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.”