key: cord-0981941-5oxsu7p6 authors: Negahdaripour, Manica; Shafiekhani, Mojtaba; Moezzi, Seyed Mohammad Iman; Amiri, Sogand; Rasekh, Shiva; Bagheri, Ashkan; Mosaddeghi, Pouria; Vazin, Afsaneh title: Administration of COVID-19 vaccines in immunocompromised patients date: 2021-07-28 journal: Int Immunopharmacol DOI: 10.1016/j.intimp.2021.108021 sha: e1c2ffdf5f6c166b83c844273ac42d05874808f3 doc_id: 981941 cord_uid: 5oxsu7p6 Since the beginning of vaccination programs against COVID-19 in different countries, several populations such as patients with specific immunological conditions have been considered as the priorities for immunization. In this regard, patients with autoimmune diseases or those receiving immunosuppressive agents and anti-cancer therapies, need special attention. However, no confirmed data is presently available regarding COVID-19 vaccines in these populations due to exclusion from the conducted clinical trials. Given the probable suppression or over-activation of the immune system in such patients, reaching a consensus for their vaccination is critical, besides gathering data and conducting trials, which could probably clarify this matter in the future. In this review, besides a brief on the available COVID-19 vaccines, considerations and available knowledge about administering similar vaccines in patients with cancer, hematopoietic stem cell transplantation, solid organ transplantation, multiple sclerosis (MS), inflammatory bowel disease (IBD), and rheumatologic and dermatologic autoimmune disorders are summarized to help in decision making. As discussed, live-attenuated viruses, which should be avoided in these groups, are not employed in the present COVID-19 vaccines. Thus, the main concern regarding efficacy could be met using a potent COVID-19 vaccine. Moreover, the vaccination timing for maximum efficacy could be decided according to the patient’s condition, indicated medications, and the guides provided here. Post-vaccination monitoring is also advised to ensure an adequate immune response. Further studies in this area are urgently warranted. Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a disastrous pandemic since its first outbreak in Dec. 2019 [1] . Until July7, 2021, more than 184million people were infected by COVID-19 leading to over fourmillion deaths [2] . While vaccines and drugs are two arms in controlling the pandemic, from the beginning of the pandemic, many efforts have been devoted to the development of both solutions [3, 4] , especially safe and effective vaccines as one of the most reliable interventions to suppress viraltransmission [5] . Presently, several vaccines are available worldwide with different platforms, administration schedules, and efficacies. However, the race is being continued with many other vaccines under evaluationin different clinical trial phases, which can boost the vaccination process if approved, especially those that are already in phase 3 (All vaccines in phase 3 and 4 clinical trials are summarized in Table 1 ). In the United States, three COVID-19 vaccines are authorized for emergency use, namely Pfizer-BioNTech, Moderna, and Janssen vaccines, which are all non-living vaccines.Pfizer-BioNTech and Moderna vaccines are nucleoside-modified mRNA vaccines. and the Janssen vaccine is a recombinant replication-incompetent adenovirus type26 (Ad26) [6] . In Britain, the United Kingdom Medicines and Healthcare Products Regulatory Agency approved the Oxford-AstraZeneca vaccine, which is a recombinant replication-incompetent chimpanzee adenovirus vector encoding SARS-CoV-2 spike (S) protein [7] . Two other adenovirus vector vaccines are produced in Russia and China named Sputnik V ® and CoronaVac ® , respectively, which are authorized by their origin countries [8, 9] and are being used in some other parts of the world as well. Considering the importance of vaccination tocontrol the pandemic, immunizationof special subgroups such as elderlies and patients with chronic diseases, is of highimportance. It is proven that theincidence ofsevere COVID-19 is much more in individuals with underlying comorbidities [10, 11] . Given this, patients with specific immunological deficits,such as patients with autoimmune diseasesor those receiving immunosuppressive oranti-cancer agents, need special attention. Besides, vaccination in these patients is somehow problematic due to the probable suppression or over-activation of the immune system.Despite a vast number of conducted studies in regards to vaccination and the approval of several SARS-CoV-2 vaccines, such special patientgroups were excluded in the performed trials. Hence, there remain questions about the efficacy and safety of vaccination in immunocompromised patients, and the lack of data to evaluate the risk/benefit balance of vaccination in thesegroups makes decision-making difficult. In light of these problems, formulating an effective and safe vaccination program for patients with immunological diseases requires attention and further investigations in this field. In this study, we tried to collect the presently published data on COVID-19 vaccination in immunocompromised patients and the recommendations from different societies so far to suggest some advice for safe and efficient vaccination in this population. As a pathogen enters the body, both innate and adaptive immunitiesare activatedin order to eliminate the pathogen. If the immune system cannot act efficiently against pathogens,an illness appears. The innate immunity provides a fast and non-specific response,whilethe adaptive immunity responses are slow, pathogen-specific, and long-lasting. With this aim, helper T cells make B cells produce antibodies. Besides, cytotoxic T cells invade thecells infected by viruses and force them to die [12] . Although the above-mentioned general immunity procedure is usually induced against SARS-CoV-2, some defects might be caused by the virus in the immune system mechanism, such as interrupting the interferon signaling pathway [13] . Inactivated vaccines are a kind of whole-cell vaccines in which the pathogenic materials of the causing pathogen or a very similar one are destroyed by chemicals (such as formaldehyde or betapropiolactone), radiation, or heat. This demolishes the pathogen's ability to replicate while keepingits immunization potential [14] . Therefore, the organism cannot revertto a more pathogenic form, and the chance of interference is quite low [15] . Both neutralizing antibody (nAb) response and seroconversion have been observed in inactivated vaccines. Besides, it is shown that there would be a more potent response when the interval between two doses expands from 14 days to 21 days (increased seroconversion from 85.7% to 100%) [16, 17] . In general, these vaccines are quite safe and very stable and have shown good results in immunocompromised patients [18] . A downside ofinactivated vaccines is the high quantity of the immunogen requiredto reach an adequate antibody response. Additionally, they can create a substantial humoral response but only a slight cellular immunity [19] .Other drawbacks include major laboratory facilities needed to grow the pathogen [20] . Moreover, producing the vaccine on a large scale and the inactivation process can be time-consuming thereby limiting vaccine production and making difficultiesin developing vaccines with sufficient titers. Hence, due to the large amountsof vaccine required to evoke sufficient antibody response, the cost might increase drastically. Besides, the physical or chemical methods used to inactivate the pathogen could weaken its immunogenicity due to altering the DNA sequence, capsid, and protein structure [21] .Ingeneral,these changes might diminish the expected cell-mediated and mucosal immune responses, which could decrease the spectrum and effectiveness of the vaccine [15] . However, utilizing two or three booster doses can help to maintain adequate immunity in long term [18] , and adding adjuvants such as aluminum or MF59 can help improve cellular or humoral responses depending on the adjuvanttype [21, 22] . Sinovac ® containing the inactivated virus and aluminum as an adjuvant. After the second injection, high neutral antibodies can be seen in patients, but the T cell response is quite low. However, the added aluminum adjuvant can help to initiate a T-helper 2 response [23, 24] . Studies indicated that the level of post-injection neutral antibody decreasedwith aging.Thus,it is recommended to elevate the dosage in [25] . Subunit vaccines merely consist of the immunogenic proteins derived from a pathogen,which can stimulate the host's immune system. The proteins can be easily produced by recombinant DNA techniques.They have some other advantages due to their structure,such as lacking active pathogens and triggering a specific immune response against the main antigenic proteins or epitopes of the pathogen. These characteristics give rise to their high safety. However,they usually generate a weak immune response [26] due to mounting a poor innate immune response, inadequate activation of antigen-presenting cells (APCs), and limited stimulation of B cells and T cells [27] . Therefore, their immunogenicity needs to be enhanced by other strategies such as using adjuvants [4] , carriers, or nanotechnology approaches [26] .Moreover, multiple doses of this kind of vaccine are advised for long-lasting immunization. To overcome these limitations, an empty virus shell with coronavirus' structure was suggested. However, manufacturing of this structure is complicated [28] . In the case of SARS-CoV-2, the S protein and its fragments including S1, as well as the RBD (receptor-binding domain) and N (nucleocapsid) proteins are candidate for subunit vaccine development. Most of the in-development vaccines have employedRBD as the antigen, since immunization against it may protect the host cells from viralbinding to ACE2 and invasion into host cells [29] . As reported, an anti-SARS-CoV vaccine based on RBD antigen and alum had a high protective immune response, and interestingly, RBD vaccines could minimize the risk of host immunopotentiation [30, 31] . It was shown that protein subunit vaccines together with adjuvants generated a potent response against SARS-CoV-2. In the case of Novavax, nAbs were 100-times higher after the second dose and 4-times higher than symptomatic outpatients after 35 days [32] . DNA vaccines are produced byinsertingthe gene of an antigenic protein into a bacteria-derived plasmid and delivering it to the host cells. The protein-producing machinery of the host cell will translate DNA to mRNA and finally, a protein that can stimulate the immune system ( Figure 1 ). Formulation of these vaccines is designed to translocate the gene to host cells' nuclei. Though, some other methods such as electroporation, gene gun, and jet injection might be used to enhance DNA entry into cells [33] . APCs are among the most important recipients of DNA plasmids, which translate themto mRNA and protein. Myocytes and dendritic cells (DCs) are other recipients of these DNA plasmids. It is shown that DNA vaccines can activate both cellular and humoral immunity. This might be due to the cross-presentation of antigens on MHC-I and MHC-II and consequently, stimulation of both CD4 + and CD8 + T cells [34] . Moreover, some intrinsic factors such as non-methylated CpG sequences can activate the innate immunity and enhance the response of adaptiveimmunity to that specific antigen [35, 36] . Some advantages and disadvantages are already addressed for DNA vaccines. Broad immunity response in both humoral and cellular arms, no risk of pathogen replication, supporting multiple antigens in a single vaccine, low-cost and large-scale production, and high storage stability are some of the benefits of this vaccine platform [35] . On the other hand, some concerns are mentioned about DNA vaccines. There is a small risk of integration of the plasmid into the host chromosome, which should be considered specifically in the enhanced DNA uptake systems. Furthermore, the long-term persistence of these vaccines increases the risk of integration and the following threat of mutagenesis and oncogenesis. Besides, antibiotic resistance markers in vector plasmids had raised some concerns about antibiotic resistance, which has been replaced in the newer generation of DNA vaccines. Furthermore, some adjuvants employed in the formulation of these vaccinesto enhance vaccine immunogenicity,for example,pattern recognition protein (PRP) ligands and IL-12, may cause unintended adverse effects [33] . Among COVID-19 in-development vaccines, Inovio is a DNA vaccine whose intradermal injection would be followed by CELLECTRA ® electroporation [37] . However, this should be considered that electroporation device, as an essential step of administration of this vaccine, might not be available everywhere. A viral vector is a modified virus used as a means to deliver a target gene to the host cell. Advantages of viral vectors include efficient gene transduction and delivery of the gene to the target cells. Furthermore, they trigger a strong immune response including T cells and antibodies produced by B cells [44] .Data obtained from the AstraZeneca-Oxford clinical trials showed that vaccination led to both T cell responses and nAbs formation. The first dose caused the immunological memory and the second dose fixed it. T cells peaked in 28 days after the first dose and stayed elevated in the body for 56 days. The second dose could be administered 4-12 weeks after the first dose.Moreover, the second administration did not affect T cell elevation but could end in more nAb production. Trials have represented a relationship between dose intervals and nAb concentration. As the time gap between the first and second doses gets longer, more nAb responses would be observed [17, 45] . Due to strong immune responses, this type of vaccine usually does not need any additive adjuvants. However, in some vectors, adjuvants may be useful [46] . Moreover, designing, modifying, and large-scale manufacturing of adenovirus vaccines are easy [17, 38] mRNA vaccinesarea type of nucleic acid vaccines.Theyshould reach the ribosomes on the endoplasmic reticulum to be translated into specific proteinsthat could trigger the immune response in a patient. mRNA vaccinesareusually made of mRNA molecules encapsulated in lipid nanoparticles (LNP), as shown in Figure 1 . LNP facilitate mRNA penetration into the host cell so that the translation process can be initiated [49] .The cellular immune response is seen when the S proteins are presented to immune cells either by the MHC class I or II complex, activating both CD4 + and CD8 + cells. However, their main mechanism is activating the humoral immune response. When naïve B cells are activated due to their exposure to the S proteins, they start to proliferate and differentiate into either memory B cells or plasma cells with the ability to secret antibodies. Hence, when the virus carrying the antigen enters the body, the antibody will bind to the antigen, A significant disadvantage of these vaccines is their unstable nature therebyrequiring a storage temperature of -70 to -20 degrees, which can cause difficulties in theiraccessand distribution. Although, utilizing specific mutations of the gene and chemical stabilizers have allowed keeping the mRNA vaccines at a temperature between 2 to 8 degrees for a short period [49]. Generally, live-attenuated vaccines are not usually recommended in primary or acquired immunodeficient patients because of the risk of infection development by the live pathogens present in the vaccine [74] . Live-attenuated vaccines are not currently under development or approved for COVID-19. However, almost all other types of vaccines are found in the list of approved or understudy vaccines (Table 1) . Numerous studies imply that cancer patients are at a greater risk of developing severe COVID-19. Patients who are on targeted therapies, such as tyrosine kinase inhibitors, could produce seroprotection against the influenza vaccine, which was comparable to healthy individuals [78] . Controversially, 7-26% of patients on ibrutinib had impaired response and experienced seroconversion following an influenza vaccine, while about 75% of patients could respond to the varicella-zoster virus (VZV) subunit vaccine [79, 80] . However, it seems that patients with cancer thatare receivingtargeted therapies can still produce enough immune response against vaccines Plasma-cell-depleting and lymphodepleting therapies, such as anti-CD20 and anti-CD38 monoclonal antibodies, reducedthe peripheral B cells for at least four months [81] . During this period, immunization with influenza, Streptococcus pneumonia, and Haemophilus influenza vaccines was impaired [82] . This suggests that patients on these medications have to postpone the vaccination for at least six months after anti-B cell therapies [83] . It should be noted that these patients are at an even higher risk for disease severity, long-time viral shedding, and death [84, 85] . On the other hand, it is also proposed that since vaccines produce stronger immune responses than SARS-CoV-2 infection itself, the possible importance of strong T cell protective immunity has to be considered as well [86] . For patients who are on immune checkpoint inhibitors (ICIs), one expects that a proper immune response would be produced, but there is a concern for immune-related adverse effects (IRAEs). IRAEs are ICI-related toxicities that are due to unintended activation of the immune system. IRAEs may occur in every organ system, but the most affected organs are the skin, gastrointestinal system/liver, endocrine, and pulmonary systems. The symptoms of IRAEs are different depending on the affected organ. Dermatologic toxicity symptoms vary from dry mouth, rash, pruritis, and mucositis to Steven-Johnson syndrome. Diarrhea, colitis, pancreatitis, and hepatitis are examples of the GI symptoms. Pulmonary symptoms include pneumonitis, sarcoidosis, and pleural effusion [87] .One study showed a great risk of IRAE in patients receiving ICIs after influenza vaccination [88] . Although, three other similar studies did not show such effects [89] . Moreover, it seems that radiotherapy could not completely impair the immune system and consequent ineffectiveness of vaccine immunization. As a result, vaccination in patients onradiotherapy could be safe [41] . COVID-19 prognosis is poor in patients receiving hematopoietic stem cell transplantation (HSCT) [90] . The 30-days overall survival for HSCT recipients was about 67% [91] . HSCT recipients should be considered as newborns, since they are immunologically naive. It is suggested that recognizing new antigens and producing an immune response would take 6-12 months in these patients. The immune response to vaccines in these patients depends on the age ofvaccination, the type of vaccine, and confrontation with the pathogen before or after HSCT [92, 93] . There are different recommendations for post-HSCT vaccination based on the type of vaccine. Inactivated vaccines should be administrated six months after HSCT. For example, inactivated trivalent influenza vaccine should be used six months after transplantation [94] . Guidelines recommend that the influenza vaccines could be administered four months after HSCT in epidemiological conditions, and a second dose should be given four weeks later. Live-attenuated vaccines are not recommended and if necessary should be administered at least 24 months after HSCT in patients who did not have graft versus host disease (GVHD) and took no immunosuppressive drugs in the last three months [94] . As an instance, live-attenuated influenza vaccines are contraindicated in HSCT recipients [95] . The trial studies regarding the effectiveness or safety of COVID-19 vaccines in cancer patients are rare, but there is one published clinical trial on the effect of COVID-19 vaccines in cancer patients. The authors showed that administration of one dose of Pfizer-BioNTech vaccine in patients with cancer was well tolerated even in those who were under immunotherapy; though, the immune response was improper at least for five weeks. Data declared that the IgG response against SARS-CoV-2 was 13% and 39% in hematologic and solid cancer patients, respectively, which is very low compared to healthy controls (97%). However, all immunological indices improved following the 21-day boost in these patients [96] . This indicates the important role of on-time second dose administration of COVID-19 vaccines in cancer patients, both for pandemic control and the individuals. Overall, most cancer treatments could not impair proper immune response against vaccines. Moreover, most patients with cancer who participated in a trial had a functional adaptive immunity during COVID-19 infection [97] . Although, the immune response might be weak in some cancer patients' subgroups including those who are on intensive immunosuppression or HSCT [98] . Furthermore, it should be considered that live vaccinesshould not be administered in patients on cytotoxic, lymphodepleting, or targeted therapies [99] . Giesen It is suggested that patients with advanced disease, particularly lung cancer, who can postpone their systematic treatment for one month and patients undergoing radical surgery whoare candidate for adjuvant systematic treatments should be vaccinated first [101] . It is proposed that the first dose of vaccine for radical surgery-undergoing patients is administered within 7-10 days after surgery.In breast cancer screening trials, due to the risk of transient lymphadenopathy after vaccination, screening examinations should be either before the first vaccine injection or 2-3 weeks after the second dose. Presently, revaccination after immunosuppressive therapies in those who received a vaccine previously is not recommended, but administration of booster doses might be helpful [102] . In another study, patients with active disease, hematologic malignancies, and recently diagnosed solid tumors were recommended as a priority for COVID-19 vaccination [98] . However, a clinical trial on using COVID-19 vaccines in patients with cancer is presently recruiting (NCT04715438), which can shed light on more details about vaccination in these patients [103] . It seems that vaccination in all cancer patients is safe, effective, and recommended, except for those who are on anti-B cell therapies, for whom a 4-6 months interval is needed after medication. It is important to complete the vaccination schedule. All types of vaccines are safe and effective in these patients, except live-attenuated vaccines.Additional data on the efficacy of the Pfizer-BioNTech vaccine has been presented. Solid organ transplant (SOT) recipients are at ahigher risk of severeCOVID-19 due to the immunosuppression needed foravoiding graft rejection [104] . Furthermore, it seems these patients experience prolonged SARS-CoV-2 shedding due to corticosteroid usage, which has been linked to the emergence of viral mutants [105, 106] . Therefore, vaccination is a crucial intervention to prevent infections and their resultant morbidity and mortality. However, the safety, efficacy, magnitude, and duration of SARS-CoV-2 vaccine response in SOT recipients are unknown because these groups have beenexcluded from the COVID-19 vaccine trials till now. Previous studies reported lower antibody titers in immunosuppressed SOT recipients than the general populations following influenza, hepatitis A and B virus, and pneumococcal vaccinations [107, 108] .Taking immunosuppressive medications as well as an underlying chronic disease may weaken the immune reaction of these patients to immunization.A meta-analysis showed a substantially decreased response rate following seasonal influenza vaccination in transplant recipients receiving antimetabolites such as mycophenolate mofetil (MMF) [109] .Another concern about the effectiveness of COVID-19 vaccines is the anti-CD20-based immunosuppressive regimen in transplant patients. Rituximab depletes naive B cells and impairs humoral immunity [110] .In a study on early influenza vaccination (4-8 weeks) versus late vaccination (6-10 months) following rituximab, the early vaccination group did not exhibit IgM or IgG responses, while a significant IgG response (2.82-fold) was observed in patients receiving the vaccine 6-10 months after rituximab usage in rheumatoid arthritis [111] . Therefore, some studies recommend a few months' interval between rituximab administration and vaccination [112] [113] [114] suggested that vaccination could be done prior to transplantation or be delayeduntil three to six months later than transplantation, when the intensity of immunosuppression reaches its lowest level [115, 116] . There are also some important issues in regards to the safety of the COVID-19 vaccines among SOT recipients. First, historically, vaccines seem to be able to induce donor-specific and nondonor-specific antibodies but have not been associated with graft rejection in SOT recipients [117] .In this regard, the results of theBoyarsky et al. study also showed no cases of acute rejection or allograft dysfunction following SARS-CoV-2 mRNA vaccination of SOT patients [118] .Considering that some SARS-CoV-2 vaccine platforms employing protein-based structures and adjuvants have not been widely studiedin transplant recipients, theoretical concerns for possible graft rejectionwere also raised, which need further studies [119] . Secondly, liveattenuated virus vaccines are usually contraindicated in SOT recipients due tothe risk of disseminated infection [120] . Presently, no approved or in-Phase-3-trial SARS-CoV-2 vaccine is available that employs an attenuated live virus platform; though, if such a vaccine is approved, it could be suitable just for some non-immunocompromised pre-transplant patients who are stable on the waitlist. Thirdly, with increasing vaccination rates around the world, some misleading information and concerns about SARS-CoV-2 vaccines are spreading, especially on social media. Some people suspect that the recently approved mRNA SARS-CoV-2 vaccines can integrate into thehuman genome and induce genetic manipulation [121] ;while the reality is that mRNA cannot replicate or integrate into the human genome, as mRNAwould be degraded following translation.Moreover, some individuals are worried about the viral vector vaccines to induce viral infections, especially in immunocompromised patients, but theCOVID-19 (chimpanzee) adenoviral vector vaccine (ChAdOx1-nCoV-19) is replication-incompetent, which is encouraging when considering vaccination of the immunocompromised transplant recipient [122] . Although concludingtherecommendations regarding vaccination among SOT patients is still early, and we should wait for the results of ongoing studies in this field, according to the published guidelines so far [112, 115, 116] , the following points can be mentioned: 1-All healthcare workers and household members who care for these patients should be prioritized for COVID-19 vaccination. 2-SOT candidates should get vaccinated against COVID-19 before transplantation whenever possible to support a proper immune response.The best time for COVID-19 vaccine indication in the post-transplantation period is probably a minimumof three months after transplantation when immunosuppression is diminished and other prophylactic medications are reduced. episodes are resolved, and corticosteroid high dose usage is not required anymore. 4-Toinduce a better immune response, waiting for six weeks after the transplantation surgery is recommended before injection of the second dose of the vaccine. 6-For SOT patients who received anti-CD20 monoclonal antibody, six months interval betweenthe last rituximab dose and COVID-19 vaccination is recommended. SOT candidates should get vaccinated against COVID-19 before transplantation. The best time for vaccination is probably minimum three months after transplantation when ACR is not presented. Multiple Sclerosis (MS) is defined as a chronic immune-mediated inflammatory disease, which causes demyelination and neurodegeneration in the central nervous system (CNS) and has become a concerning issue in the COVID-19 pandemic [123] . MS is usually associated with other health issues. The treatments used in MSpatients can affect their immune response even in mild infections due to the immunomodulatory and immunosuppressive properties of the drugs. Therefore, temporary exacerbation or even relapse and progression of MS in COVID-19 infection should be considered. Furthermore, studies showed that age, obesity [127] , and increased disability were related to severe clinical indications and even death [128, 129] . Shreds of evidence indicated that infectious diseases, especially infections in the upper respiratory tracts,were correlated with MS progression and relapse. It was revealed that about 30-40% of MS patients experienced post-upper respiratory infection relapse; though, the mechanism is still unknown [130] . Even, cases displaying exacerbation, progression, and demyelination observed by MRI were reported during COVID-19 infection. This highlights the importance of vaccinating MS patients and paying special attention to them withfollowing valid guidelines [131] . Vaccination can be an effective way to prevent infections, but MS patients may not display the anticipated immunization response because of administering immunomodulatory and immunosuppressive therapies. Moreover, discontinuing the routine therapeutic regimen for vaccination could cause progression and relapse, which needs to be taken into consideration [132, 133] . Three main questions need to be asked regarding the vaccination of MS patients: Thus, today there is no reliable proof of a connection between vaccination and relapse or progression in MS patients [134] . 2. Regarding vaccine efficacy, especially in patients using therapies such as immunomodulatory and immunosuppressive drugs, a post-vaccination checkup is necessary forMS patients to make sure that the immunization has occurred properly [132] . If an adequate response isnot seen, it is recommended to add another booster vaccine [135] . 3. Because COVID-19 vaccination is still at its early stages, there are not many reports on vaccinating patients with MS. Moreover, there is not much information on the interaction between COVID-19 vaccines and therapies used in MS patients or the measures that need to be taken to maximize vaccine efficacy and safety. But, in a recent study discussing the relationship between different medications used in MS and COVID-19, mRNA vaccines including Moderna and Pfizer-BioNTech vaccines, the following points were concluded [132] : -Patients using ß-interferons, teriflunomide, natalizumab, glatiramer acetate, or dimethyl fumarate probably have no issues regarding vaccinesafety and efficacy. Thus, the vaccine could be administered at any given time [136] . -In patients using fingolimod, alemtuzumab, ocrelizumab, rituximab, or oral cladribine, there is a possibility of insufficient response to the vaccine [137] .In particular, an inadequate response to the Pfizer-BioNTech COVID-19 mRNA vaccine was reported in a 52-year-old patient with relapsing-remitting MS using ocrelizumab (a B-cell-depleting therapy) probably due to vaccinationless than two weeks after the last ocrelizumab infusion [138] . Itproves the importance of post-vaccination monitoring and choosing the right time for vaccination to maximize the efficacy, considering the patient's therapeutic regimen. For instance, it was suggested to vaccinate patients starting B-cell-depleting therapies, such as ocrelizumab or rituximab, 4-6 weeks before their first dose. If the patient has started therapy, the best vaccination time is 4-6 months after the last infusion [139, 140] . In the case of alemtuzumab, if the medicine has been used in the last 12-24 months, a reduction in the vaccine efficacy may happen. Thus, it is recommended to postpone the treatment until vaccination is completed [141] . -In patients on immunosuppressive treatments,such as mitoxantrone, cyclophosphamide, azathioprine, and methotrexate, vaccination is probably safe, but proper immunization might not occur. Regarding high dose corticosteroid therapy, the golden time of vaccine administration is 4-6 weeks following the last corticosteroid therapy to achieve optimal immunization [132, 142] . Vaccination is recommended in all MS patients without discontinuing their disease-modifying therapies, which could increase the risk of relapse and progression. Right timing is of great importance to maximize efficacy and immunization, especially in patients using high-dose corticosteroids and B cell-depleting therapies such as rituximab and ocrelizumab. Ulcerative colitis (UC) and Crohn's disease (CD)are two types of inflammatory bowel diseases(IBD) in which the immune response ofthe gastrointestinalsystemis dysregulated [143] . As COVID-19 has become a global issue, a concern about the susceptibility and increasedriskof COVID-19infectionin IBD patients due to immunosuppressive, immunomodulatory, or biological treatments has been raised. Studies have shown thatpotential risk factors for SARS-CoV-2 infection include age, nutritional status, high comorbidities,andIBD activity [144] .Some studiesdemonstratedno association between IBD treatments and COVID-19 severe infection or mortality [145, 146] . On the other hand, inthe SECURE-IBDclinical trial,theuse of systemic corticosteroids and sulfasalazine wasshown as serious risk factors for poor clinicaloutcomes in COVID-19 patients [147, 148] . Moreover, in the cohort study of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD), UC diagnosiswas shown asa risk factorforCOVID-19 infection [146] .Additionallyin a recent report,vitamin D deficiencywas mentioned tobe probably related to the severity or increased risk ofCOVID-19in patients with IBD [149] . Based on the recentdata, IBD patients presented high GI symptoms such as diarrheabecause ofCOVID-19 infection [150] . As a result,the impact of IBD onthe risk ofCOVID-19 infection is controversial.Despite the abovementioned information,there is no solid evidence indicatingthat IBD patientsareat a higher risk of COVID-19 infection.Moreover,manystudiesdeclaredno significant difference between the incidenceandmortality of COVID-19 in IBD patients and the general population [145, 150] . Considering the importance of vaccination to protect against COVID-19, the safety, adverse effects, and immunogenicity of vaccines in immunosuppressed patients such as individuals with IBDhavebeen the subject ofdebate. Due to the exclusion of IBD patients from the third phase of clinical trials for approved vaccines, there is a lack of data regarding vaccination benefits, side effects, and the risk of disease activation. Nevertheless, these vaccines are not contraindicated for people with IBD [151] . Based on previous experiences in vaccinating IBD patients for infectious diseases such as pneumococcus,hepatitis A virus (HAV), HBV, and influenza, it is possible to conclude that immunosuppressive treatments can impair the immune reaction to vaccines and diminish the immunization process efficacy. However, administration of the mentioned vaccines in IBD patients has a low risk [151] .Moreover, the vaccination of patients with active IBD might be impaired due to concurrent anemia [152] . Although less immune response might be observed in IBD patients, non-live vaccines are generally safe, and most of them are recommended for these patients [153] . However, there is a concern about the safety of live-attenuated and inactivated vaccines as well asreplicating vaccines that may make trouble in immunosuppressed individuals [153, 154] . In this context, vaccines using adenoviruses as vectors such as the AstraZeneca-Oxford vaccine seemappropriate in IBD patients, because they provoke the immune system without integrating the viral genome into the hosts' DNA. Thus, they are highly capable of producing a proper immune response [154] . Regarding the interaction between IBD treatment and vaccination, studies indicated that patients using anti-TNFα drugs, such as infliximab and adalimumab, displayed impaired immune response and reduced antibody titers to influenza [155] , HBV [156] , and pneumococcal vaccines [157] . Treatment with vedolizumab was associated with reduced efficacy of oral cholera vaccine; but, it did not impede influenza vaccination [158] .Hence, it may pertain to the mucosal vaccine delivery, which should be taken into account for some in-development SARS-CoV-2 vaccines [153] . The British Society of Gastroenterology (BSG) published a set of recommendations on COVID-19 vaccination of IBD patients. According to BSG,patients with IBD should receive vaccination as soon as possible irrespective of the medication used, even in patients with active IBD. However, in patients with severe IBD flares or those who need hospitalization, a delay in vaccination is preferred to help them recover and be prepared for the vaccine injection. Additionally, IBD patients should receive both doses of the COVID-19 vaccines [151] . Moreover, based on the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) international consensus meeting, the following statements should be considered: -There is no association between vaccination and the onset, flares, and exacerbation of IBD. -IBD patients can receive non-live SARS-CoV-2 vaccines regardless of their immunemodifying treatments. -mRNA, replication-incompetent vector, inactivated, and recombinant SARS-CoV-2 vaccines are safe for IBD patients. -Live-attenuated COVID-19 vaccines are not safe in patients receiving immune-modifying medications or those going to receive such therapies in the next eight weeks. -Immune-modifying medications taken by people with IBD should not force them to postpone getting the vaccine [153] . Due to the reduction of vaccine efficacy in patients receiving systemic corticosteroids, it is recommended to vaccinate IBD patients when the dose of corticosteroids is at their lowest level [151] . The CLARITY IBD study indicated that antibody responses after the first dose of vaccine in patients treated with infliximab were lower than vedolizumab. This data was obtained following administration ofPfizer-BioNTech and AstraZenecavaccines. Furthermore after two doses, there was inadequate antibody response in 18% of patients who used infliximab and 8% of those administered vedolizumab [159] . Even though, patients taking infliximab should not postpone receiving their second dose of vaccine [160] . In patients with IBD, vaccination is suggested as soon as possible.Non-live vaccines are safe in such patients. However, in patients with severe IBD flares or those who need hospitalization, a delay in vaccination is preferred. It is recommended to get a vaccine when they take the lowest dose of corticosteroid medications. Patients with rheumatic diseases have been found to be at an increased risk of infection due to the underlying inflammation and use of immunomodulatory drugs+ [161] . Moreover, a higher risk of COVID-19 morbidity and mortality might be possible due to the comorbidities present in rheumatic disease patients [162] . showed no relapse or flare-up of the underlying rheumatic condition, although data is still limited [72] .Though, there is a slight probability for disease flares after vaccination [164] .Subjects with rheumatic diseases were excluded from Moderna vaccine clinical trials [70] , and probably none has been included in the clinical trials of the Janssen vaccine [165] . Vaccination against COVID-19 in subjects with an underlying rheumatic disease as a part of vulnerable subject groups has been highly recommended by the United States Center for Disease Control and Prevention (US CDC) [6] , the British Society of Rheumatology (BSR) [166] , and the American College of Rheumatology (ACR) [167] in spite of probable adverse effects following vaccination.In this context, vaccination in rheumatic disease subjects during the quiescent state of the disease is highly recommended as is the case for other vaccines in such patients [168, 169] .While in subjects with active rheumatic diseases, data is still limited regarding vaccine immunogenicity despite studies showing no evident correlation between the immunogenicity of vaccines and the state of the underlying rheumatic disease such as juvenile systemic lupus erythematosus (SLE) [170] . Another burning question in this matter is whether to continue or discontinue pharmacologic therapies in rheumatic disease patients respective to SARS-CoV-2 vaccine administration. A metaanalysis in 2018 indicated that the use of methotrexate had no significant effect on influenza vaccine immunogenicity while diminishing immunogenicity was conveyed by the pneumococcal vaccine [171] . Moreover, it was shown that discontinuation of methotrexate for two weeks before seasonal influenza vaccine administration and two weeks after that,improved the achieved immunogenicity [114, 172, 173] .Rituximab use was shown to suppress humoral immunity as opposed to cellular immunity, following the reduction of nAbs [174] . Thus, the timing of rituximab use is critical in achieving better vaccine immunogenicity [171] . In light of these findings, in vaccinated subjects, rituximabusage is recommended to be started a few weeks after vaccine administration [114, 175, 176] . Moreover, ACR and European League against Rheumatism (EULAR) have recommended the administration of pneumococcal and seasonal influenza vaccines at least six months after the last rituximab dose administration [169, 177] . In a recent update on the COVID-19 vaccination guide, BSR has advised all rheumatic disease patients to receive Medicines and Healthcare products Regulatory Agency (MHRA) approved vaccines (Pfizer-BioNTech and Oxford-AstraZeneca) but suggests that administration of rituximab in these subjects begin with at least two weeks' lay off from vaccination.Italso advises in favor of completing the two-dose vaccination before induction of immunosuppression with rituximab to achievemaximum vaccine immunogenicity.Although, administration of rituximab should not be delayed in cases with severe organ-threatening states, and vaccination should be carried out along with the use of rituximab. Additionally, in patients with rheumatic diseases, an alternative therapy should be considered instead of rituximab, if the use of DMARDs or other biological treatments is needed,noting thattreatment with other agents is appropriate and available [166] . Similarly, the continuation of other immunosuppressive drugs has been recommended along with vaccine administration [178] [179] [180] . The use of TNFα inhibitors and IL-17 inhibitors also wasshown to have minimal effect on vaccine efficacy, while data regarding the effect of abatacept on vaccine efficacy is still limited [181] . Overall, further studies should be carried out regarding the efficacy and safety of COVID-19 vaccination along with the use of DMARDs in rheumatic disease patients [182] . Given that some autoimmune dermatologic diseases, such as psoriasis and lupus, are the result of disorders in the immune system activity and inflammatory conditions, they can be regarded assimilar to rheumatologic diseases in respectto vaccination considerations (as in Table 2 ). Rheumatologicpatients should be vaccinated as soon as possible, and mRNA vaccines seem to be safe in this group. A two-week gap of methotrexate administration before and after vaccination is recommended. It is recommended to consider at least two weeks' lay off from vaccination for rituximab use or to change the medication to other DMARDs. Based on the available data, patients with immunosuppressive diseases or patients on immunosuppressive medications are prioritized to receive current COVID-19vaccines, besides following general precautions such as social distancing and using masks, to prevent COVID -19 infection. There is a paradox between this subject and the fact that immunocompromised patients were excluded in the main conducted trials of these vaccines,whichare already published. Therefore, coming to a consensus for the administration of vaccines to this population is very critical, while gathering data and conducting trials that can clarify the outcomes and conditions is also an urgent need. Though the suitability of new COVID-19 vaccines such as mRNA or viralvectored vaccines for these patients is unknown,choosing an effectiveprophylactic COVID-19 vaccineand avoiding live-attenuated vaccines are recommended. Since there is no live-attenuated vaccine available or understudy for COVID-19, all available vaccines could be regarded as almost safe. On the other hand, the efficacy would be the main concern, because the immunosuppressive medications may impair the response to vaccines. Hence, decision on delaying immunosuppressive therapy because ofCOVID-19 vaccination will need to be evaluated and discussed taking into account the prescribed medications and condition of each patient. With time, dedicated COVID-19 vaccine studies on patients with immunosuppressive diseases or thosewho take immunosuppressants will reveal the pros and cons of vaccination in this heterogeneous population. Not applicable. The battle against COVID-19: where do we stand now? Iranian journal of medical sciences World Health Organization, WHO Coronavirus (COVID-19) Dashboard Immunotherapeutic approaches to curtail COVID-19 Harnessing self-assembled peptide nanoparticles in epitope vaccine design COVID-19 Vaccine Global Access Is an Urgency Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. The Lancet Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. The Lancet infectious diseases Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area Characteristics of hospitalized adults with COVID-19 in an integrated health care system in California Immune response in COVID-19: A review Interferon-inducer antivirals: Potential candidates to combat COVID-19 SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. npj Vaccines Vaccines for Biodefense and Emerging and Neglected Diseases Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of 2 randomized clinical trials A Review of the Progress and Challenges of Developing a Vaccine for COVID-19 Fenner and white's medical virology World Health Organization, The different types of COVID-19 vaccines Vaccine Adjuvants: from 1920 to 2015 and Beyond. Vaccines Different T helper cell subsets elicited in mice utilizing two different adjuvant vehicles: the role of endogenous interleukin 1 in proliferative responses COVID-19 vaccines for patients with cancer: benefits likely outweigh risks A Review of the Progress and Challenges of Developing a Vaccine for COVID-19 Immunogenicity and safety of a SARS-CoV-2 inactivated vaccine in healthy adults aged 18-59 years: report of the randomized, double-blind, and placebo-controlled phase 2 clinical trial. medrxiv COVID-19 vaccines for patients with cancer: benefits likely outweigh risks Frontrunners in the race to develop a SARS-CoV-2 vaccine SARS-CoV-2 vaccines and autoimmune diseases amidst the COVID-19 crisis A review on Promising vaccine development progress for COVID-19 disease. Vacunas Roadmap to developing a recombinant coronavirus S protein receptor-binding domain vaccine for severe acute respiratory syndrome. Expert review of vaccines The SARS-CoV-2 Vaccine Pipeline: an Overview Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine New Vaccine Technologies to Combat Outbreak Situations DNA vaccines-how far from clinical use? International journal of molecular sciences DNA vaccines against COVID-19: Perspectives and challenges Double-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial to Evaluate the Efficacy and Safety of treating Healthcare Professionals with the Adsorbed COVID-19 (Inactivated) Vaccine Manufactured by Sinovac-PROFISCOV: A structured summary of a study protocol for a randomised controlled trial Efficacy and safety of a COVID-19 inactivated vaccine in healthcare professionals in Brazil: the PROFISCOV study Interim report: Safety and immunogenicity of an inactivated vaccine against SARS-CoV-2 in healthy chilean adults in a phase 3 clinical trial. medRxiv An in-depth investigation of the safety and immunogenicity of an inactivated SARS-CoV-2 vaccine. medRxiv The safety and immunogenicity of an inactivated SARS-CoV-2 vaccine in Chinese adults aged 18-59 years: A phase I randomized, double-blinded Safety and immunogenicity clinical trial of an inactivated SARS-CoV-2 vaccine, BBV152 (a phase 2, double-blind, randomised controlled trial) and the persistence of immune responses from a phase 1 follow-up report. medRxiv Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. The Lancet Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebocontrolled, phase 2 trial. The Lancet Safety and efficacy of single-dose Ad26. COV2. S vaccine against Covid-19 Interim Report of a Phase 2 Randomized Trial of a Plant-Produced Virus-Like Particle Vaccine for Covid-19 in Healthy Adults Aged 18-64 and Older Adults Aged 65 and Older. medRxiv Efficacy of the NVX-CoV2373 Covid-19 Vaccine Against the B. 1.1. 7 Variant. medRxiv Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials. The Lancet Infectious Diseases Safety and immunogenicity of INO-4800 DNA vaccine against SARS-CoV-2: a preliminary report of a randomized, blinded, placebo-controlled, Phase 2 clinical trial in adults at high risk of viral exposure. medRxiv Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine Effective and safe immunizations with live-attenuated vaccines for children after living donor liver transplantation. Vaccine Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. The Lancet Hepatitis B vaccination in acute lymphoblastic leukemia Antibody titers and immune response to diphtheria-tetanus-pertussis and measles-mumps-rubella vaccination in children treated for acute lymphoblastic leukemia Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination Short term results of vaccination with adjuvanted recombinant varicella zoster glycoprotein E during initial BTK inhibitor therapy for CLL or lymphoplasmacytic lymphoma Seasonal influenza vaccination in patients with chronic lymphocytic leukemia treated with ibrutinib Robust memory responses against influenza vaccination in pemphigus patients previously treated with rituximab The effect of rituximab on vaccine responses in patients with immune thrombocytopenia Anti-infective vaccination strategies in patients with hematologic malignancies or solid tumors-Guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) High rates of severe disease and death due to SARS-CoV-2 infection in rheumatic disease patients treated with rituximab: a descriptive study Biologics increase the risk of SARS-CoV-2 infection and hospitalization, but not ICU admission and death: real-life data from a large cohort during red-zone declaration while Vaccine Supply Is Limited Immune-Related Adverse Events (irAEs): Diagnosis, Management, and Clinical Pearls Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events On the use of immune checkpoint inhibitors in patients with viral infections including COVID-19 A rationale to prioritise vaccination of HSCT patients against COVID-19. The Lancet. Haematology Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study. The Lancet Haematology Vaccination of hematopoietic cell transplant recipients. Bone marrow transplantation Immune reconstitution following hematopoietic cell transplantation Current issues in vaccines for adult patients with hematologic malignancies Vaccination of the stem cell transplant recipient and the hematologic malignancy patient. Infectious Disease Clinics Interim results of the safety and immune-efficacy of 1 versus 2 doses of COVID-19 vaccine BNT162b2 for cancer patients in the context of the UK vaccine priority guidelines. medRxiv Adaptive immunity to SARS-CoV-2 in cancer patients: The CAPTURE study. medRxiv Update of the AGIHO guideline on evidence-based management of COVID-19 in cancer patients regarding diagnostics, viral shedding, vaccination and therapy Vaccination of patients with haematological malignancies who did not have transplantations: guidelines from the 2017 European Conference on Infections in Leukaemia COVID-19 vaccination: the VOICE for patients with cancer COVID Vaccination in Cancer Patients: What Vaccination Priority Strategies Should There Be? Frontiers in Oncology COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials COVID-19 vaccination: the VOICE for patients with cancer Coronavirus disease 2019 (COVID-19) and transplantation: Pharmacotherapeutic management of immunosuppression regimen Managing COVID-19 in renal transplant recipients: a review of recent literature and case supporting corticosteroid-sparing immunosuppression Impact of corticosteroids in COVID-19 outcomes: systematic review and metaanalysis A comprehensive review of immunization practices in solid organ transplant and hematopoietic stem cell transplant recipients Effectiveness of influenza vaccines in adults with chronic liver disease: a systematic review and meta-analysis A systematic review of safety and immunogenicity of influenza vaccination strategies in solid organ transplant recipients COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases Rituximab impairs immunoglobulin (Ig) M and IgG (subclass) responses after influenza vaccination in rheumatoid arthritis patients Recommendations for the use of COVID-19 vaccines in patients with immune-mediated kidney diseases Safety and immunogenicity of inactivated varicella-zoster virus vaccine in adults with hematologic malignancies receiving treatment with anti-CD20 monoclonal antibodies COVID-19 vaccination in immunocompromised patients EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients AASLD Expert Panel Consensus Statement: Vaccines to Prevent COVID-19 Infection in Patients with Liver Disease Does vaccination in solid-organ transplant recipients result in adverse immunologic sequelae? A systematic review and meta-analysis Safety of the first dose of SARS-CoV-2 vaccination in solid organ transplant recipients Alternative strategies of posttransplant influenza vaccination in adult solid organ transplant recipients Practice, Vaccination of solid organ transplant candidates and recipients: Guidelines from the American society of transplantation infectious diseases community of practice COVID-19 vaccination in our transplant recipients: The time is now Covid-19 vaccines: frequently asked questions and updated answers Multiple Sclerosis Pathology. Cold Spring Harbor Perspectives in Medicine COVID-19 in multiple sclerosis patients: susceptibility, severity risk factors and serological response Incidence and Impact of COVID-19 in MS Multiple sclerosis and COVID-19: how many are at risk? Multiple Sclerosis and SARS-CoV-2 Vaccination: Considerations for Immune-Depleting Therapies. Vaccines Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis Multiple sclerosis and COVID-19 Infection as an Environmental Trigger of Multiple Sclerosis Disease Exacerbation COVID-19 and Multiple Sclerosis: Predisposition and Precautions in Treatment. SN Comprehensive Clinical Medicine COVID-19 mRNA vaccines (Pfizer-BioNTech and Moderna) in patients with multiple sclerosis: a statement by a working group convened by the Section of Multiple Sclerosis and Neuroimmunology of the Polish Neurological Society Vaccines and multiple sclerosis: a systematic review Vaccination in Multiple Sclerosis: Friend or Foe? Frontiers in Immunology Potential Risks and Benefits of Multiple Sclerosis Immune Therapies in the COVID-19 Era: Clinical and Immunological Perspectives Risk factors for lymphopenia in patients with relapsing-remitting multiple sclerosis treated with dimethyl fumarate Multiple Sclerosis Disease-Modifying Therapy and the COVID-19 Pandemic: Implications on the Risk of Infection and Future Vaccination COVID-19 Vaccine Failure in a Patient with Multiple Sclerosis on Ocrelizumab. Vaccines B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran. Multiple Sclerosis and Related Disorders Multiple sclerosis, B cell therapy, and the COVID-19 vaccine. Eneurologicalsci Immune competence after alemtuzumab treatment of multiple sclerosis Effects of MS disease-modifying therapies on responses to vaccinations: A review. Multiple Sclerosis and Related Disorders British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic COVID-19 in IBD: The experience of a single tertiary IBD center Review article: prevention, diagnosis and management of COVID-19 in the IBD patient Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry A fatal case of COVID-19 pneumonia occurring in a patient with severe acute ulcerative colitis low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity novel coronavirus disease (COVID-19) in patients with inflammatory bowel diseases. Alimentary pharmacology & therapeutics 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 Iron deficiency anemia at time of vaccination predicts decreased vaccine response and iron supplementation at time of vaccination increases humoral vaccine response: a birth cohort study and a randomized trial follow-up study in Kenyan infants SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: recommendations from an international consensus meeting COVID-19 vaccinations in patients with inflammatory bowel disease Immunogenicity of influenza vaccine for patients with inflammatory bowel disease on maintenance infliximab therapy: a randomized trial Antibody response to hepatitis B virus vaccine is impaired in patients with inflammatory bowel disease on infliximab therapy Effects of immunosuppression on immune response to pneumococcal vaccine in inflammatory bowel disease: a prospective study. Inflammatory bowel diseases Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results SARS-CoV-2 Vaccination in Patients with Inflammatory Bowel Disease Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis & Rheumatism Temporal relationships between systemic lupus erythematosus and comorbidities Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physicianreported registry. Annals of the rheumatic diseases Immune-mediated disease flares or new-onset disease in 27 subjects following mRNA/DNA SARS-CoV-2 vaccination. Vaccines Vaccine for the Prevention of COVID-19 Principles for COVID-19 Vaccination in Musculoskeletal and Rheumatology for Clinicians American College of Rheumatology Guidance for COVID-19 Vaccination in Patients with Rheumatic and Musculoskeletal Diseases-Version 1 Italian recommendations for influenza and pneumococcal vaccination in adult patients with autoimmune rheumatic diseases update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Annals of the rheumatic diseases High disease activity: an independent factor for reduced immunogenicity of the pandemic influenza a vaccine in patients with juvenile systemic lupus erythematosus A systematic review and metaanalysis of antirheumatic drugs and vaccine immunogenicity in rheumatoid arthritis Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial Optimal time between the last methotrexate administration and seasonal influenza vaccination in rheumatoid arthritis: post hoc analysis of a randomised clinical trial. Annals of the rheumatic diseases cellular immune response to influenza vaccination is preserved in rheumatoid arthritis patients treated with rituximab. Vaccine Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial Vaccination guidelines for patients with immune-mediated disorders taking immunosuppressive therapies: executive summary. The Journal of rheumatology American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis & rheumatology Vaccination recommendations for adult patients with autoimmune inflammatory rheumatic diseases. Swiss medical weekly The Practice Guideline for Vaccinating Korean Patients with Autoimmune Inflammatory Rheumatic Disease Recommendations for COVID-19 Vaccination in People with Rheumatic Disease: Developed by the Singapore Chapter The effect of disease-modifying antirheumatic drugs on vaccine immunogenicity in adults Rheumatology and COVID-19 at 1 year: facing the unknowns The authors have no conflict of interest to declare.