Immune response to third SARS-CoV-2 vaccination in seronegative kidney transplant recipients: possible improvement by mycophenolate mofetil reduction

Abstract

Background: Modification of vaccination strategies is needed to improve the immune response to SARS-CoV-2 vaccination in kidney transplant recipients (KTRs). Methods: This multicenter observational study aimed to determine antibody kinetics among 60 seropositive KTRs and analyzed the effects of the third vaccination against SARS-CoV-2 in 174 previously seronegative KTRs. We investigated whether mycophenolate mofetil (MMF) dose reduction by 25-50% prior the third vaccination influences vaccination success. Results: 18 of 60 (30%) seropositive KTRs became seronegative in the serological assay within six months. Loss of antibodies was predicted by low initial antibody levels (<≤>206.8 BAU/ml), older age, and impaired graft function. A third vaccination in previously seronegative KTRs induced seroconversion in 56 of 174 (32.1%) KTRs with median antibody levels 119 (76-353) BAU/ml and median neutralizing capacity titer of 1:10 (0-1:40). Multivariate logistic regression revealed that initial antibody levels (OR 1.39, 95% CI 1.09-1.76), graft function (OR 0.05, 95% CI 0.01-0.39), time after transplantation (OR 1.04, 95% CI 1.02-1.07) and MMF trough levels (OR 0.43, 95% CI 0.21-0.88) correlated with seroconversion, p<0.05. After controlling for these confounders, the effect of MMF dose reduction was calculated using propensity score matching. KTRs in the MMF reduction group had significantly lower MMF serum concentrations prior to the third vaccination and were more likely to develop antibody levels <≥>35.2 BAU/ml than their matched KTRs (p=0.02). Conclusions: Temporary reduction in MMF dose might be a promising approach to improve the immune response in KTRs.

Declining Course of Humoral Immune Response in Initially Responding Kidney Transplant Recipients after Repeated SARS-CoV-2 Vaccination

“…Loss of antibodies at 2 months and 4 months after vaccination occurred in a substantial number of initially responding individuals, presumably resulting in a loss of protection against COVID-19. While it is known that patient receiving MPA have a low vaccination response rate (14,17), our results suggest that use of MPA is also associated with a delay in vaccination response resulting in increasing Ig levels over time in almost 18% of patients. Most importantly, we noted a high variability in the development of humoral protection over time between KTR.…”

Declining Course of Humoral Immune Response in Initially Responding Kidney Transplant Recipients after Repeated SARS-CoV-2 Vaccination

“…Loss of antibodies at 2 and 4 months after vaccination occurred in a substantial number of initially responding individuals, presumably resulting in a loss of protection against COVID-19. While it is known that patients receiving MPA have a low vaccination response rate [ 17 , 21 ], our results suggest that the use of MPA is also associated with a delay in vaccination response, resulting in increasing Ig levels over time in almost 18% of patients. Most importantly, we noted a high variability in the development of humoral protection over time between KTR.…”

Humoral response to SARS-CoV-2 mRNA vaccination in previous non-responder kidney transplant recipients after short-term withdrawal of mycophenolic acid

“…A few studies have examined the effect of MPA withdrawal to enhance vaccination responsiveness in small cohorts ( 55 , 56 ). After showing a dose-dependent effect of MPA on antibody levels after two COVID-19 vaccinations, Kantauskaite et al examined the effect of temporary MPA dose reduction by 25–50% in 24 KTR receiving a third mRNA vaccination matched to 24 KTR without changes in immunosuppressive maintenance therapy ( 31 , 55 ).…”

“…A few studies have examined the effect of MPA withdrawal to enhance vaccination responsiveness in small cohorts ( 55 , 56 ). After showing a dose-dependent effect of MPA on antibody levels after two COVID-19 vaccinations, Kantauskaite et al examined the effect of temporary MPA dose reduction by 25–50% in 24 KTR receiving a third mRNA vaccination matched to 24 KTR without changes in immunosuppressive maintenance therapy ( 31 , 55 ). The authors found significantly higher antibody levels in patients with MPA reduction 3 weeks prior until 1 week after third vaccination, however, patients were not followed-up on graft function or development of DSA ( 55 ).…”

“…Five patients (7%) had four vaccinations, 71 patients (93%) 3 vaccinations prior to inclusion into the study. Median (IQR) age was 57 (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63) years and 29/76 (38%) participants were females. Baseline characteristics including transplant-related data, cause of nephropathy and comorbidities are given in Table 1.…”