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Response to Vaccines in Patients with Immune-Mediated Inflammatory Diseases: A Narrative Review

Beatriz Garcillán
Miguel Salavert
José R. Regueiro
3 and
Sabela Díaz-Castroverde
Medical Affairs Department, Janssen, 28042 Madrid, Spain
Infectious Disease Unit, Department of Clinical Medicine, La Fe Health Research Institute, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
Author to whom correspondence should be addressed.
Vaccines 2022, 10(2), 297;
Submission received: 23 December 2021 / Revised: 26 January 2022 / Accepted: 13 February 2022 / Published: 15 February 2022
(This article belongs to the Section COVID-19 Vaccines and Vaccination)


Patients with immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis and inflammatory bowel disease, are at increased risk of infection. International guidelines recommend vaccination to limit this risk of infection, although live attenuated vaccines are contraindicated once immunosuppressive therapy has begun. Biologic therapies used to treat IMIDs target the immune system to stop chronic pathogenic process but may also attenuate the protective immune response to vaccines. Here, we review the current knowledge regarding vaccine responses in IMID patients receiving treatment with biologic therapies, with a focus on the interleukin (IL)-12/23 inhibitors. B cell-depleting therapies, such as rituximab, strongly impair vaccines immunogenicity, and tumor necrosis factor (TNF) inhibitors and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) fusion protein abatacept are also associated with attenuated antibody responses, which are further diminished in patients taking concomitant immunosuppressants. On the other hand, integrin, IL-6, IL-12/23, IL-17, and B-cell activating factor (BAFF) inhibitors do not appear to affect the immune response to several vaccines evaluated. Importantly, treatment with biologic therapies in IMID patients is not associated with an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or developing severe disease. However, the efficacy of SARS-CoV-2 vaccines on IMID patients may be reduced compared with healthy individuals. The impact of biologic therapies on the response to SARS-CoV-2 vaccines seems to replicate what has been described for other vaccines. SARS-CoV-2 vaccination appears to be safe and well tolerated in IMID patients. Attenuated but, in general, still protective responses to SARS-CoV-2 vaccination in the context of certain therapies warrant current recommendations for a third primary dose in IMID patients treated with immunosuppressive drugs.

1. Introduction

Immune-mediated inflammatory diseases (IMIDs) are a diverse group of clinically unrelated conditions, including, among others, rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (PsO), and inflammatory bowel disease (IBD). They share molecular mechanisms and are characterized by altered immune homeostasis that results in chronic excessive inflammation leading to tissue injury in affected organs and eventually functional disability [1].
Due to their inflammatory nature, IMIDs are often treated with immunosuppressants or immunomodulators, including steroids, methotrexate (MTX), thiopurines, small-molecule inhibitors, and a range of biologic therapies that target key molecules or cells involved in the inflammatory response. Patients with IMIDs are often at increased risk of infections because of the disease itself, the immunosuppressive or immunomodulators used to treat the disease, comorbidities, and/or hospitalizations caused by disease flares or complications [2,3,4]. Infections can be prevented through the use of chemoprophylaxis and/or vaccination; in fact, guidelines for the management of IMID patients recommend vaccination in accordance with local immunization schedules and patient-specific risks, unless there are contraindications [5,6,7,8,9].
The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and the advent of population-wide vaccination programs raise questions about the safety and efficacy of SARS-CoV-2 vaccination in IMID patients, especially those under immunomodulatory or immunosuppressive therapy. A range of SARS-CoV-2 vaccines are available or in development. Most employ non-replicating viral vectors or mRNA for the spike protein of the virus, but some use more conventional technology, such as inactivated virus or live attenuated virus [10,11]. It is likely that the vaccine’s ability to generate an effective immune response against SARS-CoV-2 will be affected by the type of medications patients are receiving. The aim of this narrative review is to summarize current knowledge regarding vaccine responses in IMID patients treated with biologic therapies, with a focus on agents that inhibit interleukin (IL)-12 and/or -23, as various new IL-23 inhibitors are being approved for several IMID conditions.

2. Increased Risk of Infections in Patients with IMIDs

Patients with IMIDs have an increased risk of infections compared with unaffected individuals, firstly, because of the immune dysfunction that characterizes these conditions and, secondly, due to the immune modulatory therapies used to treat them. Corticosteroids are associated with the highest risk of infections [12,13], and thiopurines and MTX also increase the risk of infections compared with placebo [14,15,16], but the magnitude of the risk increase is not as high as with corticosteroids.
Some biologic therapies used to treat IMIDs may also increase the risk of infections, but the risk is not uniform across all agents. The European Society of Clinical Microbiology and Infectious Disease (ESCMID) reviewed the evidence for biologic therapies and concluded that TNF inhibitors increase the risk of active tuberculosis and other granulomatous infections and may also increase the risk of other serious bacterial, fungal, opportunistic, and certain viral infections [17]. The infection risk associated with biologic therapies targeting IL-6 or the IL-6 receptor is similar to the risk with TNF inhibitors [18]. IL-1 inhibitors are associated with a moderate increase in the risk of infections, which are generally mild to moderate in most patients [18]. IL-17 inhibitors are associated with an increased risk of Candida infections [19]. IL-12/23 inhibitor ustekinumab is not associated with an appreciable increase in the risk of infections [18]. Anti-integrins do not appear to increase the risk of infections, except for anti-α4 integrins that increase the risk of progressive multifocal leukoencephalopathy (PML) by Polyomavirus JC [20]. Agents targeting CD20 (e.g., rituximab) increase the risk of infections, the most common being respiratory tract infections, hepatitis B (and, to a lesser extent, hepatitis C) reactivation, and varicella zoster infection [21].
Current data suggest that patients with IMIDs are not at increased risk of acquiring SARS-CoV-2 infection or of hospitalization/death compared with the general population [22,23,24,25]. However, older age, comorbidities, and the use of non-biologic systemic therapy (particularly corticosteroids) increases the risk of severe COVID-19 disease and/or hospitalization in patients with IBD, PsO, or rheumatic IMIDs [26,27,28,29,30,31]. Biologic therapies (except for the B-cell depleting agent rituximab [32]) were not associated with an increased risk of developing severe COVID-19 [33,34], and some of these therapies may in fact be protective against COVID-19-related hospitalization and death among infected patients [26,27,28,29,35,36].
Based on the increased risk of infection, preventive measures are an important strategy for limiting serious illness in patients with IMIDs, either by appropriate vaccination or by chemoprophylaxis to prevent reactivation of latent infections, such as tuberculosis, Pneumocystis, or hepatitis B.

3. Vaccines and IMIDs

Multiple sets of international guidelines recommend vaccination to limit the risk of infection in patients with IMIDs [5,6,7,8,9]. Before initiating systemic immunosuppressive therapy, a vaccination and infectious disease history should be undertaken to identify gaps in the patient’s vaccination schedule, and vaccinations should be administered according to the recommendations for the general population and for the specific patient group.
Ideally, patients should be vaccinated before immunosuppressive therapy is started, as therapies could impact vaccine efficacy. Moreover, live attenuated vaccines could cause disease in immunocompromised patients and are therefore contraindicated once immunosuppressive therapy has been initiated, unless the potential benefit of preventing the infection outweighs the risk of administering a live vaccine [37]. Inactivated vaccines are generally safe and do not increase the risk of IMID exacerbation, although some studies reported increased joint pain following the administration of some vaccines in patients with rheumatologic conditions [38,39].
Regular influenza and pneumococcal vaccinations are deemed particularly important in IMID patients on biologic therapy. Physicians may also consider vaccination against Haemophilus influenzae type b, Neisseria meningitidis, hepatitis B, diphtheria, and tetanus, depending on the patient’s vaccination history and clinical profile [6,7,8,40].
Despite the importance of vaccination in IMID patients, suboptimal vaccination rates are reported. Possible reasons include lack of awareness of recommendations, inadequate communication between specialist and primary care physicians, and concerns about the efficacy and safety of vaccines [7,41,42].

4. Immune Response Necessary to Generate Immunity

Vaccines are one of the key developments of modern medicine; they prevent thousands of infections and deaths worldwide and represent an important advance in public health.
Vaccination provides protective immunity by eliciting a pathogen-specific immune response against the antigenic material present in the vaccine; this immune response is often boosted by adjuvants within the vaccine that enhance the magnitude and durability of the response [43]. The main immune effectors of vaccine responses are antibodies (humoral immunity) and T cells (cellular immunity). Antigen(s) are taken up by antigen-presenting cells (APCs) and are presented to B and T cells to generate antigen-specific B- and T-cell responses [44]. Antibodies may prevent or reduce infection by binding to the pathogen, while T cells mediate elimination of infected cells. CD4+ helper T cells (Th) orchestrate the immune response by providing T-cell help to primed B cells and CD8+ cytotoxic T cells. In addition, Th cells secrete cytokines that aid pathogen clearance. In lymphoid follicles, T follicular helper cells (Tfh cells) provide T-cell help to B cells and mediate their activation and differentiation into antibody-producing plasma cells and memory B cells.
Once an infection is cleared, most of the antigen-specific cells die off through apoptosis, but antibodies and long-lived plasma cells persist along with memory B and T cells, which can mount an anamnestic response upon re-exposure to the antigen [45].
In most cases, to induce an antibody response, B cells need the aid of Tfh cells (T cell-dependent B-cell response). However, non-protein antigens, such as pure polysaccharide vaccines, activate B cells and elicit antibody production without the involvement of T cells (T cell-independent B-cell response). This T-independent response is generally considered to produce low affinity IgM antibodies and to be short-lived [44].
Vaccine-induced immune responses are often measured as a correlate of vaccine efficacy; most commonly, the humoral immune response is measured by quantifying antigen-specific antibodies in plasma (e.g., total IgG antibodies measured by ELISA) or, if feasible, functional antibodies (e.g., neutralizing antibodies). Some studies report seroprotection and/or seroconversion rates; seroprotection is defined as the antibody level needed to achieve protection, while seroconversion refers to a fold-rise in antibody levels from pre- to post-vaccination. The measurement of cellular immunity is less common and is based in the detection of antigen-specific CD4+ and CD8+ T cells and the cytokines they release following in vitro stimulation.
A key goal of vaccination is to induce long-lasting immunity; however, while some vaccine responses are durable (e.g., hepatitis A, B, and diphtheria), others are short-lived and require multiple administrations (e.g., influenza). The magnitude and duration of vaccine-induced immunity is determined by host, environmental and vaccine factors (structure of the antigen; adjuvants; dose; schedule, site, route, and timing of administration; and concomitant medications) [45,46].

5. Approved Biologic Therapies and Their Impact on Responses to Vaccines

Immunosuppressive/immunomodulatory drugs used to treat IMIDs target the immune system to stop pathogenic chronic inflammation, but, in many cases, these therapies may also impact the ability to properly respond to infections and to vaccines. A range of biologic therapies are used in IMIDs; they act at different stages of the inflammatory response, by depleting certain immune cells, or by blocking their activation or their migration. Below, we review the impact of biologic therapies on vaccine immunogenicity in IMID patients; the evidence is also summarized in Table 1 and Table 2.

5.1. Integrins

5.1.1. Anti-α4 (Natalizumab)

Integrin antagonists inhibit the trafficking of circulating immune cells to the site of inflammation. Natalizumab, a monoclonal antibody (mAb) against the α4 chain common to the α4β1 and α4β7 integrins, blocks the migration of leukocytes to the central nervous system and gastrointestinal (GI) tract by blocking the interaction between α4β1 and vascular cell adhesion molecule 1 (VCAM-1) and between α4β7 and mucosal addressin cell adhesion molecule 1 (MAdCAM-1), respectively. It is widely approved for the treatment of multiple sclerosis (MS) but carries a risk of PML. In the US, natalizumab is also available through a restricted access program for patients with moderate to severe active Crohn’s disease (CD) who have an inadequate response or cannot tolerate other therapeutic options.
Data on the effect of natalizumab on vaccine response are scarce (Table 1). Two small studies showed a reduced rate of seroconversion after seasonal influenza vaccination in MS patients compared with healthy controls [47,48]. Additionally, in a randomized open-label study in MS patients treated or not with natalizumab, all patients achieved protective levels of antibodies to a recall antigen (tetanus toxoid) or a neoantigen (keyhole limpet hemocyanin [KLH]—a carrier protein used to research antibody production) [49].

5.1.2. Anti-α4β7 (Vedolizumab)

Vedolizumab inhibits the extravasation of leukocytes to the intestinal mucosa by selectively blocking the integrin α4β7, which targets MAdCAM-1, a cell adhesion molecule that is expressed by endothelial cells in the GI tract [108]. Vedolizumab is indicated for the treatment of CD and ulcerative colitis (UC).
The effect of vedolizumab on vaccine responses was evaluated in a phase 1, randomized, double-blind, placebo-controlled trial. Healthy individuals received a single intravenous dose of vedolizumab of 750 mg (approved dose is 300 mg) (Table 1). Vedolizumab did not alter the response to a parenterally administered vaccine (hepatitis B), as antibody titers were similar between placebo and vedolizumab groups. However, the humoral response to an enterally administered vaccine (oral cholera vaccine) was significantly reduced, probably due to the gut-specific effect of this agent [51]. A recent study analyzed the immunogenicity of the trivalent or quadrivalent influenza vaccine in 19 patients with IBD who were receiving vedolizumab. The humoral response (antibody titers, seroprotection, and seroconversion rates) to seasonal influenza vaccine was similar in patients on vedolizumab and in the 20 healthy controls [50].

5.2. Co-Stimulators of T Cells

CTLA-4 Fusion Protein (Abatacept)
Abatacept is a soluble fusion protein comprising the extracellular domain of human cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). It acts by blocking T-cell activation, as it competes with CD28 for binding to CD80/86 on APCs, a required second co-stimulatory signal needed for T-cell activation [109]. Abatacept is indicated for the treatment of RA, PsA, and polyarticular juvenile idiopathic arthritis (JIA).
Vaccination effectiveness while on abatacept therapy has been assessed only in RA patients (Table 1). The response to the 23-valent polysaccharide pneumococcal vaccine (PPV-23), which induces a T cell-independent response, was analyzed in a randomized, double-blind, controlled trial, and a diminished IgG response was observed with abatacept. However, in a functional assay (opsonization index), no differences were found between groups (abatacept, MTX, or control) [52]. Moreover, in two open-label sub-studies with no control group, RA patients receiving abatacept mounted a proper immune response to PPV-23 and influenza vaccine [53]. However, the antibody response to the pneumococcal conjugate vaccine (PCV), which induces a T cell-dependent response, was shown to be impaired in a small cohort of RA patients receiving abatacept (mostly in combination with MTX) [54]. Similarly, abatacept treatment was associated with a significantly reduced IgG response to the monovalent A/H1N1 influenza vaccine compared with MTX treatment [55].
In addition to studies evaluating vaccine response during treatment with abatacept, a study in children aged 2–5 years found that starting abatacept treatment did not affect pre-existing protective antibody levels to tetanus and diphtheria vaccinations administered 21–79 months before abatacept initiation [110].

5.3. B Cells

B cells are essential for humoral immune responses but have also been implicated as drivers of several autoimmune and IMID conditions. B-cell targeted biologic therapies are now available for the treatment of IMIDs [111]. These include the CD20-specific B-cell depleting therapies, such as rituximab, and the B-cell activating factor (BAFF) inhibitor belimumab [112,113].

5.3.1. Anti-CD20 (Rituximab)

Rituximab is a mAb that binds to the B-cell surface protein CD20 and leads to the depletion of B lymphocytes. It is indicated for RA, MS, and B-cell related hematologic malignancies and has been investigated in the treatment of systemic lupus erythematosus (SLE) [111,114].
Since B cells are responsible for humoral immune responses, it is unsurprising that patients receiving rituximab show reduced antibody levels after vaccination. Bingham and colleagues found that, compared with RA patients taking MTX alone, a lower proportion of patients taking rituximab + MTX mounted a protective antibody response to the T-cell independent vaccine PPV-23. In contrast, a similar proportion responded to the T-cell dependent tetanus toxoid vaccine [56].
The magnitude of the antibody response to PCV, and the proportion of patients mounting a protective antibody response, was also reduced in patients with RA receiving rituximab monotherapy and in those receiving rituximab + MTX compared with those receiving MTX monotherapy [54]. Similarly, in the Red de Investigación en Inflamación y Enfermedades Reumáticas (RIER) study, which investigated the response to vaccines among patients receiving biologics for various IMIDs (arthropathies, connective tissue diseases, PsO, or IBD), functional antibody levels were lower after pneumococcal vaccination with PCV-7 and PPV-23 in patients receiving rituximab than in those receiving other biologic therapies [57]. The same study also reported that a lower proportion of patients under rituximab developed protective antibody titers after hepatitis B vaccination compared with patients receiving other types of biologics [58].
Response to the trivalent influenza vaccine in patients currently receiving or recently completing treatment with rituximab has been examined in several studies. Patients with RA who had received rituximab showed an impaired humoral response compared with RA patients receiving non-biologic disease modifying anti-rheumatic drugs (DMARDs) or healthy controls [59,60,61,62,63]. However, the cellular immune response to influenza vaccination was not affected by rituximab, with similar levels of influenza-specific CD4+ cells in patients treated with rituximab or DMARDs [59]. Interestingly, antibody response might be improved by a longer dose-administration schedule between rituximab administration and influenza vaccination [61,63].
Similar to responses to the trivalent influenza, a diminished antibody response to the monovalent H1N1 influenza vaccine has been reported in patients taking rituximab [64,65]. Adler and colleagues examined the response to H1N1 vaccination in IMID patients, of whom eight were receiving rituximab and none of them developed seroprotective antibody levels [65]. In a study from Sweden, RA patients receiving rituximab had a significantly reduced humoral response compared with those receiving MTX [64].
Due to the impact of rituximab treatment on vaccine immunogenicity, several guidelines have made recommendations regarding timing of vaccination while on rituximab. IMID patients normally receive rituximab cycles every 6 months and the general recommendation is to administer inactivated vaccines at least 5 months following the last rituximab dose to allow for some B-cell reconstitution [115,116].

5.3.2. Anti-BAFF (Belimumab)

The BAFF inhibitor belimumab acts by neutralizing BAFF (also known as B lymphocyte stimulator), a key cytokine involved in B-cell survival and differentiation [114,117]. Belimumab is indicated for SLE, the first biologic approved for this condition [113]. The B cell-depleting effect of belimumab is not as intense as that of rituximab, since belimumab preferentially targets transitional and naïve B cells while leaving conventional memory B cells unaffected [118]; therefore, the two different classes of B cell-depleting therapies may have different effects on the vaccine response [114]. Nevertheless, because it targets B cells, belimumab may negatively impact the response to vaccines.
Currently, data on the effects of belimumab are limited (Table 1), but studies have shown that SLE patients receiving belimumab who were immunized with PCV generated a similar antibody response to SLE patients receiving other standard immunosuppressive therapies (DMARDs, azathioprine, MTX, and/or corticosteroids) [66].
Moreover, in a phase 4, open-label study, immunization of SLE patients with PPV-23 4 weeks before or 24 weeks after starting belimumab resulted in similar humoral response [67].
Consistent with preservation of memory B cells by belimumab, pre-existing antibody titers to pneumococcus, tetanus, or influenza vaccinations received before starting belimumab were shown to be preserved in a sub-study from the phase 3 randomized placebo-controlled trial [119].

5.4. Pro-Inflammatory Cytokines

5.4.1. Anti-TNF

TNF is a proinflammatory cytokine that is important in immune responses, particularly to intracellular pathogens. However, dysregulated TNF production leads to excessive inflammation and survival of pathogenic autoreactive immune cells and, as such, TNF plays a central pathophysiologic role in a range of IMIDs [120,121].
Agents targeting TNF are widely used in the treatment of PsA, PsO, RA, spondyloarthropathies, and IBD and include infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol. Due to the central role of TNF in immunity and the widespread use of TNF inhibitors, the impact of anti-TNF therapy on vaccine responses has been extensively studied (Table 1).
Since some of the proinflammatory actions of TNF include maturation of APCs, costimulation of T cells, induction of the germinal center (GC), and stimulation of immunoglobulin synthesis [68], it is possible that inhibition of TNF may impair vaccine responses.
The antibody response to PPV-23 appears to be moderately affected by TNF inhibitor treatment, although the data are affected by the choice of comparator and by concomitant medications. Studies in patients with rheumatological IMIDs have shown that, compared with patients taking placebo or NSAIDs, those receiving TNF inhibitors generate a less robust antibody response to PPV-23 [68,71,74,75,78]. However, other studies showed no difference in antibody titer or the proportion of patients achieving protective antibody levels after PPV-23 between RA patients receiving TNF inhibitors and those receiving placebo [69,72]. Studies comparing the vaccine response in patients receiving TNF inhibitors and those receiving MTX have generally shown no significant difference between the two groups of patients [69,70,73,122], but MTX itself blunts the humoral response to PPV-23 [123,124]. The effect of TNF inhibitors and MTX administered together appears to be additive, since the most marked effect of TNF inhibitors on the antibody response to PPV-23 has been shown in patients taking concomitant MTX [69,72]. Most of these studies were undertaken in patients with rheumatological IMIDs, but studies in patients with IBD also showed lower antibody titers after PPV-23 in patients receiving TNF inhibitors ± immunosuppressive therapy (azathioprine) than in those receiving mesalamine or immunosuppressive monotherapy [74,75,76,77].
Impaired humoral responses to PCV vaccination were also seen in patients with RA, spondyloarthropathies, or IBD taking TNF inhibitors [39,74,78], particularly in the presence of concomitant MTX [39].
Lower rates of seroconversion to the hepatitis B vaccine have been reported during TNF inhibitor therapy in patients with spondyloarthropathies [68] or IBD [79,80], although another study found no difference in seroconversion rates between IBD patients receiving TNF inhibitors, or immunomodulators, or their combination [81]. The seroprotection rate after hepatitis B vaccine tends to be diminished in patients with IBD [81], but this is especially marked among IBD patients receiving TNF inhibitors [80]. Some authors suggest that IBD patients receiving TNF inhibitors should receive two full courses of hepatitis B vaccine, instead of one, to achieve protection [80]. Similarly, many patients receiving TNF inhibitors and/or MTX do not achieve seroprotection after a single dose of hepatitis A virus (HAV) vaccine [82].
A diminished antibody response to seasonal influenza vaccine in patients receiving TNF inhibitors has been reported in several studies [83,84,85,89,90,93,94]; however, some other studies have reported a normal humoral response [86,87,88]. The timing of the antibody assessment in these studies may explain this discrepancy, for example, a longitudinal study in IBD patients showed a preserved antibody response at 3 weeks but a lower antibody titer at 6 months and 2 years in TNF inhibitor recipients vs. controls [91]. As with the PPV-23 vaccine, the response to influenza vaccination may be further blunted in patients who take concomitant immunosuppressants in combination with the TNF inhibitor [89,90,92,125,126].
Live attenuated vaccines are contraindicated in patients under anti-TNF therapy; however, some small studies have reported some cases of exposure. The humoral and cellular response to measles-mumps-rubella (MMR) was preserved in 5 children with JIA on low-dose MTX in combination with etanercept [95]. Moreover, in a Brazilian case series of 17 RA patients under infliximab therapy, yellow fever revaccination resulted in an adequate humoral response [96]. Importantly, these two studies did not report adverse effects or secondary severe infections after vaccination with live attenuated vaccines. Similarly, a study evaluating the safety of the live attenuated herpes zoster (HZ) vaccine in 551 IMID patients under anti-TNF therapy did not find cases of varicella or HZ 42 days after vaccination [127]. Despite these encouraging results, larger studies are needed to evaluate the risks with this type of vaccines.
Despite a somewhat attenuated antibody response to vaccines in patients receiving TNF inhibitors, a high proportion of patients nevertheless achieve protective antibody levels, supporting current recommendations to vaccinate these patients.

5.4.2. Anti-IL-1

IL-1 is a family of 11 cytokines involved in the innate immune response, with both pro- and anti-inflammatory functions. IL-1β and IL-1α, specifically, have pro-inflammatory properties and are involved in the development of rheumatic diseases [128].
Anakinra, a recombinant IL-1 receptor antagonist, blocks the interaction of IL-1β and IL-1α with its receptor and is indicated for RA and cryopyrin-associated periodic syndromes (CAPS). Canakinumab, an anti-IL-1β mAb, is approved for periodic fever syndromes (such as CAPS) and systemic JIA.
The RIER study included only one patient taking anakinra in their analyses of the response to influenza or hepatitis B vaccines; therefore, no meaningful assessment of the effect of anakinra on vaccine response was possible [58,129].
To date, vaccine responses in patients under canakinumab therapy have been studied in children with CAPS. In an open-label phase 3 study, canakinumab had no effect on antibody titers after immunization with non-live childhood vaccines [130].

5.4.3. Anti-IL-17

IL-17 cytokines are produced by type 17 cells, which include Th17 cells, subsets of γδ T cells, invariant NK T cells, ‘natural’ Th17 cells, type 3 innate lymphoid cells (ILCs), and mucosal-associated invariant T (MAIT) cells [131]. IL-17 plays a role in protective immunity against extracellular bacterial and fungal infections [132]. IL-17-producing cells accumulate at mucosal surfaces where they are responsible for the maintenance of barrier integrity, production of antimicrobial peptides, and recruitment of neutrophils. Increased numbers of IL-17-producing cells have been found in the skin of patients with PsO and the joints of patients with RA [133,134], and increased levels of type 3 ILCs have been found in the synovia and blood of patients with PsA, which correlate with disease activity [135]. In CD, increased expression of IL-17A has been reported in the intestinal mucosa [136]. In spite of that, IL-17 inhibitors have proven to be ineffective in patients with IBD, and cases of de novo IBD or IBD exacerbation have been reported [137].
IL-17 inhibitors include the anti-IL-17A mAbs ixekizumab and secukinumab and the IL-17RA mAb brodalumab [113]. Secukinumab and ixekizumab are approved for plaque PsO, PsA, and axial spondyloarthropathies, whereas brodalumab is only approved for PsO.
The impact of IL-17 inhibition on vaccine responses has only been assessed in three small studies (Table 1). In an open-label randomized study, healthy subjects received a single 150 mg dose (approved dose 300 mg) of secukinumab or no treatment 2 weeks prior to vaccination with influenza and group C meningococcal vaccine. Seroconversion rates 4 weeks later were similar between the two groups [97]. Similarly, a separate study showed that the humoral response to the seasonal influenza vaccine in patients with PsA or ankylosing spondylitis receiving secukinumab was similar to the response observed in healthy controls [98]. In a randomized study in healthy adults, administration of two doses of ixekizumab (2 weeks before and on the day of tetanus and PPV-23 vaccination) did not significantly reduce the seroprotection rates when compared with individuals not receiving ixekizumab [99].

5.4.4. Anti-IL-6

IL-6 is a master cytokine that regulates innate and adaptive immune responses. IL-6 is secreted during infection or inflammation by many cell types, such as endothelial and synovial cells in joints [138,139]. Dysregulation of IL-6 signaling can cause persistent synovial inflammation and damage to the articular cartilage and underlying bone and eventually leads to the development of inflammatory arthritis [140]. Currently available IL-6 receptor inhibitors include tocilizumab and sarilumab, both of which are approved for RA; tocilizumab is also approved for systemic JIA.
Vaccine efficacy in patients receiving IL-6 inhibitors might be affected for several reasons: IL-6 plays an important role in naïve T cell differentiation, it is a growth factor for B cells, and promotes the development of Tfh cells [139]. However, studies investigating the impact of tocilizumab in response to PPV-23 (Table 1) suggest that tocilizumab did not significantly reduce the antibody response compared with patients receiving other treatments (MTX, anti-TNF, or conventional DMARDs) [100,101,102], Similarly, the humoral response to the conjugate pneumococcal vaccine was similar in RA patients receiving tocilizumab and those not receiving biologic therapy [54]. Tocilizumab does not appear to affect the antibody response to influenza vaccination, including in children with JIA [64,102,103,104], but concomitant treatment with MTX does abrogate the antibody response in tocilizumab recipients [102,103]. Lastly, in a single randomized study, tocilizumab had no effect on the antibody response to tetanus toxoid vaccine [100].

6. Vaccine Response in Patients Treated with IL12/23 and IL-23 Inhibitors

IL-12 and IL-23 are produced by innate immune cells, mainly macrophages and dendritic cells, and are an important link between innate and adaptive immunity. They are structurally similar but exert different functions in immunity against pathogens, as well as in the pathogenesis of disease. IL-12 and IL-23 are heterodimeric cytokines; IL-12 is composed of the p40 and p35 subunits, while IL-23 is formed by p40 and p19. In addition to sharing the p40 subunit, IL-12 and IL-23 also share receptor chains. Their corresponding receptors are heterodimeric complexes, the receptor for IL-12 consists of IL-12Rβ1 and of IL-12Rβ2, whereas the receptor for IL-23 is made up of IL-12Rβ1 and IL-23R (Figure 1) [141].
In 1989, IL-12 was identified as a potent growth factor and activator of NK cell functions, including interferon-γ (IFN-γ) production and cytotoxic activity [142]. Subsequently, IL-12 was found to drive the differentiation of naïve CD4+ T cells into Th1 cells, which orchestrate adaptive immune responses [143]. Binding of IL-12 to its receptor leads to IFN-γ production, which plays a critical role in host defense against intracellular pathogens [144].
For many years, IL-12-mediated Th1 responses were thought to be responsible for several autoimmune and autoinflammatory conditions. This notion was based on experimental animal models using mice deficient in p40 or IL-12Rβ1 and suggested that IL-12 could be an interesting therapeutic target. The discovery of IL-23 in 2000 [145] led to a paradigm-changing study by Cua and colleagues in 2003, in which the authors described that IL-23 and not IL-12 (as previously thought) was the culprit for the initiation of autoinflammation in a murine model of experimental autoimmune encephalomyelitis [146].
IL-23 stimulates type-17 cells to produce IL-17A, IL-17F, and IL-22 and is also responsible for the maintenance and expansion of Th17 cells, which have been implicated in chronic inflammation and are thought to be the drivers of several IMIDs. In fact, single nucleotide polymorphisms in IL-23R have been linked with the development of several IMIDs [147], highlighting the role of the IL-23/Th17 axis in the pathogenesis of IMIDs.
Several mAbs have been developed to target IL-12 and/or IL-23. Ustekinumab, a human mAb against the p40 subunit targets both IL-12 and IL-23, is approved for the treatment of PsO, PsA, CD, and UC. Appreciation of the predominant role of the IL-23/Th17 axis in the pathogenesis of IMIDs led to the development of antibodies against the p19 subunit, which exclusively target IL-23. Guselkumab, tildrakizumab, and risankizumab are all approved for the treatment of PsO; guselkumab and risankizumab are also approved for PsA.
More recently, IL-12 and IL-23 have also been implicated in the differentiation of CD4+ Tfh cells, which provide B-cell help in the GC to generate high-affinity antibodies and to promote the differentiation of B cells into memory B cells or long-lived plasma cells [148,149]. Owing to their functions, Tfh cells are key to immune responses to pathogens and vaccines and may be potentially impacted by IL-12/23 inhibition.
To date, there are limited clinical data on the effects of IL-12/23 inhibition on vaccine responses, but available data suggest that a sufficient vaccine response is likely in patients taking ustekinumab and, by extension, IL-23-specific inhibitors. In addition, data from individuals with complete genetic deficiency of these cytokines or their receptors may shed some light on the impact of IL-12/23 inhibition on responses to pathogens and vaccines.
Monogenic inborn errors leading to complete deficiency of IL-12 and/or IL-23 or their receptors are often characterized by an increased susceptibility to infections with poorly pathogenic mycobacteria and salmonella due to impaired IFN-γ production in otherwise healthy individuals. However, penetrance is not complete, and the phenotype differs between individuals [150,151,152].
Due to the role of IL-12/23 in Tfh cell commitment, it was hypothesized that its deficiency would impact antibody responses. Subjects lacking IL-12Rβ1 (abolished IL-12 and IL-23 signaling) are still able to generate Tfh cells [148] and are not prone to B cell-deficient associated infections [153]. Moreover, they show normal serum specific IgG titers for tetanus toxoid, rubella, Epstein-Barr virus, cytomegalovirus, and varicella virus [148] and preserved humoral and cellular immune responses to influenza vaccination [150]. These antibodies may be generated independently of the GC response, and therefore would be expected to show low avidity for their antigen. In fact, the avidities of specific IgG against the tetanus toxoid were lower in IL-12Rβ1-deficient subjects, but the avidities of rubella virus-specific IgG were comparable to healthy subjects [148].
During the early development of ustekinumab, humoral response to immunization with KLH was assessed in cynomolgus monkeys during the preclinical toxicology study. Monkeys were treated with multiple doses of ustekinumab or placebo for 26 weeks, and anti-KLH antibody titers were similar in both groups, even when using ustekinumab levels exponentially higher than those approved in humans [106].
Responses to vaccination were also assessed during phase 1 studies in patients with PsO and MS who had received a single dose of ustekinumab. Humoral recall response to the PPV-23 and tetanus toxoid vaccines were similar between patients receiving ustekinumab or placebo (Table 1) [106].
Two further studies evaluated the impact of ongoing use of ustekinumab on vaccine responses (Table 1) [105,107]. The response to tetanus toxoid and PPV-23 vaccines was assessed in a subset of PsO patients who had received ustekinumab for at least 3 years in the phase 3 PHOENIX 2 clinical trial (n = 60) and a control group of PsO patients not receiving systemic therapy (n = 56) [105]. Humoral and cellular immune responses were comparable between ustekinumab-treated and control groups. Four weeks after vaccination, seroconversion rates to the tetanus and PPV-23 vaccines were similar in the control group and in those receiving ustekinumab. Importantly, this study investigated the impact on vaccine responses of long-term treatment with ustekinumab in patients with PsO. Moreover, these data show that inhibition of IL-12/23 with ustekinumab does not compromise immune response to T-dependent (tetanus) or T-independent (PPV-23) vaccines in patients with PsO during long-term use of ustekinumab [105].
Similarly, a recent small prospective study evaluated the humoral and cellular immune response to seasonal influenza vaccine in patients with CD treated with ustekinumab and in healthy controls. Three months after vaccination, functional antibody responses were measured using hemagglutinin inhibition assays, and based on these results, seroprotection and seroconversion rates to the three influenza strains in the vaccine were calculated. Seroprotection and seroconversion rates were high and comparable between ustekinumab-treated patients and healthy controls. Importantly, this study also showed that ustekinumab did not impair cellular immune responses, as assessed by the proliferation of influenza-specific CD3+, CD4+, and CD8+ T cells [107]. The lack of effect of ustekinumab on cellular immune responses is encouraging and important since this measure of vaccine response is not always included in assessments of vaccine immunogenicity.
In conclusion, pharmacologic inhibition of IL-12/23 is probably milder than complete congenital immunodeficiency. In fact, the increased susceptibility to infections with poorly pathogenic mycobacteria and salmonella observed in immunodeficient patients has not been reported in patients treated with ustekinumab. Regarding impaired Tfh functions, data on congenital immunodeficient patients show a mild effect, whereas these functions seem to be preserved during treatment with IL-12/23 inhibitors [148,154,155].
Data are not yet available on the effects of IL-23 inhibition on vaccine responses; however, since inhibition of both IL-12 and IL-23 with ustekinumab does not seem to affect the immune response induced by several vaccines, it is likely that IL-23-specific inhibition will similarly show minimal impact on protective immunity after vaccination.

7. SARS-CoV-2 Vaccination in IMID Patients

Given the scale of the global COVID-19 pandemic, it is crucial that vaccination provides effective protection against SARS-CoV-2 infection. The current vaccines, which were rapidly developed and, in some cases, incorporate novel technologies, have proven to be effective in healthy individuals. However, patients receiving immunosuppressive therapies were excluded from the phase 3 trials, raising questions about the effectiveness and safety of the vaccines in these patients. All available SARS-CoV-2 vaccines, as well as almost all in the development pipeline, are non-live vaccines that employ non-replicating viral vectors or mRNA [156], so theoretically they are not contraindicated in patients with IMIDs receiving systemic immunosuppressive or immunomodulatory therapies.
At the time of writing this review, several reports are being published on the immunogenicity and safety of SARS-CoV-2 vaccines in IMID patients and the impact of biologic therapy (summarized in Table 3).

7.1. Humoral Responses to SARS-CoV-2 in IMIDs

The COVaRiPAD study in the US is a prospective, observational study to assess the immunogenicity of mRNA vaccines in 133 patients with chronic inflammatory diseases (CID); the most common conditions were IBD and RA. One to two weeks after the second dose of vaccine, CID patients showed a reduced humoral response compared with healthy controls. Regarding immunosuppressive medications, corticosteroids and B cell-depleting therapies substantially affected vaccine immunogenicity, with 36- and 10-fold reductions in humoral response, respectively. Janus kinase (JAK) inhibitors and antimetabolites (e.g., MTX) were also associated with attenuated antibody and neutralization titers, whereas TNF, IL-12/23, and integrin inhibitors had minimal impact on humoral response [157].
Similarly, two German studies reported that patients with CID or IMIDs may develop a less robust humoral response compared with healthy individuals; however, most patients will develop a sufficient response to be considered protected [158,159]. Simon and colleagues showed lower titers of anti-SARS-CoV-2 IgG antibodies in 84 IMID patients compared with healthy controls after vaccination with the BNT162b2 (Pfizer-BioNTech) mRNA vaccine. They found that the impaired immune response was not associated with any individual immunomodulatory treatment but rather the disease itself [158]. Similarly, Geisen and colleagues found a lower anti-SARS-CoV-2 antibody titer 7 days after vaccination with mRNA vaccines in a small cohort of CID patients (n = 26) than in healthy controls, but all the vaccinated individuals developed a protective level of neutralizing antibodies [159].
Data from Israeli patients with inflammatory rheumatic diseases showed a significant humoral response (antibody concentration >50 U/mL) in most patients (86%) following two doses of BNT162b2 (Pfizer-BioNTech) mRNA vaccine, although those receiving rituximab showed significantly impaired humoral response, particularly in older patients [160].
A Swiss study evaluated the humoral response to mRNA vaccines in 53 RA patients receiving DMARDs and found that anti-SARS-CoV-2 titers were significantly lower in RA patients compared with healthy volunteers. In fact, after one dose, only 10% of RA patients versus 90% of controls developed antibody levels associated with protection (>15 U/mL). After the second dose, 88% of RA patients and 100% of controls achieved protective antibody levels. The lowest response was found in those patients receiving JAK inhibitors, with only 67% reaching protective levels [161].
Researchers from the University Hospital of Pavia, Italy, analyzed the immunogenicity of a single dose of the BNT162b2 (Pfizer-BioNTech) mRNA vaccine in patients with rheumatologic IMIDs. Among patients not receiving glucocorticoids or MTX, the rate of response (antibody concentration > 15 U/mL) was 85.4%, similar to that reported in registration trials, whereas patients receiving both glucocorticoids and MTX showed a decreased seroconversion rate (33%). In contrast, anti-cytokine therapy showed no impact on immunogenicity [162]. Similarly, two monocentric studies showed reduced vaccine immunogenicity in IMID patients treated with MTX compared with biologics or non-MTX oral medications [163]. In contrast, Venerito and colleagues found preserved humoral responses to BNT162b2 (Pfizer-BioNTech) mRNA vaccine in PsA patients irrespective of the immunomodifying therapy (TNF inhibitors, MTX, glucocorticoids, or sulfasalazine) [164].
In PsO patients who received two doses of the BNT162b2 (Pfizer-BioNTech) mRNA vaccine, humoral response (antibody concentration > 15 U/mL) was comparable to that of healthy controls. However, antibody titers were reduced in patients treated with infliximab and MTX compared with those on biologic monotherapy [166]. In another longitudinal PsO cohort, MTX was also found to impair humoral immune response after one dose of the BNT162b2 (Pfizer-BioNTech) mRNA vaccine, while the response was preserved in patients receiving biologic therapy [167]. However, after two doses of the vaccine, humoral response in patients receiving MTX was comparable to that of healthy controls [168].
A wider breadth of evidence regarding response to SARS-CoV-2 vaccination in IMID patients comes from the IBD field. The ICARUS-IBD study evaluated the serologic response to mRNA vaccines in 48 IBD patients. All IBD patients were seropositive after completing two-dose vaccination and anti-S IgG titers were comparable to those of healthy volunteers. A multiple linear regression analysis showed no association between humoral response and timing of the infusion. They also found reduced immunogenicity in patients on anti-TNF therapy or vedolizumab, although the small sample size and clinical characteristics of the patients may have influenced the result [169]. In contrast, a single-center German cohort study found slightly reduced antibody levels in 72 IBD patients compared with matching healthy controls after two-dose vaccination; however, levels were still considered to be protective. Regarding immunomodulatory therapies, there was no impact on humoral response, but higher antibody titers were observed in patients with a longer interval between the last dose of medication and vaccination [170].
Larger registry studies with improved power to analyze the impact of different immune-modifying drugs are being published. The PREVENT-COVID study is a US prospective, observational cohort study of IBD patients. In an initial report, they noted 95% seropositivity in 317 IBD patients after two doses of mRNA COVID-19 vaccine [171]. In a more recent study of 1909 IBD patients, a positive antibody response within 90 days of the last vaccine dose was observed in 96% of patients receiving mRNA vaccination and in 81% of patients receiving adenovirus vector vaccination. Multivariate analysis found that age, corticosteroids, and anti-TNF in combination with immunomodulators were associated with lack of antibody response. In contrast, patients on vedolizumab or ustekinumab showed a more robust humoral response [172]. Similarly, additional studies have also reported reduced humoral responses in IBD patients treated with TNF inhibitors versus those treated with ustekinumab or vedolizumab [173,174,175], with one study noting more rapid decay in antibody titers in patients receiving TNF inhibitor therapy [173].
The CLARITY IBD study prospectively examined the impact of TNF inhibitor (infliximab) and vedolizumab on SARS-CoV-2 infection and immunity in more than 3000 patients with IBD in the UK. Humoral responses were impaired in infliximab-treated patients following SARS-CoV-2 infection and were further attenuated in those receiving concomitant immunomodulators [186]. After a single dose of either the BNT162b2 (Pfizer-BioNTech) or ChAdOx1-S (AstraZeneca) vaccine, rates of seroconversion (antibody concentrations > 15 U/mL) were lower in patients receiving infliximab than in those receiving vedolizumab, irrespective of the vaccine administered, with only one-third of infliximab-treated patients achieving protective antibody levels [176]. In a more recent report from the CLARITY IBD study analyzing humoral and T-cell responses after a second dose of SARS-CoV-2 vaccine, antibody concentrations were reduced five-fold in infliximab recipients compared with vedolizumab recipients. However, most patients seroconverted after the second dose, with only 6.1 and 1.3% not achieving seroconversion with infliximab and vedolizumab, respectively (p < 0.0001). The antibody response was less durable in infliximab-treated patients, with antibody concentrations decaying towards the seroconversion threshold 14–18 weeks after the second dose [177]. Evidence of long-term durability of humoral response is emerging, with several studies reporting reduced durability of humoral response in patients treated with anti-TNF [159,173,174,177].

7.2. Cellular Responses to SARS-CoV-2 in IMIDs

Apart from humoral response, cellular immune response is also crucial to generate immune protection against COVID-19. In the CLARITY-IBD study, in which cellular immune response was analyzed in 225 infliximab- and 76 vedolizumab-treated patients, T-cell response was comparable among patients treated with infliximab or vedolizumab, with 20% failing to mount a detectable T-cell response [177]. A smaller study of 28 IBD patients found comparable T-cell response among IBD patients (all receiving immunosuppressive medication) and age- and sex-matched healthy controls [178]. Interestingly, preliminary data from a study analyzing the T-cell clonal response in 303 IBD patients found that antibody and T-cell clonal responses were only modestly correlated, with low T-cell clonal response observed in patients with high antibody levels. The T-cell clonal response was preserved with ustekinumab and vedolizumab and paradoxically augmented by TNF inhibitors [179]. In PsO patients, a lower proportion of patients receiving MTX or biologic therapy showed detectable T-cell response compared with the control group (62 and 71% vs. 100%, respectively) [168]. Moreover, in 51 IMID patients, activated CD8+ T cells were not induced after vaccination in MTX recipients unlike healthy controls or patients on other therapies [165]. In the COVADIS study, which analyzed T-cell response in patients with systemic inflammatory diseases, MTX dramatically impaired T-cell response after two-dose BNT162b2 mRNA vaccination and remained impaired even after the third dose. In contrast, patients on rituximab, despite having poor humoral response, showed T-cell response that were similar to that of controls and further increased after a third dose [187].

7.3. Revaccination and New Variants

Indeed, revaccination has been shown to be safe and effective in patients with IMIDs. In a recent study evaluating the effectiveness of SARS-CoV-2 revaccination in IMID patients who failed to respond (seroconversion) to two-dose mRNA vaccination, 80% of patients not previously exposed to rituximab achieved seroconversion after revaccination, whereas only 20% of those treated with B-cell depleting agents seroconverted [188].
Since the start of the pandemic, new SARS-CoV-2 variants have arisen, and some studies have analyzed the effectiveness of vaccination against these new variants in IMID patients. In PsO patients, after two-dose BNT162b2 mRNA vaccination, neutralizing antibody titers against wild-type SARS-CoV-2, Alpha (B.1.1.7), and Delta (B.1.617.2) variants were comparable in patients receiving MTX, biologics, and in healthy controls [168]. In patients with systemic inflammatory diseases, the percentage of patients with neutralizing antibodies against the Delta variant was reduced compared with the Alpha variant for all therapies analyzed [187].

7.4. Vaccine Protection against SARS-CoV-2 Infection in IMIDs

The above-mentioned studies evaluated the ability to generate a protective humoral or cellular immune response after SARS-CoV-2 vaccination. However, the most clinically relevant question relates to the ability of these vaccines to prevent infection in patients with IMIDs. An Israeli database study analyzed the real-world effectiveness of two doses of BNT162b2 (Pfizer-BioNTech) vaccine in 12,231 patients with IBD and 36,254 matched patients. They found high vaccine effectiveness with a very low infection rate (0.1%) independent of immune-modifying treatment [180]. Another study evaluating the efficacy of mRNA vaccines against infection in a Veterans Affairs cohort of 14,697 IBD patients in the US (20% were taking TNF inhibitors) found that full vaccination status reduced the risk of infection by 69%, showing that the effectiveness of a two-dose course of an mRNA vaccine was 80.4% in this cohort, which is lower to the efficacy reported in the registration trials [181].

7.5. Safety of SARS-CoV-2 Vaccines in IMIDs

SARS-CoV-2 vaccination appears to be safe in patients with IMIDs, with adverse effects comparable to those observed in healthy individuals and no flares of the underlying condition [158,159]. Safety was also studied in PsO patients following mRNA vaccination, with none reporting any adverse effects or a psoriatic flare [182]. Similarly, mRNA vaccines were also safe and well tolerated in a small cohort of PsA patients [164]. In a cohort of 3316 patients with IBD, the PREVENT-COVID registry reported low rates of vaccine-related adverse effects, with only 2% reporting IBD exacerbations following vaccination [183]. In addition, preliminary data from the Corale-IBD registry suggest that the risk of vaccine-related adverse events is not increased after vaccination with mRNA vaccines [184] and that post-vaccination symptoms after the third dose were similar, milder, and less frequent than those after a second dose [185].

7.6. Guidelines on SARS-CoV-2 Vaccination in IMIDs

Guidelines on SARS-CoV-2 vaccination in patients with IMIDs are beginning to emerge from major international organizations, including the US National Psoriasis Foundation (NPF) [22], American Academy of Dermatology [189], American College of Rheumatology (ACR) [115], European Academy of Dermatology and Venereology [190], British Society of Gastroenterology [191], and the International Organization for the Study of IBD [25]. All recommend SARS-CoV-2 vaccination for patients with IMIDs, including those on biologic therapy [22,25,115,189,190,191,192]. Most of these guidelines were released prior to any data being available and recommend continuing biologic therapy in patients receiving SARS-CoV-2 vaccines. However, the ACR guidelines recommend withholding MTX and JAK inhibitors for 1 week after each vaccine dose and withholding abatacept for 1 week before and 1 week after the first vaccine dose. They also recommend delaying rituximab for 2–4 weeks after the second vaccine dose if the patient’s disease activity allows [115]. The lower rate of seroconversion after one dose highlights the importance of the timing of the second dose in immunocompromised patients. Moreover, the rapid decline in antibody levels after the second dose, the emergence of new variants such as Omicron, and preliminary data showing the benefits of a third dose, underline the importance of a third primary dose for individuals who are immunocompromised (i.e., those with immunocompromising conditions or receiving immunosuppressive therapy, which includes many IMID patients), as it is now recommended by the European Medicines Agency [193], the UK Joint Committee on Vaccination and Immunisation [194], and the US Centers for Disease Control and Prevention [195].

7.7. Evidence Summary on SARS-CoV-2 Vaccination in IMIDs

SARS-CoV-2 vaccination in IMID patients treated with biologic therapies appears to be safe and well tolerated. Under most immune-modifying therapies, humoral and cellular immune responses were preserved, except for B-cell depleting agents, where humoral immune response was impaired, MTX which impaired humoral and cellular response, and TNF inhibitors which blunted humoral immunity.

8. Conclusions

Patients with IMIDs may be at increased risk of developing vaccine-preventable infections, and therefore vaccination strategies are an important preventive measure in these patients. Despite blunted immunogenicity observed with some agents, vaccination is effective and safe and therefore patients and physicians should not be dissuaded from vaccination. The greatest reduction in vaccine response has been observed in patients taking B cell-depleting agents, followed by TNF inhibitors, and the CTLA-4 fusion protein abatacept; however, no attenuation has been noted with anti-integrin α4β7, anti-BAFF, anti-IL-6, anti-IL-17, or anti-IL-12/23 agents. Data on the novel SARS-CoV-2 vaccines in IMID patients are rapidly accumulating and seem to coincide with what is known about other vaccines. In general, SARS-CoV-2 vaccines are safe and effective in most IMID patients, although they may benefit from a third dose as currently indicated.

Author Contributions

B.G. and S.D.-C. conceived the article and reviewed and edited the manuscript. J.R.R. and M.S. critically reviewed the content of the paper. All authors have read and agreed to the published version of the manuscript.


Medical writing assistance in the preparation of the manuscript was funded by Janssen. JRR's work in SARS-CoV2 was funded by ANTICIPA-CM (FEDER, REACT-UE).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.


We would like to thank Catherine Rees and Fernando Sánchez Barbero of Springer Healthcare Communications who wrote the outline and first draft of this manuscript. This medical writing assistance was funded by Janssen.

Conflicts of Interest

J.R.R. declares no conflicts of interest/financial interests. M.S. has served as a speaker and an advisory board member for Janssen, Gilead, Pfizer, MSD, Angelini, Astellas Ph., and Shionogi and has received research funding from ViiV/GSK. B.G. and S.D.-C. are employees of Janssen.


  1. David, T.; Ling, S.F.; Barton, A. Genetics of immune-mediated inflammatory diseases. Clin. Exp. Immunol. 2018, 193, 3–12. [Google Scholar] [CrossRef] [Green Version]
  2. Wisniewski, A.; Kirchgesner, J.; Seksik, P.; Landman, C.; Bourrier, A.; Nion-Larmurier, I.; Marteau, P.; Cosnes, J.; Sokol, H.; Beaugerie, L.; et al. Increased incidence of systemic serious viral infections in patients with inflammatory bowel disease associates with active disease and use of thiopurines. United Eur. Gastroenterol. J. 2020, 8, 303–313. [Google Scholar] [CrossRef] [Green Version]
  3. Jani, M.; Barton, A.; Hyrich, K. Prediction of infection risk in rheumatoid arthritis patients treated with biologics: Are we any closer to risk stratification? Curr. Opin. Rheumatol. 2019, 31, 285–292. [Google Scholar] [CrossRef]
  4. Yiu, Z.Z.N.; Sorbe, C.; Lunt, M.; Rustenbach, S.J.; Kuhl, L.; Augustin, M.; Mason, K.J.; Ashcroft, D.M.; Griffiths, C.E.M.; Warren, R.B.; et al. Development and validation of a multivariable risk prediction model for serious infection in patients with psoriasis receiving systemic therapy. Br. J. Dermatol. 2019, 180, 894–901. [Google Scholar] [CrossRef]
  5. Singh, J.A.; Guyatt, G.; Ogdie, A.; Gladman, D.D.; Deal, C.; Deodhar, A.; Dubreuil, M.; Dunham, J.; Husni, M.E.; Kenny, S.; et al. 2018 American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic arthritis. Arthritis Care Res. 2019, 71, 2–29. [Google Scholar] [CrossRef] [Green Version]
  6. Menter, A.; Strober, B.E.; Kaplan, D.H.; Kivelevitch, D.; Prater, E.F.; Stoff, B.; Armstrong, A.W.; Connor, C.; Cordoro, K.M.; Davis, D.M.R.; et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J. Am. Acad. Dermatol. 2019, 80, 1029–1072. [Google Scholar] [CrossRef] [Green Version]
  7. Furer, V.; Rondaan, C.; Heijstek, M.W.; Agmon-Levin, N.; van Assen, S.; Bijl, M.; Breedveld, F.C.; D’Amelio, R.; Dougados, M.; Kapetanovic, M.C.; et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann. Rheum. Dis. 2020, 79, 39–52. [Google Scholar] [CrossRef] [PubMed]
  8. Farraye, F.A.; Melmed, G.Y.; Lichtenstein, G.R.; Kane, S.V. ACG Clinical Guideline: Preventive care in inflammatory bowel disease. Am. J. Gastroenterol. 2017, 112, 241–258. [Google Scholar] [CrossRef] [PubMed]
  9. Rahier, J.F.; Magro, F.; Abreu, C.; Armuzzi, A.; Ben-Horin, S.; Chowers, Y.; Cottone, M.; de Ridder, L.; Ehehalt, R.; Esteve, M.; et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J. Crohns Colitis 2014, 8, 443–468. [Google Scholar] [CrossRef] [PubMed]
  10. Chakraborty, R.; Parvez, S. COVID-19: An overview of the current pharmacological interventions, vaccines, and clinical trials. Biochem. Pharmacol. 2020, 180, 114184. [Google Scholar] [CrossRef] [PubMed]
  11. Chen, W.H.; Strych, U.; Hotez, P.J.; Bottazzi, M.E. The SARS-CoV-2 vaccine pipeline: An overview. Curr. Trop. Med. Rep. 2020, 7, 61–64. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Hagberg, K.W.; Li, L.; Peng, M.; Paris, M.; Shah, K.; Jick, S.S. Rates of cancers and opportunistic infections in patients with psoriatic arthritis compared with patients without psoriatic arthritis. J. Clin. Rheumatol. 2016, 22, 241–247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Tinsley, A.; Navabi, S.; Williams, E.D.; Liu, G.; Kong, L.; Coates, M.D.; Clarke, K. Increased risk of influenza and influenza-related complications among 140,480 patients with inflammatory bowel disease. Inflamm. Bowel Dis. 2019, 25, 369–376. [Google Scholar] [CrossRef] [PubMed]
  14. Bernatsky, S.; Hudson, M.; Suissa, S. Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis. Rheumatology 2007, 46, 1157–1160. [Google Scholar] [CrossRef] [Green Version]
  15. Ibrahim, A.; Ahmed, M.; Conway, R.; Carey, J.J. Risk of infection with methotrexate therapy in inflammatory diseases: A systematic review and meta-analysis. J. Clin. Med. 2019, 8, 15. [Google Scholar] [CrossRef] [Green Version]
  16. Mazaud, C.; Fardet, L. Relative risk of and determinants for adverse events of methotrexate prescribed at a low dose: A systematic review and meta-analysis of randomized placebo-controlled trials. Br. J. Dermatol. 2017, 177, 978–986. [Google Scholar] [CrossRef]
  17. Baddley, J.W.; Cantini, F.; Goletti, D.; Gomez-Reino, J.J.; Mylonakis, E.; San-Juan, R.; Fernandez-Ruiz, M.; Torre-Cisneros, J. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies: An infectious diseases perspective (soluble immune effector molecules [I]: Anti-tumor necrosis factor-alpha agents). Clin. Microbiol. Infect. 2018, 24 (Suppl. S2), S10–S20. [Google Scholar] [CrossRef] [Green Version]
  18. Winthrop, K.L.; Mariette, X.; Silva, J.T.; Benamu, E.; Calabrese, L.H.; Dumusc, A.; Smolen, J.S.; Aguado, J.M.; Fernandez-Ruiz, M. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies: An infectious diseases perspective (soluble immune effector molecules [II]: Agents targeting interleukins, immunoglobulins and complement factors). Clin. Microbiol. Infect. 2018, 24 (Suppl. S2), S21–S40. [Google Scholar]
  19. Gao, Q.; Zhao, Y.-X.; Wang, X.-J.; Shi, J.; Wang, H.-M. Efficacy and safety of IL-17 inhibitors for patients with psoriatic arthritis: A systematic review and meta-analysis. Eur. Rev. Med. Pharmacol. Sci. 2021, 25, 2958–2970. [Google Scholar]
  20. Redelman-Sidi, G.; Michielin, O.; Cervera, C.; Ribi, C.; Aguado, J.M.; Fernandez-Ruiz, M.; Manuel, O. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies: An infectious diseases perspective (immune checkpoint inhibitors, cell adhesion inhibitors, sphingosine-1-phosphate receptor modulators and proteasome inhibitors). Clin. Microbiol. Infect. 2018, 24 (Suppl. S2), S95–S107. [Google Scholar]
  21. Mikulska, M.; Lanini, S.; Gudiol, C.; Drgona, L.; Ippolito, G.; Fernandez-Ruiz, M.; Salzberger, B. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies: An infectious diseases perspective (agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52). Clin. Microbiol. Infect. 2018, 24 (Suppl. S2), S71–S82. [Google Scholar] [CrossRef] [Green Version]
  22. Gelfand, J.M.; Armstrong, A.W.; Bell, S.; Anesi, G.L.; Blauvelt, A.; Calabrese, C.; Dommasch, E.D.; Feldman, S.R.; Gladman, D.; Kircik, L.; et al. National Psoriasis Foundation COVID-19 Task Force guidance for management of psoriatic disease during the pandemic: Version 2-Advances in psoriatic disease management, COVID-19 vaccines, and COVID-19 treatments. J. Am. Acad. Dermatol. 2021, 84, 1254–1268. [Google Scholar] [CrossRef] [PubMed]
  23. Gisondi, P.; Bellinato, F.; Chiricozzi, A.; Girolomoni, G. The risk of COVID-19 pandemic in patients with moderate to severe plaque psoriasis receiving systemic treatments. Vaccines 2020, 8, 728. [Google Scholar] [CrossRef] [PubMed]
  24. Maconi, G.; Bosetti, C.; De Monti, A.; Boyapati, R.K.; Shelton, E.; Piazza, N.; Carvalhas Gabrielli, A.M.; Lenti, M.V.; Bezzio, C.; Ricci, C.; et al. Risk of COVID 19 in patients with inflammatory bowel diseases compared to a control population. Dig. Liver Dis. 2021, 53, 263–270. [Google Scholar] [CrossRef] [PubMed]
  25. Siegel, C.A.; Melmed, G.Y.; McGovern, D.P.; Rai, V.; Krammer, F.; Rubin, D.T.; Abreu, M.T.; Dubinsky, M.C.; International Organization for the Study of Inflammatory Bowel Disease. SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: Recommendations from an international consensus meeting. Gut 2021, 70, 635–640. [Google Scholar] [CrossRef]
  26. Brenner, E.J.; Ungaro, R.C.; Gearry, R.B.; Kaplan, G.G.; Kissous-Hunt, M.; Lewis, J.D.; Ng, S.C.; Rahier, J.F.; Reinisch, W.; Ruemmele, F.M.; et al. Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: Results from an international registry. Gastroenterology 2020, 159, 481–491.e483. [Google Scholar] [CrossRef]
  27. Mahil, S.K.; Dand, N.; Mason, K.J.; Yiu, Z.Z.N.; Tsakok, T.; Meynell, F.; Coker, B.; McAteer, H.; Moorhead, L.; Mackenzie, T.; et al. Factors associated with adverse COVID-19 outcomes in patients with psoriasis-insights from a global registry-based study. J. Allergy Clin. Immunol. 2021, 147, 60–71. [Google Scholar] [CrossRef]
  28. FAI2R/SFR/SNFMI/SOFREMIP/CRI/IMIDIATE Consortium and Contributors. Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: Data from the French RMD COVID-19 cohort of 694 patients. Ann. Rheum. Dis. 2020, 80, 527–538. [Google Scholar]
  29. Gianfrancesco, M.; Hyrich, K.L.; Al-Adely, S.; Carmona, L.; Danila, M.I.; Gossec, L.; Izadi, Z.; Jacobsohn, L.; Katz, P.; Lawson-Tovey, S.; et al. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: Data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann. Rheum. Dis. 2020, 79, 859–866. [Google Scholar] [CrossRef]
  30. Singh, A.K.; Jena, A.; Kumar, M.P.; Sharma, V.; Sebastian, S. Risk and outcomes of coronavirus disease in patients with inflammatory bowel disease: A systematic review and meta-analysis. United Eur. Gastroenterol. J. 2021, 9, 159–176. [Google Scholar] [CrossRef]
  31. Akiyama, S.; Hamdeh, S.; Micic, D.; Sakuraba, A. Prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases: A systematic review and meta-analysis. Ann. Rheum. Dis. 2021, 80, 384–391. [Google Scholar] [CrossRef]
  32. Schulze-Koops, H.; Krueger, K.; Vallbracht, I.; Hasseli, R.; Skapenko, A. Increased risk for severe COVID-19 in patients with inflammatory rheumatic diseases treated with rituximab. Ann. Rheum. Dis. 2021, 80, e67. [Google Scholar] [CrossRef] [PubMed]
  33. Bossa, F.; Carparelli, S.; Latiano, A.; Palmieri, O.; Tavano, F.; Panza, A.; Pastore, M.; Marseglia, A.; D’Altilia, M.; Latiano, T.; et al. Impact of the COVID-19 outbreak and the serum prevalence of SARS-CoV-2 antibodies in patients with inflammatory bowel disease treated with biologic drugs. Dig. Liver Dis. 2021, 53, 277–282. [Google Scholar] [CrossRef]
  34. Michelena, X.; Borrell, H.; Lopez-Corbeto, M.; Lopez-Lasanta, M.; Moreno, E.; Pascual-Pastor, M.; Erra, A.; Serrat, M.; Espartal, E.; Anton, S.; et al. Incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs. Semin. Arthritis Rheum. 2020, 50, 564–570. [Google Scholar] [CrossRef] [PubMed]
  35. D’Amico, F.; Danese, S.; Peyrin-Biroulet, L. Systematic review on inflammatory bowel disease patients with coronavirus disease 2019: It is time to take stock. Clin. Gastroenterol. Hepatol. 2020, 18, 2689–2700. [Google Scholar] [CrossRef] [PubMed]
  36. Giuliani, F.; Gualdi, G.; Amerio, P. Effect of immunosuppressive drugs in immune-mediated inflammatory disease during the coronavirus pandemic. Dermatol. Ther. 2020, 33, e14204. [Google Scholar] [CrossRef] [PubMed]
  37. Chiricozzi, A.; Gisondi, P.; Bellinato, F.; Girolomoni, G. Immune response to vaccination in patients with psoriasis treated with systemic therapies. Vaccines 2020, 8, 769. [Google Scholar] [CrossRef]
  38. Caso, F.; Ramonda, R.; Del Puente, A.; Darda, M.A.; Cantarini, L.; Peluso, R.; Esposito, C.; Ortolan, A.; Fiocco, U.; Punzi, L.; et al. Influenza vaccine with adjuvant on disease activity in psoriatic arthritis patients under anti-TNF-alpha therapy. Clin. Exp. Rheumatol. 2016, 34, 507–512. [Google Scholar]
  39. Kapetanovic, M.C.; Roseman, C.; Jönsson, G.; Truedsson, L.; Saxne, T.; Geborek, P. Antibody response is reduced following vaccination with 7-valent conjugate pneumococcal vaccine in adult methotrexate-treated patients with established arthritis, but not those treated with tumor necrosis factor inhibitors. Arthritis Rheum. 2011, 63, 3723–3732. [Google Scholar] [CrossRef] [PubMed]
  40. Takeshita, J.; Grewal, S.; Langan, S.M.; Mehta, N.N.; Ogdie, A.; Van Voorhees, A.S.; Gelfand, J.M. Psoriasis and comorbid diseases: Implications for management. J. Am. Acad. Dermatol. 2017, 76, 393–403. [Google Scholar] [CrossRef] [Green Version]
  41. Carrascosa, J.M.; Galan, M.; de Lucas, R.; Perez-Ferriols, A.; Ribera, M.; Yanguas, I. Expert recommendations on treating psoriasis in special circumstances (part II). Actas Dermosifiliogr. 2016, 107, 712–729. [Google Scholar] [CrossRef] [PubMed]
  42. García-Serrano, C.; Mirada, G.; Marsal, J.R.; Ortega, M.; Sol, J.; Solano, R.; Artigues, E.M.; Estany, P. Compliance with the guidelines on recommended immunization schedule in patients with inflammatory bowel disease: Implications on public health policies. BMC Public Health 2020, 20, 713. [Google Scholar] [CrossRef] [PubMed]
  43. Pulendran, B.; Arunachalam, P.S.; O’Hagan, D.T. Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov. 2021, 20, 454–475. [Google Scholar] [CrossRef]
  44. Jiskoot, W.; Kersten, G.F.A.; Mastrobattista, E.; Slutter, B. Vaccines. In Pharmaceutical Biotechnology: Fundamentals and Applications, 5th ed.; Commelin, D.J.A., Sindelar, R.D., Meibohm, B., Eds.; Springer Nature: Cham, Switzerland, 2019; pp. 281–304. [Google Scholar]
  45. Slifka, M.K.; Amanna, I.J. Role of multivalency and antigenic threshold in generating protective antibody responses. Front. Immunol. 2019, 10, 956. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Zimmermann, P.; Curtis, N. Factors that influence the immune response to vaccination. Clin. Microbiol. Rev. 2019, 32, e00084-18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Olberg, H.K.; Cox, R.J.; Nostbakken, J.K.; Aarseth, J.H.; Vedeler, C.A.; Myhr, K.M. Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: An explorative study. Mult. Scler. 2014, 20, 1074–1080. [Google Scholar] [CrossRef]
  48. Olberg, H.K.; Eide, G.E.; Cox, R.J.; Jul-Larsen, A.; Lartey, S.L.; Vedeler, C.A.; Myhr, K.M. Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy. Eur. J. Neurol. 2018, 25, 527–534. [Google Scholar] [CrossRef] [Green Version]
  49. Kaufman, M.; Pardo, G.; Rossman, H.; Sweetser, M.T.; Forrestal, F.; Duda, P. Natalizumab treatment shows no clinically meaningful effects on immunization responses in patients with relapsing-remitting multiple sclerosis. J. Neurol. Sci. 2014, 341, 22–27. [Google Scholar] [CrossRef]
  50. Caldera, F.; Hillman, L.; Saha, S.; Wald, A.; Grimes, I.; Zhang, Y.; Sharpe, A.R.; Reichelderfer, M.; Hayney, M.S. Immunogenicity of high dose influenza vaccine for patients with inflammatory bowel disease on anti-TNF monotherapy: A randomized clinical trial. Inflamm. Bowel Dis. 2020, 26, 593–602. [Google Scholar] [CrossRef]
  51. Wyant, T.; Leach, T.; Sankoh, S.; Wang, Y.; Paolino, J.; Pasetti, M.F.; Feagan, B.G.; Parikh, A. Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: Randomised controlled trial results. Gut 2015, 64, 77–83. [Google Scholar] [CrossRef]
  52. Migita, K.; Akeda, Y.; Akazawa, M.; Tohma, S.; Hirano, F.; Ideguchi, H.; Kozuru, H.; Jiuchi, Y.; Matsumura, R.; Suematsu, E.; et al. Effect of abatacept on the immunogenicity of 23-valent pneumococcal polysaccharide vaccination (PPSV23) in rheumatoid arthritis patients. Arthritis Res. Ther. 2015, 17, 357. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Alten, R.; Bingham, C.O., 3rd; Cohen, S.B.; Curtis, J.R.; Kelly, S.; Wong, D.; Genovese, M.C. Antibody response to pneumococcal and influenza vaccination in patients with rheumatoid arthritis receiving abatacept. BMC Musculoskelet. Disord. 2016, 17, 231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Crnkic Kapetanovic, M.; Saxne, T.; Jonsson, G.; Truedsson, L.; Geborek, P. Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis. Arthritis Res. Ther. 2013, 15, R171. [Google Scholar] [CrossRef] [Green Version]
  55. Ribeiro, A.C.; Laurindo, I.M.; Guedes, L.K.; Saad, C.G.; Moraes, J.C.; Silva, C.A.; Bonfa, E. Abatacept and reduced immune response to pandemic 2009 influenza A/H1N1 vaccination in patients with rheumatoid arthritis. Arthritis Care Res. 2013, 65, 476–480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Bingham, C.O., 3rd; Looney, R.J.; Deodhar, A.; Halsey, N.; Greenwald, M.; Codding, C.; Trzaskoma, B.; Martin, F.; Agarwal, S.; Kelman, A. Immunization responses in rheumatoid arthritis patients treated with rituximab: Results from a controlled clinical trial. Arthritis Rheum. 2010, 62, 64–74. [Google Scholar] [CrossRef]
  57. Richi, P.; Yuste, J.; Navío, T.; González-Hombrado, L.; Salido, M.; Thuissard-Vasallo, I.; Jiménez-Díaz, A.; Llorente, J.; Cebrián, L.; Lojo, L.; et al. Impact of biological therapies on the immune response after pneumococcal vaccination in patients with autoimmune inflammatory diseases. Vaccines 2021, 9, 203. [Google Scholar] [CrossRef]
  58. Richi, P.; Alonso, O.; Martin, M.D.; Gonzalez-Hombrado, L.; Navio, T.; Salido, M.; Llorente, J.; Andreu-Vazquez, C.; Garcia-Fernandez, C.; Jimenez-Diaz, A.; et al. Evaluation of the immune response to hepatitis B vaccine in patients on biological therapy: Results of the RIER cohort study. Clin. Rheumatol. 2020, 39, 2751–2756. [Google Scholar] [CrossRef]
  59. Arad, U.; Tzadok, S.; Amir, S.; Mandelboim, M.; Mendelson, E.; Wigler, I.; Sarbagil-Maman, H.; Paran, D.; Caspi, D.; Elkayam, O. The cellular immune response to influenza vaccination is preserved in rheumatoid arthritis patients treated with rituximab. Vaccine 2011, 29, 1643–1648. [Google Scholar] [CrossRef]
  60. Oren, S.; Mandelboim, M.; Braun-Moscovici, Y.; Paran, D.; Ablin, J.; Litinsky, I.; Comaneshter, D.; Levartovsky, D.; Mendelson, E.; Azar, R.; et al. Vaccination against influenza in patients with rheumatoid arthritis: The effect of rituximab on the humoral response. Ann. Rheum. Dis. 2008, 67, 937–941. [Google Scholar] [CrossRef] [Green Version]
  61. Van Assen, S.; Holvast, A.; Benne, C.A.; Posthumus, M.D.; van Leeuwen, M.A.; Voskuyl, A.E.; Blom, M.; Risselada, A.P.; de Haan, A.; Westra, J.; et al. Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab. Arthritis Rheum. 2010, 62, 75–81. [Google Scholar] [CrossRef]
  62. Westra, J.; van Assen, S.; Wilting, K.R.; Land, J.; Horst, G.; de Haan, A.; Bijl, M. Rituximab impairs immunoglobulin (Ig)M and IgG (subclass) responses after influenza vaccination in rheumatoid arthritis patients. Clin. Exp. Immunol. 2014, 178, 40–47. [Google Scholar] [CrossRef] [PubMed]
  63. Richi, P.; Martin, M.D.; Navio, M.T.; Gonzalez-Hombrado, L.; Salido, M.; Llorente, J.; Thuissard-Vasallo, I.; Alcocer, P.; Saa-Requejo, C.M.; Jimenez-Diaz, A.; et al. Antibody responses to influenza vaccine in patients on biological therapy: Results of RIER cohort study. Med. Clin. 2019, 153, 380–386. [Google Scholar] [CrossRef] [PubMed]
  64. Kapetanovic, M.C.; Kristensen, L.E.; Saxne, T.; Aktas, T.; Morner, A.; Geborek, P. Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis. Arthritis Res. Ther. 2014, 16, R2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Adler, S.; Krivine, A.; Weix, J.; Rozenberg, F.; Launay, O.; Huesler, J.; Guillevin, L.; Villiger, P.M. Protective effect of A/H1N1 vaccination in immune-mediated disease—A prospectively controlled vaccination study. Rheumatology 2012, 51, 695–700. [Google Scholar] [CrossRef] [Green Version]
  66. Nagel, J.; Saxne, T.; Geborek, P.; Bengtsson, A.A.; Jacobsen, S.; Svaerke Joergensen, C.; Nilsson, J.A.; Skattum, L.; Jonsen, A.; Kapetanovic, M.C. Treatment with belimumab in systemic lupus erythematosus does not impair antibody response to 13-valent pneumococcal conjugate vaccine. Lupus 2017, 26, 1072–1081. [Google Scholar] [CrossRef]
  67. Chatham, W.; Chadha, A.; Fettiplace, J.; Kleoudis, C.; Bass, D.; Roth, D.; Gordon, D. A randomized, open-label study to investigate the effect of belimumab on pneumococcal vaccination in patients with active, autoantibody-positive systemic lupus erythematosus. Lupus 2017, 26, 1483–1490. [Google Scholar] [CrossRef] [Green Version]
  68. Salinas, G.F.; De Rycke, L.; Barendregt, B.; Paramarta, J.E.; Hreggvidsdottir, H.; Cantaert, T.; van der Burg, M.; Tak, P.P.; Baeten, D. Anti-TNF treatment blocks the induction of T cell-dependent humoral responses. Ann. Rheum. Dis. 2013, 72, 1037–1043. [Google Scholar] [CrossRef]
  69. Mease, P.J.; Ritchlin, C.T.; Martin, R.W.; Gottlieb, A.B.; Baumgartner, S.W.; Burge, D.J.; Whitmore, J.B. Pneumococcal vaccine response in psoriatic arthritis patients during treatment with etanercept. J. Rheumatol. 2004, 31, 1356–1361. [Google Scholar]
  70. Kapetanovic, M.C.; Saxne, T.; Sjoholm, A.; Truedsson, L.; Jonsson, G.; Geborek, P. Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis. Rheumatology 2006, 45, 106–111. [Google Scholar] [CrossRef] [Green Version]
  71. Kivitz, A.J.; Schechtman, J.; Texter, M.; Fichtner, A.; de Longueville, M.; Chartash, E.K. Vaccine responses in patients with rheumatoid arthritis treated with certolizumab pegol: Results from a single-blind randomized phase IV trial. J. Rheumatol. 2014, 41, 648–657. [Google Scholar] [CrossRef]
  72. Kaine, J.L.; Kivitz, A.J.; Birbara, C.; Luo, A.Y. Immune responses following administration of influenza and pneumococcal vaccines to patients with rheumatoid arthritis receiving adalimumab. J. Rheumatol. 2007, 34, 272–279. [Google Scholar] [PubMed]
  73. Visvanathan, S.; Keenan, G.F.; Baker, D.G.; Levinson, A.I.; Wagner, C.L. Response to pneumococcal vaccine in patients with early rheumatoid arthritis receiving infliximab plus methotrexate or methotrexate alone. J. Rheumatol. 2007, 34, 952–957. [Google Scholar] [PubMed]
  74. Kantso, B.; Halkjaer, S.I.; Thomsen, O.O.; Belard, E.; Gottschalck, I.B.; Jorgensen, C.S.; Krogfelt, K.A.; Slotved, H.C.; Ingels, H.; Petersen, A.M. Immunosuppressive drugs impairs antibody response of the polysaccharide and conjugated pneumococcal vaccines in patients with Crohn’s disease. Vaccine 2015, 33, 5464–5469. [Google Scholar] [CrossRef] [PubMed]
  75. Lee, C.K.; Kim, H.S.; Ye, B.D.; Lee, K.M.; Kim, Y.S.; Rhee, S.Y.; Kim, H.J.; Yang, S.K.; Moon, W.; Koo, J.S.; et al. Patients with Crohn’s disease on anti-tumor necrosis factor therapy are at significant risk of inadequate response to the 23-valent pneumococcal polysaccharide vaccine. J. Crohns Colitis 2014, 8, 384–391. [Google Scholar] [CrossRef] [Green Version]
  76. Fiorino, G.; Peyrin-Biroulet, L.; Naccarato, P.; Szabo, H.; Sociale, O.R.; Vetrano, S.; Fries, W.; Montanelli, A.; Repici, A.; Malesci, A.; et al. Effects of immunosuppression on immune response to pneumococcal vaccine in inflammatory bowel disease: A prospective study. Inflamm. Bowel Dis. 2012, 18, 1042–1047. [Google Scholar] [CrossRef]
  77. Van Aalst, M.; Garcia Garrido, H.M.; van der Leun, J.; Meek, B.; van Leeuwen, E.M.M.; Löwenberg, M.; D’Haens, G.R.; Ponsioen, C.Y.I.; Grobusch, M.P.; Goorhuis, A. Immunogenicity of the currently recommended pneumococcal vaccination schedule in patients with inflammatory bowel disease. Clin. Infect. Dis. 2020, 70, 595–604. [Google Scholar] [CrossRef] [Green Version]
  78. Rakoczi, E.; Perge, B.; Vegh, E.; Csomor, P.; Pusztai, A.; Szamosi, S.; Bodnar, N.; Szanto, S.; Szucs, G.; Szekanecz, Z. Evaluation of the immunogenicity of the 13-valent conjugated pneumococcal vaccine in rheumatoid arthritis patients treated with etanercept. Jt. Bone Spine 2016, 83, 675–679. [Google Scholar] [CrossRef]
  79. Andrade, P.; Santos-Antunes, J.; Rodrigues, S.; Lopes, S.; Macedo, G. Treatment with infliximab or azathioprine negatively impact the efficacy of hepatitis B vaccine in inflammatory bowel disease patients. J. Gastroenterol. Hepatol. 2015, 30, 1591–1595. [Google Scholar] [CrossRef]
  80. Gisbert, J.P.; Villagrasa, J.R.; Rodriguez-Nogueiras, A.; Chaparro, M. Efficacy of hepatitis B vaccination and revaccination and factors impacting on response in patients with inflammatory bowel disease. Am. J. Gastroenterol. 2012, 107, 1460–1466. [Google Scholar] [CrossRef]
  81. Belle, A.; Baumann, C.; Bigard, M.A.; Zallot, C.; Gizard, E.; Gueant, J.L.; Bronowicki, J.P.; Peyrin-Biroulet, L. Impact of immunosuppressive therapy on hepatitis B vaccination in inflammatory bowel diseases. Eur. J. Gastroenterol. Hepatol. 2015, 27, 877–881. [Google Scholar] [CrossRef]
  82. Askling, H.H.; Rombo, L.; van Vollenhoven, R.; Hallen, I.; Thorner, A.; Nordin, M.; Herzog, C.; Kantele, A. Hepatitis A vaccine for immunosuppressed patients with rheumatoid arthritis: A prospective, open-label, multi-centre study. Travel Med. Infect. Dis. 2014, 12, 134–142. [Google Scholar] [CrossRef] [PubMed]
  83. Elkayam, O.; Bashkin, A.; Mandelboim, M.; Litinsky, I.; Comaheshter, D.; Levartovsky, D.; Mendelson, E.; Wigler, I.; Caspi, D.; Paran, D. The effect of infliximab and timing of vaccination on the humoral response to influenza vaccination in patients with rheumatoid arthritis and ankylosing spondylitis. Semin. Arthritis Rheum. 2010, 39, 442–447. [Google Scholar] [CrossRef] [PubMed]
  84. Kobie, J.J.; Zheng, B.; Bryk, P.; Barnes, M.; Ritchlin, C.T.; Tabechian, D.A.; Anandarajah, A.P.; Looney, R.J.; Thiele, R.G.; Anolik, J.H.; et al. Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor. Arthritis Res. Ther. 2011, 13, R209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Franca, I.L.; Ribeiro, A.C.; Aikawa, N.E.; Saad, C.G.; Moraes, J.C.; Goldstein-Schainberg, C.; Laurindo, I.M.; Precioso, A.R.; Ishida, M.A.; Sartori, A.M.; et al. TNF blockers show distinct patterns of immune response to the pandemic influenza A H1N1 vaccine in inflammatory arthritis patients. Rheumatology 2012, 51, 2091–2098. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Fomin, I.; Caspi, D.; Levy, V.; Varsano, N.; Shalev, Y.; Paran, D.; Levartovsky, D.; Litinsky, I.; Kaufman, I.; Wigler, I.; et al. Vaccination against influenza in rheumatoid arthritis: The effect of disease modifying drugs, including TNF alpha blockers. Ann. Rheum. Dis. 2006, 65, 191–194. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Kubota, T.; Nii, T.; Nanki, T.; Kohsaka, H.; Harigai, M.; Komano, Y.; Sugihara, T.; Nonomura, Y.; Hirose, W.; Nagasaka, K.; et al. Anti-tumor necrosis factor therapy does not diminish the immune response to influenza vaccine in Japanese patients with rheumatoid arthritis. Mod. Rheumatol. 2007, 17, 531–533. [Google Scholar] [CrossRef]
  88. Polachek, A.; Korobko, U.; Mader-Balakirski, N.; Arad, U.; Levartovsky, D.; Kaufman, I.; Anouk, M.; Litinsky, I.; Wigler, I.; Mendelson, E.; et al. Immunogenicity and safety of vaccination against seasonal 2012 influenza virus among patients with psoriatic arthritis and psoriasis. Clin. Exp. Rheumatol. 2015, 33, 181–186. [Google Scholar]
  89. Hagihara, Y.; Ohfuji, S.; Watanabe, K.; Yamagami, H.; Fukushima, W.; Maeda, K.; Kamata, N.; Sogawa, M.; Shiba, M.; Tanigawa, T.; et al. Infliximab and/or immunomodulators inhibit immune responses to trivalent influenza vaccination in adults with inflammatory bowel disease. J. Crohns Colitis 2014, 8, 223–233. [Google Scholar] [CrossRef] [Green Version]
  90. Andrisani, G.; Frasca, D.; Romero, M.; Armuzzi, A.; Felice, C.; Marzo, M.; Pugliese, D.; Papa, A.; Mocci, G.; De Vitis, I.; et al. Immune response to influenza A/H1N1 vaccine in inflammatory bowel disease patients treated with anti TNF-alpha agents: Effects of combined therapy with immunosuppressants. J. Crohns Colitis 2013, 7, 301–307. [Google Scholar] [CrossRef]
  91. Launay, O.; Abitbol, V.; Krivine, A.; Slama, L.B.; Bourreille, A.; Dupas, J.L.; Hebuterne, X.; Savoye, G.; Deplanque, D.; Bouhnik, Y.; et al. Immunogenicity and safety of influenza vaccine in inflammatory bowel disease patients treated or not with immunomodulators and/or biologics: A two-year prospective study. J. Crohns Colitis 2015, 9, 1096–1107. [Google Scholar] [CrossRef]
  92. Frasca, D.; Andrisani, G.; Diaz, A.; Felice, C.; Guidi, L.; Blomberg, B.B. AID in aging and autoimmune diseases. Autoimmunity 2013, 46, 168–175. [Google Scholar] [CrossRef] [PubMed]
  93. Gelinck, L.B.; van den Bemt, B.J.; Marijt, W.A.; van der Bijl, A.E.; Visser, L.G.; Cats, H.A.; Rimmelzwaan, G.F.; Kroon, F.P. Intradermal influenza vaccination in immunocompromized patients is immunogenic and feasible. Vaccine 2009, 27, 2469–2474. [Google Scholar] [CrossRef] [PubMed]
  94. Gelinck, L.B.; van der Bijl, A.E.; Beyer, W.E.; Visser, L.G.; Huizinga, T.W.; van Hogezand, R.A.; Rimmelzwaan, G.F.; Kroon, F.P. The effect of anti-tumour necrosis factor alpha treatment on the antibody response to influenza vaccination. Ann. Rheum. Dis. 2008, 67, 713–716. [Google Scholar] [CrossRef] [PubMed]
  95. Borte, S.; Liebert, U.G.; Borte, M.; Sack, U. Efficacy of measles, mumps and rubella revaccination in children with juvenile idiopathic arthritis treated with methotrexate and etanercept. Rheumatology 2009, 48, 144–148. [Google Scholar] [CrossRef] [Green Version]
  96. Scheinberg, M.; Guedes-Barbosa, L.S.; Mangueira, C.; Rosseto, E.A.; Mota, L.; Oliveira, A.C.; Lima, R.A. Yellow fever revaccination during infliximab therapy. Arthritis Care Res. 2010, 62, 896–898. [Google Scholar] [CrossRef]
  97. Chioato, A.; Noseda, E.; Stevens, M.; Gaitatzis, N.; Kleinschmidt, A.; Picaud, H. Treatment with the interleukin-17A-blocking antibody secukinumab does not interfere with the efficacy of influenza and meningococcal vaccinations in healthy subjects: Results of an open-label, parallel-group, randomized single-center study. Clin. Vaccine Immunol. 2012, 19, 1597–1602. [Google Scholar] [CrossRef] [Green Version]
  98. Richi, P.; Martín, M.; de Ory, F.; Gutiérrez-Larraya, R.; Casas, I.; Jiménez-Díaz, A.M.; Cava, F.; Muñoz-Fernández, S. Secukinumab does not impair the immunogenic response to the influenza vaccine in patients. RMD Open 2019, 5, e001018. [Google Scholar] [CrossRef] [Green Version]
  99. Gomez, E.V.; Bishop, J.L.; Jackson, K.; Muram, T.M.; Phillips, D. Response to tetanus and pneumococcal vaccination following administration of ixekizumab in healthy participants. BioDrugs 2017, 31, 545–554. [Google Scholar] [CrossRef] [Green Version]
  100. Bingham, C.O., 3rd; Rizzo, W.; Kivitz, A.; Hassanali, A.; Upmanyu, R.; Klearman, M. Humoral immune response to vaccines in patients with rheumatoid arthritis treated with tocilizumab: Results of a randomised controlled trial (VISARA). Ann. Rheum. Dis. 2015, 74, 818–822. [Google Scholar] [CrossRef] [Green Version]
  101. Mori, S.; Ueki, Y.; Akeda, Y.; Hirakata, N.; Oribe, M.; Shiohira, Y.; Hidaka, T.; Oishi, K. Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tocilizumab therapy. Ann. Rheum. Dis. 2013, 72, 1362–1366. [Google Scholar] [CrossRef] [Green Version]
  102. Tsuru, T.; Terao, K.; Murakami, M.; Matsutani, T.; Suzaki, M.; Amamoto, T.; Nakashima, H.; Akiyama, A.; Nishimoto, N. Immune response to influenza vaccine and pneumococcal polysaccharide vaccine under IL-6 signal inhibition therapy with tocilizumab. Mod. Rheumatol. 2014, 24, 511–516. [Google Scholar] [CrossRef] [PubMed]
  103. Mori, S.; Ueki, Y.; Hirakata, N.; Oribe, M.; Hidaka, T.; Oishi, K. Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2012, 71, 2006–2010. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Shinoki, T.; Hara, R.; Kaneko, U.; Miyamae, T.; Imagawa, T.; Mori, M.; Yokota, S. Safety and response to influenza vaccine in patients with systemic-onset juvenile idiopathic arthritis receiving tocilizumab. Mod. Rheumatol. 2012, 22, 871–876. [Google Scholar] [CrossRef]
  105. Brodmerkel, C.; Wadman, E.; Langley, R.G.; Papp, K.A.; Bourcier, M.; Poulin, Y.; Ho, V.; Guenther, L.; Kunynetz, R.; Nigen, S.; et al. Immune response to pneumococcus and tetanus toxoid in patients with moderate-to-severe psoriasis following long-term ustekinumab use. J. Drugs Dermatol. 2013, 12, 1122–1129. [Google Scholar] [PubMed]
  106. Brodmerkel, C.; Zhu, Y.; Jiao, Q.; Cornacoff, J.; Treacy, G.; Mascelli, M.A.; Gottlieb, A.B. Effects of ustekinumab administration on primate/human antigen-recall and humoral immune response functions. J. Drugs Dermatol. 2010, 9, 677–683. [Google Scholar]
  107. Doornekamp, L.; Goetgebuer, R.L.; Schmitz, K.S.; Goeijenbier, M.; van der Woude, C.J.; Fouchier, R.; van Gorp, E.C.M.; de Vries, A.C. High immunogenicity to influenza vaccination in Crohn’s disease patients treated with ustekinumab. Vaccines 2020, 8, 455. [Google Scholar] [CrossRef]
  108. Ley, K.; Rivera-Nieves, J.; Sandborn, W.J.; Shattil, S. Integrin-based therapeutics: Biological basis, clinical use and new drugs. Nat. Rev. Drug Discov. 2016, 15, 173–183. [Google Scholar] [CrossRef] [Green Version]
  109. Keating, G.M. Abatacept: A review of its use in the management of rheumatoid arthritis. Drugs 2013, 73, 1095–1119. [Google Scholar] [CrossRef]
  110. Brunner, H.I.; Tzaribachev, N.; Cornejo, G.V.; Joos, R.; Gervais, E.; Cimaz, R.; Calvo Penades, I.; Cuttica, R.; Lutz, T.; Quartier, P.; et al. Maintenance of antibody response to diphtheria/tetanus vaccine in patients aged 2-5 years with polyarticular-course juvenile idiopathic arthritis receiving subcutaneous abatacept. Pediatr. Rheumatol. Online J. 2020, 18, 19. [Google Scholar] [CrossRef] [Green Version]
  111. Lee, D.S.W.; Rojas, O.L.; Gommerman, J.L. B cell depletion therapies in autoimmune disease: Advances and mechanistic insights. Nat. Rev. Drug Discov. 2021, 20, 179–199. [Google Scholar] [CrossRef]
  112. Baker, K.F.; Isaacs, J.D. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann. Rheum. Dis. 2018, 77, 175–187. [Google Scholar] [CrossRef] [PubMed]
  113. Zhou, H.; Xu, Y.; Sharma, A. Antibody-based therapeutics in inflammatory diseases. In Pharmaceutical Biotechnology: Fundamentals and Applications, 5th ed.; Commelin, D.J.A., Sindelar, R.D., Meibohm, B., Eds.; Springer Nature: Cham, Switzerland, 2019; pp. 557–617. [Google Scholar]
  114. Wise, L.M.; Stohl, W. Belimumab and rituximab in systemic lupus erythematosus: A tale of two B cell-targeting agents. Front. Med. 2020, 7, 303. [Google Scholar] [CrossRef] [PubMed]
  115. Curtis, J.R.; Johnson, S.R.; Anthony, D.D.; Arasaratnam, R.J.; Baden, L.R.; Bass, A.R.; Calabrese, C.; Gravallese, E.M.; Harpaz, R.; Sadun, R.E.; et al. American College of Rheumatology Guidance for COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases: Version 1. Arthritis Rheumatol. 2021, 73, 1093–1107. [Google Scholar] [CrossRef] [PubMed]
  116. Papp, K.A.; Haraoui, B.; Kumar, D.; Marshall, J.K.; Bissonnette, R.; Bitton, A.; Bressler, B.; Gooderham, M.; Ho, V.; Jamal, S.; et al. Vaccination guidelines for patients with immune-mediated disorders on immunosuppressive therapies. J. Cutan Med. Surg. 2019, 23, 50–74. [Google Scholar] [CrossRef] [Green Version]
  117. Mackay, F.; Browning, J.L. BAFF: A fundamental survival factor for B cells. Nat. Rev. Immunol. 2002, 2, 465–475. [Google Scholar] [CrossRef]
  118. Calero, I.; Sanz, I. Targeting B cells for the treatment of SLE: The beginning of the end or the end of the beginning? Discov. Med. 2010, 10, 416–424. [Google Scholar]
  119. Chatham, W.W.; Wallace, D.J.; Stohl, W.; Latinis, K.M.; Manzi, S.; McCune, W.J.; Tegzova, D.; McKay, J.D.; Avila-Armengol, H.E.; Utset, T.O.; et al. Effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the BLISS-76 trial. J. Rheumatol. 2012, 39, 1632–1640. [Google Scholar] [CrossRef] [Green Version]
  120. Steeland, S.; Libert, C.; Vandenbroucke, R.E. A new venue of TNF targeting. Int. J. Mol. Sci. 2018, 19, 1442. [Google Scholar] [CrossRef] [Green Version]
  121. Kalliolias, G.D.; Ivashkiv, L.B. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 2016, 12, 49–62. [Google Scholar] [CrossRef]
  122. Hua, C.; Barnetche, T.; Combe, B.; Morel, J. Effect of methotrexate, anti-tumor necrosis factor alpha, and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: A systematic review and meta-analysis. Arthritis Care Res. 2014, 66, 1016–1026. [Google Scholar] [CrossRef]
  123. Subesinghe, S.; Bechman, K.; Rutherford, A.I.; Goldblatt, D.; Galloway, J.B. A systematic review and metaanalysis of antirheumatic drugs and vaccine immunogenicity in rheumatoid arthritis. J. Rheumatol. 2018, 45, 733–744. [Google Scholar] [CrossRef] [PubMed]
  124. Van Aalst, M.; Langedijk, A.C.; Spijker, R.; de Bree, G.J.; Grobusch, M.P.; Goorhuis, A. The effect of immunosuppressive agents on immunogenicity of pneumococcal vaccination: A systematic review and meta-analysis. Vaccine 2018, 36, 5832–5845. [Google Scholar] [CrossRef] [PubMed]
  125. De Bruyn, J.; Fonseca, K.; Ghosh, S.; Panaccione, R.; Gasia, M.F.; Ueno, A.; Kaplan, G.G.; Seow, C.H.; Wrobel, I. Immunogenicity of influenza vaccine for patients with inflammatory bowel disease on maintenance infliximab therapy: A randomized trial. Inflamm. Bowel Dis. 2016, 22, 638–647. [Google Scholar] [CrossRef] [PubMed]
  126. Gelinck, L.B.; van der Bijl, A.E.; Visser, L.G.; Huizinga, T.W.; van Hogezand, R.A.; Rijkers, G.T.; Kroon, F.P. Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine. Vaccine 2008, 26, 3528–3533. [Google Scholar] [CrossRef] [PubMed]
  127. Zhang, J.; Xie, F.; Delzell, E.; Chen, L.; Winthrop, K.L.; Lewis, J.D.; Saag, K.G.; Baddley, J.W.; Curtis, J.R. Association between vaccination for herpes zoster and risk of herpes zoster infection among older patients with selected immune-mediated diseases. JAMA 2012, 308, 43–49. [Google Scholar] [CrossRef] [Green Version]
  128. Zhang, F.; Wei, K.; Slowikowski, K.; Fonseka, C.Y.; Rao, D.A.; Kelly, S.; Goodman, S.M.; Tabechian, D.; Hughes, L.B.; Salomon-Escoto, K.; et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 2019, 20, 928–942. [Google Scholar] [CrossRef]
  129. Richi, P.; Martin, M.D.; Andreu-Vazquez, C.; Jimenez-Diaz, A.; Steiner, M.; Munoz-Fernandez, S. Serological response to influenza vaccine in patients with autoimmune inflammatory diseases: Results of RIER study. Med. Clin. 2021, 156, 118–122. [Google Scholar] [CrossRef]
  130. Brogan, P.; Hofer, M.; Kuemmerle-Deschner, J.B.; Lauwerys, B.R.; Speziale, A.; Wei, X.; Laxer, R. Effectiveness of childhood vaccinations in CAPS patients treated with canakinumab: Results from an open-label phase III extension study [abstract THU0495]. Arthritis Rheum. 2015, 69, 393. [Google Scholar]
  131. Valeri, M.; Raffatellu, M. Cytokines IL-17 and IL-22 in the host response to infection. Pathog. Dis. 2016, 74, ftw111. [Google Scholar] [CrossRef] [Green Version]
  132. Iwakura, Y.; Nakae, S.; Saijo, S.; Ishigame, H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol. Rev. 2008, 226, 57–79. [Google Scholar] [CrossRef]
  133. Blauvelt, A.; Chiricozzi, A. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clin. Rev. Allergy Immunol. 2018, 55, 379–390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Kugyelka, R.; Kohl, Z.; Olasz, K.; Mikecz, K.; Rauch, T.A.; Glant, T.T.; Boldizsar, F. Enigma of IL-17 and Th17 cells in rheumatoid arthritis and in autoimmune animal models of arthritis. Mediat. Inflamm. 2016, 2016, 6145810. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Soare, A.; Weber, S.; Maul, L.; Rauber, S.; Gheorghiu, A.M.; Luber, M.; Houssni, I.; Kleyer, A.; von Pickardt, G.; Gado, M.; et al. Cutting edge: Homeostasis of innate lymphoid cells is imbalanced in psoriatic arthritis. J. Immunol. 2018, 200, 1249–1254. [Google Scholar] [CrossRef] [Green Version]
  136. Gaffen, S.L.; Jain, R.; Garg, A.V.; Cua, D.J. The IL-23-IL-17 immune axis: From mechanisms to therapeutic testing. Nat. Rev. Immunol. 2014, 14, 585–600. [Google Scholar] [CrossRef]
  137. Fauny, M.; Moulin, D.; D’Amico, F.; Netter, P.; Petitpain, N.; Arnone, D.; Jouzeau, J.Y.; Loeuille, D.; Peyrin-Biroulet, L. Paradoxical gastrointestinal effects of interleukin-17 blockers. Ann. Rheum. Dis. 2020, 79, 1132–1138. [Google Scholar] [CrossRef]
  138. Favalli, E.G. Understanding the role of interleukin-6 (IL-6) in the joint and beyond: A comprehensive review of IL-6 Inhibition for the management of rheumatoid arthritis. Rheumatol. Ther. 2020, 7, 473–516. [Google Scholar] [CrossRef] [PubMed]
  139. Garbers, C.; Heink, S.; Korn, T.; Rose-John, S. Interleukin-6: Designing specific therapeutics for a complex cytokine. Nat. Rev. Drug Discov. 2018, 17, 395–412. [Google Scholar] [CrossRef] [PubMed]
  140. Tanaka, T.; Narazaki, M.; Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol. 2014, 6, a016295. [Google Scholar] [CrossRef]
  141. Tait Wojno, E.D.; Hunter, C.A.; Stumhofer, J.S. The immunobiology of the interleukin-12 family: Room for discovery. Immunity 2019, 50, 851–870. [Google Scholar] [CrossRef]
  142. Kobayashi, M.; Fitz, L.; Ryan, M.; Hewick, R.M.; Clark, S.C.; Chan, S.; Loudon, R.; Sherman, F.; Perussia, B.; Trinchieri, G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 1989, 170, 827–845. [Google Scholar] [CrossRef]
  143. Manetti, R.; Parronchi, P.; Giudizi, M.G.; Piccinni, M.P.; Maggi, E.; Trinchieri, G.; Romagnani, S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J. Exp. Med. 1993, 177, 1199–1204. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Szabo, S.J.; Kim, S.T.; Costa, G.L.; Zhang, X.; Fathman, C.G.; Glimcher, L.H. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000, 100, 655–669. [Google Scholar] [CrossRef] [Green Version]
  145. Oppmann, B.; Lesley, R.; Blom, B.; Timans, J.C.; Xu, Y.; Hunte, B.; Vega, F.; Yu, N.; Wang, J.; Singh, K.; et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000, 13, 715–725. [Google Scholar] [CrossRef] [Green Version]
  146. Cua, D.J.; Sherlock, J.; Chen, Y.; Murphy, C.A.; Joyce, B.; Seymour, B.; Lucian, L.; To, W.; Kwan, S.; Churakova, T.; et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003, 421, 744–748. [Google Scholar] [CrossRef] [PubMed]
  147. Floss, D.M.; Moll, J.M.; Scheller, J. IL-12 and IL-23-close relatives with structural homologies but distinct immunological functions. Cells 2020, 9, 2184. [Google Scholar] [CrossRef] [PubMed]
  148. Schmitt, N.; Bustamante, J.; Bourdery, L.; Bentebibel, S.E.; Boisson-Dupuis, S.; Hamlin, F.; Tran, M.V.; Blankenship, D.; Pascual, V.; Savino, D.A.; et al. IL-12 receptor beta1 deficiency alters in vivo T follicular helper cell response in humans. Blood 2013, 121, 3375–3385. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Schmitt, N.; Morita, R.; Bourdery, L.; Bentebibel, S.E.; Zurawski, S.M.; Banchereau, J.; Ueno, H. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 2009, 31, 158–169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  150. De Boer, T.; van Dissel, J.T.; Kuijpers, T.W.; Rimmelzwaan, G.F.; Kroon, F.P.; Ottenhoff, T.H. Influenza virus vaccination induces interleukin-12/23 receptor beta 1 (IL-12/23R beta 1)-independent production of gamma interferon (IFN-gamma) and humoral immunity in patients with genetic deficiencies in IL-12/23R beta 1 or IFN-gamma receptor I. Clin. Vaccine Immunol. 2008, 15, 1171–1175. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  151. Martínez-Barricarte, R.; Markle, J.G.; Ma, C.S.; Deenick, E.K.; Ramírez-Alejo, N.; Mele, F.; Latorre, D.; Mahdaviani, S.A.; Aytekin, C.; Mansouri, D.; et al. Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23. Sci. Immunol. 2018, 3, eaau6759. [Google Scholar] [CrossRef]
  152. Van de Vosse, E.; Haverkamp, M.H.; Ramirez-Alejo, N.; Martinez-Gallo, M.; Blancas-Galicia, L.; Metin, A.; Garty, B.Z.; Sun-Tan, C.; Broides, A.; de Paus, R.A.; et al. IL-12Rß1 deficiency: Mutation update and description of the IL12RB1 variation database. Hum. Mutat. 2013, 34, 1329–1339. [Google Scholar] [CrossRef] [Green Version]
  153. De Beaucoudrey, L.; Samarina, A.; Bustamante, J.; Cobat, A.; Boisson-Dupuis, S.; Feinberg, J.; Al-Muhsen, S.; Janniere, L.; Rose, Y.; de Suremain, M.; et al. Revisiting human IL-12Rbeta1 deficiency: A survey of 141 patients from 30 countries. Medicine 2010, 89, 381–402. [Google Scholar] [CrossRef] [Green Version]
  154. Odegard, J.M.; Marks, B.R.; DiPlacido, L.D.; Poholek, A.C.; Kono, D.H.; Dong, C.; Flavell, R.A.; Craft, J. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J. Exp. Med. 2008, 205, 2873–2886. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Ma, C.S.; Avery, D.T.; Chan, A.; Batten, M.; Bustamante, J.; Boisson-Dupuis, S.; Arkwright, P.D.; Kreins, A.Y.; Averbuch, D.; Engelhard, D.; et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 2012, 119, 3997–4008. [Google Scholar] [CrossRef] [PubMed]
  156. Uddin, M.; Mustafa, F.; Rizvi, T.A.; Loney, T.; Suwaidi, H.A.; Al-Marzouqi, A.H.H.; Eldin, A.K.; Alsabeeha, N.; Adrian, T.E.; Stefanini, C.; et al. SARS-CoV-2/COVID-19: Viral genomics, epidemiology, vaccines, and therapeutic interventions. Viruses 2020, 12, 526. [Google Scholar] [CrossRef] [PubMed]
  157. Deepak, P.; Kim, W.; Paley, M.A.; Yang, M.; Carvidi, A.B.; El-Qunni, A.A.; Haile, A.; Huang, K.; Kinnett, B.; Liebeskind, M.J.; et al. Glucocorticoids and B cell depleting agents substantially impair immunogenicity of mRNA vaccines to SARS-CoV-2. medRxiv 2021. preprint. [Google Scholar] [CrossRef]
  158. Simon, D.; Tascilar, K.; Fagni, F.; Kronke, G.; Kleyer, A.; Meder, C.; Atreya, R.; Leppkes, M.; Kremer, A.E.; Ramming, A.; et al. SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases. Ann. Rheum. Dis. 2021, 80, 1312–1316. [Google Scholar] [CrossRef]
  159. Geisen, U.M.; Berner, D.K.; Tran, F.; Sumbul, M.; Vullriede, L.; Ciripoi, M.; Reid, H.M.; Schaffarzyk, A.; Longardt, A.C.; Franzenburg, J.; et al. Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort. Ann. Rheum. Dis. 2021, 80, 1306–1311. [Google Scholar] [CrossRef]
  160. Braun-Moscovici, Y.; Kaplan, M.; Braun, M.; Markovits, D.; Giryes, S.; Toledano, K.; Tavor, Y.; Dolnikov, K.; Balbir-Gurman, A. Disease activity and humoral response in patients with inflammatory rheumatic diseases after two doses of the Pfizer mRNA vaccine against SARS-CoV-2. Ann. Rheum. Dis. 2021, 80, 1317–1321. [Google Scholar] [CrossRef]
  161. Rubbert-Roth, A.; Vuilleumier, N.; Ludewig, B.; Schmiedeberg, K.; Haller, C.; von Kempis, J. Anti-SARS-CoV-2 mRNA vaccine in patients with rheumatoid arthritis. Lancet Rheumatol. 2021, 3, e470–e472. [Google Scholar] [CrossRef]
  162. Bugatti, S.; De Stefano, L.; Balduzzi, S.; Greco, M.I.; Luvaro, T.; Cassaniti, I.; Bogliolo, L.; Mazzucchelli, I.; D’Onofrio, B.; di Lernia, M.; et al. Methotrexate and glucocorticoids, but not anticytokine therapy, impair the immunogenicity of a single dose of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic inflammatory arthritis. Ann. Rheum Dis. 2021. online ahead of print June 25. [Google Scholar] [CrossRef]
  163. Al-Janabi, A.; Littlewood, Z.; Griffiths, C.E.M.; Hunter, H.J.A.; Chinoy, H.; Moriarty, C.; Yiu, Z.Z.N.; Warren, R.B. Antibody responses to single-dose SARS-CoV-2 vaccination in patients receiving immunomodulators for immune-mediated inflammatory disease. Br. J. Dermatol. 2021, 185, 646–648. [Google Scholar] [CrossRef] [PubMed]
  164. Venerito, V.; Stefanizzi, P.; Fornaro, M.; Cacciapaglia, F.; Tafuri, S.; Perniola, S.; Iannone, F.; Lopalco, G. Immunogenicity of BNT162b2 mRNA SARS-CoV-2 vaccine in patients with psoriatic arthritis on TNF inhibitors. RMD Open 2022, 8, e001847. [Google Scholar] [CrossRef]
  165. Haberman, R.H.; Herati, R.; Simon, D.; Samanovic, M.; Blank, R.B.; Tuen, M.; Koralov, S.B.; Atreya, R.; Tascilar, K.; Allen, J.R.; et al. Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease. Ann. Rheum. Dis. 2021, 80, 1339–1344. [Google Scholar] [CrossRef]
  166. Cristaudo, A.; Graceffa, D.; Pimpinelli, F.; Sperati, F.; Spoletini, G.; Bonifati, C.; Pellini, R.; Lora, V.; Pontone, M.; Di Bella, O.; et al. Immunogenicity and safety of anti-SARS-CoV-2 BNT162b2 vaccine in psoriasis patients treated with biologic drugs. J. Eur. Acad. Dermatol. Venereol. 2021. [Google Scholar] [CrossRef] [PubMed]
  167. Mahil, S.K.; Bechman, K.; Raharja, A.; Domingo-Vila, C.; Baudry, D.; Brown, M.A.; Cope, A.P.; Dasandi, T.; Graham, C.; Lechmere, T.; et al. The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: A cohort study. Lancet Rheumatol. 2021, 3, e627–e637. [Google Scholar] [CrossRef]
  168. Mahil, S.K.; Bechman, K.; Raharja, A.; Domingo-Vila, C.; Baudry, D.; Brown, M.A.; Cope, A.P.; Dasandi, T.; Graham, C.; Khan, H.; et al. Humoral and cellular immunogenicity to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: A longitudinal cohort study. Lancet Rheumatol. 2022, 4, e42–e52. [Google Scholar] [CrossRef]
  169. Wong, S.Y.; Dixon, R.; Martinez Pazos, V.; Gnjatic, S.; Colombel, J.F.; Cadwell, K.; Group, I.-I.W. Serologic response to messenger RNA coronavirus disease 2019 vaccines in inflammatory bowel disease patients receiving biologic therapies. Gastroenterology 2021, 161, 715–718.e714. [Google Scholar] [CrossRef]
  170. Classen, J.M.; Muzalyova, A.; Nagl, S.; Fleischmann, C.; Ebigbo, A.; Rommele, C.; Messmann, H.; Schnoy, E. Antibody response to SARS-CoV-2 vaccination in patients with inflammatory bowel disease-results of a single-center cohort study in a tertiary hospital in Germany. Dig. Dis. 2021, 10, 1–9. [Google Scholar] [CrossRef]
  171. Kappelman, M.D.; Weaver, K.N.; Boccieri, M.; Firestine, A.; Zhang, X.; Long, M.D.; PREVENT-COVID Study Group. Humoral immune response to messenger RNA COVID-19 vaccines among patients with inflammatory bowel disease. Gastroenterology 2021, 161, 1340–1343.e1342. [Google Scholar] [CrossRef]
  172. Kappelman, M.D.; Weaver, K.N.; Zhang, X.; Dai, X.; Watkins, R.; Adler, J.; Dubinsky, M.C.; Kastl, A.; Bousvaros, A.; Strople, J.A.; et al. Factors affecting initial humoral immune response to SARS-CoV-2 vaccines among patients with inflammatory bowel diseases. Am. J. Gastroenterol. 2021. online ahead of print December 29. [Google Scholar] [CrossRef]
  173. Charilaou, P.; Tricarico, C.; Battat, R.; Scherl, E.J.; Longman, R.S.; Lukin, D.J. Impact of inflammatory bowel disease therapies on durability of humoral response to SARS-CoV-2 vaccination. Clin. Gastroenterol. Hepatol. 2021. online ahead of print December 9. [Google Scholar] [CrossRef] [PubMed]
  174. Frey, S.; Chowdhury, R.; Connolly, C.M.; Werbel, W.A.; Segev, D.L.; Parian, A.M.; IBD Group; Tsipotis, E.; Dudley-Brown, S.; Lazarev, M.; et al. Antibody response six months after SARS-CoV-2 mRNA vaccination in patients with inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 2022. online ahead of print January 5. [Google Scholar] [CrossRef]
  175. Shehab, M.; Alrashed, F.; Alfadhli, A.; Alotaibi, K.; Alsahli, A.; Mohammad, H.; Cherian, P.; Al-Khairi, I.; Alphonse Thanaraj, T.; Channanath, A.; et al. Serological response to BNT162b2 and ChAdOx1 nCoV-19 vaccines in patients with inflammatory bowel disease on biologic therapies. Vaccines 2021, 9, 1471. [Google Scholar] [CrossRef] [PubMed]
  176. Kennedy, N.A.; Lin, S.; Goodhand, J.R.; Chanchlani, N.; Hamilton, B.; Bewshea, C.; Nice, R.; Chee, D.; Cummings, J.F.; Fraser, A.; 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, 1884–1893. [Google Scholar] [CrossRef]
  177. Lin, S.; Kennedy, N.A.; Saifuddin, A.; Muñoz Sandoval, D.; Reynolds, C.; Castro Seoane, R.; Kottoor, S.; Pieper, F.; Lin, K.-M.; Butler, D.K.; et al. COVID-19 vaccine-induced antibodies are attenuated and decay rapidly in infliximab treated patients. Res. Sq. 2021. preprint. [Google Scholar] [CrossRef]
  178. Reuken, P.A.; Andreas, N.; Grunert, P.C.; Glockner, S.; Kamradt, T.; Stallmach, A. T cell response after SARS-CoV-2 vaccination in immunocompromised patients with inflammatory bowel disease. J. Crohns Colitis 2021. online ahead of print Aug 11. [Google Scholar] [CrossRef]
  179. Li, D.; Xu, A.; Mengesha, E.; Elyanow, R.; Gittelman, R.M.; Chapman, H.; Prostko, J.C.; Frias, E.C.; Stewart, J.L.; Pozdnyakova, V.; et al. The T-cell clonal response to SARS-CoV-2 vaccination in inflammatory bowel disease patients is augmented by anti-TNF therapy and often deficient in antibody-responders. medRxiv 2021. preprint. [Google Scholar]
  180. Ben-Tov, A.; Banon, T.; Chodick, G.; Kariv, R.; Assa, A.; Gazit, S.; Collaborators of the Maccabi Institute for Research & Innovation COVID-19 Task Force. BNT162b2 messenger RNA COVID-19 vaccine effectiveness in patients with inflammatory bowel disease: Preliminary real-world data during mass vaccination campaign. Gastroenterology 2021, 161, 1715–1717.e1711. [Google Scholar] [CrossRef] [PubMed]
  181. Khan, N.; Mahmud, N. Effectiveness of SARS-CoV-2 vaccination in a veterans affairs cohort of patients with inflammatory bowel disease with diverse exposure to immunosuppressive medications. Gastroenterology 2021, 161, 827–836. [Google Scholar] [CrossRef] [PubMed]
  182. Musumeci, M.L.; Caruso, G.; Trecarichi, A.C.; Micali, G. Safety of SARS-CoV-2 vaccines in psoriatic patients treated with biologics: A real life experience. Dermatol. Ther. 2022, 35, e15177. [Google Scholar] [CrossRef]
  183. Weaver, K.N.; Zhang, X.; Dai, X.; Watkins, R.; Adler, J.; Dubinsky, M.C.; Kastl, A.; Bousvaros, A.; Strople, J.A.; Cross, R.K.; et al. Impact of SARS-CoV-2 vaccination on inflammatory bowel disease activity and development of vaccine-related adverse events: Results from PREVENT-COVID. Inflamm. Bowel Dis. 2021, izab302. [Google Scholar] [CrossRef] [PubMed]
  184. Botwin, G.J.; Li, D.; Figueiredo, J.; Cheng, S.; Braun, J.; McGovern, D.P.B.; Melmed, G.Y. Adverse events following SARS-CoV-2 mRNA vaccination among patients with inflammatory bowel disease. medRxiv 2021. preprint. [Google Scholar] [CrossRef]
  185. Li, D.; Debbas, P.; Cheng, S.; Braun, J.; McGovern, D.P.B.; Melmed, G.Y. Post-vaccination symptoms after a third dose of mRNA SARS-CoV-2 vaccination in patients with inflammatory bowel disease. medRxiv 2021. preprint. [Google Scholar] [CrossRef]
  186. Kennedy, N.A.; Goodhand, J.R.; Bewshea, C.; Nice, R.; Chee, D.; Lin, S.; Chanchlani, N.; Butterworth, J.; Cooney, R.; Croft, N.M.; et al. Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab. Gut 2021, 70, 865–875. [Google Scholar] [CrossRef]
  187. Hadjadj, J.; Planas, D.; Ouedrani, A.; Buffier, S.; Delage, L.; Nguyen, Y.; Bruel, T.; Stolzenberg, M.C.; Staropoli, I.; Ermak, N.; et al. Immunogenicity of BNT162b2 vaccine against the Alpha and Delta variants in immunocompromised patients with systemic inflammatory diseases. Ann. Rheum. Dis. 2022. online ahead of print January 12. [Google Scholar] [CrossRef]
  188. Simon, D.; Tascilar, K.; Fagni, F.; Schmidt, K.; Kronke, G.; Kleyer, A.; Ramming, A.; Schoenau, V.; Bohr, D.; Knitza, J.; et al. Efficacy and safety of SARS-CoV-2 revaccination in non-responders with immune-mediated inflammatory disease. Ann. Rheum. Dis. 2021. online ahead of print November 24. [Google Scholar] [CrossRef]
  189. American Academy of Dermatology. COVID-19 Vaccine Administration Guidance. 2021. Available online: (accessed on 19 March 2021).
  190. European Academy of Dermatology and Venereology. COVID-19 Vaccination: Advice of the EADV Task Forces. 2021. Available online: (accessed on 19 March 2021).
  191. Alexander, J.L.; Moran, G.W.; Gaya, D.R.; Raine, T.; Hart, A.; Kennedy, N.A.; Lindsay, J.O.; MacDonald, J.; Segal, J.P.; Sebastian, S.; et al. SARS-CoV-2 vaccination for patients with inflammatory bowel disease: A British Society of Gastroenterology Inflammatory Bowel Disease section and IBD Clinical Research Group position statement. Lancet Gastroenterol. Hepatol. 2021, 6, 218–224. [Google Scholar] [CrossRef]
  192. American College of Rheumatology. COVID-19 Vaccine Clinical Guidance Summary for Patients with Rheumatic and Musculoskeletal Diseases. 2021. Available online: (accessed on 19 March 2021).
  193. European Medicines Agency. Comirnaty and Spikevax: EMA Recommendations on Extra Doses and Boosters. 2021. Available online: (accessed on 25 January 2022).
  194. Department of Health & Social Care. Joint Committee on Vaccination and Immunisation (JCVI) Advice on Third Primary Dose Vaccination. 2021. Available online: (accessed on 25 January 2022).
  195. Centers for Disease Control and Prevention. Considerations for COVID-19 Vaccination in Moderately or Severely Immunocompromised People. Available online: (accessed on 25 January 2022).
Figure 1. Schematic representation of IL-12 and IL-23 cytokines and its receptors. Figure created with [141].
Figure 1. Schematic representation of IL-12 and IL-23 cytokines and its receptors. Figure created with [141].
Vaccines 10 00297 g001
Table 1. Effect of biologic therapies on response to vaccination in IMID patients.
Table 1. Effect of biologic therapies on response to vaccination in IMID patients.
Biologic TherapyVaccinePopulationImpact on Vaccine Response
Integrin inhibitors
Natalizumab (anti-α4β1)InfluenzaMSReduced humoral response [47,48]
Tetanus MSNormal humoral response [49]
Vedolizumab (anti-α4β7)InfluenzaIBDNormal humoral response [50]
Oral cholera Healthy volunteersReduced humoral response [51]
Hepatitis BHealthy volunteersNormal humoral response [51]
CTLA-4 fusion protein
Abatacept PPV-23RAReduced antibody titers, but normal functional antibodies [52]
Normal humoral response [53]
PCV-7RAImpaired humoral response [54]
InfluenzaRANormal humoral response [53]
Impaired humoral response [55]
CD20 inhibitor
Rituximab PPV-23RAImpaired humoral response [56]
IMIDsImpaired humoral response [57]
PCV-7RAImpaired humoral response [54]
IMIDsImpaired humoral response [57]
Hepatitis BIMIDsImpaired humoral response [58]
TetanusRAPreserved humoral response to recall antigen [56]
InfluenzaRAImpaired humoral [59,60,61,62], but preserved cellular response [59]
IMIDsImpaired humoral response [63]
RA or vasculitisImpaired humoral response [64,65]
BAFF inhibitor
BelimumabPCV-13SLENormal humoral response [66]
PPV-23SLENormal humoral response [67]
TNF inhibitors (aggregated)
PPV-23SpAReduced humoral response [68]
PsANormal humoral response [69]
RAReduced humoral response [70]
Normal humoral response [71,72,73]
IBDReduced humoral response [74,75,76,77]
PCV-13 then PPV-23IBDImpaired humoral response [77]
PCV-13RAImpaired humoral response [78]
CDImpaired humoral response [74]
Hepatitis BSpAReduced humoral response [68]
IBDImpaired humoral response [79,80], or seroconversion rates similar to thiopurine or MTX [81]
Hepatitis ARAImpaired humoral response [82]
InfluenzaRANormal humoral response [71,72,83,84,85,86,87]
ASNormal humoral response [83]
SpAReduced humoral response [85]
PsA or PsONormal humoral response [88]
IBDReduced humoral response [89,90,91,92]
IMIDsReduced humoral response [93,94]
MMRJIANormal humoral and cellular response [95]
Yellow feverRAPreserved antibody response to revaccination [96]
IL-17 inhibitors
Secukinumab Meningococcal conjugateHealthy volunteersNormal humoral response [97]
InfluenzaHealthy volunteersNormal humoral response [97]
PsA or ASNormal humoral response [98]
IxekizumabPPV-23Healthy volunteersNormal humoral response [99]
TetanusHealthy volunteersNormal humoral response [99]
IL-6 inhibitor
TocilizumabPPV-23RANormal humoral response [100,101,102]
PCV-13 then PPV-23IMIDsNormal humoral response [57]
PCV-7RANormal humoral response [54]
InfluenzaRANormal humoral response [64,102,103]
SJIANormal humoral response [104]
TetanusRANormal humoral response [100]
IL-12/IL-23 inhibitors
UstekinumabPPV-23PsONormal humoral response [105]
PsO or MSNormal humoral response [106]
InfluenzaCDNormal humoral response [107]
Tetanus PsO or MSNormal humoral response [106]
PsONormal humoral response [105]
AS, ankylosing spondylitis; BAFF, B-cell activating factor; CD, Crohn’s disease; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IBD, inflammatory bowel disease; IL, interleukin; MS, multiple sclerosis; IMID, immune-mediated inflammatory diseases; JIA, juvenile idiopathic arthritis; MMR, measles-mumps-rubella; MS, multiple sclerosis; NSAID, non-steroidal anti-inflammatory drugs; PCV-7 or PCV-13, 7-valent or 13-valent pneumococcal conjugate vaccine; PPV-23, 23-valent pneumococcal polysaccharide vaccine; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; SJIA, systemic juvenile idiopathic arthritis; SLE, systemic lupus erythematosus; SpA, spondyloarthropathy; TNF, tumor necrosis factor.
Table 2. Graphical summary on the effect of biologic therapies on response to vaccination in IMID patients.
Table 2. Graphical summary on the effect of biologic therapies on response to vaccination in IMID patients.
Biologic TherapyImpact on Vaccine Response a
CD20+ cell depletion
CTLA-4 fusion protein
TNF inhibitors
Integrin inhibitors Oral cholera
BAFF inhibitor
IL-17 inhibitors
IL-6 inhibitor
IL-12/IL-23 inhibitors
a Red shading indicates impaired humoral response, orange indicates reduced humoral response, and green indicates normal humoral response. BAFF, B-cell activating factor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IL, interleukin; TNF, tumor necrosis factor.
Table 3. Immunogenicity and safety of SARS-CoV-2 vaccines in IMIDs.
Table 3. Immunogenicity and safety of SARS-CoV-2 vaccines in IMIDs.
SARS-CoV-2 VaccinePatient PopulationBiologic TherapyEffect on ImmunogenicitySafety Reference
mRNA-1273 and BNT162b2 CID (n = 133)29% receiving anti- TNF, 9% anti-integrin, 8% anti-CD20, 8% anti-IL-12/23 or anti-IL-23, 2% anti-BAFF, 2% CTLA-4, and 1% each anti-IL-6 and anti-IL-1Corticosteroids and B cell-depleting therapies strongly impaired humoral response. JAKi and antimetabolites (e.g., MTX) blunted humoral responses. Anti-
TNF, UST, and VDZ had minimal impact
Not reportedDeepak et al. 2021 [157]
BNT162b2 IMID (n = 84)13% receiving anti-TNF, 8% anti-IL-17, 7% anti-IL-23, 4% anti-IL-6, 1% anti-IL-1, 1% anti-integrinImpaired humoral response compared with healthy controls independent of treatmentAE similar to general population Simon et al. 2021 [158]
mRNA-1273 and BNT162b2 CID (n = 26)50% receiving anti-TNF, 12% anti-IL-17, and 4% each anti-IL-6, anti-IL-12/23, and anti-integrinSlightly reduced humoral responseAE comparable to general population and no flares of CIDGeisen et al. 2021 [159]
BNT162b2IRD (n = 264)24% receiving anti-TNF, 18% anti-CD20, 15% anti-interleukins, and 3% CTLA-4Significant humoral response in majority of patients, except those receiving RTXMinor adverse effects and no flares of IRDBraun-Moscovici et al. 2021 [160]
mRNA-1273 and BNT162b2 RA (n = 53)47% receiving biologic therapySignificantly lower antibody response in patients with RA vs. healthy individuals. Lowest rate of response in patients receiving JAKi Not reportedRubbert-Roth et al. 2021 [161]
BNT162b2RA (n = 83)
PsA (n = 29)
SpA (n = 28)
44% receiving anti-TNF, 21% CTLA-4, 14% anti-IL-12/23, and 10% anti-IL-6Impaired immunogenicity after one dose in patients treated with MTX, glucocorticoids, and abatacept. No effect of cytokine inhibitorsNot reportedBugatti et al. 2021 [162]
BNT162b2 and ChAdOx1-S IMID (n = 120), mostly PsO83% receiving biologic therapyImpaired immunogenicity after one dose in patients treated with MTX compared to biologicsNot reportedAl-Janabi et al. 2021 [163]
BNT162b2 PsA (n = 40)100% receiving anti-TNFAnti-TNF numerically (not significantly) decreased humoral response vs. healthy controls; MTX, glucocorticoids, and sulfasalazine had no impact AE similar to general population; no changes in clinical disease activityVenerito et al. 2022 [164]
BNT162b2 IMID (n = 51) mostly PsO and/or PsA (n = 24)
RA (n = 22)
55% receiving biologic therapyImpaired humoral and cellular responses in patients receiving MTX vs. IMID patients on other DMARDS or healthy controlsNot reportedHaberman et al. 2021 [165]
BNT162b2 PsO (n = 48)44% receiving anti-TNF, 27% anti-IL-23, 17% anti-IL-12/23, 13% anti-IL-17Reduced humoral response in patients receiving biologics in combotherapy vs. monotherapy No increase in AEs and no flaresCristaudo et al. 2021 [166]
BNT162b2 PsO (n = 84)80% receiving biologic therapyImpaired humoral response with MTX after first dose but preserved with biologics; after 2 doses, responses comparable to controlsNot reportedMahil et al. 2021, 2022 [167,168]
mRNA-1273 and BNT162b2 IBD (n = 48)33% receiving anti-TNF, 42% anti-integrin, 8% anti-IL-12/23, and 2% anti-IL-23100% seropositivity after 2 doses but reduced serologic response in patients on anti-TNF or VDZNot reportedWong et al. 2021 [169]
mRNA-1273, BNT162b2 and ChAdOx1-S IBD (n = 72)
Healthy controls (n = 72)
37% receiving anti-TNF, 26% anti-integrin, and 19% anti-IL-12/23Slightly decreased antibody titers in IBD patients compared to healthy controlsWell tolerated with only mild side effectsClassen et al. 2021 [170]
mRNA-1273 and BNT162b2 IBD (n = 317)42% receiving anti-TNF, 15% anti-integrin, and 12% anti-IL-12/2395% had detectable antibodiesNot reportedKappelman et al. 2021a [171]
mRNA-1273, BNT162b2 and Ad26.COV2.S IBD (n = 1909)47% receiving anti-TNF, 15% anti-IL-12/23, and 12% anti-integrin96% achieved positive antibody response; age, corticosteroids, and anti-TNF + IMM associated with reduced odds of antibody responseNot reportedKappelman et al. 2021b [172]
mRNA-1273 and BNT162b2IBD (n = 176)27% receiving anti-TNF, 27% anti-IL-12/23, and 11% anti-integrinSignificantly lower antibody titers and more rapid decay with anti-TNF ± IMM vs. UST, VDZ, or no therapyNot reportedCharilaou et al. 2021 [173]
mRNA-1273 and BNT162b2 IBD (n = 75)51% receiving anti-TNF, 23% anti-IL-12/23, and 8% anti-integrinDetectable antibodies 6 months after 2-dose vaccination; patients receiving anti-TNF had lower antibody titersNot reportedFrey et al. 2022 [174]
BNT162b2 and ChAdOx1-SIBD (n = 126)76% receiving anti-TNF, 12% anti-IL-12/23, and 12% anti-integrinMajority of patients receiving anti-TNF and VDZ and all on UST seroconverted; neutralizing antibody concentrations were higher with UST and VDZNot reportedShehab et al. 2021 [175]
BNT162b2 and ChAdOx1-S IBD (n = 2977)69% receiving anti-TNF and 31% anti-integrin Five-fold reduction in humoral response with IFX vs. VDZ; more rapid decay in antibody levels in IFX-treated patientsNot reportedKennedy et al. 2021 [176]
Lin et al. 2021 [177]
BNT162b2 and ChAdOx1-S IBD (n = 28)
Healthy controls (n = 27)
32% receiving anti-TNF, 29% anti-IL-12/23, 11% anti-integrinComparable T-cell responses between IBD patients and healthy controlsNot reportedReuken et al. 2021 [178]
mRNA-1273, BNT162b2 and Ad26.COV2.S IBD (n = 303)35% receiving anti-TNF, 43% anti-IL-12/23 or anti-integrinPreserved T-cell clonal response with UST and VDZ and augmented by anti-TNFNot reportedLi et al. 2021 [179]
BNT162b2 IBD (n = 12,231) and matched patients (n = 36,254)11% receiving anti-TNF, 4% anti-integrin, and 2% anti-IL-12/23Similar risk of infection between controls and IBD patients, with no effect of immune-modifying therapiesNot reportedBen-Tov et al. 2021 [180]
mRNA-1273 and BNT162b2 IBD (n = 14,697)Not reportedTwo-dose vaccination reduced the hazard of infection by 69%, with an estimated efficacy of 80.4%Not reportedKhan et al. 2021 [181]
mRNA-1273 and BNT162b2 PsO (n = 50)100% receiving biologic therapyNot reportedAE similar to general populationMusumeci et al. 2021 [182]
mRNA-1273, BNT162b2 and Ad26.COV2.S IBD (n = 3316)46% receiving anti-TNF, 15% anti-IL-12/23, and 12% anti-integrinNot reportedLow rates (2%) of IBD flare following vaccination and relatively few vaccine-related AEsWeaver et al. 2021 [183]
mRNA-1273 and BNT162b2 IBD (n = 246)37% receiving anti-TNF, 17% anti-IL-12/23, and 13% anti-integrinNot reportedAE similar to general populationBotwin et al. 2021 [184]
mRNA-1273 and BNT162b2 IBD (n = 524)89% receiving biologic therapyNot reportedPost-vaccination symptoms after third dose are generally milder and less frequent than after second dose Li et al. 2021 [185]
AE, adverse event; CID, chronic inflammatory diseases; CTLA-4, cytotoxic T-lymphocyte-associated protein 4 fusion protein; IBD, inflammatory bowel disease; IFX, infliximab; IL, interleukin; IMID, immune-mediated inflammatory diseases; IMM, immunomodulator; IRD, inflammatory rheumatic diseases; JAKi, Janus kinase inhibitors; MTX, methotrexate; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; RTX, rituximab; SpA, spondyloarthritis; TNF, tumor necrosis factor; UST, ustekinumab; VDZ, vedolizumab. mRNA-1273 (Moderna, Cambridge, US), BNT162b2 (Pfizer-BioNTech, NYC, US), Ad26.COV2.S (Janssen, Beerse, Belgium), and ChAdOx1-S (AstraZeneca, Cambridge, UK).
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Garcillán, B.; Salavert, M.; Regueiro, J.R.; Díaz-Castroverde, S. Response to Vaccines in Patients with Immune-Mediated Inflammatory Diseases: A Narrative Review. Vaccines 2022, 10, 297.

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Garcillán B, Salavert M, Regueiro JR, Díaz-Castroverde S. Response to Vaccines in Patients with Immune-Mediated Inflammatory Diseases: A Narrative Review. Vaccines. 2022; 10(2):297.

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Garcillán, Beatriz, Miguel Salavert, José R. Regueiro, and Sabela Díaz-Castroverde. 2022. "Response to Vaccines in Patients with Immune-Mediated Inflammatory Diseases: A Narrative Review" Vaccines 10, no. 2: 297.

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