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Article

COVID-19 Vaccination in Kidney Transplant Candidates and Recipients

by
Claudio Ponticelli
1 and
Mariarosaria Campise
2,*
1
Independent Researcher, 20122 Milan, Italy
2
Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
*
Author to whom correspondence should be addressed.
Vaccines 2022, 10(11), 1808; https://doi.org/10.3390/vaccines10111808
Submission received: 29 September 2022 / Revised: 14 October 2022 / Accepted: 20 October 2022 / Published: 27 October 2022
(This article belongs to the Section COVID-19 Vaccines and Vaccination)
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Abstract

:
Kidney transplant candidates and kidney transplant recipients (KTRs) are at particular risk of severe complications of COVID-19 disease. In Western countries, mortality in affected hospitalized KTRs ranges between 19% and 50%. COVID-19 vaccination remains the most important measure to prevent the severity of infection in candidates and recipients of kidney transplant. However, the uraemic condition may affect the vaccine-induced immunity in patients with advanced chronic kidney disease (CKD) and in KTRs. Retention of uraemic toxins, dysbiosis, dysmetabolism, and dialysis can diminish the normal response to vaccination, leading to dysfunction of inflammatory and immune cells. In KTRs the efficacy of vaccines may be reduced by the immunosuppressive medications, and more than half of kidney transplant recipients are unable to build an immune response even after four administrations of anti-COVID-19 vaccines. The lack of antibody response leaves these patients at high risk for SARS-CoV-2 infection and severe COVID-19 disease. The aim of the present review is to focus on the main reasons for the impaired immunological response among candidates and kidney transplant recipients and to highlight some of the present options available to solve the problem.

1. Introduction

Kidney transplant recipients (KTRs) are at particular risk of severe complications of COVID-19 disease. In Western countries, mortality in affected hospitalized KTRs ranges between 19% and 50% [1,2,3,4,5]. Different measures have been adopted to prevent infections in KTRs, including personal hygiene, pretransplant screening, tapering of immunosuppression, and immunoglobulin replacement therapy in hypogammaglobulinemic patients. COVID-19 vaccination remains the most important measure to prevent the severity of infection and is highly recommended by Health Authorities in candidates and recipients of kidney transplant. However, the uraemic condition may affect the vaccine-induced immunity in patients with advanced chronic kidney disease (CKD). On the other hand, in KTRs, the efficacy of vaccines may be reduced by the immunosuppressive medications.
In this narrative review, the main issues of COVID-19 vaccination in transplant candidates and kidney transplant recipients are discussed, keeping in mind that according to the World Health Organization (WHO), after the original SARS-CoV-2 strain (WA1) five variants have been identified, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529), with further mutations of the spike protein.

2. Methods

Open-access databases, including PubMed/Elsevier and other relevant sources, including government health organizations, were searched. Only the articles published in English up to 1 September 2022, were included. Searching terms were: “SARS-CoV-2”, “COVID-19”, “CORONAVIRUS,” “COVID VACCINES, “UREMIA”, “KIDNEY TRANPLANTATION”, “IMMUNOSUPPRESSION” or combinations.

3. Pretransplant Vaccination

The recently available anti-COVID-19 vaccines are highly recommended for candidates of solid organ transplantation.
The first two vaccines granted Emergency Use Authorizations (EUAs) are BNT162b2 and mRNA-1273, both mRNA vaccines.
Approaches to vaccine development have included protein subunits, nucleic acids (RNA and DNA), viral vectors (non-replicating and replicating), viruses (live attenuated and inactivated), and virus-like particles [6]. All of the SARS-CoV-2 vaccines approved by the World Health Organization (WHO) were developed based on a variety of approaches and have shown different levels of efficacy (Table 1).
Both inactivated and live attenuated vaccines can be given before transplantation. However, a major issue with pretransplant vaccination is represented by a poor response to vaccine due to the impaired immune response in patients with severe CKD. Kidney transplant candidates are usually affected by CKD stage 5, a condition that can impair their immune status. The main factors that contribute to an abnormal immune status in patients with CKD include retention of uraemic toxins, intestinal dysbiosis, dysmetabolism, and dialysis.
Retention of uraemic toxins. Reduced glomerular filtration rate (GFR) and tubular dysfunction lead to the accumulation of a large number of uraemic toxins. Several molecules in the middle molecular range, e.g., immunoglobulin light chains, retinol-binding protein, the neuropeptides met-enkephalin and neuropeptide Y, endothelin-1, and the adipokines leptin and resistin, can exert detrimental effects on several cells of the innate and adaptive immunity [15]. As a result of toxin accumulation, plasmacytoid dendritic cells counts are decreased in patients with CKD [16], and this reduction is proportional to the loss of GFR [17]. There is also a dendritic cell dysfunction [18]. The reasons for dendritic cell malfunction are unknown but they may be partially explained by their inhibited maturation and activation caused by inositol 3-sulfate accumulation in renal failure [19]. Polymorphonuclear cell dysfunction is frequent in CKD [20] and is proportional to the increasing severity of uraemia [21]. Glucose-modified serum proteins can lead to a spontaneous apoptosis of neutrophils [22], while an accumulation of leptin, spermidine, p-cresol, and free immunoglobulin light chains can impair neutrophil chemotaxis, contributing to the disturbed immune function [23,24,25]. Uraemic toxins can also affect the function of monocytes and macrophages. Even in the early phases of CKD, monocytes show altered adhesion molecule expression [26]. In more advanced phases the retention of sulphates may modify surface molecule expression, cytokine production, and function of monocytes [27]. In end-stage renal disease (ESRD) sulphates may induce monocyte differentiation toward pro-inflammatory, profibrotic macrophages, leading to chronic inflammation [28,29]. In patients with ESRD, mitogen stimulation demonstrates a pro-inflammatory phenotype of CD4+ and CD8+ T cells with increased interferon-γ and tumour necrosis factor-α. These changes are associated with increased frequency of exhausted CD4+ T cells and CD8+ T cells [30]. End-stage renal disease can also increase apoptosis of naïve T cells, resulting in T-cell depletion of CD4 and CD8 T cell compartments [31] and may contribute to the expansion of the pro-inflammatory phenotype of memory T cells, resulting in a reinforcement of the inflammatory state already present in ESRD patients [32]. The decreased number and function of T helper (Th) cells is associated with normal or elevated numbers of myeloid cells with production of inflammatory cytokines and reactive oxygen species (ROS), a condition similar to the immunological aging observed in late elderly that leads to a defective T-cell response [33]. (Figure 1)
Dysbiosis. There is a continuous interaction between the microbiota and the immune system. In patients with CKD, the microbiota is completely different from that of the healthy subjects and is associated with dysbiosis, a compositional and functional alteration in the microbiota [34]. The microbiota strongly influences the transcriptional programming of innate immune cells, and specific bacterial species can directly influence T regulator cells and the balance between Th1 and Th2 cells. In addition, the microbiome has been implicated in the regulation of inflammatory processes.
Dysbiosis may produce a large quantity of end products of the bacterial metabolism that work as uraemic toxins. Gut-derived protein-bound molecules include advanced glycation end products, hippurates, indoles, phenols, polyamines, and other toxins such as methionine-enkephalin [35]. During the course of CKD, p-cresyl sulphate, p-cresyl glucuronide, trimethylamine, indoxyl sulphate, and indole-3-acetic acid tend to accumulate and affect the intestinal barrier structure and function, while in the circulation they can stimulate cells of the immune system [36]. Toxins can interfere with different functions. As an example, p-cresyl sulphate might be associated with an immune deficiency status, while indoxyl sulphate would be a main responsible of inflammation [37]. In addition, dysbiosis favours an increased translocation of living bacteria and bacterial components. This process has the potential to activate innate immunity and systemic inflammation [38]. Thus, dysbiosis may result in dysregulation of the immune system and inflammatory response [39]. This particular condition may be involved in inefficacy of COVID-19 vaccines [40]. Dietary interventions and pharmacological strategies can improve microbiome dysbiosis and reduce the burden of uraemic toxins [41].
Dysmetabolism. In CKD, abnormal metabolic activities of the kidney can lead to abnormal production of renin, erythropoietin, and vitamin D. Stimulation of the renin–angiotensin system is a frequent finding in patients with CKD. Activated angiotensin1 receptors can induce a shift from Th1 to T-cell regulators, thus reducing the immune response [42]. Anaemia is a constant disorder in patients with kidney function impairment and is often associated with low iron levels. Hypoferremia can blunt the immune response, because T cells need iron to support their metabolism [43,44]. Serum levels of vitamin D are usually low in CKD. Vitamin D receptors and vitamin D metabolic enzymes are present in immune cells such as antigen-presenting-cells (APC), T cells, B cells, and monocytes [45]. This may explain why vitamin D deficiency is often associated with poor immune response and increased risk of infection [46,47]. Elevated serum levels of fibroblast growth factor 23 (FGF23) are common in CKD patients. Fibroblast growth factor 23 is a phosphaturic hormone that impairs the immune response by suppressing active vitamin D, through an inhibition of the 1alpha hydroxylase and a stimulation of the 24 hydroxylases [48]. FGF23 is elevated during inflammation and can further aggravate this condition by favouring the production of pro-inflammatory cytokines [49].
Inflammation may also dysregulate innate immunity and alter T-cell or B-cell maturation and differentiation [50]. Several factors may be responsible for an inflammatory state in CKD, including increased production of pro-inflammatory cytokines [51], oxidative stress [52], hyperuricemia [53], and adipose tissue dysfunction [54]. Furthermore, the anti-inflammatory properties of high-density lipoproteins are lost in uraemia. Rather, they may contribute to the systemic inflammation in uraemic patients by modulating polymorphonuclear functions [55] (Figure 2).
Dialysis. The removal of uraemic toxins and the contact of blood with semipermeable membranes differ with the modality of dialysis and may have different effects on the immune response. Conventional haemodialysis (HD) is not very effective in removing middle and large molecules. In hemofiltration, solutes are removed by convection and their movement depends on membrane characteristics. The hemodiafiltration combines diffusive and convective transport. In patients treated with regular HD, T-cell immune response is deficient and the interaction between the APCs and the T-lymphocyte is impaired [56]. Even a single HD can induce a significant decrease in CD8+ T cells [57]. The immunodeficiency status in HD patients can be attributed to both the accumulation of uraemic toxins and the continuous activation of mononuclear cells, eventually resulting in apoptosis and accelerated senescence of monocytes [58]. Hemofiltration can remove inflammatory cytokines and improve monocyte function, improving the uraemic immune dysfunction [59]. A prospective study in chronic dialysis patients during influenza season showed that patients treated with hemodiafiltration demonstrated sustained seroprotection for longer periods in comparison with patients on HD [60]. Some reports outlined that peritoneal dialysis (PD) may better protect from decrease inflammatory status and premature ageing of the immune system in comparison with HD [61,62,63]. However, these data cannot be applied to all transplant candidates, as the immune-nutritional status in PD patients is variable. Some patients on PD may show malnutrition, increased oxidative stress, inflammation, and disrupted immune status
Response to anti-COVID-19 vaccine. In uraemic patients waiting for kidney transplantation, multiple factors can lead to dysfunction of inflammatory and immune cells. These abnormalities can diminish the normal response to vaccination and may require a booster. Studies evaluating the response to SARS-CoV-2 vaccines in dialysis patients reported a diminished response in comparison to healthy individuals [64]. The type of vaccine may also influence the response. An mRNA vaccine (BNT162b2, Pfizer/BioNTech) is currently the only COVID-19 vaccine that has received full FDA approval for use in the United States. Another mRNA vaccine (mRNA-1273, Moderna TX, Inc., Houston, TX, USA) is also authorized for emergency use in the United States and by the European Medical Association (EMA). A third COVID-19 vaccine (ChAdOx1-S, Astra Zeneca) has been approved by the EMA. An attenuated vaccine (Ad26.COV2.S) is authorized for emergency use in the United States as a single shot and is under critical revision by the EMA.
A study on 2367 dialysis patients vaccinated against COVID-19 with mRNA (mRNA1273 or BNT162b2) or live attenuated virus (Ad26.COV2.S) showed that most dialysis patients who received mRNA vaccines seroconverted, while 33.3% of patients receiving the attenuated adenovirus vaccine did not seroconvert and another 36% had undetectable or diminished response even 28–60 days post vaccination [65]. On the other hand, if humoral response is poor, BNT162b2 vaccination may obtain a cellular response [66]. Another study in dialysis patients confirmed an inconsistent antibody response to Ad26.COV2.S, but no difference was detected in clinical effectiveness between BNT162b2 and Ad26.COV2.S in the first 6 months after vaccination [67]. Further studies should clarify whether a change in vaccine type may be suggested for those dialysis patients who fail to seroconvert.
The response to the anti-COVID-19 vaccine may be improved after two consecutive doses of anti-SARS-CoV-2 vaccines [68,69,70,71,72]. A meta-analysis reported that 84.3% of patients on HD and 92.4% of those on PD achieved seroconversion after two doses. However, the response was less than the general population. Compared with healthy controls, HD and PD patients were 18% and 11% less likely to develop antibodies after vaccination, respectively [73]. Thus, in the maintenance dialysis population two doses of anti-SARS-CoV-2 vaccines provide moderate protection against acquiring SARS-CoV-2 infection but are highly protective against severe outcomes. However, non-responders are at risk for severe COVID-19 [74].
Patients with low antibody levels after the second dose can obtain an increase in anti-spike antibody levels after a third dose, while non-responders to two doses became low responders after the third dose. Adverse events did not seem to be more common or severe after a third vaccine dose [75,76,77,78]. Thus, a third dose of the BNT162b2 vaccine can substantially increase antibody levels in patients receiving maintenance dialysis and appeared to be as well tolerated as a second dose. In 17 HD and 28 PD patients who received a three-dose regimen of the mRNA BNT162b2, followed by a fourth “booster” dose of the mRNA vaccine (BNT162b2, n = 43, or mRNA-1273, n = 2), after a median of 7.6 months after the third dose, a significant increase in anti-spike antibody titre was found. Dose four was well tolerated [79].
Another issue is the short duration of the anti-COVID-19 mRNA vaccine in dialysis patients. Studies reported that anti-SARS-CoV-2 antibody titres declined after 6 months [80,81,82], and a more recent report showed that vaccine-specific humoral and cellular immunity waned 4 months after two vaccine doses in dialysis patients [83]. More information is also needed to assess the durability of vaccine protection against new variants. These data support the recommendation of further “booster” doses in dialysis patients. Transplant candidates should be vaccinated at least 14 days before transplantation, as immunosuppression may reduce the response to vaccines [84].

4. Post-Transplant Vaccination

Until few years ago, vaccination in organ transplant recipients was underutilized [85]. Live viral and bacterial vaccines were not used for fear of systemic infection [86]; inactivated vaccines were administered at least six months after transplantation when the immune reactivity was less blunted by anti-rejection therapy [87]. Vaccines were often avoided because rare cases of de novo production of anti-HLA antibodies or rejection were reported [88,89,90,91,92].
The scenario changed after the outbreak of the COVID-19 pandemic. The high risk of severe morbidity and mortality in immunosuppressed individuals prompted to recommend vaccination to kidney transplant recipients. These patients are particularly susceptible to COVID-19 infection, not only because their immune response is blunted by anti-rejection therapies but also because the kidney has abundant angiotensin-converting enzyme 2 (ACE2). ACE2 is the main receptor for SARS-CoV-2 infection. Proteolytic cleavage of viral spike protein and ACE2 by type II transmembrane serine protease (TMPRSS2) favours the physical binding of ACE2 to S-protein and plays a critical role in spreading the infection of the virus [93,94,95] (Figure 3).
Both mRNA vaccines and live attenuated vaccines have been used in transplant recipients. Yet, resistance to accept vaccination may persist. An online survey on 473 kidney transplant recipients showed that 346 (73.1%) participants planned to receive vaccination, but 105 (22.2%) were undecided, and 22 (4.7%) refused vaccination [97]. Thus, many KTRs are not vaccinated against COVID-19 and are at increased risk for infection.
Response to vaccines. After kidney transplantation, many dysfunctions related to the uraemic status may reverse, but immunosuppressive therapy impairs humoral and cellular reactions. A poor antibody response to vaccination has been found in KTRs even after two doses of mRNA vaccine [98,99,100]. African Americans, individuals with advanced age, and patients who received full-dose antimetabolite drugs and/or depleting therapy in the year before vaccination were at elevated risk of developing low seroconversion rates after vaccination [101,102,103]. An even lower antibody response has been obtained with Ad26.COV2.S, tested in few transplant patients [104]. Although the response to neutralizing antibodies is correlated with viral load and better outcome in patients with severe disease, vaccines might exert some protection even in patients with low levels of neutralizing antibodies, since other immune effector mechanisms including T cells and innate immune mechanisms may exert some protection [105]. Indeed, CD4+/CD8+ T-cell immunity can be detected even in the absence of seroconversion [106]. However, in spike-specific T helper cell responses, frequencies can be significantly reduced in KTRs compared with those in controls and dialysis patients, and this is accompanied by a broad impairment in effector cytokine production [98]. To define the efficacy of COVID-19 vaccination can be difficult and depends on the established end points. The conclusions may be different according to the chosen outcome measure, i.e., absence of positivity, asymptomatic disease, need of hospitalization, and/or death [107].
Booster vaccine doses. With the antibody response to two doses of mRNA vaccines being low, a third administration has been recommended to organ transplant recipients. In a French study, among 73 kidney transplant patients whose serum did not neutralize SARS-CoV-2 in vitro after two doses of vaccine, 14 (19%) responded after a third dose of BNT162b2 vaccine. Short time from transplantation and high maintenance immunosuppression resulted to be detrimental factors for the response to the third dose in univariate analysis. The presence of anti-SARS-CoV-2 antibodies or cellular response after the second dose predicted a response to the third dose [108]. Further studies reported rates of seroconversion ranging between 39% and 49% in infection-naive transplant recipients. Patients with low antibody titres at baseline were more likely to respond to the third dose [109,110,111,112]. The humoral response against SARS-CoV-2 in persons with a history of COVID-19 infection was greater than the response in previously uninfected participants [113,114]. Seroconversion was often associated with significant changes in cellular immunity [115,116,117]. However, the immunity to the Omicron variant is low and less than to Delta in the general population [118], and in transplant recipients the percentage of positivity against Omicron variant was low, about 18%, even after the third dose [119]. Studies with a fourth vaccine administration in kidney transplant patients reported that in spite of increased anti-spike IgG and neutralizing capacity against some variants in a few responders, transplant patients remain at high risk for Omicron [120,121,122,123]. In summary, despite booster vaccination a substantial number of kidney transplant recipients are unable to build an immune response to a COVID-19 vaccine. Emerging variants of SARS-CoV-2 are responsible of further outbreaks of COVID-19 illness.
Immunosuppressive drugs. As a general rule, the stronger the immunosuppressive therapy, the lower the immune response to COVID-19 vaccines. Usually, kidney transplant recipients not only lack a humoral response to COVID-19 vaccines but may also display impairment of the cellular response to SARS-CoV-2 antigens. However, some medications are more frequently associated with poor response.
Corticosteroids (CSs) have pleiotropic effects on the immune system that are time- and dose-dependent. Prednisone doses of 20 mg/day do not interfere with the immune response to inactivated vaccines [84]. The potential effect of CSs on the immunogenicity of COVID-19 vaccines has not been thoroughly investigated. The current recommendations for COVID-19 vaccines and CS administration are mostly based on the available evidence for inactivated vaccines. Ideally, vaccination should be performed when prednisone dose is ≤10 mg/day. It is still uncertain what to do in patients treated with higher doses of prednisone. However, boosters are important to maximize protection in those cases.
Mycophenolate salts are prodrugs that release active mycophenolic acid. The main mechanism of action rests on a marked reduction in guanosine triphosphate necessary for DNA synthesis and the de novo pathway of guanosine nucleotide synthesis. T- and B-lymphocytes are more dependent on this pathway than other cell types. Some investigators reported that poor response to vaccines was more frequent in kidney transplant recipients taking mycophenolate [124,125,126]. In a study, patients on mycophenolate mofetil (2 gm daily) had significantly lower SARS-CoV-2 spike-specific IgG levels as compared to patients on no or a reduced dose of mycophenolate [127]. However, it is unclear whether this is the result of a specific effect of mycophenolate or of the reinforcement of standard immunosuppression with the addition of mycophenolate.
The pharmacological activity of azathioprine rests on the formation of the active intracellular nucleotides thioinosinic acid and 6-thioguanine. Thioinosinic acid inhibits enzymes that mediate the first step of de novo pathways of purine synthesis. The administration of azathioprine may concur with other immunosuppressive drugs to impair the antibody response to two doses of SARS-CoV-2 mRNA vaccination [128].
Calcineurin inhibitors (CNI) are the mainstay of the immunosuppressive therapy in organ transplantation. Through the inhibition of calcineurin, tacrolimus and cyclosporine inhibit the synthesis of interleukin-2 and other cytokines. In comparison with healthy controls, CNI-treated transplant patients show lower humoral response and antibody titres to mRNA-vaccines [129]. On the other hand, CNI might also inhibit SARS-CoV-2 replication, at least on experimental models. Cyclophilins are required by several viruses, including SARS-CoV-2, for their replication [130].
Different than other immunosuppressive drugs, the mTOR-inhibitors, sirolimus and everolimus, can stimulate anti-SARS-CoV-2 T-cell response. Accordingly, these drugs may exert a potential beneficial role in enhancing an immune response to COVID-19 vaccine in KTRs [131].
Rituximab and anti-CD20 antibodies have limited influence on T cells, but vaccination responses can be blunted until naive B cells repopulate [132,133]. In addition, hypogammaglobulinemia may develop after rituximab [134].
Belatacept is a fusion protein that blocks the interaction between the antigen-presenting cell and the costimulatory proteins CD80-CD86. Kidney transplant recipients under treatment with belatacept showed a weak response not only to two doses [135] but also to three doses and four doses of mRNA-vaccine [136,137].
Duration of anti-COVID-19 antibodies. In the general population, protection against SARS-CoV-2 infection declines over time. The antibody titre usually declines around six months after vaccination [138]. A more rapid reduction has been reported in KTRs; in a study on 14 KTRs, the titre of anti-SARS-CoV-2–receptor-binding domain (RBD) antibodies dropped to 54% at 28 days and 87% at 100 days [139].
How to improve antibody response. Some studies are evaluating the possibility of improving the response to COVID-19 vaccines in kidney transplant recipients. In Germany, 29 patients who could not mount an antibody response to previous vaccinations received a fourth dose of a SARS-CoV-2 vaccine. To improve their immune reactivity, mycophenolate was stopped for 5 weeks in 28 participants and azathioprine in 1 participant. Seroconversion and virus neutralizing capacity after vaccination were observed in 21 (76%) participants. All the responders and four non-responders were taking CNI. Among four patients treated with belatacept, only one responded. Together with humoral-response-specific B cells, plasmablasts significantly increased. The cellular markers of T-cell proliferation (Ki67 and programmed death cell protein1) significantly increased after booster vaccination and mycophenolate hold [117]. The National Institutes of Health (NIH) is organizing another study involving 400 adults with kidney or liver transplantation. The goal is to determine if reducing immunosuppressive therapy in the days before and after a booster dose of an mRNA COVID-19 vaccine may obtain better antibody responses to vaccination in kidney and liver transplant recipients. Participants must have no recent transplant rejection or change in immunosuppression and a negative antibody response at least 30 days after two to four doses of mRNA COVID-19. Participants will be randomly assigned to one of two groups. One group will receive an additional dose of a COVID-19 mRNA vaccine with no further intervention. The other group will take a reduced dose of their immunosuppressive therapy with tacrolimus for five days before and two weeks after receiving an additional dose of a COVID-19 mRNA vaccine. Investigators will measure the antibody response to vaccination 30 days after the additional vaccine dose. The endpoint is to determine the proportion of participants who achieve a predefined antibody response. Participants will be followed for one year after enrolment. This writer is concerned about the safety of this approach. A transient reduction in immunosuppression may be well tolerated by some transplant recipients, but others who are borderline of an operational tolerance may develop a chronic rejection in the long term.
Side effects of vaccinations. Reactions to COVID-19 vaccination are usually mild. Fever, headache, muscle pain, nausea, vomiting, itching, and/or joint pain are common but reversible. Anaphylactic shock rarely occurs [140]. The possibility that anti-COVID-19 vaccines may increase the risk of rejection is not substantiated by the available data [141,142]. A prospective study in 58 renal transplant recipients followed for 3 months reported that SARS-CoV-2 mRNA vaccination did not elicit a significant alloimmune response [143]. However, two cases of biopsy-proven acute rejection have been described. Rejection occurred a few days after BNT162b2, ChAdOx1, and AZD1222 vaccines. Histology showed a cell-mediated rejection in both biopsies, but in one of the two there were also deposits of C4d. Both patients responded to appropriate therapy with a partial recovery [144,145]. In the general population, several cases of interstitial nephritis or glomerulopathies have been reported after COVID-19 vaccination, including minimal change disease, focal glomerulosclerosis, IgA nephropathy, and collapsing glomerulonephritis [146,147,148,149,150,151,152]. A single case of collapsing glomerulonephritis has been seen in a kidney transplant recipient after COVID-19 vaccination [153]. In healthy volunteers, alterations in haemoglobin A1c, serum sodium and potassium levels, coagulation profiles, and renal functions have been reported after vaccination with an inactivated SARS-CoV-2 vaccine, suggesting that vaccination mimicked an infection. Relevant reduction in CD8+ T cells and increase in classic monocyte contents were also observed. Moreover, nuclear factor kinase B signalling and reduced type I interferon responses were documented by biological assays [154]. The low incidence of side effects after vaccination in kidney transplant recipients is strange, since these patients should be particularly susceptible to side effects in view of their compromised immune response.

5. Conclusions

Vaccination in kidney transplant candidates and recipients remains a major issue mainly because most patients do not respond to both vaccination and the following boosters. Almost 50% of kidney transplant recipients are unable to build an immune response, particularly if treated with antimetabolites. The lack of antibody response leaves kidney transplant recipients at high risk for SARS-CoV-2 infection and severe COVID-19 disease. Responders do not achieve effective immune protection against Omicron variants, although develop a less severe disease. Thus far, an effective measure to prevent the contact with SARS-CoV-2 remains in maintaining physical distance of at least 1 m and using a face mask and eye protection in public and health-care settings [155].
The effectiveness of injectable vaccines wanes over time, and COVID-19 variants can evade the vaccines. A means to prevent COVID-19 disease may rest on infusion of anti-SARS-CoV-2 hyperimmune globulins obtained by convalescent individuals [156].
A new option may consist in nasal vaccines. Two needle-free COVID-19 vaccines that are delivered through the nose or mouth have been recently approved for use in China and India. This type of vaccine could prevent the virus from entering the body in the first place. SARS-CoV-2 relies on its obligate receptor ACE2 for infection [157,158]. Experimental studies showed that a human recombinant soluble ACE2 variant can block early stages of SARS-CoV-2 infections in human kidney and vascular organoids [159]. Soluble ACE2 prevented internalization of the ACE2-SARS-CoV-2 complex and minimized the development of COVID-19 disease in a mouse model [160]. Furthermore, the protease TMPRSS2, which is critical for inducing the binding between ACE2 and coronavirus, represents a potential target for antiviral intervention. The entry of SARS-CoV-2 might be blocked by protease inhibitors [161]. Finally, another approach deserving mention is the administration of protective monoclonal antibodies such as Ronapreve® (casirivimab and imdevimab) and Evusheld® (Tixagevimab and Cilgavimab). These two drugs consist of two monoclonal antibodies that can be used [162] either for prophylaxis or treatment.
In conclusion, COVID-19 vaccinations provided certain protection among patients with impaired immunological response, such as candidates and recipients of kidney transplant, by reducing mortality and gravity of infection. Furthermore, the newly available antiviral drugs contribute to a better management of the infection itself. However, the pandemic is not over yet and all the innovative approaches that will be available are welcome for future prevention and treatment of this severe infection in frail populations.

Author Contributions

Both authors have equally contributed to the conceptualizatio, methodology, software, validation, etc. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Bossini, N.; Alberici, F.; Delbarba, E.; Valerio, F.; Manenti, C.; Possenti, S.; Econimo, L.; Maffei, C.; Pola, A.; Terlizzi, V.; et al. Kidney transplant patients with SARS-CoV-2 infection: The Brescia Renal COVID task force experience. Am. J. Transplant. 2020, 20, 3019–3029. [Google Scholar] [CrossRef] [PubMed]
  2. Elias, M.; Pievani, D.; Randoux, C.; Louis, K.; Denis, B.; DeLion, A.; Le Goff, O.; Antoine, C.; Greze, C.; Pillebout, E.; et al. COVID-19 Infection in Kidney Transplant Recipients: Disease Incidence and Clinical Outcomes. J. Am. Soc. Nephrol. 2020, 31, 2413–2423. [Google Scholar] [CrossRef]
  3. Favà, A.; Cucchiari, D.; Montero, N.; Toapanta, N.; Centellas, F.J.; Vila-Santandreu, A.; Coloma, A.; Meneghini, M.; Manonelles, A.; Sellarés, J.; et al. Clinical characteristics and risk factors for severe COVID-19 in hospitalized kidney transplant recipients: A multicentric cohort study. Am. J. Transplant. 2020, 20, 3030–3041. [Google Scholar] [CrossRef] [PubMed]
  4. Akalin, E.; Azzi, Y.; Bartash, R.; Seethamraju, H.; Parides, M.; Hemmige, V.; Ross, M.; Forest, S.; Goldstein, Y.D.; Ajaimy, M.; et al. COVID-19 and Kidney Transplantation. N. Engl. J. Med. 2020, 382, 2475–2477. [Google Scholar] [CrossRef] [PubMed]
  5. Mahalingasivam, V.; Craik, A.; Tomlinson, L.A. A Systematic Review of COVID-19 and Kidney Transplantation. Kidney Int. Rep. 2020, 6, 24–45. [Google Scholar] [CrossRef]
  6. Savina, K.; Sreekumar, R.; Soonu, V.K.; Variyar, E.J. Various vaccine platforms in the field of COVID-19. Beni. Suef. Univ. J. Basic Appl. Sci. 2022, 11, 35. [Google Scholar] [CrossRef]
  7. Polack, F.P.; Thomas, S.J.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Perez, J.L.; Pérez Marc, G.; Moreira, E.D.; Zerbini, C.; et al. Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine. N. Engl. J. Med. 2020, 383, 2603–2615. [Google Scholar] [CrossRef] [PubMed]
  8. Baden, L.R.; El Sahly, H.M.; Essink, B.; Kotloff, K.; Frey, S.; Novak, R.; Diemert, D.; Spector, S.A.; Rouphael, N.; Creech, C.B.; et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N. Engl. J. Med. 2021, 384, 403–416. [Google Scholar] [CrossRef]
  9. Voysey, M.; Costa Clemens, S.A.; Madhi, S.A.; Weckx, L.Y.; Folegatti, P.M.; Aley, P.K.; Angus, B.; Baillie, V.L.; Barnabas, S.L.; Bhorat, Q.E.; et al. 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. Lancet 2021, 397, 881–891. [Google Scholar] [CrossRef]
  10. Das, S.; Kar, S.S.; Samanta, S.; Banerjee, J.; Giri, B.; Dash, S.K. Immunogenic and reactogenic efficacy of Covaxin and Covishield: A comparative review. Immunol. Res. 2022, 70, 289–315. [Google Scholar] [CrossRef]
  11. Janssen. Johnson & Johnson Announces Single-Shot Janssen COVID-19 Vaccine Candidate Met Primary Endpoints in Interim Analysis of Its Phase 3 ENSEMBLE Trial. Available online: https://www.janssen.com/johnson-johnson-announces-single-shot-janssen-covid-19-vaccine-candidate-met-primary-endpoints (accessed on 13 October 2022).
  12. Kim, J.H.; Marks, F.; Clemens, J.D. Looking beyond COVID-19 vaccine phase 3 trials. Nat. Med. 2021, 27, 205–211. [Google Scholar] [CrossRef] [PubMed]
  13. COVAXIN® (BBV152) Booster Dose Study Shows Promising Results. Available online: https://www.bharatbiotech.com/covaxin.html (accessed on 13 October 2022).
  14. Heath, P.T.; Galiza, E.P.; Baxter, D.N.; Boffito, M.; Browne, D.; Burns, F.; Chadwick, D.R.; Clark, R.; Cosgrove, C.; Galloway, J.; et al. Safety and Efficacy of NVX-CoV2373 COVID-19 Vaccine. N. Engl. J. Med. 2021, 385, 1172–1183. [Google Scholar] [CrossRef] [PubMed]
  15. Cohen, G.; Vanholder, R. Special Issue: Immune Dysfunction in Uremia. Toxins 2021, 13, 70. [Google Scholar] [CrossRef]
  16. Agrawal, S.; Gollapudi, P.; Elahimehr, R.; Pahl, M.V.; Vaziri, N.D. Effects of end-stage renal disease and haemodialysis on dendritic cell subsets and basal and LPS-stimulated cytokine production. Nephrol. Dial Transplant. 2010, 25, 737–746. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Hesselink, D.A.; Betjes, M.G.H.; Verkade, M.A.; Athanassopoulos, P.; Baan, C.C.; Weimar, W. The effects of chronic kidney disease and renal replacement therapy on circulating dendritic cells. Nephrol. Dial Transplant. 2005, 20, 1868–1873. [Google Scholar] [CrossRef]
  18. Kim, J.U.; Kim, M.; Kim, S. Dendritic Cell Dysfunction in Patients with End-stage Renal Disease. Immune Netw. 2017, 17, 152–162. [Google Scholar] [CrossRef] [Green Version]
  19. Ghimire, S.; Matos, C.; Caioni, M. Indoxyl 3-sulfate inhibits maturation and activation of human monocyte-derived dendritic cells. Immunobiology 2018, 223, 239–245. [Google Scholar] [CrossRef]
  20. Cendoroglo, M.; Jaber, B.L.; Balakrishnan, V.S.; Perianayagam, M.; King, A.J.; Pereira, B.J.G. Neutrophil Apoptosis and Dysfunction in Uremia. J. Am. Soc. Nephrol. 1999, 10, 93–100. [Google Scholar] [CrossRef]
  21. Mahajan, S.; Kalra, O.P.; Asit, K.T.; Ahuja, G.; Kalra, V. Phagocytic polymorphonuclear function in patients with progressive uremia and the effect of acute hemodialysis. Ren Fail. 2005, 27, 357–360. [Google Scholar] [CrossRef] [PubMed]
  22. Cohen, G.; Rudnicki, M.; Walter, F.; Niwa, T.; Hörl, W.H. Glucose-Modified Proteins Modulate Essential Functions and Apoptosis of Polymorphonuclear Leukocytes. J. Am. Soc. Nephrol. 2001, 12, 1264–1271. [Google Scholar] [CrossRef]
  23. Ottonello, L.; Gnerre, P.; Bertolotto, M. Leptin as a Uremic Toxin Interferes with Neutrophil Chemotaxis. J. Am. Soc. Nephrol. 2004, 15, 2366–2372. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. de Carvalho, J.T.G.; Dalboni, M.A.; Watanabe, R.; Peres, A.T.; Goes, M.A.; Manfredi, S.R.; Canziani, M.E.; Cendoroglo, G.S.; Guimarães-Souza, N.; Batista, M.C.; et al. Effects of spermidine and p-cresol on polymorphonuclear cell apoptosis and function. Artif Organs. 2011, 35, E27–E32. [Google Scholar] [CrossRef] [PubMed]
  25. Cohen, G.; Hörl, W.H. Free Immunoglobulin Light Chains as a Risk Factor in Renal and Extrarenal Complications. Semin. Dial. 2009, 22, 369–372. [Google Scholar] [CrossRef] [PubMed]
  26. Wallquist, C.; Mansouri, L.; Norrbäck, M.; Hylander, B.; Jacobson, S.H.; Lundahl, J. Early Changes in Monocyte Adhesion Molecule Expression and Tumor Necrosis Factor-α Levels in Chronic Kidney Disease—A 5-Year Prospective Study. Am. J. Nephrol. 2016, 44, 268–275. [Google Scholar] [CrossRef] [Green Version]
  27. Girndt, M.; Trojanowicz, B.; Ulrich, C. Monocytes in Uremia. Toxins 2020, 12, 340. [Google Scholar] [CrossRef]
  28. Barisione, C.; Garibaldi, S.; Furfaro, A.L.; Nitti, M.; Palmieri, D.; Passalacqua, M.; Garuti, A.; Verzola, D.; Parodi, A.; Ameri, P.; et al. Moderate Increase of Indoxyl Sulfate Promotes Monocyte Transition into Profibrotic Macrophages. PLoS ONE 2016, 11, e0149276. [Google Scholar] [CrossRef] [Green Version]
  29. Bonan, N.B.; Schepers, E.; Pecoits-Filho, R. Contribution of the uremic milieu to an increased pro-inflammatory monocytic phenotype in chronic kidney disease. Sci. Rep. 2019, 9, 10236. [Google Scholar] [CrossRef] [Green Version]
  30. Hartzell, S.; Bin, S.; Cantarelli, C.; Haverly, M.; Manrique, J.; Angeletti, A.; La Manna, G.; Murphy, B.; Zhang, W.; Levitsky, J.; et al. Kidney Failure Associates with T Cell Exhaustion and Imbalanced Follicular Helper T Cells. Front. Immunol. 2020, 11, 583702. [Google Scholar] [CrossRef]
  31. Yoon, J.-W.; Gollapudi, S.; Pahl, M.; Vaziri, N. Naïve and central memory T-cell lymphopenia in end-stage renal disease. Kidney Int. 2006, 70, 371–376. [Google Scholar] [CrossRef] [Green Version]
  32. Betjes, M.G.H. Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses. Toxins 2020, 12, 224. [Google Scholar] [CrossRef]
  33. Betjes, M.G.H.; Meijers, R.W.J.; Litjens, N.H.R. Loss of renal function causes premature aging of the immune system. Blood Purif. 2013, 36, 173–178. [Google Scholar] [CrossRef] [PubMed]
  34. Rysz, J.; Franczyk, B.; Ławiński, J.; Olszewski, R.; Ciałkowska-Rysz, A.; Gluba-Brzózka, A. The Impact of CKD on Uremic Toxins and Gut Microbiota. Toxins 2021, 13, 252. [Google Scholar] [CrossRef] [PubMed]
  35. Graboski, A.L.; Redinbo, M.R. Gut-Derived Protein-Bound Uremic Toxins. Toxins 2020, 12, 590. [Google Scholar] [CrossRef] [PubMed]
  36. Glorieux, G.; Gryp, T.; Perna, A. Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease. Toxins 2020, 12, 245. [Google Scholar] [CrossRef] [Green Version]
  37. Rocchetti, M.T.; Cosola, C.; Ranieri, E.; Gesualdo, L. Protein-Bound Uremic Toxins and Immunity. Methods Mol. Biol. 2021, 2325, 215–227. [Google Scholar] [CrossRef]
  38. Anders, H.-J.; Andersen, K.; Stecher, B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int. 2013, 83, 1010–1016. [Google Scholar] [CrossRef] [Green Version]
  39. Levy, M.; Kolodziejczyk, A.A.; Thaiss, C.A.; Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 2017, 17, 219–232. [Google Scholar] [CrossRef]
  40. Chen, J.; Vitetta, L.; Henson, J.D.; Hall, S. The intestinal microbiota and improving the efficacy of COVID-19 vaccinations. J. Funct. Foods 2021, 87, 104850. [Google Scholar] [CrossRef]
  41. Caggiano, G.; Cosola, C.; Di Leo, V.; Gesualdo, M.; Gesualdo, L. Microbiome modulation to correct uremic toxins and to preserve kidney functions. Curr. Opin. Nephrol. Hypertens. 2020, 29, 49–56. [Google Scholar] [CrossRef]
  42. Heijnen, B.F.J.; Nelissen, J.; Van Essen, H. Irreversible Renal Damage after Transient Renin-Angiotensin System Stimulation: Involvement of an AT1-Receptor Mediated Immune Response. PLoS ONE 2013, 8, e57815. [Google Scholar] [CrossRef]
  43. Frost, J.N.; Tan, T.K.; Abbas, M.; Wideman, S.K.; Bonadonna, M.; Stoffel, N.U.; Wray, K.; Kronsteiner, B.; Smits, G.; Campagna, D.R.; et al. Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection. Medicine 2021, 2, 164–179.e12. [Google Scholar] [CrossRef]
  44. Zimmermann, P.; Curtis, N. Factors That Influence the Immune Response to Vaccination. Clin. Microbiol. Rev. 2019, 32, e00084-18. [Google Scholar] [CrossRef] [Green Version]
  45. Prietl, B.; Treiber, G.; Pieber, T.R.; Amrein, K. Vitamin D and Immune Function. Nutrients 2013, 5, 2502–2521. [Google Scholar] [CrossRef]
  46. Vanherwegen, A.-S.; Gysemans, C.; Mathieu, C. Regulation of Immune Function by Vitamin D and Its Use in Diseases of Immunity. Endocrinol. Metab. Clin. N. Am. 2017, 46, 1061–1094. [Google Scholar] [CrossRef]
  47. Ismailova, A.; White, J.H. Vitamin D, infections and immunity. Rev. Endocr. Metab. Disord. 2022, 23, 265–277. [Google Scholar] [CrossRef]
  48. Bacchetta, J.; Salusky, I.B.; Hewison, M. Beyond mineral metabolism, is there an interplay between FGF23 and vitamin D in innate immunity? Pediatr. Nephrol. 2013, 28, 577–582. [Google Scholar] [CrossRef]
  49. Czaya, B.; Faul, C. FGF23 and inflammation—A vicious coalition in CKD. Kidney Int. 2019, 96, 813–815. [Google Scholar] [CrossRef]
  50. Pinti, M.; Appay, V.; Campisi, J. Aging of the immune system: Focus on inflammation and vaccination. Eur. J. Immunol. 2016, 46, 2286–2301. [Google Scholar] [CrossRef] [Green Version]
  51. Mihai, S.; Codrici, E.; Popescu, I.D. Inflammation-Related Mechanisms in Chronic Kidney Disease Prediction, Progression, and Outcome. J. Immunol. Res. 2018, 2018, 2180373. [Google Scholar] [CrossRef] [Green Version]
  52. Rapa, S.F.; Di Iorio, B.R.; Campiglia, P.; Heidland, A.; Marzocco, S. Inflammation and Oxidative Stress in Chronic Kidney Disease—Potential Therapeutic Role of Minerals, Vitamins and Plant-Derived Metabolites. Int. J. Mol. Sci. 2019, 21, 263. [Google Scholar] [CrossRef]
  53. Ponticelli, C.; Podestà, M.A.; Moroni, G. Hyperuricemia as a trigger of immune response in hypertension and chronic kidney disease. Kidney Int. 2020, 98, 1149–1159. [Google Scholar] [CrossRef] [PubMed]
  54. Varghese, M.; Song, J.; Singer, K. Age and Sex: Impact on adipose tissue metabolism and inflammation. Mech. Ageing Dev. 2021, 199, 111563. [Google Scholar] [CrossRef] [PubMed]
  55. Raupachova, J.; Kopecky, C.; Cohen, G. High-Density Lipoprotein from Chronic Kidney Disease Patients Modulates Polymorphonuclear Leukocytes. Toxins 2019, 11, 73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Eleftheriadis, T.; Antoniadi, G.; Liakopoulos, V.; Kartsios, C.; Stefanidis, I. Disturbances of acquired immunity in hemodialysis patients. Semin. Dial. 2007, 20, 440–451. [Google Scholar] [CrossRef] [PubMed]
  57. Lisowska, K.A.; Pindel, M.; Pietruczuk, K. The influence of a single hemodialysis procedure on human T lymphocytes. Sci. Rep. 2019, 9, 5041. [Google Scholar] [CrossRef] [Green Version]
  58. Carracedo, J.; Ramírez, R.; Madueño, J.A. Cell apoptosis and hemodialysis-induced inflammation. Kidney Int Suppl. 2002, 61, S89–S93. [Google Scholar] [CrossRef] [Green Version]
  59. Yu, C.; Liu, Z.H.; Chen, Z.H.; Gong, D.H.; Ji, D.X.; Li, L.S.H. Improvement of monocyte function and immune homeostasis by high volume continuous venovenous hemofiltration in patients with severe acute pancreatitis. Int. J. Artif. Organs 2008, 31, 882–890. [Google Scholar] [CrossRef]
  60. Nongnuch, A.; Ngampongpan, W.; Srichatrapimuk, S.; Wongsa, A.; Thongpraphai, S.; Boonarkart, C.; Sanmeema, N.; Chittaganpitch, M.; Auewarakul, P.; Tassaneetrithep, B.; et al. Immune response to influenza vaccination in ESRD patients undergoing hemodialysis vs. hemodiafiltration. PLoS ONE 2020, 15, e0227719. [Google Scholar] [CrossRef]
  61. Xiaoyan, J.; Rongyi, C.; Xuesen, C. The difference of T cell phenotypes in end stage renal disease patients under different dialysis modality. BMC Nephrol. 2019, 20, 301. [Google Scholar] [CrossRef] [Green Version]
  62. Caprara, C.; Corradi, V.; Scalzotto, E. Differential effects of peritoneal and hemodialysis on circulating regulatory T cells one month post initiation of renal replacement therapy. Clin. Nephrol. 2021, 95, 37–44. [Google Scholar] [CrossRef]
  63. Ducloux, D.; Legendre, M.; Bamoulid, J. ESRD-associated immune phenotype depends on dialysis modality and iron status: Clinical implications. Immun. Ageing 2018, 15, 16. [Google Scholar] [CrossRef] [PubMed]
  64. Simon, B.; Rubey, H.; Treipl, A. Haemodialysis patients show a highly diminished antibody response after COVID-19 mRNA vaccination compared with healthy controls. Nephrol. Dial. Transplant. 2021, 36, 1709–1716. [Google Scholar] [CrossRef] [PubMed]
  65. Garcia, P.; Anand, S.; Han, J. COVID-19 vaccine type and humoral immune response in patients receiving dialysis. J. Am. Soc. Nephrol. 2022, 33, 33–37. [Google Scholar] [CrossRef] [PubMed]
  66. Thieme, C.J.; Blazquez-Navarro, A.; Safi, L.; Kaliszczyk, S.; Paniskaki, K.; Neumann, I.E.; Schmidt, K.; Stockhausen, M.; Hörstrup, J.; Cinkilic, O.; et al. Impaired Humoral but Substantial Cellular Immune Response to Variants of Concern B1.1.7 and B.1.351 in Hemodialysis Patients after Vaccination with BNT162b2. J. Am. Soc. Nephrol. 2021, 32, 2725–2727. [Google Scholar] [CrossRef] [PubMed]
  67. Brunelli, S.M.; Sibbel, S.; Karpinski, S.; Marlowe, G.; Walker, A.G.; Giullian, J.; Van Wyck, D.; Kelley, T.; Lazar, R.; Zywno, M.L.; et al. Comparative Effectiveness of mRNA-based BNT162b2 Vaccine versus Adenovirus Vector–Based Ad26.COV2. S Vaccine for the Prevention of COVID-19 among Dialysis Patients. J. Am. Soc. Nephrol. 2022, 33, 688–697. [Google Scholar] [CrossRef]
  68. Ashby, D.R.; Caplin, B.; Corbett, R.W.; Asgari, E.; Kumar, N.; Sarnowski, A.; Hull, R.; Makanjuola, D.; Cole, N.; Chen, J.; et al. Severity of COVID-19 after Vaccination among Hemodialysis Patients: An Observational Cohort Study. Clin. J. Am. Soc. Nephrol. 2022, 17, 843–850. [Google Scholar] [CrossRef]
  69. Ikizler, T.A.; Coates, P.T.; Rovin, B.H.; Ronco, P. Immune response to SARS-CoV-2 infection and vaccination in patients receiving kidney replacement therapy. Kidney Int. 2021, 99, 1275–1279. [Google Scholar] [CrossRef]
  70. Oliver, M.J.; Thomas, D.; Balamchi, S.; Ip, J.; Naylor, K.; Dixon, S.N.; McArthur, E.; Kwong, J.; Perl, J.; Atiquzzaman, M.; et al. Vaccine Effectiveness Against SARS-CoV-2 Infection and Severe Outcomes in the Maintenance Dialysis Population in Ontario, Canada. J. Am. Soc. Nephrol. 2022, 33, 839–849. [Google Scholar] [CrossRef]
  71. Zitt, E.; Davidovic, T.; Schimpf, J. The Safety and Immunogenicity of the mRNA-BNT162b2 SARS-CoV-2 Vaccine in Hemodialysis Patients. Front. Immunol. 2021, 12, 704773. [Google Scholar] [CrossRef]
  72. Bertrand, D.; Hamzaoui, M.; Lemée, V.; Lamulle, J.; Hanoy, M.; Laurent, C.; Lebourg, L.; Etienne, I.; Lemoine, M.; Le Roy, F.; et al. Antibody and T Cell Response to SARS-CoV-2 Messenger RNA BNT162b2 Vaccine in Kidney Transplant Recipients and Hemodialysis Patients. J. Am. Soc. Nephrol. 2021, 32, 2147–2152. [Google Scholar] [CrossRef]
  73. Ma, B.M.; Tam, A.R.; Chan, K.W. Immunogenicity and Safety of COVID-19 Vaccines in Patients Receiving Renal Replacement Therapy: A Systematic Review and Meta-Analysis. Front. Med. 2022, 9, 827859. [Google Scholar] [CrossRef] [PubMed]
  74. Hou, Y.-C.; Lu, K.-C.; Kuo, K.-L. The Efficacy of COVID-19 Vaccines in Chronic Kidney Disease and Kidney Transplantation Patients: A Narrative Review. Vaccines 2021, 9, 885. [Google Scholar] [CrossRef] [PubMed]
  75. Bensouna, I.; Caudwell, V.; Kubab, S. SARS-CoV-2 Antibody Response After a Third Dose of the BNT162b2 Vaccine in Patients Receiving Maintenance Hemodialysis or Peritoneal Dialysis. Am. J. Kidney Dis. 2022, 79, 185–192.e1. [Google Scholar] [CrossRef] [PubMed]
  76. Dekervel, M.; Henry, N.; Torreggiani, M.; Pouteau, L.-M.; Imiela, J.-P.; Mellaza, C.; Garnier, A.-S.; Dujardin, A.; Asfar, M.; Ducancelle, A.; et al. Humoral response to a third injection of BNT162b2 vaccine in patients on maintenance haemodialysis. Clin. Kidney J. 2021, 14, 2349–2355. [Google Scholar] [CrossRef] [PubMed]
  77. Biedunkiewicz, B.; Tylicki, L.; Ślizień, W.; Lichodziejewska-Niemierko, M.; Dąbrowska, M.; Kubanek, A.; Rodak, S.; Polewska, K.; Tylicki, P.; Renke, M.; et al. Waning Humoral Response after COVID-19 mRNA Vaccination in Maintenance Dialysis Patients and Recovery after a Complementary Third Dose. Vaccines 2022, 10, 433. [Google Scholar] [CrossRef] [PubMed]
  78. Yahav, D.; Rahamimov, R.; Mashraki, T.; Ben-Dor, N.; Steinmetz, T.; Agur, T.; Zingerman, B.; Herman-Edelstein, M.; Lichtenberg, S.; Ben-Zvi, H.; et al. Immune Response to Third Dose BNT162b2 COVID-19 Vaccine Among Kidney Transplant Recipients—A Prospective Study. Transpl. Int. 2022, 35, 10204. [Google Scholar] [CrossRef]
  79. Housset, P.; Kubab, S.; Hanafi, L. Humoral response after a fourth “booster” dose of a Coronavirus disease 2019 vaccine following a 3-dose regimen of mRNA-based vaccination in dialysis patients. Kidney Int. 2022, 101, 1289–1290. [Google Scholar] [CrossRef] [PubMed]
  80. Jahn, M.; Korth, J.; Dorsch, O.; Anastasiou, O.E.; Krawczyk, A.; Brochhagen, L.; van de Sand, L.; Sorge-Hädicke, B.; Tyczynski, B.; Witzke, O.; et al. Decline of Humoral Responses 6 Months after Vaccination with BNT162b2 (Pfizer–BioNTech) in Patients on Hemodialysis. Vaccines 2022, 10, 327. [Google Scholar] [CrossRef]
  81. Clarke, C.L.; Prendecki, M.; Dhutia, A.; Gan, J.; Edwards, C.; Prout, V.; Lightstone, L.; Parker, E.; Marchesin, F.; Griffith, M.; et al. Longevity of SARS-CoV-2 immune responses in hemodialysis patients and protection against reinfection. Kidney Int. 2021, 99, 1470–1477. [Google Scholar] [CrossRef]
  82. Agur, T.; Ben-Dor, N.; Herman-Edelstein, M. Longevity of Humoral Response Six Months Following BNT162b2 Vaccine in Dialysis Patients. Front. Med. 2022, 9, 781888. [Google Scholar] [CrossRef]
  83. Dulovic, A.; Strengert, M.; Ramos, G.M.; Becker, M.; Griesbaum, J.; Junker, D.; Lürken, K.; Beigel, A.; Wrenger, E.; Lonnemann, G.; et al. Diminishing Immune Responses against Variants of Concern in Dialysis Patients 4 Months after SARS-CoV-2 mRNA Vaccination. Emerg. Infect. Dis. 2022, 28, 743–750. [Google Scholar] [CrossRef] [PubMed]
  84. Rubin, L.G.; Levin, M.J.; Ljungman, P.; Davies, E.G.; Avery, R.; Tomblyn, M.; Bousvaros, A.; Dhanireddy, S.; Sung, L.; Keyserling, H.; et al. 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host. Clin. Infect. Dis. 2013, 58, e44–e100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Lee, D.; Boyle, S.; Malat, G.; Sharma, A.; Bias, T.; Doyle, A. Low rates of vaccination in listed kidney transplant candidates. Transpl. Infect. Dis. 2016, 18, 155–159. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am. J. Transplant. 2009, 9, S1–S155. [Google Scholar] [CrossRef]
  87. Duchini, A.; Goss, J.A.; Karpen, S.; Pockros, P.J. Vaccinations for Adult Solid-Organ Transplant Recipients: Current Recommendations and Protocols. Clin. Microbiol. Rev. 2003, 16, 357–364. [Google Scholar] [CrossRef] [Green Version]
  88. Katerinis, I.; Hadaya, K.; Duquesnoy, R.; Ferrari-Lacraz, S.; Meier, S.; Van Delden, C.; Martin, P.-Y.; Siegrist, C.-A.; Villard, J. De Novo Anti-HLA Antibody After Pandemic H1N1 and Seasonal Influenza Immunization in Kidney Transplant Recipients. Am. J. Transplant. 2011, 11, 1727–1733. [Google Scholar] [CrossRef]
  89. Fairhead, T.; Hendren, E.; Tinckam, K.; Rose, C.; Sherlock, C.; Shi, L.; Crowcroft, N.; Gubbay, J.; Landsberg, D.; Knoll, G.; et al. Poor seroprotection but allosensitization after adjuvanted pandemic influenza H1N1 vaccine in kidney transplant recipients. Transpl. Infect. Dis. 2012, 14, 575–583. [Google Scholar] [CrossRef]
  90. Blumberg, E.A.; Fitzpatrick, J.; Stutman, P.C. Safety of influenza vaccine in heart transplant recipients. J. Heart Lung Transplant. 1998, 17, 1075–1080. Available online: https://pubmed.ncbi.nlm.nih.gov/9855446/ (accessed on 12 October 2022).
  91. Salles, M.J.C.; Sens, Y.A.S.; Malafronte, P.; Souza, J.F.; Vilas Boas, L.S.; Machado, C.M. Antibody response to the non-adjuvanted and adjuvanted influenza A H1N1/09 monovalent vaccines in renal transplant recipients. Transpl. Infect. Dis. 2012, 14, 564–574. [Google Scholar] [CrossRef]
  92. Bosaeed, M.; Kumar, D. Seasonal influenza vaccine in immunocompromised persons. Hum. Vaccin. Immunother. 2018, 14, 1311–1322. [Google Scholar] [CrossRef]
  93. Zipeto, D.; da Fonseca Palmeira, J.; Argañaraz, G.A.; Argañaraz, E.R. ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19. Front. Immunol. 2020, 11, 576745. [Google Scholar] [CrossRef] [PubMed]
  94. Senapati, S.; Banerjee, P.; Bhagavatula, S.; Kushwaha, P.P.; Kumar, S. Contributions of human ACE2 and TMPRSS2 in determining host–pathogen interaction of COVID-19. J. Genet. 2021, 100, 12. [Google Scholar] [CrossRef] [PubMed]
  95. Perico, L.; Benigni, A.; Remuzzi, G. Angiotensin-converting enzyme 2: From a vasoactive peptide to the gatekeeper of a global pandemic. Curr. Opin. Nephrol. Hypertens. 2021, 30, 252–263. [Google Scholar] [CrossRef]
  96. Murgolo, N.; Therien, A.G.; Howell, B.; Klein, D.; Koeplinger, K.; Lieberman, L.A.; Adam, G.C.; Flynn, J.; McKenna, P.; Swaminathan, G.; et al. SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development. PLoS Pathog. 2021, 17, e1009225. [Google Scholar] [CrossRef] [PubMed]
  97. Tharmaraj, D.; Dendle, C.; Polkinghorne, K.R.; Mulley, W.R. Kidney transplant recipients’ attitudes toward COVID-19 vaccination and barriers and enablers to vaccine acceptance. Transpl. Infect. Dis. 2022, 24, e13749. [Google Scholar] [CrossRef]
  98. Sattler, A.; Schrezenmeier, E.; Weber, U.A.; Potekhin, A.; Bachmann, F.; Straub-Hohenbleicher, H.; Budde, K.; Storz, E.; Proß, V.; Bergmann, Y.; et al. Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients. J. Clin. Investig. 2021, 131, e150175. [Google Scholar] [CrossRef]
  99. Mazzola, A.; Todesco, E.; Drouin, S.; Hazan, F.; Marot, S.; Thabut, D.; Varnous, S.; Soulié, C.; Barrou, B.; Marcelin, A.-G.; et al. Poor Antibody Response After Two Doses of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine in Transplant Recipients. Clin. Infect. Dis. 2022, 74, 1093–1096. [Google Scholar] [CrossRef]
  100. Grupper, A.; Rabinowich, L.; Schwartz, D.; Schwartz, I.F.; Ben-Yehoyada, M.; Shashar, M.; Katchman, E.; Halperin, T.; Turner, D.; Goykhman, Y.; et al. Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus. Arab. Archaeol. Epigr. 2021, 21, 2719–2726. [Google Scholar] [CrossRef]
  101. Magicova, M.; Zahradka, I.; Fialova, M.; Neskudla, T.; Gurka, J.; Modos, I.; Hojny, M.; Raska, P.; Smejkal, P.; Striz, I.; et al. Determinants of Immune Response to Anti–SARS-CoV-2 mRNA Vaccines in Kidney Transplant Recipients: A Prospective Cohort Study. Transplantation 2022, 106, 842–852. [Google Scholar] [CrossRef]
  102. Azzi, Y.; Raees, H.; Wang, T.; Cleare, L.; Liriano-Ward, L.; Loarte-Campos, P.; Pynadath, C.; Ajaimy, M.; Alani, O.; Bao, Y.; et al. Risk factors associated with poor response to COVID-19 vaccination in kidney transplant recipients. Kidney Int. 2021, 100, 1127–1128. [Google Scholar] [CrossRef]
  103. Russo, G.; Lai, Q.; Poli, L.; Perrone, M.P.; Gaeta, A.; Rossi, M.; Mastroianni, C.M.; Garofalo, M.; Pretagostini, R. SARS-CoV-2 vaccination with BNT162B2 in renal transplant patients: Risk factors for impaired response and immunological implications. Clin. Transplant. 2022, 36, e14495. [Google Scholar] [CrossRef] [PubMed]
  104. Boyarsky, B.J.; Chiang, T.P.-Y.; Ou, M.T. Antibody Response to the Janssen COVID-19 Vaccine in Solid Organ Transplant Recipients. Transplantation 2021, 105, e82–e83. [Google Scholar] [CrossRef] [PubMed]
  105. Sadarangani, M.; Marchant, A.; Kollmann, T.R. Immunological mechanisms of vaccine-induced protection against COVID-19 in humans. Nat. Rev. Immunol. 2021, 21, 475–484. [Google Scholar] [CrossRef]
  106. Zhang, R.; Shin, B.; Gadsden, T.M.; Petrosyan, A.; Vo, A.; Ammerman, N.; Sethi, S.; Huang, E.; Peng, A.; Najjar, R.; et al. Assessment of humoral and cellular immune responses to SARS-CoV-2 vaccination (BNT162b2) in immunocompromised renal allograft recipients. Transpl. Infect. Dis. 2022, 24, e13813. [Google Scholar] [CrossRef] [PubMed]
  107. Hodgson, S.H.; Mansatta, K.; Mallett, G.; Harris, V.; Emary, K.R.W.; Pollard, A.J. What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2. Lancet Infect. Dis. 2021, 21, e26–e35. [Google Scholar] [CrossRef]
  108. Charmetant, X.; Espi, M.; Barba, T. Predictive factors of a viral neutralizing humoral response after a third dose of COVID-19 mRNA vaccine. Am. J. Transplant. 2022, 22, 1442–1450. [Google Scholar] [CrossRef]
  109. Werbel, W.A.; Boyarsky, B.J.; Ou, M.T. Safety and Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series. Ann. Intern. Med. 2021, 174, 1330–1332. [Google Scholar] [CrossRef]
  110. Reindl-Schwaighofer, R.; Heinzel, A.; Mayrdorfer, M.; Jabbour, R.; Hofbauer, T.M.; Merrelaar, A.; Eder, M.; Regele, F.; Doberer, K.; Spechtl, P.; et al. Comparison of SARS-CoV-2 Antibody Response 4 Weeks After Homologous vs. Heterologous Third Vaccine Dose in Kidney Transplant Recipients: A Randomized Clinical Trial. JAMA Intern. Med. 2022, 182, 165–171. [Google Scholar] [CrossRef]
  111. Marlet, J.; Gatault, P.; Maakaroun, Z. Antibody Responses after a Third Dose of COVID-19 Vaccine in Kidney Transplant Recipients and Patients Treated for Chronic Lymphocytic Leukemia. Vaccines 2021, 9, 1055. [Google Scholar] [CrossRef]
  112. Benotmane, I.; Gautier, G.; Perrin, P. Antibody Response After a Third Dose of the mRNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients with Minimal Serologic Response to 2 Doses. JAMA 2021, 326, 1063–1065. [Google Scholar] [CrossRef]
  113. Anichini, G.; Terrosi, C.; Gandolfo, C. SARS-CoV-2 Antibody Response in Persons with Past Natural Infection. N. Engl. J. Med. 2021, 385, 90–92. [Google Scholar] [CrossRef] [PubMed]
  114. Tylicki, L.; Dębska-Ślizień, A.; Muchlado, M. Boosting Humoral Immunity from mRNA COVID-19 Vaccines in Kidney Transplant Recipients. Vaccines 2021, 10, 56. [Google Scholar] [CrossRef] [PubMed]
  115. Massa, F.; Cremoni, M.; Gérard, A.; Grabsi, H.; Rogier, L.; Blois, M.; Couzin, C.; Ben Hassen, N.; Rouleau, M.; Barbosa, S.; et al. Safety and cross-variant immunogenicity of a three-dose COVID-19 mRNA vaccine regimen in kidney transplant recipients. eBioMedicine 2021, 73, 103679. [Google Scholar] [CrossRef]
  116. Schrezenmeier, E.; Rincon-Arevalo, H.; Jens, A.; Stefanski, A.-L.; Hammett, C.; Osmanodja, B.; Koch, N.; Zukunft, B.; Beck, J.; Oellerich, M.; et al. Temporary antimetabolite treatment hold boosts SARS-CoV-2 vaccination–specific humoral and cellular immunity in kidney transplant recipients. JCI Insight 2022, 7, e157836. [Google Scholar] [CrossRef] [PubMed]
  117. Stumpf, J.; Tonnus, W.; Paliege, A.; Rettig, R.; Steglich, A.; Gembardt, F.; Kessel, F.; Kröger, H.; Arndt, P.; Sradnick, J.; et al. Cellular and Humoral Immune Responses After 3 Doses of BNT162b2 mRNA SARS-CoV-2 Vaccine in Kidney Transplant. Transplantation 2021, 105, E267–E269. [Google Scholar] [CrossRef] [PubMed]
  118. Andrews, N.; Stowe, J.; Kirsebom, F.; Toffa, S.; Rickeard, T.; Gallagher, E.; Gower, C.; Kall, M.; Groves, N.; O’Connell, A.-M.; et al. COVID-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant. N. Engl. J. Med. 2022, 386, 1532–1546. [Google Scholar] [CrossRef]
  119. Kumar, D.; Hu, Q.; Samson, R. Neutralization against Omicron variant in transplant recipients after three doses of mRNA vaccine. Am. J. Transplant. 2022, 22, 2089–2093. [Google Scholar] [CrossRef]
  120. Caillard, S.; Thaunat, O.; Benotmane, I.; Masset, C.; Blancho, G. Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case Series. Ann. Intern. Med. 2022, 175, 455–456. [Google Scholar] [CrossRef]
  121. Karaba, A.H.; Johnston, T.S.; Aytenfisu, T.Y.; Akinde, O.; Eby, Y.; Ruff, J.E.; Abedon, A.T.; Alejo, J.L.; Blankson, J.N.; Cox, A.L.; et al. A Fourth Dose of COVID-19 Vaccine Does Not Induce Neutralization of the Omicron Variant Among Solid Organ Transplant Recipients with Suboptimal Vaccine Response. Transplantation 2022, 106, 1440–1444. [Google Scholar] [CrossRef]
  122. Alejo, J.L.; Mitchell, J.; Chiang, T.P.-Y.; Abedon, A.T.; Boyarsky, B.J.; Avery, R.K.; Tobian, A.A.; Levan, M.L.; Massie, A.B.; Garonzik-Wang, J.M.; et al. Antibody Response to a Fourth Dose of a SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series. Transplantation 2021, 105, E280–E281. [Google Scholar] [CrossRef]
  123. Masset, C.; Benotmane, I.; Dantal, J. A fourth SARS-CoV-2 mRNA vaccine in strictly seronegative kidney transplant recipients. Kidney Int. 2022, 101, 825–826. [Google Scholar] [CrossRef]
  124. Cucchiari, D.; Egri, N.; Bodro, M.; Herrera, S.; Del Risco-Zevallos, J.; Casals-Urquiza, J.; Cofan, F.; Moreno, A.; Rovira, J.; Banon-Maneus, E.; et al. Cellular and humoral response after MRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients. Am. J. Transplant. 2021, 21, 2727–2739. [Google Scholar] [CrossRef]
  125. Chukwu, C.A.; Mahmood, K.; Elmakki, S. Evaluating the antibody response to SARS-CoV-2 vaccination amongst kidney transplant recipients at a single nephrology centre. PLoS ONE 2022, 17, e0265130. [Google Scholar] [CrossRef]
  126. Kantauskaite, M.; Müller, L.; Kolb, T.; Fischer, S.; Hillebrandt, J.; Ivens, K.; Andree, M.; Luedde, T.; Orth, H.M.; Adams, O.; et al. Intensity of mycophenolate mofetil treatment is associated with an impaired immune response to SARS-CoV-2 vaccination in kidney transplant recipients. Am. J. Transplant. 2022, 22, 634–639. [Google Scholar] [CrossRef]
  127. Altheaby, A.; Alloqmani, D.; AlShammari, R. Safety and Efficacy of the COVID-19 Vaccine in Kidney Transplant Recipients. Cureus 2022, 14, e24753. [Google Scholar] [CrossRef]
  128. Boyarsky, B.J.; Werbel, W.A.; Avery, R.K. Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients. JAMA 2021, 325, 2204–2206. [Google Scholar] [CrossRef]
  129. Boedecker-Lips, S.C.; Lautem, A.; Runkel, S.; Klimpke, P.; Kraus, D.; Keil, P.; Holtz, S.; Tomalla, V.; Marczynski, P.; Boedecker, C.B.; et al. Six-Month Follow-Up after Vaccination with BNT162b2: SARS-CoV-2 Antigen-Specific Cellular and Humoral Immune Responses in Hemodialysis Patients and Kidney Transplant Recipients. Pathogens 2022, 11, 67. [Google Scholar] [CrossRef]
  130. Lai, Q.; Spoletini, G.; Bianco, G. SARS-CoV-2 and immunosuppression: A double-edged sword. Transpl. Infect. Dis. 2020, 22, e13404. [Google Scholar] [CrossRef]
  131. Netti, G.S.; Infante, B.; Troise, D.; Mercuri, S.; Panico, M.; Spadaccino, F.; Catalano, V.; Gigante, M.; Simone, S.; Pontrelli, P.; et al. mTOR inhibitors improve both humoral and cellular response to SARS-CoV-2 messenger RNA BNT16b2 vaccine in kidney transplant recipients. Am. J. Transplant. 2022, 22, 1475–1482. [Google Scholar] [CrossRef]
  132. Baker, D.; Roberts, C.A.K.; Pryce, G. COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases. Clin. Exp. Immunol. 2020, 202, 149–161. [Google Scholar] [CrossRef]
  133. Prendecki, M.; Clarke, C.; Edwards, H.; McIntyre, S.; Mortimer, P.; Gleeson, S.; Martin, P.; Thomson, T.; Randell, P.; Shah, A.; et al. Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression. Ann. Rheum. Dis. 2021, 80, 1322–1329. [Google Scholar] [CrossRef] [PubMed]
  134. Wade, S.D.; Kyttaris, V.C. Rituximab-associated hypogammaglobulinemia in autoimmune rheumatic diseases: A single-center retrospective cohort study. Rheumatol. Int. 2021, 41, 1115–1124. [Google Scholar] [CrossRef] [PubMed]
  135. Ou, M.T.; Boyarsky, B.J.; Chiang, T.P. Immunogenicity and Reactogenicity After SARS-CoV-2 mRNA Vaccination in Kidney Transplant Recipients Taking Belatacept. Transplantation 2021, 105, 2119–2123. [Google Scholar] [CrossRef] [PubMed]
  136. Chavarot, N.; Ouedrani, A.; Marion, O.; Leruez-Ville, M.; Vilain, E.; Baaziz, M.; Del Bello, A.; Burger, C.; Sberro-Soussan, R.; Martinez, F.; et al. Poor Anti-SARS-CoV-2 Humoral and T-cell Responses After 2 Injections of mRNA Vaccine in Kidney Transplant Recipients Treated with Belatacept. Transplantation 2021, 105, E94–E95. [Google Scholar] [CrossRef]
  137. Osmanodja, B.; Ronicke, S.; Budde, K.; Jens, A.; Hammett, C.; Koch, N.; Seelow, E.; Waiser, J.; Zukunft, B.; Bachmann, F.; et al. Serological Response to Three, Four and Five Doses of SARS-CoV-2 Vaccine in Kidney Transplant Recipients. J. Clin. Med. 2022, 11, 2565. [Google Scholar] [CrossRef]
  138. Doria-Rose, N.; Suthar, M.S.; Makowski, M.; O’Connell, S.; McDermott, A.B.; Flach, B.; Ledgerwood, J.E.; Mascola, J.R.; Graham, B.S.; Lin, B.C.; et al. Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for COVID-19. N. Engl. J. Med. 2021, 384, 2259–2261. [Google Scholar] [CrossRef]
  139. Fernandes, G.; Devresse, A.; Scohy, A.; Yombi, J.C.; Belkhir, L.; De Greef, J.; De Meyer, M.; Mourad, M.; Darius, T.; Buemi, A.; et al. Rapid Decline in Vaccine-induced Anti-SARS-CoV-2 Antibody Titers 3 Months After Kidney Transplantation: A Case Series from Belgium. Transplantation 2022, 106, E98–E99. [Google Scholar] [CrossRef]
  140. Meo, S.A.; Bukhari, I.A.; Akram, J.; Meo, A.S.; Klonoff, D.C. COVID-19 vaccines: Comparison of biological, pharmacological characteristics and adverse effects of Pfizer/BioNTech and Moderna Vaccines. Eur. Rev. Med. Pharmacol. Sci. 2021, 25, 1663–1669. [Google Scholar] [CrossRef]
  141. Boyarsky, B.J.; Ou, M.T.; Greenberg, R.S. Safety of the First Dose of SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients. Transplantation 2021, 105, e56–e57. [Google Scholar] [CrossRef]
  142. Phadke, V.K.; Scanlon, N.; Jordan, S.C.; Rouphael, N.G. Immune Responses to SARS-CoV-2 in Solid Organ Transplant Recipients. Curr. Transplant. Rep. 2021, 8, 127–139. [Google Scholar] [CrossRef]
  143. Jurdi, A.A.; Gassen, R.B.; Borges, T.J.; Solhjou, Z.; Hullekes, F.E.; Lape, I.T.; Efe, O.; Alghamdi, A.; Patel, P.; Choi, J.Y.; et al. Non-Invasive Monitoring for Rejection in Kidney Transplant Recipients After SARS-CoV-2 mRNA Vaccination. Front. Immunol. 2022, 13, 838985. [Google Scholar] [CrossRef]
  144. del Bello, A.; Marion, O.; Delas, A.; Congy-Jolivet, N.; Colombat, M.; Kamar, N. Acute rejection after anti–SARS-CoV-2 mRNA vaccination in a patient who underwent a kidney transplant. Kidney Int. 2021, 100, 238–239. [Google Scholar] [CrossRef]
  145. Vnučák, M.; Graňák, K.; Beliančinová, M. Acute kidney rejection after anti-SARS-CoV-2 virus-vectored vaccine—Case report. NPJ Vaccines 2022, 7, 30. [Google Scholar] [CrossRef]
  146. Lim, J.-H.; Han, M.-H.; Kim, Y.-J. New-onset Nephrotic Syndrome after Janssen COVID-19 Vaccination: A Case Report and Literature Review. J. Korean Med. Sci. 2021, 36, 1011–8934. [Google Scholar] [CrossRef] [PubMed]
  147. Maas, R.J.; Gianotten, S.; van der Meijden, W.A.G. An Additional Case of Minimal Change Disease Following the Pfizer-BioNTech COVID-19 Vaccine. Am. J. Kidney Dis. 2021, 78, 312. [Google Scholar] [CrossRef] [PubMed]
  148. Mancianti, N.; Guarnieri, A.; Tripodi, S.; Salvo, D.P.; Garosi, G. Minimal change disease following vaccination for SARS-CoV-2. J. Nephrol. 2021, 34, 1039–1040. [Google Scholar] [CrossRef] [PubMed]
  149. Unver, S.; Haholu, A.; Yildirim, S. Nephrotic syndrome and acute kidney injury following CoronaVac anti-SARS-CoV-2 vaccine. Clin. Kidney J. 2021, 14, 2608–2611. [Google Scholar] [CrossRef]
  150. Wu, H.H.L.; Kalra, P.A.; Chinnadurai, R. New-Onset and Relapsed Kidney Histopathology Following COVID-19 Vaccination: A Systematic Review. Vaccines 2021, 9, 1252. [Google Scholar] [CrossRef]
  151. Caza, T.N.; Cassol, C.A.; Messias, N.; Hannoudi, A.; Haun, R.S.; Walker, P.D.; May, R.M.; Seipp, R.M.; Betchick, E.J.; Amin, H.; et al. Glomerular Disease in Temporal Association with SARS-CoV-2 Vaccination: A Series of 29 Cases. Kidney360 2021, 2, 1770–1780. [Google Scholar] [CrossRef]
  152. Rieckmann, S.; Seibert, F.S.; Hogeweg, M. Acute interstitial nephritis after vaccination with BNT162b2. J. Nephrol. 2022, 35, 779–782. [Google Scholar] [CrossRef]
  153. Jefferis, J.; Kassianos, A.J.; Grivei, A. SARS-CoV-2 vaccination–associated collapsing glomerulopathy in a kidney transplant recipient. Kidney Int. 2022, 101, 635–636. [Google Scholar] [CrossRef] [PubMed]
  154. Liu, J.; Wang, J.; Xu, J.; Xia, H.; Wang, Y.; Zhang, C.; Chen, W.; Zhang, H.; Liu, Q.; Zhu, R.; et al. Comprehensive investigations revealed consistent pathophysiological alterations after vaccination with COVID-19 vaccines. Cell Discov. 2021, 7, 99. [Google Scholar] [CrossRef]
  155. Chu, D.K.; Duda, S. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: A systematic review and meta-analysis. Lancet 2020, 395, 1973–1987. [Google Scholar] [CrossRef]
  156. Vandeberg, P.; Cruz, M.; Diez, J.M. Production of anti-SARS-CoV-2 hyperimmune globulin from convalescent plasma. Transfusion 2021, 61, 1705–1709. [Google Scholar] [CrossRef] [PubMed]
  157. Wang, Q.; Zhang, Y.; Wu, L.; Niu, S.; Song, C.; Zhang, Z.; Lu, G.; Qiao, C.; Hu, Y.; Yuen, K.Y.; et al. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell 2020, 181, 894–904.e9. [Google Scholar] [CrossRef]
  158. Shang, J.; Ye, G.; Shi, K. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020, 581, 221–224. [Google Scholar] [CrossRef] [Green Version]
  159. Monteil, V.; Kwon, H.; Prado, P.; Hagelkrüys, A.; Wimmer, R.A.; Stahl, M.; Leopoldi, A.; Garreta, E.; Del Pozo, C.H.; Prosper, F.; et al. Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell 2020, 181, 905–913.e7. [Google Scholar] [CrossRef]
  160. Hassler, L.; Wysocki, J.; Gelarden, I.; Sharma, I.; Tomatsidou, A.; Ye, M.; Gula, H.; Nicoleascu, V.; Randall, G.; Pshenychnyi, S.; et al. A Novel Soluble ACE2 Protein Provides Lung and Kidney Protection in Mice Susceptible to Lethal SARS-CoV-2 Infection. J. Am. Soc. Nephrol. 2022, 33, 1293–1307. [Google Scholar] [CrossRef]
  161. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280.e8. [Google Scholar] [CrossRef]
  162. Loo, Y.-M.; McTamney, P.M.; Arends, R.H.; Abram, M.E.; Aksyuk, A.A.; Diallo, S.; Flores, D.J.; Kelly, E.J.; Ren, K.; Roque, R.; et al. The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans. Sci. Transl. Med. 2022, 14, eabl8124. [Google Scholar] [CrossRef]
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Figure 1. Accumulation of uraemic toxins can lead to depletion and dysfunction of dendritic cells (DCs), polymorphonuclear cells (PMNCs), and monocytes, eventually resulting in an inflammatory state. In addition, uraemic toxins can cause apoptosis of effector T cells, which stimulates the production of inflammatory cytokines and reactive oxygen species (ROS), further increasing inflammation.
Figure 1. Accumulation of uraemic toxins can lead to depletion and dysfunction of dendritic cells (DCs), polymorphonuclear cells (PMNCs), and monocytes, eventually resulting in an inflammatory state. In addition, uraemic toxins can cause apoptosis of effector T cells, which stimulates the production of inflammatory cytokines and reactive oxygen species (ROS), further increasing inflammation.
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Figure 2. Metabolic alterations in CKD that can impair the immune response. Loss of renal function causes retention of uraemic toxins and cytokines, leading to inflammation and increased oxidative stress. The resulting pro-inflammatory uraemic milieu causes activation and decreased function of virtually all immune cells. Uraemia might also cause epigenetic changes that could result in a shift in haematopoietic stem cell populations from lymphoid to myeloid, explaining why lymphoid cell numbers are reduced. These patients also have expanded populations of circulating pro-inflammatory cells of both the lymphoid (CD4+CD28− T cells) and myeloid cell lineages (CD14+CD16++ monocytes).
Figure 2. Metabolic alterations in CKD that can impair the immune response. Loss of renal function causes retention of uraemic toxins and cytokines, leading to inflammation and increased oxidative stress. The resulting pro-inflammatory uraemic milieu causes activation and decreased function of virtually all immune cells. Uraemia might also cause epigenetic changes that could result in a shift in haematopoietic stem cell populations from lymphoid to myeloid, explaining why lymphoid cell numbers are reduced. These patients also have expanded populations of circulating pro-inflammatory cells of both the lymphoid (CD4+CD28− T cells) and myeloid cell lineages (CD14+CD16++ monocytes).
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Figure 3. Coronavirus entry mechanisms. ACE2 is a transmembrane protein and is a main receptor for SARS-CoV-2. After binding to ACE2 the virus enters the cell where it co-opts to diverse cellular functions. Viral spike protein binds to ACE2 on responsive cells. Virus spike protein is either processed by TMPRSS2 and other serine proteases, facilitating cell surface entry, or endocytosis into endosomes, where spike is processed by cathepsin L (CTSL) in the lysosome. Viral RNA is replicated as partial and complete genome copies and translated in the ER to form new SARS-CoV-2 virions. Processing of spike protein by furin occurs prior to release of new viruses into the extracellular environment. ACE2, angiotensin converting enzyme 2; CTSL, cathepsin L; ER, endoplasmic reticulum; NRP1, Neuropilin 1; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2 [96].
Figure 3. Coronavirus entry mechanisms. ACE2 is a transmembrane protein and is a main receptor for SARS-CoV-2. After binding to ACE2 the virus enters the cell where it co-opts to diverse cellular functions. Viral spike protein binds to ACE2 on responsive cells. Virus spike protein is either processed by TMPRSS2 and other serine proteases, facilitating cell surface entry, or endocytosis into endosomes, where spike is processed by cathepsin L (CTSL) in the lysosome. Viral RNA is replicated as partial and complete genome copies and translated in the ER to form new SARS-CoV-2 virions. Processing of spike protein by furin occurs prior to release of new viruses into the extracellular environment. ACE2, angiotensin converting enzyme 2; CTSL, cathepsin L; ER, endoplasmic reticulum; NRP1, Neuropilin 1; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2 [96].
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Table
Table 1. WHO-approved COVID-19 vaccines.
Table 1. WHO-approved COVID-19 vaccines.
Vaccine NameBrand NameManufacturerApproachDose RegimensVaccine Efficacy% (95% CI)
BNT162b2ComirnatyPfizer-BioNTechmRNA2 doses (21 days apart)94.6% [7]
mRNA-1273SpikevaxModernamRNA2 doses (28 days apart)94.1% [8]
AZD1222VaxzevriaAstraZeneca-OxfordViral vector2 doses (28 days apart)66.7%
55.1%
(2 doses < 6 weeks apart) 81.3%
(2 doses > 12 weeks apart) [9]
CovishieldSerum Institute of IndiaViral vector2 doses (4–8 weeks apart)~90% [10]
Ad26.COV2.SJanssen COVID-19 VaccineJohnson & JohnsonViral vector1 dose66% [11]
BBIBP-CorVCoviloSinopharmInactivated virus2 doses (21 days apart)79% [12]
COVID-19 VaccineCoronaVacSinovac BiotechInactivated virus2 doses (14 days apart)50.4% (Brazil),
67% (Chile),
65% (Indonesia),
78% (Brazil),
84% (Turkey)
BBV152CovaxinBharat BiotechViral vector2 doses (28 days apart)81% [13]
NVX-CoV2373NuvaxoidNovavaxProtein subunit2 doses (21 days apart)89.7% [14]
CovovaxSerum Institute of IndiaProtein subunit2 doses (21 days apart)90.4% (USA)
89.7% (UK and Mexico) COVOVAX
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Ponticelli, C.; Campise, M. COVID-19 Vaccination in Kidney Transplant Candidates and Recipients. Vaccines 2022, 10, 1808. https://doi.org/10.3390/vaccines10111808

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Ponticelli C, Campise M. COVID-19 Vaccination in Kidney Transplant Candidates and Recipients. Vaccines. 2022; 10(11):1808. https://doi.org/10.3390/vaccines10111808

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Ponticelli, Claudio, and Mariarosaria Campise. 2022. "COVID-19 Vaccination in Kidney Transplant Candidates and Recipients" Vaccines 10, no. 11: 1808. https://doi.org/10.3390/vaccines10111808

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