The culpable agent for the coronavirus disease 2019 (COVID-19) pandemic is the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [1]. It causes acute respiratory distress syndrome (ARDS) in a large number of individuals with severe pulmonary injury [2]. However, the pandemic has raised significant concerns about managing immunocompromised patients. Recent research reveals that these patients have more severe disease courses due to their underlying changed immunological status and immunosuppressive medicines [3]. Furthermore, Kim et al. reported a 40% additional risk for in-hospital mortality and 30% for intensive care unit (ICU) admission among these patients [4].

In response to the high mortality rate and casualties of the COVID-19 pandemic globally, pharmaceutical companies have produced effective vaccines against the SARS-CoV-2 infection. Therefore, immunization against SARS-CoV-2 is considered the most suitable tool in the hands of physicians. Several vaccine candidates and tactics were developed shortly after the onset of SARS-CoV-2 pandemic [5]. However, they were not fully successful in managing or controlling the COVID-19 pandemic. The spread of COVID-19 is mostly influenced by the appearance of novel viral variants brought on by the acquisition of genetic alterations in SARS-CoV-2 in various regions of the world and subsequent rapid transmission across the continents [5].

Additionally, depending on the population and variations, the efficacy of the approved vaccinations against the newly emerging SARS-CoV-2 mutations varied. This highlights the need for a broad-spectrum vaccine that could elicit a more effective immune response toward all new variants [6].

Different types of COVID-19 vaccines have been developed, including live-attenuated vaccines, protein-based vaccines, and gene vaccines (mRNA, vector-based, and VLPs) ^[5][6][5,6]. Nevertheless, the hastened course of vaccine development raises several concerns, especially in particular groups of patients, such as those with an altered immune system. Moreover, many individuals with immune-mediated chronic diseases, including autoimmune liver and gut diseases, have been excluded from vaccine clinical trials [7]. This resulted in an evidence gap for the long-term safety and efficacy of COVID-19 vaccines in patients with autoimmune diseases.

Some of the theoretical concerns are related to the complex pathogenesis of autoimmune diseases, including liver and gut conditions, immunosuppressive therapy, and the cumulative risk of flare [8]. ResWearchers rely on real-world data from vaccination after vaccine approval for these patients.

Nevertheless, autoimmune disease patients still experience high levels of COVID-19 vaccine hesitancy. Some concerns are stopping immunosuppression before vaccination and minimizing the risk of relapse and adverse effects. The COVID-19 Vaccination in Autoimmune Diseases (COVAD) study, a long-term ongoing global self-reported study that includes patients with autoimmune disease, collected data on short and long-term adverse effects and disease flares in patients following COVID-19 vaccines ^[9][10][9,10].

A questionnaire-based study among Chinese people with IBD also showed COVID-19 vaccination hesitancy, mostly related to the history of immune-modifying therapies, potential adverse reactions, and effectiveness [11].

2. Autoimmune Gut Diseases and COVID-19 Vaccines

Autoimmune diseases are characterized by hyperreactivity of the immune system and loss of immune tolerance, which damage and destroy healthy tissues, cells, and organs [12]. Patients diagnosed with inflammatory bowel disease (IBD), especially those who have undergone biological or immunosuppressive therapy, are a subject of interest due to the risk factors that arise from the illness regarding COVID-19 morbidity [13]. Currently, risk factors associated with a higher risk of infection due to IBD morbidity are nutrition status, age, comorbidity, and pharmacotherapy. The most enduring hypothesis is that malnutrition and food deficiency lead to a compromised immune response. Food deficiency relates to decreased phagocyte function and abnormal cell-mediated immunity [13]. Additionally, patients suffering from IBD often have vitamin D deficiency, increasing the severity of COVID-19 infection [14]. Going further down the road, reswearchers reviewed the role of vitamin D in deficient patients not only for COVID-19 severity but as a potential adjuvant for COVID-19 vaccination, as seen for other vaccines [15]. Many previously described studies underline that treating IBD patients with immunomodulators (TNF-antagonists, non-TNF targeted biologics), immunosuppressive therapy, or corticosteroids can increase the risk of infections, or the complications associated with various infections [16]. On the other hand, managing the activity of IBD is also of paramount importance because it plays a risk factor for infections or associated complications. That is why IBD treatment should be as optimal as possible and the treatment course uninterrupted ^[17][18][17,18]. Up to now, there are some clinical studies that involve patients with autoimmune gut diseases and assess the safety and effectiveness of COVID-19 vaccines. Thus, rwesearchers conducted a literature researchview and summarize theiour findings in Table 1. One of the first that reported on the COVID-19 vaccine and patients with autoimmune gut disease was Botwin et al. They discovered that only 3% had severe adverse events (that affect daily activity), mainly presented by malaise [19]. Three patients needed hospitalization (one of them for gastrointestinal complaints). Studies demonstrated that despite common adverse effects in the general population after COVID-19 vaccination, most of which are mild and local site reactions, there is a noticeable percentage, especially in patients with autoimmune rheumatic diseases ^[18][20][42][18,20,42]. The latter group mainly complained of localized pain (70.2%), fatigue (34.7%), headache (30.6%), and muscle ache (29.3%), with no serious adverse effects. Similar side effects were observed in IBD patients (Table 1). Additionally, it was confirmed that IBD patients on advanced therapy with biological agents showed lesser adverse effects than non-IBD patients using other treatment strategies. No data exist comparing IBD patients with other patients with autoimmune diseases, i.e., rheumatoid arthritis and other rheumatic diseases. Regarding the general population, the side effects are comparable [19]. However, they also exerted decreased antibody production while on infliximab and vedolizumab ^[21][24][21,24]. Thus, Botwin et al.’s findings are helpful for physicians and patients by confirming the similar safety profile for mRNA vaccines for IBD patients [19]. Furthermore, the authors observed a difference in adverse reactions following the first and second doses. Higher rates of adverse reactions were found after the second dose ^[18][19][18,19]. However, patients who recovered from COVID-19 had more reactions than patients with no previous antispike response after the first dose but not the second one. Nevertheless, more studies are needed to confirm this observation. Lev-Tzion et al. confirmed that the incidence rate of disease exacerbation after COVID-19 vaccination is comparable to unvaccinated IBD patients. Moreover, immunosuppressive treatment did not influence the effectiveness of the Pfizer-BioNTech BNT162 b2 vaccine [23]. Additionally, patients on immunosuppression may have reduced immune response (i.e., anti-TNFa but not azathioprine; for corticosteroids—depending on the dose) [43]. Furthermore, the Crohn’s and Colitis Foundation’s statement supports the COVID-19 vaccine in IBD patients without measuring antibody levels ^[44][45][44,45]. Other ongoing studies on the safety and effectiveness of COVID-19 in IBD patients are CORALE-Vaccine IBD (https://www.corale-study.org/ibd, accessed on 30 November 2022) and PREVENT COVID (with children, https://www.ibdpartners.org/preventcovid, accessed on 30 November 2022). Thus, the Center for Disease Control and the American College of Obstetricians and gynecologists recommend COVID-19 vaccination in female IBD patients planning pregnancy and currently pregnant or lactating women [44]. However, solid organ transplantation patients may not receive sufficient protection after vaccination. D’Amico et al. suggested more pros than cons for SARS-CoV-2 vaccination in IBD patients. However, despite insufficient data, itwe can be eextrapolated information from data reported in patients with other autoimmune diseases [46]. This is why the American College of Rheumatology recommends COVID-19 vaccines for patients with autoimmune inflammatory diseases based on the previously available data for other vaccines [47]. The recently published systemic review and meta-analysis by Sung et al. focused on efficacy, seroconversion rate (antibody titer against SARS-CoV-2 S protein), and the adverse effects in 27,454 IBD patients from 11 studies. As expected from the data from other studies, COVID-19 incidence was comparable in IBD and non-IBD patients and 8.63 times lower than observed in unvaccinated IBD patients. However, the reported adverse event rate after vaccination was 69%, the severe adverse rate was 3%, and mortality was 0% [48]. Doherty et al. published similar results in their paper—reduced immune responses after vaccination in IBD patients on anti-TNF therapy and other immunomodulators. However, the overall conclusion is that patients with IBD still benefit from COVID-19 vaccination, and recommendations included minimizing corticosteroid doses before vaccination if possible [49]. Jena et al. in their systematic review and meta-analysis on effectiveness and durability of COVID-19 vaccination in IBD patients confirmed the lower pooled seroconversion rate. However, the pooled relative risk of infection breakthrough was similar to control subjects [50]. Tabesh et al. also conducted a systematic scoping review of 15 studies, concluding that COVID-19 vaccines are effective and safe for patients with IBD on different therapeutic regimens [51]. One of the most significant limitations of the published studies so far is that they cover effectiveness or adverse effects solely, but rarely both. Additionally, adapted immunization techniques may be appropriate in some IBD patients to maximize immunogenicity, according to prior experience ^[52][53][52,53]. Still, the main concerns for patients with IBD remain a lack of immune protection after vaccination (17.6% of respondents), worsened adverse effects (24.6%) due to IBD, and flare following vaccination (21.1%), according to an international web-based survey [33]. Duong et al. also reported that 2/3 of surveyed IBD patients were willing to get vaccinated against COVID-19 [54], which was also reported by Hudhud et al. [55].