Morning administration enhances humoral response to SARS-CoV-2 vaccination in kidney transplant recipients.

Although severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid (SARS-CoV-2 mRNA) vaccines are effective in kidney transplant recipients (KTRs), their immune response to vaccination is blunted by immunosuppression. Other tools enhancing vaccination response are therefore needed. Interestingly, aligning vaccine administration with circadian rhythms (chronovaccination) has been shown to boost immune response. However, its applicability in KTRs, whose circadian rhythms are likely disrupted by immunosuppressants, remains unclear. To assess the impact of vaccination timing on seroconversion in the KTRs population, we analyzed data from 553 virus-naïve KTRs who received 2 doses of messenger ribonucleic acid (mRNA) vaccine. Bayesian logistic regression was employed, adjusting for previously identified predictors of seroconversion, including allograft function, maintenance immunosuppressants, or time since transplantation. SARS-CoV-2 immunoglobulin G (IgG) levels were measured with a median of 47 days after the second dose. The results did not reveal a reliable effect of timing of the first dose but did indicate that earlier timing for the second dose brings a notable benefit-every 1-hour delay in the application was associated with a 16% reduction in the odds of seroconversion (OR 0.84, 95% CI 0.71, 0.998). Similar results were obtained from quantile regression modeling IgG levels. In conclusion, morning vaccination is emerging as a promising and easily implementable strategy to enhance vaccine response in KTRs.

Association Between SARS-CoV-2 Messenger RNA Vaccines and Lower Infection Rates in Kidney Transplant Recipients : A Registry-Based Report.

BACKGROUND: The real-world protection provided by SARS-CoV-2 messenger RNA (mRNA) vaccines to kidney transplant recipients (KTRs) remains uncertain. OBJECTIVE: To study the association between mRNA vaccination and SARS-CoV-2 infection rate in KTRs. DESIGN: Retrospective observational cohort study. SETTING: The Czech Republic (17 February to 16 May 2021). PATIENTS: 2101 KTRs followed in the Department of Nephrology at the Institute for Clinical and Experimental Medicine. MEASUREMENTS: Positive result for SARS-CoV-2 on polymerase chain reaction test and vaccination status of KTRs. RESULTS: The incidence rate in the vaccinated group was 0.474 per 1000 person-days (33 cases in 69 672 days at risk). The incidence rate in the unvaccinated group was 1.370 per 1000 person-days (79 cases in 57 658 days at risk). The unadjusted incidence rate ratio (IRR; incidence rate of vaccinated/incidence rate of unvaccinated) for KTRs was 0.346 (95% CI, 0.227 to 0.514). The multivariable adjusted IRR for KTRs was 0.544 (CI, 0.324 to 0.876). LIMITATION: Retrospective observational design, uneven follow-up of patient groups, and different exposition to SARS-CoV-2 stemming from strong temporal trends and differences in clinical and probably behavioral characteristics. CONCLUSION: Vaccination of KTRs is associated with lower risk for SARS-CoV-2 infection. PRIMARY FUNDING SOURCE: The Ministry of Health of the Czech Republic.

Covid-19 in kidney transplant recipients.

Kidney transplant recipients are a very vulnerable population at risk of severe course and death from Covid-19. Several antiviral drugs are now available for the treatment of nonhospitalized individuals with mild to moderate Covid-19 and hospitalized patients with severe disease. The combination of monoclonal antibodies is also available to be used as pre-exposure prophylaxis in elderly patients. Previously used monoclonal antibodies for post-exposure prophylaxis are no longer effective because of the new mutations and are no longer recommended. Although the immune response to Covid-19 vaccines is impaired in kidney transplant recipients, the effectiveness of the Covid-19 vaccines was described even in this immunocompromised group. Therefore vaccination, together with anti-epidemic measures, remains the most important tool to prevent Covid-19.

Humoral response to SARS-CoV-2 is well preserved and symptom dependent in kidney transplant recipients.

Data on the immune response to SARS-CoV-2 in kidney transplant recipients are scarce. Thus, we conducted a single-center observational study to assess the anti-SARS-CoV-2 IgG seroprevalence in outpatient kidney transplant recipients (KTR; n = 1037) and healthcare workers (HCW; n = 512) during the second wave of the COVID-19 pandemic in fall 2020 and evaluated the clinical variables affecting antibody levels. Antibodies against S1 and S2 subunit of SARS-CoV-2 were evaluated using immunochemiluminescent assay (cut off 9.5 AU/ml, sensitivity of 91.2% and specificity of 90.2%). Anti-SARS-CoV-2 IgG seroprevalence was lower in KTR than in HCW (7% vs. 11.9%, p = .001). Kidney transplant recipients with SARS-CoV-2 infection were younger (p = .001) and received CNI-based immunosuppression more frequently (p = .029) than seronegative KTR. Anti-SARS-CoV-2 IgG positive symptomatic KTR had a higher BMI (p = .04) than asymptomatic KTR. Interestingly, anti-SARS-CoV-2 IgG levels were higher in KTR than in HCW (median 31 AU/ml, IQR 17-84 vs. median 15 AU/ml, IQR 11-39, p < .001). The presence of moderate to severe symptoms in KTR was found to be the only independent factor affecting IgG levels (Beta coefficient = 41.99, 95% CI 9.92-74.06, p = .011) in the multivariable model. In conclusion, KTR exhibit a well-preserved symptom-dependent humoral response to SARS-CoV-2 infection.

Safety and Immunogenicity of SARS-CoV-2 mRNA Vaccine Booster Doses in Kidney Transplant Recipients: Results of a 12-mo Follow-up From a Prospective Observational Study.

Background: Booster doses of SARS-CoV-2 mRNA vaccines are commonly used in kidney transplant recipients (KTRs). However, there is uncertainty regarding the waning of vaccination responses and immunological safety in KTRs. Methods: A total of 123 KTRs were included in the final analysis of this prospective observational cohort study. The aim was to evaluate the immunogenicity and immunological safety. SARS-CoV-2 antispike IgG antibodies and anti-HLA antibodies were measured at baseline and then at months 3, 6, and 12 after vaccination with the first booster dose (ie, the third vaccine dose). Antibodies against S1 and S2 subunits of SARS-CoV-2 were evaluated using an immunochemiluminescent assay (cutoff 9.5 AU/mL, sensitivity 91.2%, and specificity 90.2%). Anti-HLA antibodies were analyzed using single-antigen bead technology. Results: Seroconversion was reached in 65% of KTRs previously nonresponding to 2-dose mRNA vaccination; the overall seroconversion rate 3 mo after the first booster dose was 83%. Vaccination induced a durable humoral response, and the antibody levels were stable during the 12-mo study follow-up. Higher age (exponentiated beta coefficient [eß] 0.97; 95% confidence interval [CI], 0.943-0.997) and a full dose of mycophenolate (eß 0.296; 95% CI, 0.089-0.984) were negatively associated with SARS-CoV-2 IgG antibody levels, whereas better graft function (eß1.021; 95% CI, 1.005-1.037) was associated positively. There were no systematic signs of anti-HLA antibody development after vaccination. However, during the follow-up, there was a nonsignificant signal of an increase in anti-HLA antibodies in those who developed COVID-19. Conclusions: Additional booster doses of SARS-CoV-2 mRNA vaccines induce durable antibody response even in a large subset of previous nonresponders and are not associated with the risk of allosensitization. Furthermore, a signal linking COVID-19 to the development of anti-HLA antibodies was observed, and this should be confirmed and further examined (NCT05483725).

The impact of frailty syndrome on humoral response to SARS-CoV-2 mRNA vaccines in older kidney transplant recipients.

PURPOSE: Advanced age is associated with an impaired humoral immune response to SARS-CoV-2 mRNA vaccination in kidney transplant recipients (KTR). The mechanisms are, however, poorly understood. Frailty syndrome assessment may determine the most vulnerable population. METHODS: This study is a secondary analysis of a prospective study (NCT04832841) regarding seroconversion after BNT162b2 vaccination, including 101 SARS-CoV-2 naïve KTR 70 years and older. The Fried frailty components were evaluated, and antibodies against S1 and S2 subunits of SARS-CoV-2 were examined > 14 days after the second dose of BNT162b2 vaccine. RESULTS: Seroconversion was observed in 33 KTR. Male gender, eGFR, MMF-free immunosuppression, and a lower frailty score were associated with higher seroconversion rates in univariable regression. Concerning frailty components, physical inactivity had the most negative effect on seroconversion (OR = 0.36, 95% CI 0.14-0.95, p = 0.039). In a multivariable regression adjusted for eGFR, MMF-free immunosuppression, time from transplant and gender, pre-frail (OR = 0.27, 95% CI 0.07-1.00, p = 0.050), and frail status (OR = 0.14, 95% CI 0.03-0.73, p = 0.019) were associated with an increased risk of unresponsiveness to SARS-CoV-2 vaccines. CONCLUSION: Frailty was associated with an impaired humoral response to SARS-CoV-2 mRNA vaccination in older SARS-CoV-2 naïve KTR. TRAIL REGISTRATION: This study is registered under the identifier NCT04832841 on ClinicalTrials.gov.

Determinants of Immune Response to Anti-SARS-CoV-2 mRNA Vaccines in Kidney Transplant Recipients: A Prospective Cohort Study.

BACKGROUND: Immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has been recently shown to be impaired in kidney transplant recipients (KTRs), but the underlying factors affecting vaccine effectiveness need to be further elucidated. METHODS: In this prospective cohort study, antibodies against S1 and S2 subunits of SARS-CoV-2 were evaluated using an immunochemiluminescent assay (cutoff 9.5 AU/mL, sensitivity 91.2%, and specificity 90.2%) in 736 KTRs, who were previously either naive or infected with SARS-CoV-2 and vaccinated before or after transplantation. Cellular response was analyzed in a subset of patients using an interferon gamma release assay (cutoff 0.15 IU/mL, sensitivity 92%, and specificity 100%). RESULTS: Seroconversion was significantly more impaired in SARS-CoV-2-naive KTRs than in those previously infected (40.1% versus 97.1%; P < 0.001). Mycophenolate use (odds ratio, 0.15; 95% confidence interval, 0.09-0.24; P < 0.001) and depleting therapy in the past year (odds ratio, 0.19; 95% confidence interval, 0.05-0.8; P = 0.023) were found to be among independent factors associated with impaired humoral response. Similarly, the interferon gamma release assay tested in 50 KTRs (cutoff 0.15 IU/mL, sensitivity 92%, specificity 100%) showed that specific T-cell responses against spike protein epitopes are impaired in SARS-CoV-2-naive KTRs, as compared to previously infected KTRs (9.4% versus 90%, P < 0.001). All 35 KTRs vaccinated on the waiting list before transplantation exhibited sustained seroconversion persisting after transplantation. CONCLUSIONS: Survivors of coronavirus disease 2019 and those vaccinated while on the waiting list exhibited a marked immune response to mRNA vaccines, contrary to poor response in naive KTRs vaccinated after transplantation (NCT04832841).