bowel disease (IBD) and healthcare professionals caring for them need to reflect on the challenges faced by the COVID-19 pandemic over the last three years.
In this issue of the journal, two papers [4, 5] shine light on the potential for natural immunity and vaccine-induced immunity in the Indian setting among two cohorts of IBD patients. In the first study from All India Institute of Medical Sciences, New Delhi [4], the authors report a high seroprevalence of COVID-19 in one third of their unvaccinated IBD patients when evaluated for immunoglobulin G (IgG) against antigen- S1 receptor‐binding domain (S1RBD) between July 2020 and April 2021, with progressive increase in proportion with positive titres as the study progressed. Furthermore, they also propose that, in the Indian context, the use of immunosuppressants may not have any influence in COVID-19 infection risk. These findings are intriguing and in contrast to published reports from western countries, where the prevalence rates among unvaccinated IBD patients during the corresponding period in the pandemic were in single digits [6,7,8,9]. The results of this study should be taken in the context of the varied evolution and emergence of variants during the pandemic across different countries. Importantly, none of the patients included in this study were on biologics or small molecules. Furthermore, the impact of adherence to public health measures and the differences in the assays used in studies should be kept in mind before providing advice to IBD patients relating to their individual risks based on this study.
The development of COVID-19 vaccines and their mass administration has been the key tool in our global fight against the COVID-19 virus, which threatened to cause even higher death rates in immunosuppressed individuals. Antibody titres are recognized as an important indicator of vaccine effectiveness in the general population, with lower antibody titres after COVID-19 vaccination being associated with a higher risk of breakthrough infections [10]. In the second study in this issue of the journal relating to this, Mathur et al. [5] report antibody titres using an indigenous qualitative antibody estimation kit, on sera obtained three weeks after the administration of the vaccine's second dose. While the timing of this study recruitment (January 2021 to June 2021) undoubtedly had an impact, like the study from Kante et al. [4], the seroprevalence rate of 57.7% in unvaccinated and 87% in the healthy controls is very high when compared to those of other populations. In addition, this study also could not correct for the confounding effects of shielding and other public health measures or indeed the impact of age, comorbidity or IBD activity, which does have an impact on seroconversion following natural infection or vaccination [11, 12]. It is, however, noted that the vaccinated individual did have almost a doubling of the antibody titres.
Another aspect relating to the study of Mathur et al. [5] is that the small sample size precluded a detailed analysis of the impact of therapies, including steroids, immunosuppressants and biologics, on vaccine responses. The CLARITY study results from the UK suggested for the first time in 2021 [13, 14] attenuated vaccine antibody responses in IBD patients on thiopurines and on anti-tumor necrosis factors (TNFs) alone or in combination with immunomodulators with the large sample sizes in these studies enabling drug-specific analysis. In the VIP study [15], anti-S RBD antibody concentrations were lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of both BNT162b2 and ChAdOx1 nCoV-19 vaccines. Breakthrough infections were particularly higher in those who mounted lower titres of antibody response. In addition, one fifth of the patients did not mount a T-cell response. An earlier systematic review looked at reported excellent seroconversion rates following vaccination in most IBD patients, including those on biologics, although attenuation was reported in patients on thiopurines and JAK kinase inhibitors [16]. As Mathur et al. did not include IBD patients on biologics or combination therapy, the impact of these commonly used drugs could not be ascertained. Furthermore, the assays used in these two studies are different to other studies including the CLARITY and VIP study, which used Roche Elecsys anti-SARS-CoV-2 spike electrochemiluminescence immunoassay to measure anti-SARS-CoV-2 spike protein antibody concentrations.
Another aspect of particular importance for management in IBD patients on immunomodulators will be the consideration of potential for antibody decay in patients with herd or vaccine-derived immunity. The paired samples available in a small proportion of patients in the study from Mathur et al. [5] indicated a persistent seroconversion rate and they report no breakthrough infections. The authors opine that the herd immunity status may determine the need for further vaccine schedules in the Indian setting. This is a matter for debate, as there is some evidence for reduction in seroprevalence rates in general and IBD populations as the pandemic has progressed [17] and the impact of waning vaccine-induced or herd immunity on future risk of serious infection remains uncertain. A pooled review of nearly 10,000 IBD patients [18] demonstrated decay in immunity over time thereby highlighting the need for booster doses of vaccination. None of the patients included in the Mathur et al. [5] study received booster doses of vaccine. Many more recent studies have shown antibody decay, waning of T-cell immunity and breakthrough infections after two and even three doses of vaccination in patients on biologics and individual medication management system [19, 20]. In addition, the impact of new and emerging variants on the efficacy and durability of vaccines in this populations needs to be determined. There are studies reporting increased vaccine escape and increased breakthrough as well as re-infection rates after three-dose vaccination in infliximab- and tofacitinib-treated IBD patients following the emergence of the Omicron variant [21,22,23]. Clearly, any messaging relating to the efficacy of vaccines and the need for periodic boosters in this cohort of patients should be balanced against the potential negative mental health consequences of such messages among IBD patients and the likelihood of delaying effective IBD therapies such as anti-TNFs in this group of patients due to fears of decreased vaccine response [24].
The million-dollar question among researchers as we enter 2023 is whether the COVID-19 pandemic is truly over; if so, more COVID-19-related research in IBD will be of limited value. Recent reports of acceleration in numbers from some countries such as China suggest that we are far from being out of the woods for this virus. The end of the pandemic may be based on a high proportion of the global population having a degree of immunity from natural infection or vaccination. While the move from a pandemic to endemicity may be a ray of hope for the world, for immunosuppressed patients with conditions such as IBD, the need for hypervigilance and ongoing research remains important. We as healthcare providers and our patients can be assured that our knowledge has advanced significantly over the last two years and we are better placed to support and protect our patients for this and any future pandemics [25]. The IBD community across the world is learning through collaborative research how to tackle the current and emerging challenges, which will be posed by the COVID-19 virus and its future variants. The two studies published in this edition of the journal add to this body of knowledge and give a vital perspective from a country with increasing prevalence of IBD. As the COVID-19 pandemic evolves, new variants will inevitably emerge and/or we may indeed be faced with other emerging viral pandemics. Healthcare providers will continue to be educated through ongoing research and adjust their practice as we close the gaps further in our knowledge of dealing with pandemics. As Will Durant says, “education is a progressive discovery of our own ignorance.”
References
Sebastian S, Gonzalez HA, Peyrin-Biroulet L. Safety of drugs during previous and current coronavirus pandemics: lessons for inflammatory bowel disease. J Crohns Colitis. 2020;14:1632–43.
Kennedy NA, Jones GR, Lamb CA, et al. British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic. Gut. 2020;69:984–90.
Abreu MT, Peyrin-Biroulet L. Providing guidance during a global viral pandemic for the care of patients with inflammatory bowel disease. J Crohns Colitis. 2020;14 14 Suppl 3:S767–8.
Kante B, Vuyyuru SK, Gupta R, et al. High seroprevalence against SARS-Cov-2 in non-vaccinated patients with inflammatory bowel disease from Northern India. Indian J Gastroenterol. 2023;42. https://doi.org/10.1007/s12664-022-01310-y.
Mathur A, Sahu S, Rai S, Ghoshal U, Ghoshal UC. Serological response to vaccination against coronavirus disease-19 in patients with inflammatory bowel disease. Indian J Gastroenterol. 2023;42. https://doi.org/10.1007/s12664-022-01323-7.
Simon D, Tascilar K, Krönke G, et al. Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion. Nat Commun. 2020;11:3774.
Khan N, Patel D, Xie D, Pernes T, Lewis J, Yang YX. Are patients with inflammatory bowel disease at an increased risk of developing SARS-CoV-2 than patients without inflammatory bowel disease? Results from a nationwide Veterans' Affairs Cohort Study. Am J Gastroenterol. 2021;116:808–10.
Attauabi M, Poulsen A, Theede K, et al. Prevalence and outcomes of COVID-19 among patients with inflammatory bowel disease—a Danish prospective population-based cohort study. J Crohns Colitis. 2021;15:540–50.
Chanchlani N, Lin S, Chee D, et al. Adalimumab and infliximab impair SARS-CoV-2 antibody responses: results from a therapeutic drug monitoring study in 11 422 biologic-treated patients. J Crohns Colitis. 2022;16:389–97.
Khoury DS, Cromer D, Reynaldi A, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021;27:1205–11.
Singh AK, Jena A, Kumar MP, Sharma V, Sebastian S. Risk and outcomes of coronavirus disease in patients with inflammatory bowel disease: a systematic review and meta-analysis. United European Gastroenterol J. 2021;9:159–76.
Sebastian S, Walker GJ, Kennedy NA, et al. Assessment, endoscopy, and treatment in patients with acute severe ulcerative colitis during the COVID-19 pandemic (PROTECT-ASUC): a multicentre, observational, case-control study. Lancet Gastroenterol Hepatol. 2021;6:271–81. Erratum in: Lancet Gastroenterol Hepatol. 2021;6:e3.
Kennedy NA, Lin S, Goodhand JR, et al. Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD. Gut. 2021;70:1884–93.
Kennedy NA, Goodhand JR, Bewshea C, et al. Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab. Gut. 2021;70:865–75.
Alexander JL, Kennedy NA, Ibraheim H, et al. COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study. Lancet Gastroenterol Hepatol. 2022;7:342–52.
Jena A, Mishra S, Deepak P, et al. Response to SARS-CoV-2 vaccination in immune mediated inflammatory diseases: systematic review and meta-analysis. Autoimmun Rev. 2022;21:102927.
Kaplan GG, Ma C, Charlton C, et al. Antibody response to SARS-CoV-2 among individuals with IBD diminishes over time: a serosurveillance cohort study. Gut. 2022;71:1229–31.
Jena A, James D, Singh AK, Dutta U, Sebastian S, Sharma V. Effectiveness and durability of COVID-19 vaccination in 9447 patients with IBD: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022;20:1456-79.e18.
Lin S, Kennedy NA, Saifuddin A, et al Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab. Nat Commun. 2022;13:1379.
Alexander JL, Liu Z, Muñoz Sandoval D, et al. COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study. Lancet Gastroenterol Hepatol. 2022;7:1005–15.
Kennedy NA, Janjua M, Chanchlani N, et al. Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic. Gut. 2022 28:gutjnl-2022–327570.
Liu Z, Le K, Zhou X, et al. Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study. Lancet Gastroenterol Hepatol. 2023;8:145–56.
Liu Z, Alexander JL, Lin KW; et al. Infliximab and tofacitinib attenuate neutralizing antibody responses against SARS-CoV-2 ancestral and Omicron variants in inflammatory bowel disease patients after 3 doses of COVID-19 vaccine. Gastroenterology. 2022;19:S0016–5085(22)01184–2.
Chhibba T, Targownik LE. Is the attenuated humoral response to COVID-19 vaccination in anti-TNF users relevant? Lancet Gastroenterol Hepatol. 2022;7:280–2.
Saifuddin A, Kent AJ, Mehta SJ, et al. Treatment adaptations and outcomes of patients experiencing inflammatory bowel disease flares during the early COVID-19 pandemic: the PREPARE-IBD multicentre cohort study. Aliment Pharmacol Ther. 2022;56:1460–74.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
SS holds research grants from Biogen, Takeda, AbbVie, Tillotts Pharma, Ferring and Biohit; served on the advisory boards of Takeda, AbbVie, Merck, Ferring, Pharmacocosmos, Warner Chilcott, Janssen, Falk Pharma, Biohit, TriGenix, Celgene and Tillots Pharma; and has received speaker fees from AbbVie, Biogen, Janssen, Merck, Warner Chilcott and Falk Pharma.
Disclaimer
The authors are solely responsible for the data and the contents of the paper. In no way is the Honorary Editor-in-Chief, Editorial Board Members, the Indian Society of Gastroenterology or the printer/publishers responsible for the results/findings and content of this article.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Sebastian, S. Coronavirus disease - 19 immunity in inflammatory bowel disease patients: The progressive discovery from ignorance. Indian J Gastroenterol 42, 11–13 (2023). https://doi.org/10.1007/s12664-023-01342-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12664-023-01342-y