*Purpose: mRNA SARS-CoV-2 vaccines are highly efficacious in the general population but have shown a diminished response in immunosuppressed adolescent kidney allograft recipients. We investigated immunological parameters that could be associated with a blunted antibody response. We also analyzed whether a third vaccine dose could improve the antibody response.

*Methods: Adolescent kidney transplant recipients who received mRNA SARS-CoV-2 vaccine had SARS-CoV-2 spike protein antibody levels measured 4-8 weeks after their second vaccine dose and again after the third vaccine dose. Immunological labs including lymphocyte subsets, immunoglobulin levels, and vaccine titers and immunosuppressive medication dosing were evaluated prior to vaccination. Patients were compared in groups of vaccine responders vs non-responders via a Mann-Whitney U test. The impact of mycophenolate mofetil dosage on immune parameters was analyzed via a linear regression model.

*Results: 14 of 27 (52%) vaccinated pts had a positive spike antibody level. There was no significant difference in immunoglobulin levels, T-cell populations, or vaccine titers. There was a trend toward negative spike antibodies with higher doses of mycophenolate mofetil, MMF, at 91 mg/m²/day median difference (p=0.06). All four patients receiving azathioprine instead of MMF developed spike antibodies. Non-responders had lower hemoglobin levels (β=-1.30, p=0.009) and lower platelet count (β=-56.00, p=0.057). MCV levels were normal in both groups. Non-responders showed a trend toward increased naïve B-cell percentage (β= 12.50, p=0.11) and decreased total memory B-cell percentage (β=-12.54, p=0.080). Increasing MMF dosage was associated with an increase in naïve B-cell percentage (β=0.016, p=0.0032) decrease in total memory B-cell percentage (β=-0.016, p=0.0034), and decreased in IgG level (β=-0.35, p=0.012). Of the 13 patients that did not develop spike antibodies after the second vaccine dose, 9 pts (69%) developed antibodies after the third dose. In total, 23/27 (85%) patients vaccinated developed spiked antibodies.

*Conclusions: Disruption in B-cell population could be due to immunosuppression with MMF. Non-responders showed trends toward high MMF dosage, increased naïve B-cell percentage, and decreased total memory B-cell percentage. Increasing MMF dosage was associated with all trends as well as decreased IgG levels. Decreased hemoglobin levels and normal MCV supports that anemia could be due to bone marrow suppression caused by MMF. Altered B-cell populations and MMF therapy are a potential biomarker for reduced efficacy of SARS-CoV-2 vaccine in adolescent kidney allograft recipients. Interestingly, a third vaccine dose can overcome the immunosuppressive effects and improve vaccine efficacy.

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