Development and Validation of Multivariable Prediction Models of Serological Response to SARS-CoV-2 Vaccination in Kidney Transplant Recipients (preprint)

Background 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 in KTR. Methods 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 KTR. Using 27 candidate predictor variables, we applied statistical and machine learning approaches including logistic regression (LR), LASSO-regularized LR, random forest, and gradient boosted regression trees. For development and internal validation, data from 585 vaccinations were used. External validation was performed in four independent, international validation datasets comprising 191, 184, 254, and 323 vaccinations, respectively. Findings LASSO-regularized LR performed on the whole development dataset yielded a 23- and 11- variable model, respectively. External validation showed AUC-ROC of 0.855, 0.749, 0.828, and 0.787 for the sparser 11-variable model, yielding an overall performance 0.819. Interpretation An 11-variable LASSO-regularized LR model predicts vaccination response in KTR with good overall accuracy. Implemented as an online tool, it can guide decisions when choosing between different immunization strategies to improve protection against COVID-19 in KTR.

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

BackgroundModification of vaccination strategies is needed to improve the immune response to SARS-CoV-2 vaccination in kidney transplant recipients (KTRs). MethodsThis 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. Results18 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). ConclusionsTemporary reduction in MMF dose might be a promising approach to improve the immune response in KTRs.