COVID-19 Vaccination Induces a Poor Interleukin-21 Memory T-cell Response in Kidney Transplant Recipients

Purpose: COVID-19-related morbidity and mortality is high among kidney patients. Several studies recently suggested low humoral and cellular immune responses after two doses of mRNA-1273 (Moderna) in these patients. Interleukin (IL)-21 is key in orchestrating an effective immune response against viral infections, is mainly produced by activated CD4+ T-cells and stimulates both humoral and cellular immunity. However, T-cell function may be impaired in kidney patients and this may explain the poor response to vaccination. Currently, there is limited data available on the vaccine-induced IL-21 memory T-cell response in these patients. We studied the induction of SARS-CoV-2-specific IL-21 memory T-cell response after mRNA- 1273 vaccination in 3 groups of kidney patients. Method(s): 113 participants were randomly selected from a prospective controlled multicenter cohort study, including 38 controls, 19 chronic kidney disease (CKD) stages G4/5 (eGFR <30 mL/min/1.73m2), 20 dialysis and 36 kidney transplant patients. All participants received 2 doses of mRNA-1273. To assess the vaccineinduced IL-21 memory T-cell response, we performed an IL-21 ELISpot (per 3.105 PBMCs) in these participants at baseline and 28 days after the second vaccination. SARS-CoV-2 S1-specific IgG antibody levels were already measured in the context of the multicenter cohort study. Result(s): Kidney transplant recipients had a significantly lower number of SARSCoV- 2-specific IL-21 producing memory T-cells when compared to controls (median of 46 versus 146, P<0.001). Participants with CKD G4/5 or on dialysis also had reduced SARS-CoV-2-specific IL-21 producing memory T-cells compared to controls (median of 128 [19-658] and 124 [7-654] versus 146 [10-635], p=0.43 and p=0.45, respectively), but the difference was less pronounced. In addition, a positive correlation was found between the number of SARS-CoV-2-specific IL-21 producing memory T-cells and SARS-CoV-2 S1-specific IgG antibody levels for all groups (Pearson correlation coefficient of 0.2, p=0.028). Conclusion(s): Kidney transplant recipients have an impaired antibody response after two doses of mRNA-1273 (Moderna), which correlates with poor SARS-CoV- 2-specific T-cell reactivity. These findings suggest that poor IL-21 memory T-cell response might hamper protection against COVID-19.

COVID-19 Vaccination Response in Tacrolimus Treated Kidney Transplant Recipients with and without Mycophenolate Mofetil: Follow-Up of a Randomized Controlled Trial

Purpose: To investigate the effect of mycophenolate mofetil (MMF) on SARSCoV- 2 vaccination response in kidney transplant recipients using the standard immunosuppressive regimen of tacrolimus (TAC) and MMF. Method(s): A randomized controlled trial in immunologically low risk kidney transplant recipients was performed (EudraCT nr.: 2014-001372-66). Patients were randomized to standard TAC/MMF or TAC monotherapy (TACmono) from 9 months onwards, without steroids. Antibody based immune responses to SARS-CoV-2 vaccination (mRNA-1273 or BNT162b2) were investigated in a central laboratory, as part of the RECOVAC Antibody study (EudraCT nr.: 2021-283 001520-18), 4-8 weeks after the second vaccination. Measurement involved the presence of antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 S-protein (IgG anti-RBD antibody) using the Sanquin anti-SARS-CoV-2 RBD IgG ELISA assay. Patients were classified as non-responders (<=50 BAU/mL), low-responders (50-300 BAU/ mL) and responders (>300 BAU/mL). Result(s): Between 2015 and 2018, 79 recipients were randomized to TAC/MMF (n=41) and TACmono (n=38). At the outbreak of the COVID-19 pandemic in early 2020, 67 patients were alive with a functioning graft (TAC/MMF n=35, TACmono n=32). In 27 patients antibody responses could be established: Ten patients were excluded from the analyses due to symptomatic COVID-19 infection and 1 due to a positive nucleocapsid test, possibly from an asymptomatic infection. The rest did not participate in the vaccination study, because of ChAdOx1-S, age >80 years or lack of informed consent. Mean age was 64 (43-75) years, median time after transplantation 4.2 (3.0-6.5) years and eGFR was 53 (36-105) ml/min/1.73m2. TAC trough levels were 6.6 (+/-0.3) mug/L in both groups, and MMF dose was 1000 mg daily (range 500- 2000) in TAC/MMF. Median SARS-CoV-2 Spike S1-specific IgG antibody levels were 37.3 BAU/ml in TAC/MMF (5 non, 7 low, 1 responder) and 715.6 BAU/ml in TACmono (1 non, 6 low, 7 responders, p =0.004, figure 1). Of note is that antibody levels of >1000 BAU/ml, as a presumed threshold for protection against Omicron (B.1.1.529), was reached in 1/13 TAC/MMF and 7/14 TACmono patients (p=0.03). Conclusion(s): In this controlled study mycophenolate mofetil on top of tacrolimus severely hampered serological COVID-19 vaccination response.

Dynamic prediction of mortality in COVID-19 patients in the intensive care unit: A retrospective multi-center cohort study.

Background: The COVID-19 pandemic continues to overwhelm intensive care units (ICUs) worldwide, and improved prediction of mortality among COVID-19 patients could assist decision making in the ICU setting. In this work, we report on the development and validation of a dynamic mortality model specifically for critically ill COVID-19 patients and discuss its potential utility in the ICU. Methods: We collected electronic medical record (EMR) data from 3222 ICU admissions with a COVID-19 infection from 25 different ICUs in the Netherlands. We extracted daily observations of each patient and fitted both a linear (logistic regression) and non-linear (random forest) model to predict mortality within 24 h from the moment of prediction. Isotonic regression was used to re-calibrate the predictions of the fitted models. We evaluated the models in a leave-one-ICU-out (LOIO) cross-validation procedure. Results: The logistic regression and random forest model yielded an area under the receiver operating characteristic curve of 0.87 [0.85; 0.88] and 0.86 [0.84; 0.88], respectively. The recalibrated model predictions showed a calibration intercept of -0.04 [-0.12; 0.04] and slope of 0.90 [0.85; 0.95] for logistic regression model and a calibration intercept of -0.19 [-0.27; -0.10] and slope of 0.89 [0.84; 0.94] for the random forest model. Discussion: We presented a model for dynamic mortality prediction, specifically for critically ill COVID-19 patients, which predicts near-term mortality rather than in-ICU mortality. The potential clinical utility of dynamic mortality models such as benchmarking, improving resource allocation and informing family members, as well as the development of models with more causal structure, should be topics for future research.

HIGHER ANTIBODY RESPONSE AFTER 2 VACCINATIONS WITH MRNA-1273 AS COMPARED WITH BNT162B2 AND AZD1222 IN HIGH-RISK KIDNEY PATIENTS

BACKGROUND AND AIMS: Lower antibody responses after SARS-Cov-2 vaccination have been reported in patients with severely impaired kidney function or patients with kidney replacement treatment. We compared humoral responses and reported adverse events of three vaccines (mRNA-1273, BNT162b2 and AZD1222) in kidney transplant recipients (KTRs), dialysis patients, patients with CKD stages G4-G5 and control subjects without kidney disease. METHOD: KTRs, dialysis patients and patients with CKD stages G4-G5 were vaccinated with either mRNA-1273, BNT162b2 or AZD1222 during the Dutch SARSCoV- 2 vaccination program. Control subjects were all vaccinated with mRNA-1273. Blood samples were obtained at 1 month after two vaccinations by home-based finger prick tests and were analysed for the presence of IgG antibodies against the receptorbinding domain of the spike protein of SARS-CoV-2 using the Sanquin anti-SARSCoV- 2 RBD IgG ELISA assay. Primary endpoints were the antibody titer and reported systemic adverse events (AEs) at 1 month after the second vaccination. Multivariate regression analysis was performed on the difference between vaccines with respect to antibody titer and AEs after correction for sex, ethnicity, BMI, eGFR, dialysis vintage, transplantation characteristics and use of immunosuppressive drugs. RESULTS: A total of 2468 KTRs, 480 dialysis patients, 400 patients with CKD stages G4-G5 and 186 control subjects were enrolled. KTRs had lower antibody titers (66 [8-573] BAU/mL) in comparison to dialysis patients [1375 (431-2896) BAU/mL], patients with CKD stages G4-G5 [2097 (828-4077) BAU/mL] and control subjects [3713 (2291-6451) BAU/mL]. mRNA-1273 demonstrated a higher antibody titer compared with BNT162b2 in KTR [72 (9-638) versus 21 (6-128) BAU/mL;P < .001), dialysis patients [1675 (573-3031) versus 636 (216-1416) BAU/mL;P < .001] and patients with CKD stages G4-G5 [2879 (1425-5311) versus 1063 (389-1939) BAU/mL;P < .001). In a similar pattern, mRNA-1273 demonstrated a higher antibody titer compared with AZD1222 (P < .001 in all groups). Multivariate analysis revealed that BNT162b2 and AZD1222 were significantly associated with lower antibody levels compared with mRNA-1273 in all 3 patient groups. BNT162b2 demonstrated less frequently systemic AEs compared with mRNA-1273 in KTRs (12% versus 27%;P < .001), dialysis patients (12% versus 29%;P = .007) and in patients with CKD G4- G5 (18% versus 67%, P < .001). AZD1222 demonstrated less systemic AEs compared with mRNA-1273 only in patients with CKD stages G4-G5 (39% versus 67%;P = .03). Multivariate analysis revealed that BNT162b2 was associated with fewer systemic AEs in only dialysis patients (P = .04) and patients with CKD stages G4-G5 (P = .02). CONCLUSION: mRNA-1273 demonstrated significantly higher antibody levels at 1 month after 2 vaccinations as compared with BNT162b2 and AZD1222 in high-risk patients with kidney disease. BNT162b2 was associated with a fewer systemic AEs in dialysis patients and patients with CKD stages G4-G5, although these AEs were mild and self-limiting. mRNA-1273 may therefore be considered as the preferred SARS-CoV-2 vaccine in high-risk patients with kidney disease. Whether the higher antibody response following vaccination with mRNA-1273 sustains and results in a better protection against COVID-19 is yet to be analysed.

DEVELOPMENT AND VALIDATION OF A MULTIVARIABLE PREDICTION MODEL FOR NONSEROCONVERSION AFTER SARS-COV-2 VACCINATION IN KIDNEY TRANSPLANT RECIPIENTS

BACKGROUND AND AIMS: Kidney transplant recipients (KTRs) are still at risk of fatal COVID-19 disease after SARS-CoV-2 vaccination, even after a third booster vaccination. With the spread of new SARS-CoV-2 variants, great urgency exists for a better understanding of the factors that impact the immune response in these patients. Our aim was to predict nonseroconversion after SARS-CoV-2 vaccination to understand the factors that may disrupt the humoral response in KTRs. METHOD: A multivariable logistic regression model was developed and validated that uses routinely available clinical and laboratory information to predict nonseroconversion after two doses of SARS-CoV-2 mRNA vaccination in KTRs. KTRs were prospectively enrolled to the Dutch REnal patients COVID-19 VACcination (RECOVAC) consortium, specifically to the Immune Response (IR) study with four participating university medical centres in the Netherlands. The discovery cohort consisted of three participating centres (Amsterdam UMC, Radboud UMC Nijmegen and Erasmus MC Rotterdam), and the validation cohort of patients treated in UMC Groningen. A large second validation set from the RECOVAC consortium (LESS-CoV- 2) was used to test a more simplified version of the model without lymphocyte counts. All participants received two doses of the mRNA-1273 COVID-19 vaccine (Moderna) and had no history of SARS-CoV-2 infection. Participants were classified as responder or non-responder based on seroconversion at day 28 following the second vaccination with a threshold for seropositivity based on receiver operator curve analysis set at S1-specific IgG antibody concentration ≥10 BAU/mL. RESULTS: The discovery cohort included 215 KTRs of which 126 responders and 89 non-responders. After backward selection, 6 out of 19 factors remained predictive for nonseroconversion: increased age, lower lymphocyte count, lower estimated glomerular filtration rate (eGFR), shorter time after transplantation, not using steroids and the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) (Figure 1). The area under the curve (AUC) of the receiver operating characteristics was 0.83 (95% confidence interval 0.78-0.89) in the discovery cohort after adjustment for optimism and 0.84 (0.74-0.94) in external validation of the UMC Groningen cohort (n = 73), and 0.75 (0.72-0.77) in external validation of the LESS-CoV-2 dataset (n = 2484). In addition, MMF/MPA appeared to have a dose-dependent unfavourable association with the S1 IgG antibody titer (Figure 2). CONCLUSION: Six predictors allow for a better understanding of the process of the development of the humoral response in KTRs. These predictors could be applied to individualized patient counseling and treatment strategy during the COVID-19 pandemic and future innovative vaccine trial design for this complex patient group. (Figure Presented).

Long-term efficacy and safety of SARS-CoV-2 vaccination in patients with chronic kidney disease, on dialysis or after kidney transplantation: a national prospective observational cohort study.

BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. METHODS: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. RESULTS: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. CONCLUSION: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. TRIAL REGISTRATION: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.

Immediate impact of COVID-19 on transplant activity in the Netherlands.

The rapid emergence of the COVID-19 pandemic is unprecedented and poses an unparalleled obstacle in the sixty-five year history of organ transplantation. Worldwide, the delivery of transplant care is severely challenged by matters concerning - but not limited to - organ procurement, risk of SARS-CoV-2 transmission, screening strategies of donors and recipients, decisions to postpone or proceed with transplantation, the attributable risk of immunosuppression for COVID-19 and entrenched health care resources and capacity. The transplant community is faced with choosing a lesser of two evils: initiating immunosuppression and potentially accepting detrimental outcome when transplant recipients develop COVID-19 versus postponing transplantation and accepting associated waitlist mortality. Notably, prioritization of health care services for COVID-19 care raises concerns about allocation of resources to deliver care for transplant patients who might otherwise have excellent 1-year and 10-year survival rates. Children and young adults with end-stage organ disease in particular seem more disadvantaged by withholding transplantation because of capacity issues than from medical consequences of SARS-CoV-2. This report details the nationwide response of the Dutch transplant community to these issues and the immediate consequences for transplant activity. Worrisome, there was a significant decrease in organ donation numbers affecting all organ transplant services. In addition, there was a detrimental effect on transplantation numbers in children with end-organ failure. Ongoing efforts focus on mitigation of not only primary but also secondary harm of the pandemic and to find right definitions and momentum to restore the transplant programs.