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BACKGROUND: The impact of immunosuppression in solid organ transplant recipients with SARS-CoV-2 infection is unknown. The knowledge about the behavior of different immunosuppression schemes in clinical outcomes is scarce. This study aimed to determine the risk of death in kidney transplant recipients with COVID-19 under two different schemes of immunosuppression. METHODS: We describe our experience in kidney transplant recipients with SARS-CoV-2 infection in seven transplant centers during the first year of the pandemic before starting the vaccination programs in the city of Bogotá. Demographic characteristics, clinical presentation, immunosuppression schemes at presentation, and global treatment strategies were compared between recovered and dead patients; survival analysis was carried out between calcineurin inhibitors based regimen and free calcineurin inhibitors regimen. RESULTS: Among 165 confirmed cases, 28 died (17%); the risk factors for mortality identified in univariate analysis were age older than 60 years (p=.003) diabetes (p=.001), immunosuppression based on calcineurin inhibitors (CNI) (p=.025) and patients receiving steroids (p=.041). In multivariable analysis, hypoxemia (p=.000) and calcineurin inhibitors regimen (p=.002) were predictors of death. Survival analysis showed increased mortality risk in patients receiving CNI based immunosuppression regimen vs. CNI free regimens mortality rates were, respectively, 21.7% and 8.5% (p=.036). CONCLUSIONS: Our results suggest that the calcineurin inhibitors probably do not provide greater protection compared to calcineurin inhibitor free schemes being necessary to carry out analyzes that allow us to evaluate the outcomes with different immunosuppression schemes in solid organ transplant recipients with SARS-CoV-2 infection.
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Purpose: The purpose of this study was to assess the clinical characteristics of serologic non-responders to COVID-19 booster vaccination in a cohort of solid organ transplant recipients. Method(s): All solid organ transplant recipients our center who received COVID-19 booster vaccination and had SARS-CoV-2 Spike IgG antibodies checked at least 4 weeks after the dose were included. We evaluated the patients who were found to have negative SARS-CoV-2 Spike IgG antibodies despite booster vaccination (i.e. serologic non-responders). Result(s): Among 657 solid organ transplant patients who had received a booster COVID-19 vaccination, 168 patients had Spike IgG antibodies checked during the study period. Forty-nine patients (29.2%) were found to be seronegative and were included in the analysis. 69% were male with a median age of 60 years. The majority of the cohort (47%) were kidney transplant recipients who had received primary vaccination series at a median of 206 days post-transplant. 65% had received basiliximab for induction immunosuppression. Most of the patients (65%) received primary vaccination with Pfizer COVID-19 vaccine and 67% received Pfizer COVID-19 booster vaccination at a median of 187 days after primary vaccination series. Spike IgG antibodies were checked at a median of 41 days from booster vaccination. No patients received rATG within 90 days of booster administration. Similarly, no patients received high dose (>250mg methylprednisolone equivalent) steroids within 30 days prior to booster vaccination. For immunosuppression, 27% were maintained on belatacept and 82% were on anti-metabolites at the time of the booster vacciantion. Ten patients (20%) experienced a COVID-19 infection postcompletion of their booster vaccination. Conclusion(s): In our solid organ transplant cohort, the majority of serologic nonresponders underwent basiliximab induction and were on an antimetabolite for maintenance immunosuppression. A limitation of our study was the use of different laboratory assays for determining IgG levels. Future work includes evaluating the clinical characteristics of COVID 19 booster serologic responders and comparing the two populations. (Table Presented).
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Purpose: Liver transplant (LT) recipients have a decreased response to 2 doses of SARS-CoV-2 vaccine compared to the general population, so we aimed to understand response to a third dose to inform vaccination strategies. Method(s): LT recipients in our observational cohort who received 3 homologous mRNA vaccines and available antibody levels pre- and post-dose 3 (D3) were identified. Those who reported a prior COVID-19 diagnosis or used belatacept were excluded. The peak anti-spike antibody level collected between the second (D2) and third dose (D3), was compared to the antibody level at 1 month post-D3. Samples were tested with Roche Elecsys Anti-Sars-CoV-2 enzyme immunoassay (EIA) (positive >=0.8 U/mL) or EUROIMMUN EIA (positive >=1.1 AU). Result(s): 146 participants completed 3 homologous doses of BNT162b2 (53%) or mRNA-1273 (47%) vaccines between 5/15/2021 - 11/8/2021. The median (IQR) time of peak pre-D3 antibody collection was 89 (31, 104) days post-D2. The median time of 1-month post-D3 antibody collection was 30 (23, 33) days. The median time between D2 and D3 was 168 (149-188) days. Overall, 125/146 (86%) were seropositive pre-D3, and 139/146 (95%) were seropositive post-D3 (Figure 1). There were no seroreversions post D3, and among the 21 seronegative recipients pre-D3, 14 (67%) seroconverted post-D3. Risk factors significantly associated with persistent seronegativity post-D3 were less time since LT (1.3 vs 6 years, p=0.042), mycophenolate use (100% vs 37%, p=0.001), BNT162b2 series (100% vs 50%, p=0.01), and pre-D3 seronegative status (86% vs 10%, p<0.001). Conclusion(s): Most LT recipients have excellent responses to a third homologous mRNA vaccine dose, greater than that seen in other transplant recipients. Persons seronegative after D2, however, show weaker response and may remain at high risk for SARS-CoV-2 infection despite D3.
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Purpose: The new kidney allocation system has caused increased organ travel times and therefore increased cold ischemia time. Furthermore, the change in the priority to larger transplant centers has caused deprioritized centers to accept higher risk extended criteria donors. These factors lead to increased risk of delayed graft function (DGF). Method(s): To mitigate these risk factors of delayed graft function we have adopted an immunosuppression regimen of de novo belatacept with reduced dose tacrolimus with trough goal level of 5. We hypothesize that the use of belatacept will allow protection against rejection while allowing the renal allogaft to recover from ischemia reperfusion injury without concomitant calcineurin toxicity or vasoconstriction. The delayed addition of low dose tacrolimus can then aid in rejection prevention in addition to belatacept. Result(s): In a cohort of 83 patients we observed one graft loss, two episodes of rejection and three deaths. Of the 130 standard dose tacrolimus with no belatacept we observed no graft losses, seven rejections and one death. Two patients were converted from tacrolimus alone therapy to belatacept plus tacrolimus therapy after the diagnosis of rejection with concomitant tacrolimus toxicity. The belatacept group had a lower rate of rejection, but a higher rate of patient death with a P value <0.001 as calculated with the Z score test. The death in the tacrolimus group was due to covid. Two of the deaths in the belatacept group were cardiovascular, one was a cerebrovascular accident possible related to skull based osteomyelitis. The graft loss in the belatacept group was related to non-compliance. Conclusion(s): Despite initial reports of increased rates of rejection;we report decreased rejection with our belatacept for DGF regimen. We believe this regimen can be a useful tool to utilize more extended criteria donor kidneys in the new kidney allocation system.
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Purpose: The demand for kidney transplant continues to rise, and limited supply has encouraged acceptance of marginal donor organs, such as those at risk for acute kidney injury (AKI). We evaluated the utilization of such organs (defined as donation after cardiac death, pediatric donors, kidneys with a cold ischemic time >24 hrs, terminal serum creatinine (SCr) >2mg/dL or rising SCr with decreasing urine output at donation) at our center who were discharged on belatacept based maintenance immunosuppression with mycophenolate and steroids (BBMS). Method(s): This retrospective, descriptive study examined kidney transplant recipients (KTR) who received AKI organs and were discharged on BBMS between 1/2019-4/2021. Primary outcome assessed graft function and rejection at 6 & 12 months (mos) post-transplant (txp). Secondary outcomes evaluated graft failure, mortality, infection, DSA & changes to BBMS. All outcomes were evaluated at 1yr if records were available. Result(s): 68 KTR w/1 yr results & 52 w/6 mo results on BBMS were included. Baseline characteristics (Table 1) show most KTR received a DCD or en bloc organ and lymphocyte depleting induction. Mean eGFR improved from 1 to 6 mo post-txp and was stable through 1yr. Episodes of biopsy proven rejection were more common during the first 6mos post-txp. There were 2 deaths during the study period, due to COVID, and no graft failures. Twelve KTR developed DSA. There were 21 KTR with CMV viremia, mostly in moderate risk group, & 12 with BK viremia. Table 4 shows changes to BBMS occurred in 32 KTR. Most KTR required multiple BBMS changes with most common dose adjustments to mycophenolate due to leukopenia or neutropenia. Conclusion(s): Utilization of AKI organs with BBMS in KTR at our center resulted in no graft failures & sustained eGFR despite more rejection episodes during the first 6mos post-txp. Although 32 KTR had changes to BBMS, only 5 KTR had rejection following a change. Incidence of CMV was common but did not impact KTR outcomes. Overall, BBMS could be a promising option in AKI organs to avoid nephrotoxicity associated with CNI based regimens. These findings suggest the need to further evaluate the impact of long-term outcomes associated with changes made to BBMS in AKI donor organs.
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Purpose: Kidney transplant recipients taking belatacept (KTR-B) have poor immune response to two-dose SARS-CoV-2 vaccination. We sought to characterize the impact of an additional vaccine dose on plasma neutralizing capacity and cellular responses as compared to that of KTRs controls (KTR-C) not taking belatacept. Method(s): Within an observational cohort, we tested 26 KTR-Bs and 27 KTR-Cs for anti-spike antibody responses before and after a third SARS-CoV-2 vaccine dose (D3) using two clinical assays (Roche Elecsys anti-S Ig and EUROIMMUN anti-S1 IgG). For a subset of 5 KTR-Bs and for all KTR-Cs we used a research assay (Meso Scale Diagnostics V-Plex [MSD]) to further assess anti-spike and RBD IgG, as well as surrogate plasma neutralizing activity (% ACE2 inhibition) versus the ancestral and delta variants. For 3 KTR-Bs, post D3 T cell response was assessed via IFN-y ELISpot and deemed positive if spot forming units > 20 per million PBMC and stimulation index > 3. Result(s): KTR-Bs had significant lower clinical anti-spike seroconversion than KTR-Cs (31% vs 74%, p=0.001) after D3 despite similar demographics, clinical factors, and vaccines administered (Table 1). No KTR-B (0/5) was seropositive by MSD anti-spike or anti-RBD IgG (Figure 1). % ACE2 inhibition versus the ancestral variant was significantly lower in KTR-Bs than in KTR-Cs (Median [IQR] 5.2 [2.8, 6.5] vs 12.5 [7.7, 23.9], p<0.01);all KTR-Bs were below a level consistent with detectable neutralizing antibody. All tested KTR-Bs (3/3) had a negative ELISpot, consistent with negligible cellular response. Conclusion(s): These results suggest minimal humoral or cellular immunogenicity of additional vaccine doses for KTR-Bs and indicates the need for alternative strategies to improve vaccine response such as immunosuppression alteration or use of passive immunoprophylaxis with monoclonal anti-spike antibody to improve protection versus SARS-CoV-2.
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Purpose: SARS CoV-2 vaccination elicits both robust humoral and T-cell immune responses in healthy individuals. However, a comprehensive assessment of immune responses to SARS-CoV-2 vaccination in renal allograft recipients is variable and dependent primarily on Spike IgG levels. Here, we analyzed the humoral and T-cell responses in vaccinated transplant recipients. Method(s): 61Tx patients maintained either on Tacrolimus (TAC, 32) or Belatacept (BELA, 29) who were greater than one month post 2nd dose of the Pfizer BNT162b2, and 41 healthy individuals were enrolled. Fresh whole blood was incubated with SARS CoV-2 Spike peptides pool and the activated CD4+ (IL-2/TNF-alpha)+ and CD8+ (TNF-alpha/IFN-gamma)+ T cells were enumerated by flow cytometry and defined as CoV-2-specific T cells. Plasma was analyzed for Spike Receptor Binding Domain (RBD)-specific IgG by ELISA. The Spike RBD-specific IgG levels and Spikespecific CD4+/CD8+ T-cell immune responses were analyzed in TAC- and Bela- Tx patients along with healthy controls. Result(s): Our data demonstrated poor Spike IgG and T cell immune responses in Tx patients1M post-2nd dose of vaccine (21% v. 93% in positive Spike IgG and 37% v. 88% in positive T cell responses, Tx v. controls, respectively). However, 34% of Spike IgG (-) patients demonstrated positive CD4+ and/or CD8+ T-cell immune responses. No significant difference in T cell immunity was found between TAC and BELA treated patients. Conclusion(s): Immunocompromised Tx patients demonstrated significant defects in humoral and T cell immune response after vaccination. Patients maintained on TAC v. BELA demonstrated similar depressions in immune responses post-vaccination. 34% of vaccinated Tx patients, demonstrated Spike-specific T cell immunity despite being Spike IgG negative. This is suggestive of a divergent immune response with dominant cellular immunity. These observations are important since activation of T-cell immunity early after exposure to SARS-CoV2, while not preventing infection will likely modify severity of disease. (Table Presented).
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Purpose: Mortality from COVID-19 among kidney transplant recipients (KTR) is unacceptably high, and their response to up to three vaccinations against SARSCoV- 2 is strongly impaired. We provide the first systematic analysis of serological response to up to five repeated vaccinations in nonresponding KTR. Method(s): We retrospectively analyzed serological response to basic immunization, as well as administration of three, four and five doses of SARS-CoV-2 vaccine in KTR from December 27, 2020 until December 31, 2021. In particular, the influence of different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. Result(s): In total, 4.277 vaccinations against SARS-CoV-2 in 1.478 patients were analyzed. Serological response was 19.5% after 1.203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% after 603 third, 250 fourth and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7% (figure 1A-B). Patients with belatacept immunosuppression show impaired cumulative serological response (4.4%, 12.4%, and 16.4%) in comparison to patients with calcineurin inhibitor (CNI)- based immunosuppression (19.1%, 37.6%, and 70.1%) after basic immunization, three, and four vaccinations (figure 1C-F). In patients with CNI and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased serological response rate to 75% in comparison to no dose adjustment (52%) or dose reduction (46%) without occurence of rejections (figure 2). Conclusion(s): Repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination. Patients with belatacept immunosuppression are unlikely to achieve sufficient serological response and require different approaches.
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Purpose: Kidney transplant recipients (KTR) are at increased risk of mortality from COVID-19. We conducted a cohort study among KTR from the French Solid Organ Transplant COVID-19 (SOT COVID) registry to investigate the association between maintenance immunosuppressive drugs and 60-day mortality in KTR with COVID-19. Method(s): Data from all KTR with COVID-19 included in SOT COVID 02/28/2020 and 12/30/2020 were retrieved. Among them, 116 were excluded because of missing data on immunosuppressive therapy. We evaluated associations between immunosuppressive drugs and death <=60 days of 1st symptoms using logistic regression, with all baseline characteristics considered to influence outcome or immunosuppressive regimen. Benjamini-Hochberg correction was used for controlling false positive rate;40 multiple imputations were performed. Adjusted p-value <0.05 was considered statistically significant. Result(s): There were 1,451 KTR included. Median age was 58 years, 963 (66.4%) were men. Most frequent comorbidities were hypertension (n=1188, 81.9%), diabetes (501, 34.5%), cardiovascular disease (428, 29.5%). Median time since transplant was 71 months. Maintenance immunosuppression regimen included calcineurin inhibitors (1295, 89.2%), antimetabolites (1205, 83%), corticosteroids (1094, 75.4%), Mammalian Target of Rapamycin inhibitors (144, 9.9%) and belatacept (58, 4.0%). Among 1,451 KTR, 201 (13.9%) died <=60 days. Older age and baseline creatininemia were associated with mortality (OR: 1.09 [1.07-1.11];1.01 [1.005- 1.009], p<0.001). Corticosteroid-free regimens were associated with a significantly lower risk of death (OR: 0.48 [0.31;0.76], p=0.011). All other variables yielded non-significant adjusted p-values. Conclusion(s): Corticosteroid-free regimens were associated with a lower risk of death in KTR with COVID-19. While a short course of high-dose corticosteroids is beneficial in severely ill COVID-19 patients, prolonged maintenance corticosteroids expose to chronic immune disorders that may predispose KTR to severe forms of COVID-19.
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Purpose: Data shows COVID vaccine response after 2 doses in patients on Belatacept immunosuppression (IS) is low, with reported rates of seroconversion (as measured by COVID spike IgG antibody (IgG Ab) detection) of <10%. It is suggested that T cell immunity provides more nuanced marker of immunity. We seek to describe immune response with third dose of vaccine using T cell immunity and spike Ab as surrogate markers. Method(s): 12 kidney transplant patients on long term belatacept maintenance therapy were included. All patients received induction rabbit anti thymocyte globulin at transplant and were maintained on triple IS with mycophenolate and steroids. All patients received 3 doses of the Pfizer BioNTech SARS CoV2 mRNA vaccine. IgG Ab and T cell immunity response were monitored after 2 doses of vaccine, on the date of 3rd dose with repeat testing done about 4 weeks after 3rd dose. Due to small sample size, T cell response detection was treated qualitatively as "detected" and "negative" results based upon manufacturer instructions (Eurofins Viracor). IgG Ab response was treated qualitatively as "detected" and "negative", as many responses were too low to be reliably quantifiable. Result(s): Of the 12 included patients, 58% were female, 50% were African American, at mean of 77 months post transplant. After 2 vaccine doses, immunity was detected using the T cell based assay in 6/12 [50.0%, 95% CI: (21.1%-78.9%)];after 3 doses, T cell immunity detection remained the same (6/12). After 2 doses, IgG was detected in 2/12 patients [16.7%, 95% CI: (2.1%-48.4%)]. After 3 doses, this rate doubled to 4/12 [33.3%, 95% CI: (9.9%-65.1%)]. All IgG Ab detected patients were within the T Cell detected patients. There were statistically significant differences between patients that showed a response vs those that did not although patients with no response had been on a numerically higher duration of belatacept (mean=56 months) vs those with any response (mean=34 months;p=0.23). No patients developed a COVID 19 infection during the study period. Conclusion(s): In this cohort, T cell response identified a bigger subset of patients with vaccine response with 2 mRNA vaccine doses compared with those identified with an IgG response only. However, both T cell immunity and IgG Ab response remained low after 2 or 3 doses, and no patient in in the 2 dose group developed new T cell immunity response after third vaccination. IgG Ab response increased in half of the patients, but these were patients who already had developed a T cell immune response after second dose of vaccine. Total change in COVID spike IgG response after the third dose was up to 33% from an initial 16%, which may demonstrate improved total response to 3 doses. Further research is needed to assess if response rates improve with additional (fourth) doses of COVID vaccine or 'mix and match' strategies.
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Purpose: To compare antibody response to a third dose (D3) of SARS-CoV-2 vaccine in solid organ transplant recipients (SOTRs) with negative or low-positive antibody levels after 2-dose mRNA vaccination across D3 platforms. Method(s): From our observational study, 532 SOTRs who developed suboptimal antibody responses to 2-dose mRNA vaccination (Roche<50 U/mL or EUROIMMUN <1.1 AU) were selected. Belatacept recipients and persons with any COVID-19 diagnosis were excluded. We compared post-D3 antibody levels among SOTRs who received an mRNA vaccine for D3 (n=487) versus Ad.26.COV2.S for D3 (n=45). Poisson regression with robust standard error was used to study the association between vaccine platform and seroconversion, adjusting for immunosuppression, age, time since transplant, and liver transplant status. Result(s): Pre-D3, 342 SOTRs (64%) were seronegative, of whom 107 (31%) developed high-positive antibody levels post-D3. In contrast, of the 190 (36%) with low-positive pre-D3 antibody levels, 172 (91%) were high-positive post-D3 (Figure 1). Among SOTRs seronegative pre-D3, 1.8x more Ad.26.COV2.S D3 recipients seroconverted compared to mRNA D3 recipients (49.7% vs 27.8%, Fisher's exact=0.014) (Figure 2). Among the pre-D3 seronegative group, there was a 2x higher chance of developing high-positive post-D3 levels with Ad.26.COV2.S compared to mRNA D3 (IRR =1.42.02.9, p<0.001). This was despite the Ad.26. COV2.S D3 group having fewer younger patients and liver transplant recipients, factors that are associated with higher odds of positive antibody response. 165 SOTRs (31%) remained seronegative after D3 (22% of Ad.26.COV2.S recipients vs 32% of mRNA recipients). Conclusion(s): Heterologous boosting with Ad.26.COV2.S may be a promising vaccination option for SOTRs with poor response to the 2-dose mRNA series, particularly among those who are seronegative. (Table Presented).
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The development of donor-specific antibodies (DSA) after lung transplantation is common and results in adverse outcomes. In kidney transplantation, Belatacept has been associated with a lower incidence of DSA, but experience with Belatacept in lung transplantation is limited. We conducted a two-center pilot randomized controlled trial of de novo immunosuppression with Belatacept after lung transplantation to assess the feasibility of conducting a pivotal trial. Twenty-seven participants were randomized to Control (Tacrolimus, Mycophenolate Mofetil, and prednisone, n = 14) or Belatacept-based immunosuppression (Tacrolimus, Belatacept, and prednisone until day 89 followed by Belatacept, Mycophenolate Mofetil, and prednisone, n = 13). All participants were treated with rabbit anti-thymocyte globulin for induction immunosuppression. We permanently stopped randomization and treatment with Belatacept after three participants in the Belatacept arm died compared to none in the Control arm. Subsequently, two additional participants in the Belatacept arm died for a total of five deaths compared to none in the Control arm (log rank p = .016). We did not detect a significant difference in DSA development, acute cellular rejection, or infection between the two groups. We conclude that the investigational regimen used in this study is associated with increased mortality after lung transplantation.
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Lung Transplantation , Tacrolimus , Abatacept/therapeutic use , Antilymphocyte Serum/therapeutic use , Graft Rejection/drug therapy , Graft Rejection/etiology , Graft Rejection/prevention & control , Graft Survival , Humans , Immunosuppression Therapy , Immunosuppressive Agents/therapeutic use , Lung Transplantation/adverse effects , Mycophenolic Acid/therapeutic use , Pilot Projects , PrednisoneABSTRACT
INTRODUCTION: In kidney transplant recipients, belatacept is usually pursued indefinitely after it has been started. In the setting of the belatacept shortage and after having evaluated the benefit-risk ratio, we established a strategy consisting of time-limited belatacept therapy/transient calcineurin inhibitor withdrawal, whose results are analyzed in that study. METHODS: We considered all the kidney transplant recipients that had been switched from conventional immunosuppressive therapy to belatacept and then for whom belatacept has been withdrawn intentionally. Furthermore, in the first 8 patients, we assessed changes in peripheral blood mononuclear cells (PBMC) transcriptome using RNAseq before and 3 months after belatacept withdrawal. RESULTS: Over the study period, 28 out of 94 patients had belatacept intentionally withdrawn including 25 (89%) switched to low-dose CNI. One rejection due to poor compliance occurred. The eGFR after 12 months remained stable from 48 ± 19 mL.1.73 m-2 to 46 ± 17 mL.1.73 m-2 (p = 0.68). However, patients that resumed belatacept/withdrew CNIs (n = 10) had a trend towards a better eGFR comparing with the others (n = 15): 54 ± 20 mL.1.73 m-2 vs. eGFR 43 ± 16 mL.1.73 m-2, respectively (p = 0.15). The only factor associated with belatacept resumption was when the withdrawal took place during the COVID-19 outbreak. Transcriptome analysis of PBMCs, did not support rebound in alloimmune response. CONCLUSIONS: These findings underpin the use of belatacept as part of a time-limited therapy, in selected kidney transplant recipients, possibly as an approach to allow efficient vaccination against SARS-CoV-2.
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BACKGROUND: Assessing the composition of immune responses to SARS-CoV-2 vaccines is critical for our understanding of protective immunity, especially for immune compromised patients. The Pfizer (BNT162b2) vaccination showed >90% efficacy in protecting individuals from infection. However, these studies did not examine responses in immunocompromised kidney transplant patients (KT). Subsequent reports in KT have shown severe deficiencies in Spike-specific immunoglobin G (IgG) responses prompting booster vaccinations, but a broader understanding of T-cell immunity to vaccinating is lacking. METHODS: We examined SARS-CoV-2 Spike IgG and CD4+/CD8+ Spike-specific T-cell responses in 61 KT patients maintained on different immunosuppressive protocols (ISP) (Tac + mycophenolate mofetil + prednisone) versus (belatacept + MMF + prednisone) and compared to 41 healthy controls. We also examined cytomegalovirus-cytotoxic T-cell responses (CMV-Tc) in both groups to assess T-cell memory. RESULTS: Our data confirmed poor Spike IgG responses in vaccinated KT patients with both ISP (21% demonstrating Spike IgG 1M post-second dose of BNT162b2 vs. 93% in controls). However, 35% of Spike IgG (-) patients demonstrated CD4+ and/or CD8+ T-cell responses. All but one CMV-IgG+ patient demonstrated good CMV-Tc responses. No differences in T-cell immunity by ISP were seen. CONCLUSION: Immunocompromised KT recipients showed severe defects in humoral and T-cell immune response after vaccination. No differences in immune responses to SARS-CoV-2 Spike peptides were observed in KT patients by ISP post-vaccination. The detection of Spike-specific T-cell immunity in the absence of Spike IgG suggests that vaccination in immunocompromised KT patients may provide partial immunity, although not preventing infection, T-cell immunity may limit its severity.
Subject(s)
COVID-19 , Kidney Transplantation , Allografts , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunity, Cellular , Immunity, Humoral , Kidney Transplantation/adverse effects , SARS-CoV-2 , Vaccination/methodsABSTRACT
INTRODUCTION: Belatacept is a common immunosuppressive therapy used after kidney transplantation (KT) to avoid calcineurin-inhibitor (CNI) use and its related toxicities. It is unclear whether its use exposes KT recipients (KTx) to a greater risk of infection or a poorer response to vaccines. Areas covered: We reviewed PubMed and the Cochrane database. We then summarized the mechanisms and impacts of belatacept use on the risk of infection, particularly opportunistic, in two settings, i.e., de novo KTx and conversion from CNIs. We also focused on COVID-19 infection risk and response to SARS-CoV-2 vaccination in patients whose maintenance immunosuppression relies on belatacept. Expert opinion: When belatacept is used de novo, or after drug conversion the safety profile regarding the risk of infection remains good. However, there is an increased risk of opportunistic infections, mainly CMV disease and Pneumocystis pneumonia, particularly in those with a low eGFR, in older people, in those receiving steroid-based therapy, or those that have an early conversion from CNI to belatacept (i.e.,
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Poor responses to mRNA COVID-19 vaccine have been reported after 2 vaccine injections in kidney transplant recipients (KTRs) treated with belatacept. We analyzed the humoral response in belatacept-treated KTRs without a history of SARS-CoV-2 infection who received three injections of BNT162b2-mRNA COVID-19 vaccine. We also investigated vaccine immunogenicity in belatacept-treated KTRs with prior COVID-19 and characterized symptomatic COVID-19 infections after the vaccine in belatacept-treated KTRs. Among the 62 belatacept-treated KTRs (36 [58%] males), the median age (63.5 years IQR [51-72]), without COVID-19 history, only four patients (6.4%) developed anti-SARS-CoV-2 IgG with low antibody titers (median 209, IQR [20-409] AU/ml). 71% were treated with mycophenolic acid and 100% with steroids in association with belatacept. In contrast, in all the 5 KTRs with prior COVID-19 history, mRNA vaccine induced a strong antibody response with high antibody titers (median 10 769 AU/ml, IQR [6410-20 069]) after two injections. Seroprevalence after three-vaccine doses in 35 non-belatacept-treated KTRs was 37.1%. Twelve KTRs developed symptomatic COVID-19 after vaccination, including severe forms (50% of mortality). Breakthrough COVID-19 occurred in 5% of fully vaccinated patients. Administration of a third dose of BNT162b2 mRNA COVID-19 vaccine did not improve immunogenicity in KTRs treated with belatacept without prior COVID-19. Other strategies aiming to improve patient protection are needed.
Subject(s)
COVID-19 , Kidney Transplantation , Abatacept/therapeutic use , Aged , Antibody Formation , COVID-19 Vaccines , Humans , Kidney Transplantation/adverse effects , Male , Middle Aged , SARS-CoV-2 , Seroepidemiologic Studies , Vaccines, SyntheticABSTRACT
INTRODUCTION: During the coronavirus disease 2019 (Covid-19) pandemic, several physicians have questioned pursuing belatacept in kidney-transplant patients in order to reduce the risk of nosocomial transmission during the monthly infusion. The effect of the conversion from belatacept to another immunosuppressive regimen is underreported. The aim of the present retrospective study was to assess the effect on kidney function and the clinical outcome of the conversion from belatacept to another regimen. METHODS: We have identified 44 maintenance kidney transplantation patients from five French kidney transplantation centers who were converted from belatacept to another regimen either because of a complication (n = 28) or another reason (patients' request or belatacept shortage, n = 13). The follow-up after the conversion from belatacept was 27.5 ± 25.3 months. RESULTS: Overall, mean estimated glomerular filtration rate (eGFR) decreased from 44.2 ± 16 ml/min per 1.73 m2 at conversion from belatacept to 35.7 ± 18.4 ml/min per 1.73 m2 at last follow-up (P = 0.0002). eGFR significantly decreased in patients who had been given belatacept at transplantation as well as in those who had been converted to belatacept earlier. The decrease was less significant in patients who had stopped belatacept without having experienced any complications. Finally, eGFR decreased more severely in patients who were converted to calcineurin inhibitors (CNIs), compared to those who received mammalian target of rapamycin inhibitor (mTORi). Few patients also developed diabetes and hypertension. CONCLUSIONS: Thus, transplantation physicians should avoid stopping belatacept when not clinically required.