key: cord-0750484-2q36qu4p authors: Mohseni Afshar, Zeinab; Babazadeh, Arefeh; Janbakhsh, Alireza; Mansouri, Feizollah; Sio, Terence T.; Sullman, Mark J. M.; Carson‐Chahhoud, Kristin; Hosseinzadeh, Rezvan; Barary, Mohammad; Ebrahimpour, Soheil title: Coronavirus disease 2019 (Covid‐19) vaccination recommendations in special populations and patients with existing comorbidities date: 2021-10-22 journal: Rev Med Virol DOI: 10.1002/rmv.2309 sha: d9fcb91be7b0a5da484e3b2409f3f65a6a2c99f6 doc_id: 750484 cord_uid: 2q36qu4p Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a crucial step in ending the current worldwide pandemic. However, several particularly vulnerable groups in the population were not included in sufficient numbers in coronavirus disease 2019 (Covid‐19) vaccine trials. Therefore, as science advances, the advice for vaccinating these special populations against Covid‐19 will continue to evolve. This focused review provides the latest recommendations and considerations for these special populations (i.e., patients with rheumatologic and autoimmune disorders, cancer, transplant recipients, chronic liver diseases, end‐stage renal disease, neurologic disorders, psychiatric disorders, diabetes mellitus, obesity, cardiovascular diseases, chronic obstructive pulmonary disease, human immunodeficiency virus, current smokers, pregnant and breastfeeding women, the elderly, children, and patients with allergic reactions) using the currently available research evidence. The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in many individuals becoming infected, more than four million deaths, and has placed an unprecedented burden on public health services worldwide. [1] [2] [3] Vaccinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a crucial step in ending the current worldwide pandemic. However, several particularly vulnerable groups in the population were not included in sufficient numbers in coronavirus disease 2019 (Covid- 19) vaccine trials. 4 Table 1 summarises the current Covid-19 vaccination recommendations in these special populations and patients with existing comorbidities. Therefore, as science advances, the advice for vaccinating these special populations against Covid-19 will continue to evolve. This focused review provides the latest recommendations and considerations for these special populations using available research evidence. Individuals on immunosuppressive therapies are among those most susceptible to Covid-19-related morbidity and mortality. Although vaccinating these populations should be a high priority for healthcare providers and governments, they have mostly been excluded from vaccine trials. 5 The most important reason behind such exclusions is that immunosuppressive therapies can impair the vaccine-induced humoral and cellular immune responses, making it difficult to measure its effectiveness on the immune system. 6 It is important to note that there are many such diseases, and we do not fully understand the pathogenesis of any of them. Thus, it is essential to consider the diseases and the treatments for them when considering vaccination. For example, does the disease or treatment suppress T cell or B cell responses, and will this differ according to the vaccine used? In the following section, we discuss the impact of several immunosuppressive agents on vaccine response. It is essential to know that some of the information has been generalised from experiences with influenza, pneumococcal, and tetanus vaccines. The effect of corticosteroids on vaccine-induced antibody production is dose-dependent. Prednisolone doses higher than 10 mg daily, or equivalent doses of other corticosteroids, impair vaccine response, and thus, tapering the dose around the time of vaccination would appear necessary. 7 Disease-modifying antirheumatic drugs (DMARDs) are agents used for decreasing inflammation in rheumatic disorders. Methotrexate (MTX), hydroxychloroquine, sulfasalazine, leflunomide, cyclophosphamide, mycophenolate, and azathioprine are examples of these agents. 8 All DMARDs can affect antibody responses, but none of them, except MTX and cyclophosphamide, lower immunologic responses below the threshold of seroprotection. 8 In addition, MTX suppresses humoral response by interacting with the B cell activation factor (BAFF). 9 Thus, it is reasonable to withhold MTX for at least two weeks before and after vaccination. However, withholding the medication for more than two weeks may lead to a flare-up in the underlying disease. 10 Thus, the timing of withholding medication should be carefully monitored to lower the risk of adverse events. Anti-tumour necrosis factors (TNFs) and interleukin (IL)-17 blockers seem to have no significant effect on vaccine-induced immunity unless used concurrently with MTX. 11,12 IL-6 inhibitors, such as tocilizumab (TCZ), seem to have no substantial effect on vaccineinduced seroprotection unless co-administered with MTX. 13 However, while some studies have reported there should be at least 12 weeks between tocilizumab administration and vaccination to have the ideal antibody response, 13 other research has shown that TCZ does not impair antibody production for other types of vaccines (not . 14 Information about the impact of IL-1 antagonists, including anakinra, and canakinumab, on vaccine-induced seroprotection, is scarce, and more studies are urgently needed. 15 Janus kinase (JAK) inhibitors, such as baricitinib and tofacitinib, might trigger drug interactions with mRNA vaccines, primarily when used concurrently with MTX. 16 Therefore, it is better to withhold JAK inhibitors for 1-2 weeks on either side of the vaccination date. 16 Anti-CD20 agents (e.g., rituximab) impair B cell production, making patients prone to severe forms of Covid-19. These agents are also believed to profoundly affect vaccine-induced antibody responses, even several months after their use. 17 Therefore, it is recommended that their use be limited only to essential cases or administered with a minimum gap of four weeks before and six months after vaccination. 17 The impact of T-cell lymphocyte activation inhibitors, such as abatacept (ABA), on vaccine-induced immunity, is controversial and more studies are needed to clarify any interactions. 18 In general, TNF inhibitors, such as TCZ, ABA, and IL-17 antagonists, seem to impact vaccine efficacy negatively. The Centers for Disease Control and Prevention (CDC) recommends at least a twoweek spacing between administration of these agents and vaccination. 14 Thus, the decision to vaccinate rheumatologic patients who use the medications mentioned above should be individually made since it appears that low-dose immunosuppressive agents do not significantly affect the vaccine-induced antibody response. 14 Overall, it appears best to vaccinate these patients when their underlying disease is under control. 14 It is also noteworthy that allergic reactions in these patients may happen following vaccination, especially in patients with systemic lupus erythematosus (SLE), necessitating a more extended period (at least 2 h) of monitoring following vaccination. 14 Another important consideration is the safety profile of the Covid-19 vaccines in rheumatology patients, which do not seem to be contraindicated since none of the treatments attenuate vaccines. 19 However, it is currently unknown whether Covid-19 vaccines can • Corticosteroids: Taper to <10 mg/day prior to vaccination. • MTX: Withhold 2 weeks before and after vaccination. • MTX: Withhold 2 weeks before and after vaccination. • Anti-TNF and IL-17 medications: No specific dose reduction is required. • Anti-TNF and IL-17: No specific dose reduction is required. • Anti-IL-6 medications: Vaccination should be 12 weeks before/after TCZ administration. • Anti-IL-6: Vaccination should be 12 weeks before/after TCZ administration. • JAK inhibitors: Withhold 1-2 weeks before and after vaccination. • JAK inhibitors: Withhold 1-2 weeks before and after vaccination. • Anti-CD20 medications: Withhold 4 weeks before until 6 months after vaccination. • Anti-CD20 medications: Withhold 4 weeks before until 6 months after vaccination. • ABA: Data are not yet available. • ABA: Data are not yet available. Cancer • Anti-CD20 or cytotoxic therapies inactivate the mRNA vaccine. • Cytotoxic chemotherapy: Start chemotherapy courses 2 weeks after vaccination. • Cytotoxic chemotherapy: 2 weeks after vaccination • If chemotherapy has already been given, vaccination should be given between courses of chemotherapy. • If chemotherapy is already initiated, vaccination should be given between courses of chemotherapy. • Lymphocyte or plasma cell-depleting regimens: Vaccination should be 2 weeks before or 3 months after the end of treatment. • Lymphocyte or plasma cell-depleting regimens: Vaccination should be 2 weeks before or 3 months after the end of treatment. Transplant patients • Vaccination is recommended early in the course of the underlying disease. • Vaccination is recommended early in the course of the underlying disease. • After transplantation, postpone vaccination for 3-6 months. • After transplantation, postpone vaccination for 3-6 months. • If the first dose is received before the transplantation, the second dose should be administered at least 4 weeks after transplantation • If the first dose is received before the transplantation, the second dose should be administered at least 4 weeks after transplantation • A third dose may be warranted for optimal immunity. • A third dose may be warranted for optimal immunity. CLD • Recommended, with priority given to patients with higher MELD scores. • Recommended, with priority given to patients with higher MELD scores. • Vaccination of patients with CLD undergoing treatment for HBV, HCV, PBC, and autoimmune hepatitis should be performed without discontinuing their therapy. • Vaccination of patients with CLD undergoing treatment for HBV, HCV, PBC, and autoimmune hepatitis should be performed without discontinuing their therapy. • Vaccination is safe and recommended for patients with HCC. • Vaccination is safe and recommended for patients with HCC. • Patients on the transplant list should receive two doses of the vaccine before the transplant. • Patients on the transplant list should receive two doses of the vaccine before the transplant. (Continues) MOHSENI AFSHAR ET AL. • If the patient received the first dose before the transplant, the next dose could be given to him/her at 6 weeks to 3 months after the transplant. • If the patient received the first dose before the transplant, the next dose could be given to him/her at 6 weeks to 3 months after the transplant. • Vaccination should be withheld in liver transplant recipients with active ACR or those receiving high-dose corticosteroids until the condition is resolved. • Vaccination should be withheld in liver transplant recipients with active ACR or those receiving high-dose corticosteroids until the condition is resolved. • Taper steroid doses below 20 mg prednisone equivalent daily before vaccination. • Taper steroid doses below 20 mg prednisone equivalent daily before vaccination. • If the patient received anti-CD20 medication, vaccination should be delayed for at least 6 months after the last dose of the therapy. • If the patient received anti-CD20 medication, vaccination should be delayed for at least 6 months after the last dose of the therapy. • If an active underlying disease is present in these patients, immunosuppressive therapy is prioritised over vaccination. • If an active underlying disease is present in these patients, immunosuppressive therapy is prioritised over vaccination. Neurologic disorders • Vaccination is recommended for MS patients. • Vaccination is recommended for MS patients. • MS patients receiving ocrelizumab can receive the vaccine 4-6 weeks before starting the treatment or 4-6 months after ending the treatment. • MS patients receiving ocrelizumab can receive the vaccine 4-6 weeks before starting the treatment or 4-6 months after ending the treatment. • DMTs for MS can reduce the antibody response of vaccines. • DMTs for MS can reduce the antibody response of vaccines. • Patients receiving IRT, including alemtuzumab, rituximab, and ocrelizumab, can be vaccinated 6 months after the treatment. • Patients receiving IRT, including alemtuzumab, rituximab, and ocrelizumab, can be vaccinated 6 months after the treatment. • In high-dose or long-term treatments with corticosteroids, vaccination is allowed 4-6 weeks after cessation of the treatment. • In high-dose or long-term treatments with corticosteroids, vaccination 4 to 6 weeks after cessation of treatment • Antipsychotic agents suppress vaccine-induced antibody formation. • Antipsychotic agents suppress vaccine-induced antibody formation. • Antidepressant therapy would normalise the vaccineinduced immune response. • Antidepressant therapy would normalise the vaccineinduced immune response. Patients with cancer are particularly vulnerable to adverse outcomes from moderate and severe Covid-19 infections, which may be due to their underlying malignancy, cytotoxic chemotherapy, radiotherapy, other existing comorbidities, and advanced age. 22 We must consider the diseases and their treatments when considering vaccination. For example, some treatments may impair cellular or humoral immunity to affect the overall vaccine response. It should also be noted that these effects might differ according to the vaccine used. Leukaemia, non-Hodgkin's lymphoma, and lung cancer are the most commonly seen malignancies related to severe Covid-19 cases. 22 Therefore, owing to the relatively high fatality rate of Covid-19 in active cancer patients, this group is among the most highly prioritised to be vaccinated against the disease. 22 Currently, there is no preferred Covid-19 vaccine for these patients, and so these individuals can receive any approved vaccine under their physician's supervision. In general, although it is believed that the natural-or vaccineinduced antibody response in cancer patients is suboptimal, especially among those with haematologic malignancies, there are no absolute contraindications to the Covid-19 vaccine in cancer patients undergoing glucocorticoid therapy, chemotherapy, radiotherapy, hormonal therapy, immunotherapy, or surgery. 23 The efficacy of mRNA vaccines in patients with solid tumours and haematological malignancies has been reported to be 83% and 72%, respectively. Anti-CD20 or cytotoxic therapies in these patients is thought to be the reason for the lower-than-expected immune response in cancer patients, making mRNA vaccines less effective in these patients. 24 However, the T-cell response induced by current vaccines is strong enough to recommend immunisation in these patients, except during the intensive phase of chemotherapy. 24 Thus, carefully considering the timing and interval between the vaccine and the last cycle of chemotherapy would be an essential factor in the adequate vaccine immune response in this population. 24 For patients planning to start cytotoxic chemotherapy, it is better to administer the first dose of the vaccine at least two weeks before initiating the first chemotherapy cycle. However, for those already on cytotoxic chemotherapy, the first dose of the vaccine can be administered between chemotherapy cycles. 25 Several potential concerns regarding using checkpoint inhibitors and targeted therapies, such as tyrosine kinase inhibitors, including erlotinib and imatinib, and its potential interference with viral vaccines exist. 27 However, there is no reported data at this time. The prevalence of immune-related adverse events (IRAEs) following vaccination is unknown for checkpoint inhibitors, yet this side effect may occur within 2-3 days following vaccination. 27 Therefore, avoiding vaccination may be reasonable in cases of significant concern. 28 Patients receiving lymphocyte or plasma cell-depleting regimens should delay Covid-19 vaccination for at least 3 months following the end of their immunotherapeutic treatment to get the best antibody response. However, if they are about to start these regimens, it is reasonable to administer the first dose of the vaccine at least two weeks before starting the immunotherapy course. 24 It is also believed that the Covid-19 vaccine is safe and effective in patients undergoing radiation therapy. 25 32 Therefore, SARS-CoV-2 vaccination is strongly recommended for these patients. 32 Nonetheless, it is also probable that the immunosuppressed condition in these patients may cause a lower anti-SARS-CoV-2 antibody response, depending on the period since the transplantation, the intensity of the immunosuppression, and the type of transplantation. 33 The conditioning and maintenance of immunosuppressive regimens and their dosing and intensity vary significantly between solid organ transplant (SOT) recipients and haematopoietic stem cell transplant (HSCT) recipients. 34 It has been suggested that antimetabolite maintenance therapy can lead to a weaker post-vaccination antibody response than other regimens. 34 Therefore, those patients should be vaccinated early in the course of their underlying disease, as the timing of vaccination is a significant factor in determining its effectiveness. 35 Also, it is better to postpone vaccination to at least 3-6 months after transplantation when the immunosuppression is lower. 36 Nevertheless, if the first dose of the vaccine is received before transplantation, the second dose should be postponed until at least four weeks post-transplant. 36 Some experts believe that a third dose is needed in transplant patients, considering shorter longevity and lower antibodies' efficacy. 37 condition is highest, usually occurring in the first 3-6 months after the transplant. 38 Fortunately, none of the current Covid-19 vaccines are live-attenuated, meaning it is possible to administer the vaccine to this vulnerable population. 38 Apart from vaccine-related efficacy, durability, and safety issues, vaccine-associated allograft rejection is a unique concern in this population, although this has not been reported with any Covid-19 vaccines. 38 Nevertheless, although extremely rare, there would appear to be a slight chance of stimulating immunologic rejection reactions via the vaccinationinduced immune response. 38 Patients with chronic liver disorders (CLD), including cirrhosis, hepatobiliary malignancies, and transplant candidates (or recipients), are vulnerable populations at risk of more severe forms of Covid-19 and higher mortality. 39 This population needs special attention due to their underlying disease, and many operations or treatments were delayed due to the hospitals being overwhelmed or not wanting to put patients at more risk. 39 Therefore, vaccination should also be a priority for these patients. 39 Vaccination seems to be safe in stable CLDs, such as compensated cirrhosis and viral hepatitis. 39 Patients with end-stage renal disease (ESRD) are also more prone to infection with Covid-19 due to their regular or occasional dialysis sessions, where they are exposed to a densely populated environment with a high possibility of SARS-CoV-2 transmission. 42 Moreover, these patients may present with atypical manifestations of SARS-CoV-2 infection, leading to a delay in diagnosing the disease. 43 In addition, patients often have multiple comorbidities and higher rates of polypharmacy. 44 Therefore, the risk of developing a severe or lethal SARS-CoV-2 infection is likely higher in this population, and vaccinating them early against Covid-19 is highly recommended. 45 Moreover, although ESRD patients develop seroconversion following vaccination, they are well-established to achieve a less robust and perhaps less durable antibody response. 46 The seropositivity rate after SARS-CoV-2 vaccination does not appear to differ between haemodialysis and peritoneal dialysis (PD) patients. 47 The extent of the immune response to SARS-CoV-2 vaccination depends on the vaccine type, the time spent since ESRD onset, and possibly age, body mass index (BMI), and nutritional status, as indicated by serum albumin and iron levels. With that in mind, several studies have suggested that a third or booster dose of vaccine would be necessary for these individuals to produce an optimal antibody response. 37, [48] [49] [50] There does not appear to be a preference for one vaccine type over another, with adenoviral vector vaccines, such as the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine, and the mRNA vaccines (i.e., Pfizer/BioNTech, and Moderna) used for vaccinating ESRD patients. 49, 51 In addition, patients with autoimmune renal diseases (e.g., IgA nephropathy) undergoing anti-CD20 therapy (e.g., rituximab) should replace their immunosuppressive treatment with another noninterfering regimen until a few weeks after vaccination. 52 For example, it is reasonable for these individuals to taper steroid doses below 20 mg prednisone (or equivalent) daily or wait for at least six months after the last rituximab dose before being vaccinated. 52 However, if their underlying disease is active, the immunosuppressive therapy is prioritised over-vaccination, 53 although the activation or relapse of the underlying autoimmune kidney disease has only rarely been reported following vaccination. 54 62 However, in MS patients scheduled to start ocrelizumab therapy, the two-dose vaccine regimen should be administered at least 4-6 weeks before the initiation of their treatment course, or at least 4-6 months after the treatment course last ocrelizumab infusion. 63 In patients treated with immunereconstitution therapies, including alemtuzumab, and oral cladribine, it is better to delay vaccination until at least six months after the last course of treatment. 64 In patients on high-dose or long-term corticosteroids, vaccination should be delayed until 4-6 weeks after treatment. 65 Nonetheless, if these patients are not on DMTs, they should receive the SARS-CoV-2 vaccine as soon as possible. There are theoretical concerns that mRNA-based Covid-19 vaccines may trigger the development of de novo neurodegenerative or neurologic disorders, such as demyelinating diseases or fever-induced seizures. In this case, the potential vaccine-induced adverse reaction could be even more debilitating than the viral infection. 66, 67 The adjuvants used in vaccines, including anti-SARS-CoV-2, might be responsible for potential neurologic adverse effects. 68 Another potential neurological adverse event that may result from vaccination is the immunisation stress-related response (ISRR), which manifests itself as psychogenic non-epileptic seizures (PNES). 69 Transverse MOHSENI AFSHAR ET AL. Another potential adverse effect of these vaccines might be an exacerbation of MG and chronic inflammatory demyelinating polyneuropathy (CIDP). 76 The demyelinating disease has most commonly been reported following viral-vector vaccines, which should be further investigated. 77 Patients with diabetes mellitus, due to their comorbidities and acquired immunodeficiency, are at increased Covid-19-related morbidity and mortality. 88 Diabetes is one of the comorbidities most associated with adverse outcomes in Covid-19 patients. However, there seems to be no difference in the severity or mortality of SARS-CoV-2 infection, based on whether they have diabetes type 2 (DMT2) or type 1 (DMT1). 89 Nonetheless, the CDC prioritised vaccination among patients with DMT2 over those with DMT1. 90 Therefore, vaccination is critical and necessary for this population, and endocrinologists should encourage their patients to be vaccinated as soon as possible. 91 It appears that the immune response following Covid-19 vaccination is not affected by the serum glucose levels, as diabetic patients show an optimal antibody response. 92 Furthermore, Covid-19 infected patients are at increased risk of developing new-onset diabetes. Therefore, vaccination can also help to prevent an increase in diabetes mellitus in the community. 93 The association between obesity and viral infections was first demonstrated during the H1N1 epidemic in 2009, with the more body fat, the higher the risks of developing more severe illness and more extended hospitalisation in an intensive care unit (ICU). [94] [95] [96] The reason behind this association was thought to be the impairment of humoral and cellular immunity, along with lower vaccine-induced immunity in these patients. 97 Another reason could be the marked rise of angiotensin-converting enzyme 2 (ACE2) expression associated with high-fat diets. 98 Another factor that plays a crucial role in making obese children more susceptible to infections, such as Covid-19, is hyperinsulinism, which is due to the compensatory mechanisms of their pancreatic β cells to overcome insulin resistance in their body. 99 Thus, when higher amounts of insulin are required in intense metabolic activity, such as activating immune cells in response to the SARS-CoV-2 infection, their β cells cannot produce more insulin, as they are already working near their limit. 100 Moreover, SARS-CoV-2 can enter the pancreatic β cells via ACE2 receptors, causing virus-triggered cell death or immune-mediated loss of infected pancreatic β cell mass. 100, 101 Insulin resistance in these patients can also impair the anti-inflammatory and vasoactive characteristics of nitric oxide (NO) by reducing phosphatidylinositol 3-kinases (PI3K). 102 Previous research has shown obesity as prevalent comorbidity among patients admitted into the ICU, especially among children and adolescents. 103, 104 This research shows that a higher BMI may increase the likelihood of getting a severe disease. 105 with COPD being among the most commonly reported comorbidities, alongside hypertension, dementia, diabetes, and heart failure. 118 Of these deaths, 37 were reported among residents of long-term care facilities. 118 However, the report concluded that the benefits of the Covid-19 vaccination outweighed the potential risks in the older frail populations. 118 Therefore, the recommendation is that individuals with COPD be prioritised for Covid-19 vaccination, regardless of age and frailty. Patients with human immunodeficiency virus (HIV), similar to other comorbidities and immunocompromising conditions, are prone to severe Covid-19. 119 However, the risk is higher in patients with advanced immunosuppression, defined as a CD4 + T cell count of <200/μL. 120 Moreover, if they become infected with SARS-CoV-2, negative impacts on their antiretroviral treatments would also be expected. 121 Unfortunately, few studies have investigated the safety and efficacy of the Covid-19 vaccines in this population. However, one study has reported the mRNA Covid-19 vaccines, such as the BNT162b2 vaccine, to be both immunogenic and safe in patients with HIV. 122 Nevertheless, there remains some level of mistrust in these patients about Covid-19 vaccines, and therefore, discussing this issue with these individuals to address their hesitancy is essential. 123 It is well established that cigarette smoking causes structural changes in the respiratory tract and decreases immune responsiveness, both systemically and locally within the lungs. 124 Therefore, smoking is a This included negative disease progression and adverse outcomes, such as increased ICU admission, the need for mechanical ventilation, and increased mortality when compared to non-smokers. 128 Another recent study confirms these findings, reporting that smokers are overrepresented in fatalities, especially in populations where current smoking is high. 116 The authors suggest that higher rates of Covid-19 would be expected in countries with a higher prevalence of smoking. A more recent study reported that cumulative exposure to cigarette smoke is an independent risk factor for increased hospital admission and death from Covid-19. 129 Given the increased likelihood of contracting SARS-CoV-2 and the propensity for greater disease severity, it concerns that a study from the United Kingdom (UK) found that current smokers were more likely to be undecided or unwilling to be vaccinated against Covid-19. 130 Jackson et al. suggest that due to the disproportionately high number of current smokers among socioeconomically disadvantaged groups, lower vaccination uptake in these clusters could exacerbate the already extant health inequalities. 130 As a result, targeted interventions may be necessary to prevent the compounding of health inequalities in these populations. 130 The recommendation for Covid-19 vaccination among otherwise healthy smokers is that vaccination should occur, and in some cases vaccination is understandably prioritised in this group. 161 Therefore, prevention of SARS-CoV-2 infection seems to be the most desirable approach in these patients. There is substantial concern that these people would not achieve favourable protective immunity postvaccination, considering this population's relatively weak antibody response. 162 However, despite the lower efficacy of the Covid-19 vaccine in the elderly, the vaccines are still effective against preventing mortality. Therefore, vaccination is strongly recommended for this age group, 163 and all currently approved Covid-19 vaccines are safe and effective in the geriatric population. Until the evolution of the most recent SARS-CoV-2 variants, it was believed that children did not become afflicted with Covid-19, or at least not in its most severe forms. Thus, paediatric vaccination did not seem to be necessary. 164 Nonetheless, reports of more severe forms of the disease and increases in the hospitalisation of children infection. 168 However, if proved to be safe and effective, there are still significant challenges to persuade hesitant parents to accept the vaccination of their children. Preventive measures, such as face masks, hand hygiene, and social distancing, are less applicable in pediatrics than adults since adults adhere more strictly to the health protocols. 169 Therefore, the need for a vaccine for children seems to be increasingly important. Several factors should be considered in considering vaccine responses in children, including congenital or developmental disorders, nutritional status, and maturational changes. 103 However, immunocompromised children are also likely to show lower antibody response to Covid-19 vaccines. 103 Presently, no children younger than 12 years old have been enrolled in Covid-19 vaccination trials since it was believed that only older children were at risk of developing severe SARS-CoV-2 infection, and therefore, the vaccine trials could be extended to younger children at a later date. 170 The FDA has approved Covid-19 vaccines for those older than 12 years, but the age limit can perhaps be lowered again after further research. 171 In the period December 14-23, 2020, almost 1.9 million doses of Pfizer/BioNTech Covid-19 vaccine were administered in the US, among which 21 cases of anaphylaxis were reported to the CDC, corresponding to an estimated rate of 11.1 cases per million. 172 Allergic reactions to vaccines and medications can be caused by two primary mechanisms: IgE-mediated and IgE-independent pathways. 173, 174 These reactions are mainly triggered by non-active vaccine ingredients, such as formaldehyde, thimerosal, egg protein, and gelatin, rather than the active vaccine ingredients. 175 Other ingredients commonly used in vaccines to improve their solubility in water are polyethylene glycol (PEG) and polysorbate. 175 The IgE-independent pathway is another proposed mechanism behind vaccine-related allergic reactions. 174 In these cases, activating complement elements, including C3a, C4a, and C5a, would trigger these inflammatory responses. 174 Sciences, for their kind support. 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