Response In Kidney Transplant Recipients Research Articles

Persistent SARS-CoV-2–specific immune defects in kidney transplant recipients following third mRNA vaccine dose

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBDNEG; n = 42 anti-RBDLO), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8+%, and SARS-CoV-2–reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBDNEG remained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P < .001). Day 30 spike-specific CD8+% was negative in 91% KTRs (vs 20% HCs; P = .07), without correlation to anti-RBD (rs = 0.17). Day 30 SARS-CoV-2–reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P = .11). Spike-specific CD4+ TCR expansion was similar between KTRs and HCs, yet KTR CD8+ TCR depth was 7.6-fold lower (P = .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P = .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8+ responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4+ expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263)

Comparison of Humoral Response in Kidney Transplant Recipients and Donors and Healthy Volunteers Following Second Dose of SARS-CoV-2 mRNA Vaccine

To investigate the kinetics and durability of anti-spike glycoprotein (S) immunoglobulin G (IgG) after the second dose of mRNA-based SARS-CoV-2 vaccine in kidney transplant recipients (recipients) compared with those in kidney donors (donors) and healthy volunteers (HVs) and identify factors negatively associated with SARS-CoV-2 vaccine effectiveness in recipients. We enrolled 378 recipients with no history of COVID-19 and no anti-S-IgG before the first vaccine and who received a second mRNA-based vaccine dose. Antibodies were detected using an immunoassay more than 4 weeks after the second vaccine dose. Anti-S-IgG <0.8, ≥0.8 to 15, and ≥15 U/mL were considered negative, weak positive, and strongly positive, respectively, whereas anti-nucleocapsid protein IgG was negative. Anti-S-IgG titer was determined in 990 HVs and 102 donors. Anti-S-IgG titers were 154, 2475, and 1181 U/mL in the recipient, HV, and donor groups, respectively, with values significantly lower in recipients. The anti-S-IgG-positivity rate of recipients gradually increased following the second vaccination, suggesting that recipients had a delayed response compared with the HV and donor groups, who had a 100% positivity rate at an earlier time point. Anti-S-IgG titers decreased in donors and HVs, whereas they remained stable in recipients, although at a significantly lower level. Independent negative factors associated with anti-S-IgG titers in recipients were age >60 years and lymphocytopenia (odds ratio: 2.35 and 2.44, respectively). Kidney transplant recipients demonstrate delayed and attenuated responses, with lower SARS-CoV-2 antibody titers after the second dose of the mRNA-based COVID-19 vaccine.

Factors associated with the humoral response after three doses of COVID-19 vaccination in kidney transplant recipients.

Kidney transplant recipients showed a weak humoral response to the mRNA COVID-19 vaccine despite receiving three cumulative doses of the vaccine. New approaches are still needed to raise protective immunity conferred by the vaccine administration within this group of high-risk patients. To analyze the humoral response and identify any predictive factors within these patients, we designed a prospective monocentric longitudinal study of Kidney transplant recipients (KTR) who received three doses of mRNA-1273 COVID-19 vaccine. Specific antibody levels were measured by chemiluminescence. Parameters related to clinical status such as kidney function, immunosuppressive therapy, inflammatory status and thymic function were analyzed as potential predictors of the humoral response. Seventy-four KTR and sixteen healthy controls were included. One month after the administration of the third dose of the COVID-19 vaccine, 64.8% of KTR showed a positive humoral response. As predictive factors of seroconversion and specific antibody titer, we found that immunosuppressive therapy, worse kidney function, higher inflammatory status and age were related to a lower response in KTR while immune cell counts, thymosin-a1 plasma concentration and thymic output were related to a higher humoral response. Furthermore, baseline thymosin-a1 concentration was independently associated with the seroconversion after three vaccine doses. In addition to the immunosuppression therapy, condition of kidney function and age before vaccination, specific immune factors could also be relevant in light of optimization of the COVID-19 vaccination protocol in KTR. Therefore, thymosin-a1, an immunomodulatory hormone, deserves further research as a potential adjuvant for the next vaccine boosters.

BK virus genotypes and humoral response in kidney transplant recipients with BKV associated nephropathy.

Among kidney transplant recipients (KTR) with BK virus associated nephropathy (BKVN), BKV genotypes' evolution and anti-BKV humoral response are not well established. We aim to analyze BKV replication and genetic evolution following transplantation, and characterize concomitant anti-BKV-VP1 humoral response. We retrospectively analyzed 32 cases of biopsy-proven BKVN. Stored plasma and kidney biopsies were tested for BKV viral load, and VP1 sequencing performed on positive samples. BKV-VP1 genotype-specific neutralizing antibodies (NAbs) titers were determined at transplantation and BKVN. At the time of BKVN diagnosis, BKV viral load was 8.2 log10 IU/106 cells and 5.4 log10 IU/mL in kidney and plasma, respectively. VP1 sequencing identified the same BKV-subtype in both compartments in 31/32 cases. At the time of transplantation, 8/20 (40%) of biopsies tested positive for BKV detection, whereas concomitant BKV viremia was negative. VP1 sequencing identified a different subtype compared to BKVN in 5/6 of these samples. This was confirmed following transplantation: 8 patients had a BKV+ biopsy before BKV viremia, and VP1 sequencing identified a different subtype compared to BKVN in all of them. After the onset of BKV viremia and prior to BKVN diagnosis, the BKV subtype in BKV+ plasma and kidney biopsy was the same as the one isolated at BKVN. BKV-VP1 NAbs titers were significantly higher at the time of BKVN compared to transplantation (p=.0031), with similar titers across genotypes. Altogether, our data suggest that among some KTR with BKVN, the BKV genotype from the donor may not be responsible for BKVN pathogenesis.

Humoral Responses in the Omicron Era Following 3-Dose SARS-CoV-2 Vaccine Series in Kidney Transplant Recipients.

We profiled antibody responses in KTRs pre- and at 1 and 3 mo post-third-dose SARS-CoV-2 mRNA-based vaccine. Binding antibody levels were determined by ELISA. Neutralization against wild type, Beta, Delta, and Omicron (BA.1) variants was determined using a SARS-CoV-2 spike-pseudotyped lentivirus assay. Forty-four KTRs were analyzed at 1 and 3 mo (n = 26) post-third dose. At 1 mo, the proportion of participants with a robust antibody response had increased significantly from baseline, but Omicron-specific neutralizing antibodies were detected in just 45% of KTRs. Median binding antibody levels declined at 3 mo, but the proportion of KTRs with a robust antibody response was unchanged; 38.5% KTRs maintained Omicron-specific neutralization at 3 mo. No clinical variables were significantly associated with Omicron-neutralizing antibodies, but antireceptor binding domain titers appeared to identify those with Omicron-specific neutralizing capacity. Over 50% of KTRs lack Omicron-specific neutralization capacity 1 mo post-third mRNA-vaccine dose. Antibody levels of responders were well preserved at 3 mo. Anti receptor binding domain antibody titers may identify patients with a detectable Omicron-neutralizing antibody response.

Rapamycin and inulin for third-dose vaccine response stimulation (RIVASTIM): Inulin – study protocol for a pilot, multicentre, randomised, double-blinded, controlled trial of dietary inulin to improve SARS-CoV-2 vaccine response in kidney transplant recipients

IntroductionKidney transplant recipients (KTRs) are at an increased risk of hospitalisation and death from COVID-19. Vaccination against SARS-CoV-2 is our primary risk mitigation strategy, yet vaccine effectiveness in KTRs is...

Left Atrial Structural and Functional Response in Kidney Transplant Recipients Treated With Mesenchymal Stromal Cell Therapy and Early Tacrolimus Withdrawal

Autologous bone marrow-derived mesenchymal stromal cell (MSC) therapy and withdrawal of calcineurin inhibitors (CNIs) has been shown to improve systemic blood pressure control and left ventricular hypertrophy regression in kidney transplant recipients. In the current subanalysis, we aimed to evaluate the impact of this novel immunosuppressive regimen on the longitudinal changes of left atrial (LA) structure and function after kidney transplantation. Kidney transplant recipients randomized to MSC therapy-infused at weeks 6 and 7 after transplantation, with complete discontinuation at week 8 of tacrolimus (MSC group)-or standard tacrolimus dose (control group) were evaluated with transthoracic echocardiography at weeks 4 and 24 after kidney transplantation. The changes in echocardiographic parameters were compared between the randomization arms using an analysis of covariance model adjusted for baseline variable. Fifty-four participants (MSC therapy=27; tacrolimus therapy=27) were included. There was no significant interaction between the allocated treatment and the changes of indexed maximal LA volume (LAVImax) over the study period. Conversely, between 4 and 24weeks post-transplantation, an increase in indexed minimal LA volume (LAVImin) was observed in control subjects, while it remained unchanged in the MSC group, leading to a significant difference between groups (P=.021). Additionally, patients treated with MSC therapy showed a benefit in LA function, assessed by a significant interaction between changes in LA emptying fraction and LA reservoir strain and the randomization arm (P=.012 and P=.027, respectively). The combination of MSC therapy and CNIs withdrawal prevents progressive LA dilation and dysfunction in the first 6months after kidney transplantation. LAVImin and LA reservoir strain may be more sensitive markers of LA reverse remodeling, compared with LAVImax.

An additional dose of viral vector COVID-19 vaccine and mRNA COVID-19 vaccine in kidney transplant recipients: A randomized controlled trial (CVIM 4 study)

Immunogenicity following an additional dose of Coronavirus disease 2019 (COVID‐19) vaccine was investigated in an extended primary series among kidney transplant (KT) recipients. Eighty‐five KT participants were randomized to receive either an mRNA (M group; n = 43) or viral vector (V group; n = 42) vaccine. Among them, 62% were male, with a median (IQR) age of 50 (43–59) years and post‐transplantation duration of 46 (26–82) months. At 2 weeks post‐additional dose, there was no difference in the seroconversion rate between the M and V groups (70% vs. 65%, p = .63). A median (IQR) of anti‐RBD antibody level was not statistically different between the M group compared with the V group (51.8 [5.1–591] vs. 28.5 [2.9–119.3] BAU/ml, p = .18). Furthermore, the percentage of participants with positive SARS‐CoV‐2 surrogate virus neutralization test results was not statistically different between groups (20% vs. 15%, p = .40). S1‐specific T cell and RBD‐specific B cell responses were also comparable between the M and V groups (230 [41–420] vs. 268 [118–510], p = .65 and 2 [0–10] vs. 2 [0–13] spot‐forming units/106 peripheral blood mononuclear cells, p = .60). In conclusion, compared with an additional dose of viral vector COVID‐19 vaccine, a dose of mRNA COVID‐19 vaccine did not elicit significantly different responses in KT recipients, regarding either humoral or cell‐mediated immunity. (TCTR20211102003).

Alternative strategies to increase the immunogenicity of COVID-19 vaccines in kidney transplant recipients not responding to two or three doses of an mRNA vaccine (RECOVAC): a randomised clinical trial

An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs). We aimed to compare three alternative strategies with a control single dose mRNA-1273 vaccination: a double vaccine dose, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid. This open-label randomised trial, done in four university medical centres in the Netherlands, enrolled KTRs without seroconversion after two or three doses of an mRNA vaccine. Between Oct 20, 2021, and Feb 2, 2022, 230 KTRs were randomly assigned block-wise per centre by a web-based system in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination, assessed in all participants who had a baseline measurement and who completed day 28 after vaccination without SARS-CoV-2 infection. Safety was assessed as a secondary outcome in all vaccinated patients by incidence of solicited adverse events, acute rejection or other serious adverse events. This trial is registered with ClinicalTrials.gov, NCT05030974 and is closed. Between April 23, 2021, and July 2, 2021, of 12 158 invited Dutch KTRs, 3828 with a functioning kidney transplant participated in a national survey for antibody measurement after COVID-19 vaccination. Of these patients, 1311 did not seroconvert after their second vaccination and another 761 not even after a third. From these seronegative patients, 345 agreed to participate in our repeated vaccination study. Vaccination with 2 × mRNA-1273 or Ad26.COV2-S was not superior to single mRNA-1273, with seroresponse rates of 49 (68%) of 72 (95% CI 56-79), 46 (63%) of 73 (51-74), and 50 (68%) of 73 (57-79), respectively. The difference with single mRNA-1273 was -0·4% (-16 to 15; p=0·96) for 2 × mRNA-1273 and -6% (-21 to 10; p=0·49) for Ad26.COV2-S. Mycophenolate mofetil- was also not superior to mycophenolate mofetil+, with seroresponse rates of 37 (80%) of 46 (66-91) and 31 (67%) of 46 (52-80), and a difference of 13% (-5 to 31; p=0·15). Local adverse events were more frequent after a single and double dose of mRNA-1273 than after Ad26.COV2-S (65 [92%] of 71, 67 [92%] of 73, and 38 [50%] of 76, respectively; p<0·0001). No acute rejection occurred. There were no serious adverse events related to vaccination. Repeated vaccination increases SARS-CoV-2-specific antibodies in KTRs, without further enhancement by use of a higher dose, a heterologous vaccine, or 2 weeks discontinuation of mycophenolate mofetil or mycophenolic acid. To achieve a stronger response, possibly required to neutralise new virus variants, repeated booster vaccination is needed. The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.

Assessing T-Cell Immunity in Kidney Transplant Recipients with Absent Antibody Production after a 3rd Dose of the mRNA-1273 Vaccine.

The vulnerable population of kidney transplant recipients (KTRs) are low responders to COVID-19 vaccines, so specific immune surveillance is needed. The interferon-gamma (IFN-γ) release assay (IGRA) is effective in assessing T cell-mediated immunity. We assessed SARS-CoV-2-directed T cell responses in KTRs with absent antibody production after a third dose of the mRNA-1273 vaccine, using two different IGRAs. A cohort of 57 KTRs, who were actively followed up, received a third dose of the mRNA-1273 vaccine. After the evaluation of humoral immunity to SARS-CoV-2, 14 seronegative patients were tested with two commercial IGRAs (SD Biosensor and Euroimmun). Out of 14 patients, one and three samples were positive by IGRAs with Euroimmun and SD Biosensor, respectively. The overall agreement between the two assays was 85.7% (κ = 0.444). In addition, multivariate linear regression analysis showed no statistically significant association between the IFN-γ concentration, and the independent variables analyzed (age, gender, years since transplant, total lymphocytes cells/mcl, CD3+ cells/mcl, CD3+ CD4+ cells/mcl, CD3+ CD8+ cells/mcl, CD19+ cells/mcl, CD3-CD16+CD56+ cells/mcl) (p > 0.01). In a vulnerable setting, assessing cellular immune response to complement the humoral response may be advantageous. Since the two commercial IGRAs showed a good agreement on negative samples, the three discordant samples highlight the need for further investigations.

Development and validation of multivariable prediction models of serological response to SARS-CoV-2 vaccination in kidney transplant recipients.

Repeated vaccination against SARS-CoV-2 increases serological response in kidney transplant recipients (KTR) with high interindividual variability. No decision support tool exists to predict SARS-CoV-2 vaccination response to third or fourth vaccination in KTR. We developed, internally and externally validated five different multivariable prediction models of serological response after the third and fourth vaccine dose against SARS-CoV-2 in previously seronegative, COVID-19-naïve KTR. Using 20 candidate predictor variables, we applied statistical and machine learning approaches including logistic regression (LR), least absolute shrinkage and selection operator (LASSO)-regularized LR, random forest, and gradient boosted regression trees. For development and internal validation, data from 590 vaccinations were used. External validation was performed in four independent, international validation cohorts comprising 191, 184, 254, and 323 vaccinations, respectively. LASSO-regularized LR performed on the whole development dataset yielded a 20- and 10-variable model, respectively. External validation showed AUC-ROC of 0.840, 0.741, 0.816, and 0.783 for the sparser 10-variable model, yielding an overall performance 0.812. A 10-variable LASSO-regularized LR model predicts vaccination response in KTR with good overall accuracy. Implemented as an online tool, it can guide decisions whether to modulate immunosuppressive therapy before additional active vaccination, or to perform passive immunization to improve protection against COVID-19 in previously seronegative, COVID-19-naïve KTR.

Humoral Response After SARS-CoV-2 Vaccination in Kidney Transplant Recipients: Role of Immunosuppression Therapy

BackgroundMessenger RNA vaccination against COVID-19 has been shown to produce an immune response with sufficient efficacy to prevent natural infection in immunocompetent recipients. However, the response in kidney transplant recipients is low. We aimed to evaluate the specific humoral response to SARS-CoV-2 after vaccination in a population of kidney transplant recipients and assess the main factors associated with a lack of response.MethodsWe undertook a prospective study of 105 kidney transplant recipients and 11 recipients of a combined kidney-pancreas transplant. We analyzed immunoglobulin G and immunoglobulin M antibodies after the patients received their second and third doses of the messenger RNA 1273 (Moderna) or BNT162b1 (BionTECH-Pfizer) vaccinations between February and November 2021.ResultsMean (SD) age of the 116 patients was 50 (16) years, and 65% were men. They had their transplants for 40 months (IQR, 15-123 months), with 14% undergoing retransplant and 11% sensitized. The maintenance immunosuppression regimen was steroids + tacrolimus + mycophenolate (MMF) in 68% of the patients and any combination with mammalian target of rapamycin inhibitor (mTORi) in 28%. A humoral response developed in 40% of the patients 6 weeks (IQR, 4-10 weeks) after receiving the second dose of the vaccine. Of the 67 patients with no response to the second dose, 51 had an analysis of the humoral response after the third dose, which was positive in 16 (31%). A total of 80% received the Moderna vaccine and 20% the BionTECH-Pfizer. No patient experienced major adverse effects after the vaccination.Factors associated with a lack of humoral response to the vaccine were recipient age (odds ratio [OR], 1.02; 95% CI, 1.001-1.05; P = .04), diabetes (OR, 2.8; 95% CI, 1.2-6.9; P = .02), and treatment with MMF (OR, 2.6; 95% CI, 1.08-6.8; P = .03). Treatment with mTORi was associated with a better response to vaccination (OR, 0.3; 95% CI, 0.1-0.9; P = .04).ConclusionsThe humoral response to the COVID-19 vaccine in kidney transplant recipients is poor. Factors related with this lack of immunity are recipient age and diabetes, plus MMF therapy, whereas mTORi therapy was associated with a better response to vaccination.

Rapamycin and inulin for booster vaccine response stimulation (RIVASTIM)—rapamycin: study protocol for a randomised, controlled trial of immunosuppression modification with rapamycin to improve SARS-CoV-2 vaccine response in kidney transplant recipients

Kidney transplant recipients are at an increased risk of severe COVID-19-associated hospitalisation and death. Vaccination has been a key public health strategy to reduce disease severity and infectivity, but the effectiveness of COVID vaccines is markedly reduced in kidney transplant recipients. Urgent strategies to enhance vaccine efficacy are needed.Methods: RIVASTIM-rapamycin is a multicentre, randomised, controlled trial examining the effect of immunosuppression modification prior to a third dose of COVID-19 vaccine in kidney transplant recipients who have failed to develop protective immunity to a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to either remain on standard of care immunosuppression with tacrolimus, mycophenolate, and prednisolone (control) or cease mycophenolate and commence sirolimus (intervention) for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm who develop protective serological neutralisation of live SARS-CoV-2 virus at 4–6 weeks following a third COVID-19 vaccination. Secondary outcomes include SARS-CoV-receptor binding domain IgG, vaccine-specific immune cell populations and responses, and the safety and tolerability of sirolimus switch.Discussion: Immunosuppression modification strategies may improve immunological vaccine response. We hypothesise that substituting the mTOR inhibitor sirolimus for mycophenolate in a triple drug regimen will enhance humoral and cell-mediated responses to COVID vaccination for kidney transplant recipients.Trial registration: Australia New Zealand Clinical Trials Registry ACTRN12621001412820. Registered on 20 October 2021; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382891&isReview=true

210.16: Antibody Response to Booster mRNA COVID-19 Vaccine After Standard Doses of Various Homologous and Heterologous Vaccines in Kidney Transplant Recipients

The immune response to standard doses of COVID-19 vaccines in kidney transplant recipients (KTRs) is suboptimal and additional doses are being recommended. The type of COVID-19 vaccine one had access to during the initial standard doses of vaccination was largely dependent on its availability. Thus some had homologous vaccines (i.e. 2 doses of viral vector vaccine or 2 doses of mRNA vaccine) and others had heterologous vaccines during the initial standard vaccination. The effect of such different vaccine combinations on the effectiveness of booster shots using mRNA vaccines in KTRs is largely unknown.The current study is a noninterventional prospective study examining the efficacy of the additional dosage of the COVID-19 vaccine in KTRs. Patients with standard doses of COVID-19 vaccines were enrolled. Reactogenicity to COVID-19 was assessed two weeks before and one month after the additional dose (booster shot) by examining anti-SARS-CoV-2 IgG antibodies against the receptor-binding domain of the S1 subunit of the spike protein using SARS-CoV-2 IgG II Quant assay (Abbott). A total of 235 KTRs with standard doses of COVID-19 vaccine were enrolled. During the initial vaccination, 106 (45.1%) had two doses of mRNA vaccine (BNT162b2 or mRNA-1273), 73 had ChAdOX1-S/ BNT162b2 52 (22.1%) had ChAdOX1-S/ ChAdOX1-S, and one (0.4%) had Janssen COVID-19 vaccine. All patients had mRNA vaccines (BNT162b2 or mRNA-1273) for booster.After the booster dose, seropositivity improved from 55.3% (130/235) to 81.3% (191/235) with seroconversion in 58.1% (61/105) of the initially seronegative patients. Antibody titer also was significantly increased (median, 62.3 to 1382.8 AU/mL, p<0.01 by Wilcoxon rank sum test). Risk factors for negative antibody response to booster mRNA were low eGFR (OR 0.95, 95% CI 0.93-0.98) and having two doses of viral vector vaccines during the standard vaccination (OR 5.43, 95%CI 1.59-18.49; reference-mRNA/mRNA vaccine). This was likely due to the relatively low immunity before the third vaccine dose within this patient group (negative response in 69.2%).The use of an additional dose of COVID-19 mRNA vaccine is effective in eliciting antibody response in KTRs, especially for those in whom the primary vaccination failed. Overall response after an additional dose of mRNA vaccine was affected by the type of vaccines used during the standard vaccination.

314.2: MTOR Inhibitors Promote Highly Functional T Cell Immunity in Kidney Transplant Recipients Vaccinated Against COVID-19

Introduction: Kidney transplant recipients (KTRs) are highly vulnerable to severe COVID-19, however are poorly protected by vaccination. Additional vaccine doses have achieved limited improvements in serological neutralisation or T cell response. A novel strategy to boost vaccine response is needed. Inhibition of mechanistic target of rapamycin (mTOR) has been found to enhance the formation of memory T cells following vaccination of non-human primates. Methods: KTRs and age-matched healthy controls (HC) were recruited from a transplant centre in South Australia to undergo a 2-dose vaccination schedule with BNT162b2 or ChAdOx1. KTRs were receiving standard-of-care (SOC) triple therapy (tacrolimus, mycophenolate mofetil, prednisolone; n=15), sirolimus-inclusive (n=15), or everolimus-inclusive (n=11) protocols. Patients on mTORi-inclusive protocols were most commonly receiving sirolimus or everolimus, mycophenolate mofetil, and prednisolone. Following 2 vaccine doses, spike-specific IgG and T cell responses (by IFNγ ELISpot) were measured to assess vaccine immunogenicity, and live virus neutralisation and anti-receptor binding domain (RBD) IgG (Elecsys, Roche) were evaluated as correlates of protection from infection and disease. Function and phenotype of antigen-specific T cells were further interrogated by flow cytometry. Results: KTRs on mTORi-inclusive protocols demonstrated improved humoral immunity, with 46.7% and 63.6% seroconversion rates in the sirolimus and everolimus groups, respectively, compared with 26.3% in the SOC group. This was mirrored by improved serological neutralisation of live SARS-CoV-2 virus (ancestral strain) by patients on mTOR inhibitors. Serological neutralisation of the Omicron variant was achieved by 20% of KTRs on sirolimus, but by none in the SOC nor everolimus groups. Remarkably, sirolimus use was associated with a median antiviral T cell response 55-fold greater than SOC therapy, and 5-fold greater than HCs. SARS-CoV-2-specific CD4+ and CD8+ T cells in these patients were highly polyfunctional and formed robust central memory out to 3 months post second vaccine dose. While the phenotype of antigen-specific memory T cells from KTRs on SOC therapy was skewed relative to healthy individuals, this abnormality was corrected in the sirolimus group. Conclusions: These data support a randomised controlled trial of immunosuppression modification with sirolimus as a strategy to directly improve vaccine responses in KTRs. Funded by The Hospital Research Foundation Group, South Australia. The following reagent was obtained through BEI Resources, NIAID, NIH: Peptide Array, SARS-Related Coronavirus 2 Spike (S) Glycoprotein, NR-52402.

336.1: Spatial Transcriptomic Profiling Reveals Immunosuppression And Immunosenescence-Driven Skewing of Immune Response in Cutaneous Squamous Cell Carcinoma Immune Response in Kidney Transplant Recipients, Associating With Adverse Cancer-Related Outcomes

336.1: Spatial Transcriptomic Profiling Reveals Immunosuppression And Immunosenescence-Driven Skewing of Immune Response in Cutaneous Squamous Cell Carcinoma Immune Response in Kidney Transplant Recipients, Associating With Adverse Cancer-Related Outcomes

246.1: Antibody Response and Cellular Phenotyping in Kidney Transplant Recipients Following SARS-CoV-2 Vaccination

Introduction: Correlates of protection for SARS-CoV-2 vaccines are not yet well-established in kidney transplant recipients (KTRs). Studies have highlighted the importance of neutralizing antibodies (Abs), however data suggests T cell responses may play a secondary role in preventing reinfection. We performed a longitudinal assessment of immunogenicity and T and B cell responses in KTRs following SARS-CoV-2 vaccination. Methods: KTRs eligible for SARS-CoV-2 vaccination were screened through medical records from March 12, 2021. Baseline and weekly blood samples were collected for routine assessment, SARS-CoV-2 spike protein Ab titers and cellular phenotyping for 12 weeks. Ab response was defined as a 10-fold increase in total binding IgG titers. To determine if T cell responses were induced by vaccination, we considered the proportion of activated non-naive CD4+ and CD8+ T cells after vaccination. Results: 49 KTRs with a mean age of 54 years were enrolled (Table 1). 10 patients (20.4%) mounted an Ab response following completed vaccination. A history of COVID-19 was associated with an increased likelihood of developing an Ab response (OR: 18.3, 95% CI 3.2, 105.0, p=0.0005). For non-naive CD8+ T cells, a subset co-expressing CD38+Ki67+ was induced 1 week after the 1st immunization in some SARS-CoV-2-naiive patients (P=0.12 versus P=0.14 for SARS-CoV-2-experienced adults, Figure 1A/B). For non-naive CD4+ T cells, induction of a subset co-expressing CD38+Ki67+ was observed at 1 week after the 1st immunization for SARS-CoV-2-naïve participants (P = 0.09 for SARS-CoV-2-naïve, P=0.03 for SARS-CoV-2-experienced adults, Figure 1C/D). For CD8+ and CD4+ T cells, dose 2 stimulated weak induction of the CD38+Ki67+ subset in the SARS-CoV-2-naïve patients only (Figure 1A-D). Conclusions: Quantitative Ab responses were strongly associated with prior SARS-CoV-2 infection. Activated CD4+ and CD8+ T cell responses were evident in most patients, with wide variation, irrespective of COVID-19 history. Further studies are needed to determine whether these activated CD4+ and CD8+ T cell responses were antigen-specific or confer immunity.

Efficacy and Safety of COVID-19 Vaccine in Patients on Renal Replacement Therapy.

Patients with CKD on RRT are at high risk for severe disease and mortality in COVID-19 disease. We decided to conduct an observational prospective study to evaluate antibody response after vaccination for COVID-19 in a cohort of 210 adult patients on RRT (148 on HD; 20 on PD; and 42 kidney transplant recipients). Blood samples were taken before and 4 weeks after vaccination. Antibody levels were evaluated with CLIA immunoassay testing for IgG anti-trimeric spike protein of SARS-CoV-2. A positive antibody titer was present in 89.9% of HD patients, 90% of PD patients, and 52.4% of kidney transplant recipients. Non-responders were more frequent among patients on immunosuppressive therapy. Mycophenolate use in kidney transplant patients was associated with lower antibody response. The median antibody titer was 626 (228–1480) BAU/mL; higher in younger patients and those previously exposed to the virus and lower in HD patients with neoplasms and/or on immunosuppressive therapy. Only two patients developed COVID-19 in the observation period: they both had mild disease and antibody titers lower than 1000 BAU/mL. Our data show a valid response to COVID-19 mRNA vaccination in HD and PD patients and a reduced response in kidney transplant recipients. Mycophenolate was the most relevant factor associated with low response.

Factors Associated With Reduced Anti-SARS-CoV-2 Antibody Responses After mRNA Vaccination in Kidney Transplant Recipients on Belatacept

Belatacept is a costimulation blocker used for maintenance immunosuppression in kidney transplant recipients (KTRs) as an alternative to calcineurin inhibitors.1 Studies evaluating SARS-CoV-2 vaccine responses in KTRs have shown reduced antibody responses in KTRs on belatacept.2-4 Nevertheless, many of these studies included only a small number of patients on belatacept,5 and had low rates of seroconversion, limiting the ability to evaluate factors associated with the development of antibody responses.

Serological Response to Three, Four and Five Doses of SARS-CoV-2 Vaccine in Kidney Transplant Recipients.

Mortality from COVID-19 among kidney transplant recipients (KTR) is high, and their response to three vaccinations against SARS-CoV-2 is strongly impaired. We retrospectively analyzed the serological response of up to five doses of the SARS-CoV-2 vaccine in KTR from 27 December 2020 until 31 December 2021. Particularly, the influence of the different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. In total, 4277 vaccinations against SARS-CoV-2 in 1478 patients were analyzed. Serological response was 19.5% after 1203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% in response to 603 third, 250 fourth, and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7%. In patients with calcineurin inhibitor and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased the serological response rate to 75% in comparison to the no dose adjustment (52%) or dose reduction (46%). Belatacept-treated patients had a response rate of 8.7% (4/46) after three vaccinations and 12.5% (3/25) after four vaccinations. Except for belatacept-treated patients, 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.