First Booster of SARS-COV-2 mRNA Vaccine Is Not Associated With Alloimmunization and Subclinical Injury of Kidney Allograft

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As the protection provided by 2 doses of an mRNA vaccine substantially wanes over time and with the emergence of new viral variants,1 administration of booster doses was recommended for kidney transplant recipients (KTRs).2–4 Vaccination-associated immune activation might be associated with allorecognition and graft injury,5 and safety data in KTRs are insufficient. This prospective, observational study aims to evaluate vaccine safety, the dynamics of anti-HLA antibodies and donor-derived cell-free DNA (dd-cfDNA),6–9 and seroconversion rates following the first booster dose of an mRNA vaccine. The 3-mo follow-up of 108 SARS-CoV-2 naive KTRs is reported. Anti-HLA antibodies, SARS-CoV-2 IgG S1/S2 antibodies, kidney graft function were measured at baseline (D0) and at 3 mo (M3); dd-cfDNA was analyzed in 79 KTRs. Anti-HLA antibodies were measured with the single-antigen bead technology (LabScreen Mixed and LabScreen Single Antigen Luminex). The presence of donor-specific antibodies (DSAs) was assessed using HLA fusion 4.6.0 software (all One Lambda, Inc). The cutoff of 500 mean fluorescent intensity (MFI) was set as a threshold for DSA/anti-HLA antibody positivity.10 A significant increase in anti-HLA antibodies or DSAs was defined with the emergence of a de novo antibody with MFI >500 and a >50% increase in MFI of a preformed antibody. Calculated virtual panel-reactive antibodies were computed using the Eurotransplant Reference Laboratory calculator.11 The dd-cfDNA was measured with the Prospera test, with 1% cutoff.6 After vaccination, all study participants were contacted and asked about any reactions. SARS-CoV-2 S1/S2 IgG was tested using the LIAISON SARS-CoV-2 S1/S2 IgG chemiluminescence immunoassay (DiaSorin S.p.A., Italy). Cutoff of 9.5 arbitrary units (kAU/ml) was used to define seroconversion. One-sided, paired Wilcoxon test was used to compare the differences in MFI, dd-cfDNA, anti-SARS-CoV-2 IgG, and estimated glomerular filtration rate at D0 and M3. Anti-HLA antibodies at the D0 visit were found in 27% of KTRs (sensitized KTRs); 4 became negative by the M3 visit. One KTR developed de novo anti-HLA antibodies. DSAs at the D0 visit were found in 6 KTRs; by the M3 visit‚ 2 became negative; in 4 KTRs‚ MFI remained stable. One KTR developed de novo DSAs with a low MFI. No increases in the average MFI nor in up to 2 immunodominant anti-HLA MFIs were found (Figure 1A–D). No increase in calculated virtual panel-reactive antibodies was found (Figure 1E–F).FIGURE 1.: Dynamics of HLA specific antibodies after vaccination. In box plots, the bold horizontal lines represent the median; upper and lower box boundaries are 25th and 75th quantiles; individual participants are denoted as points. A, Average MFI of anti-HLA antibodies in class I between D0 and M3. B, Average MFI of anti-HLA antibodies in class II between D0 and M3. C, MFI of up to 2 immunodominant anti-HLA antibodies in class I between D0 and M3. D, MFI of up to 2 immunodominant anti-HLA antibodies in class II between D0 and M3. E, Calculated virtual panel-reactive antibodies (cPRA) change between D0 and M3 in the whole cohort. F, cPRA change between D0 and M3 in anti-HLA Ab positive KTRs only. A 1-sided paired Wilcoxon test was used to calculate the P values. Ab, antibody; cPRA, calculated panel-reactive antibodies; D0 visit, day of administration of third vaccine dose; KTR, kidney transplant recipient; M3 visit, 3 mo after third dose of vaccine; MFI, mean fluorescence intensity.There was no KTR with a new increase of dd-cfDNA above 1% at M3, nor with any overall increase in dd-cfDNA in the whole cohort including sensitized KTRs (Figure 2A,B). The dd-cfDNA at M3 increased in nonsensitized KTRs (Figure 2C); however, this increase was mild and far below the 1% threshold. Sensitized KTRs presented higher dd-cfDNA (Figure 2D).FIGURE 2.: Donor-derived cell-free DNA dynamics and eGFR dynamics. In boxplots, the bold horizontal lines represent the median; upper and lower box boundaries are 25th and 75th quantiles; individual participants are denoted as points; the dashed line leveled at 1% represents the cutoff for positivity. A‚ dd-cfDNA in all participants between D0 and M3. B‚ dd-cfDNA in participants without anti-HLA antibodies between D0 and M3. C‚ dd-cfDNA in participants with anti-HLA antibodies between D0 and M3. D‚ dd-cfDNA compared between participants with and without anti-HLA antibodies at D0 and M3. E‚ eGFR in all participants between D0 and M3. F‚ eGFR in participants without anti-HLA antibodies between D0 and M3. G‚ eGFR in participants with anti-HLA antibodies between D0 and M3, (F, G). A 1-sided paired Wilcoxon test was used to calculate the P value for plots (A–C) and (E–G); a 2-sided Wilcoxon test was used to calculate the P value for plot (D). Ab, antibody; dd-cfDNA, donor-derived cell-free DNA; D0 visit, day of administration of third vaccine dose; eGFR, estimated glomerular filtration rate; M3 visit, 3 mo after third dose of vaccine.No difference in estimated glomerular filtration rate was found (Figure 2E–G); no for cause graft biopsy was performed. Seroconversion was detectable in 52 (48%) at D0 and in 85 (81%) KTRs at M3, respectively. In conclusion, we found no evidence of allosensitization or subclinical kidney allograft injury following the first booster dose. ACKNOWLEDGMENTS We wish to thank the outpatient clinic nursing staff for obtaining patient samples; Transplant Laboratory technicians for sample handling; Petr Raska, MSc, and Michal Hojny, PharmD, for organizing the booster dose campaign at IKEM; Hedvika Cacarova for English proofreading; Cesar Escrig for fruitful discussion; and Natera Inc for blood sample processing and Prospera results.