Repeated COVID-19 Vaccination Drives Memory T- and B-cell Responses in Kidney Transplant Recipients: Results From a Multicenter Randomized Controlled Trial.

BACKGROUND: Insight into cellular immune responses to COVID-19 vaccinations is crucial for optimizing booster programs in kidney transplant recipients (KTRs). METHODS: In an immunologic substudy of a multicenter randomized controlled trial (NCT05030974) investigating different repeated vaccination strategies in KTR who showed poor serological responses after 2 or 3 doses of an messenger RNA (mRNA)-based vaccine, we compared SARS-CoV-2-specific interleukin-21 memory T-cell and B-cell responses by enzyme-linked immunosorbent spot (ELISpot) assays and serum IgG antibody levels. Patients were randomized to receive: a single dose of mRNA-1273 (100 µg, n = 25), a double dose of mRNA-1273 (2 × 100 µg, n = 25), or a single dose of adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein (Ad26.COV2.S) (n = 25). In parallel, we also examined responses in 50 KTR receiving 100 µg mRNA-1273, randomized to continue (n = 25) or discontinue (n = 25) mycophenolate mofetil/mycophenolic acid. As a reference, the data were compared with KTR who received 2 primary mRNA-1273 vaccinations. RESULTS: Repeated vaccination increased the seroconversion rate from 21% to 66% in all patients, which was strongly associated with enhanced levels of SARS-CoV-2-specific interleukin-21 memory T cells (odd ratio, 3.84 [1.89-7.78]; P < 0.001) and B cells (odd ratio, 35.93 [6.94-186.04]; P < 0.001). There were no significant differences observed in these responses among various vaccination strategies. In contrast to KTR vaccinated with 2 primary vaccinations, the number of antigen-specific memory B cells demonstrated potential for classifying seroconversion after repeated vaccination (area under the curve, 0.64; 95% confidence interval, 0.37-0.90; P = 0.26 and area under the curve, 0.95; confidence interval, 0.87-0.97; P < 0.0001, respectively). CONCLUSIONS: Our study emphasizes the importance of virus-specific memory T- and B-cell responses for comprehensive understanding of COVID-19 vaccine efficacy among KTR.

SARS-CoV-2-specific immune responses converge in kidney disease patients and controls with hybrid immunity.

Healthy individuals with hybrid immunity, due to a SARS-CoV-2 infection prior to first vaccination, have stronger immune responses compared to those who were exclusively vaccinated. However, little is known about the characteristics of antibody, B- and T-cell responses in kidney disease patients with hybrid immunity. Here, we explored differences between kidney disease patients and controls with hybrid immunity after asymptomatic or mild coronavirus disease-2019 (COVID-19). We studied the kinetics, magnitude, breadth and phenotype of SARS-CoV-2-specific immune responses against primary mRNA-1273 vaccination in patients with chronic kidney disease or on dialysis, kidney transplant recipients, and controls with hybrid immunity. Although vaccination alone is less immunogenic in kidney disease patients, mRNA-1273 induced a robust immune response in patients with prior SARS-CoV-2 infection. In contrast, kidney disease patients with hybrid immunity develop SARS-CoV-2 antibody, B- and T-cell responses that are equally strong or stronger than controls. Phenotypic analysis showed that Spike (S)-specific B-cells varied between groups in lymph node-homing and memory phenotypes, yet S-specific T-cell responses were phenotypically consistent across groups. The heterogeneity amongst immune responses in hybrid immune kidney patients warrants further studies in larger cohorts to unravel markers of long-term protection that can be used for the design of targeted vaccine regimens.

Post COVID-19 condition imposes significant burden in patients with advanced chronic kidney disease: A nested case-control study.

BACKGROUND: The burden of post COVID-19 condition (PCC) is not well studied in patients with advanced kidney disease. METHODS: A large prospective cohort of SARS-CoV-2 vaccinated patients with chronic kidney disease stages G4-G5 (CKD G4/5), on dialysis, and kidney transplant recipients (KTR) were included. Antibody levels were determined after vaccination. Presence of long-lasting symptoms was assessed in patients with and without prior COVID-19 and compared using logistic regression. In patients with prior COVID-19, PCC was defined according to the WHO definition. RESULTS: Two hundred sixteen CKD G4/5 patients, 375 dialysis patients, and 2005 KTR were included. Long-lasting symptoms were reported in 204/853 (24%) patients with prior COVID-19 and in 297/1743 (17%) patients without prior COVID-19 (aOR: 1.45 (1.17-1.78)], P < 0.001). PCC was prevalent in 29% of CKD G4/5 patients, 21% of dialysis patients, and 24% of KTR. In addition, 69% of patients with PCC reported (very) high symptom burden. Odds of PCC was lower per 10-fold increase in antibody level after vaccination (aOR 0.82 [0.70-0.96], P = 0.01) and higher in case of COVID-19 related hospital admission (aOR 4.64 [2.61-8.25], P = 0.003). CONCLUSIONS: CKD G4/5 patients, dialysis patients, and KTR are at risk for PCC with high symptom burden after SARS-CoV-2 vaccination, especially if antibody levels are low and in case of hospitalization due to COVID-19.

Current Perspectives on the Management of Herpesvirus Infections in Solid Organ Transplant Recipients.

Solid organ transplant recipients (SOTRs) are at high risk of human herpesvirus (HHV)-related morbidity and mortality due to the use of immunosuppressive therapy. We aim to increase awareness and understanding of HHV disease burden in SOTRs by providing an overview of current prevention and management strategies as described in the literature and guidelines. We discuss challenges in both prevention and treatment as well as future perspectives.

The role of interleukin-21 in COVID-19 vaccine-induced B cell-mediated immune responses in patients with kidney disease and kidney transplant recipients.

T-cell-mediated help to B cells is required for the development of humoral responses, in which the cytokine interleukin (IL)-21 is key. Here, we studied the mRNA-1273 vaccine-induced SARS-CoV-2-specific memory T-cell IL-21 response, memory B cell response, and immunoglobulin (Ig)G antibody levels in peripheral blood at 28 days after the second vaccination by ELISpot and the fluorescent bead-based multiplex immunoassay, respectively. We included 40 patients with chronic kidney disease (CKD), 34 patients on dialysis, 63 kidney transplant recipients (KTR), and 47 controls. We found that KTR, but not patients with CKD and those receiving dialysis, showed a significantly lower number of SARS-CoV-2-specific IL-21 producing T cells than controls (P < .001). KTR and patients with CKD showed lower numbers of SARS-CoV-2-specific IgG-producing memory B cells when compared with controls (P < .001 and P = .01, respectively). The T-cell IL-21 response was positively associated with the SARS-CoV-2-specific B cell response and the SARS-CoV-2 spike S1-specific IgG antibody levels (both Pearson r = 0.5; P < .001). In addition, SARS-CoV-2-specific B cell responses were shown to be IL-21 dependent. Taken together, we show that IL-21 signaling is important in eliciting robust B cell-mediated immune responses in patients with kidney disease and KTR.

Th1-dominant cytokine responses in kidney patients after COVID-19 vaccination are associated with poor humoral responses.

Cytokines are regulators of the immune response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the contribution of cytokine-secreting CD4+ and CD8+ memory T cells to the SARS-CoV-2-specific humoral immune response in immunocompromised kidney patients is unknown. Here, we profiled 12 cytokines after stimulation of whole blood obtained 28 days post second 100 µg mRNA-1273 vaccination with peptides covering the SARS-CoV-2 spike (S)-protein from patients with chronic kidney disease (CKD) stage 4/5, on dialysis, kidney transplant recipients (KTR), and healthy controls. Unsupervised hierarchical clustering analysis revealed two distinct vaccine-induced cytokine profiles. The first profile was characterized by high levels of T-helper (Th)1 (IL-2, TNF-α, and IFN-γ) and Th2 (IL-4, IL-5, IL-13) cytokines, and low levels of Th17 (IL-17A, IL-22) and Th9 (IL-9) cytokines. This cluster was dominated by patients with CKD, on dialysis, and healthy controls. In contrast, the second cytokine profile contained predominantly KTRs producing mainly Th1 cytokines upon re-stimulation, with lower levels or absence of Th2, Th17, and Th9 cytokines. Multivariate analyses indicated that a balanced memory T cell response with the production of Th1 and Th2 cytokines was associated with high levels of S1-specific binding and neutralizing antibodies mainly at 6 months after second vaccination. In conclusion, seroconversion is associated with the balanced production of cytokines by memory T cells. This emphasizes the importance of measuring multiple T cell cytokines to understand their influence on seroconversion and potentially gain more information about the protection induced by vaccine-induced memory T cells.

Clinical Characteristics and Outcomes of Immunocompromised Patients With Coronavirus Disease 2019 Caused by the Omicron Variant: A Prospective, Observational Study.

BACKGROUND: Illness after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is less severe compared with previous variants. Data on the disease burden in immunocompromised patients are lacking. We investigated the clinical characteristics and outcomes of immunocompromised patients with coronavirus disease 2019 (COVID-19) caused by Omicron. METHODS: Organ transplant recipients, patients on anti-CD20 therapy, and allogenic hematopoietic stem cell transplantation recipients infected with the Omicron variant were included. Characteristics of consenting patients were collected and patients were contacted regularly until symptom resolution. To identify possible risk factors for hospitalization, a univariate logistic analysis was performed. RESULTS: 114 consecutive immunocompromised patients were enrolled. Eighty-nine percent had previously received 3 mRNA vaccinations. While only 1 patient died, 23 (20%) were hospitalized for a median of 11 days. A low SARS-CoV-2 immunoglobulin G (IgG) antibody response (<300 BAU [binding antibody units]/mL) at diagnosis, being older, being a lung transplant recipient, having more comorbidities, and having a higher frailty score were associated with hospital admission (all P < .01). At the end of follow-up, 25% had still not fully recovered. Of the 23 hospitalized patients, 70% had a negative and 92% had a low IgG (<300 BAU/mL) antibody response at admission. Sotrovimab was administered to 17 of these patients, and 1 died. CONCLUSIONS: While the mortality in immunocompromised patients infected with Omicron was low, hospital admission was frequent and the duration of symptoms often prolonged. In addition to vaccination, other interventions are needed to limit the morbidity from COVID-19 in immunocompromised patients.

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.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.

Boosting the VZV-Specific Memory B and T Cell Response to Prevent Herpes Zoster After Kidney Transplantation.

Background: Solid organ transplant recipients are at high risk to develop (complicated) herpes zoster (HZ). Booster vaccination could prevent HZ. However, end-stage renal disease (ESRD) patients show poor immunological responses to vaccinations. We studied the effect of a live attenuated VZV booster vaccine on VZV-specific B and T cell memory responses in ESRD patients and healthy controls. NL28557.000.09, www.toetsingonline.nl. Methods: VZV-seropositive patients, aged ≥50 years, awaiting kidney transplantation, were vaccinated with Zostavax®. Gender and age-matched VZV-seropositive potential living kidney donors were included as controls. VZV-specific IgG titers were measured before, at 1, 3 and 12 months post-vaccination. VZV-specific B and T cell responses before, at 3 months and 1 year after vaccination were analysed by flow-cytometry and Elispot, respectively. Occurrence of HZ was assessed at 5 years post-vaccination. Results: 26 patients and 27 donors were included. Median VZV-specific IgG titers were significantly higher at all time-points post-vaccination in patients (mo 1: 3104 IU/ml [1967-3825], p<0.0001; mo 3: 2659 [1615-3156], p=0.0002; mo 12: 1988 [1104-2989], p=0.01 vs. pre: 1397 [613-2248]) and in donors (mo 1: 2981 [2126-3827], p<0.0001; mo 3: 2442 [2014-3311], p<0.0001; mo 12: 1788 [1368-2460], p=0.0005 vs. pre: 1034 [901-1744]. The patients' IgG titers were comparable to the donors' at all time-points. The ratio VZV-specific B cells of total IgG producing memory B cells had increased 3 months post-vaccination in patients (0.85 [0.65-1.34] vs. pre: 0.56 [0.35-0.81], p=0.003) and donors (0.85 [0.63-1.06] vs. pre: 0.53 [0.36-0.79], p<0.0001) and remained stable thereafter in donors. One year post-vaccination, the percentage of CD4+ central memory cells had increased in both patients (0.29 [0.08-0.38] vs. 0.12 [0.05-0.29], p=0.005) and donors (0.12 [0.03-0.37] vs. 0.09 [0.01-0.20], p=0.002) and CD4+ effector memory cells had increased in donors (0.07 [0.02-0.14] vs. 0.04 [0.01-0.12], p=0.007). Only 1 patient experienced HZ, which was non-complicated. Conclusion: VZV booster vaccination increases VZV-specific IgG titers and percentage VZV-specific memory T-cells for at least 1 year both in ESRD patients and healthy controls. VZV-specific memory B cells significantly increased in patients up to 3 months after vaccination. Prophylactic VZV booster vaccination prior to transplantation could reduce HZ incidence and severity after transplantation.

The RECOVAC Immune-response Study: The Immunogenicity, Tolerability, and Safety of COVID-19 Vaccination in Patients With Chronic Kidney Disease, on Dialysis, or Living With a Kidney Transplant.

BACKGROUND: In kidney patients COVID-19 is associated with severely increased morbidity and mortality. A comprehensive comparison of the immunogenicity, tolerability, and safety of COVID-19 vaccination in different cohorts of kidney patients and a control cohort is lacking. METHODS: This investigator driven, prospective, controlled multicenter study included 162 participants with chronic kidney disease (CKD) stages G4/5 (eGFR < 30 mL/min/1.73m2), 159 participants on dialysis, 288 kidney transplant recipients, and 191 controls. Participants received 2 doses of the mRNA-1273 COVID-19 vaccine (Moderna). The primary endpoint was seroconversion. RESULTS: Transplant recipients had a significantly lower seroconversion rate when compared with controls (56.9% versus 100%, P < 0.001), with especially mycophenolic acid, but also, higher age, lower lymphocyte concentration, lower eGFR, and shorter time after transplantation being associated with nonresponder state. Transplant recipients also showed significantly lower titers of neutralizing antibodies and T-cell responses when compared with controls. Although a high seroconversion rate was observed for participants with CKD G4/5 (100%) and on dialysis (99.4%), mean antibody concentrations in the CKD G4/5 cohort and dialysis cohort were lower than in controls (2405 [interquartile interval 1287-4524] and 1650 [698-3024] versus 3186 [1896-4911] BAU/mL, P = 0.06 and P < 0.001, respectively). Dialysis patients and especially kidney transplant recipients experienced less systemic vaccination related adverse events. No specific safety issues were noted. CONCLUSIONS: The immune response following vaccination in patients with CKD G4/5 and on dialysis is almost comparable to controls. In contrast, kidney transplant recipients have a poor response. In this latter, patient group development of alternative vaccination strategies are warranted.