Persistent SARS-CoV-2–specific immune defects in kidney transplant recipients following third mRNA vaccine dose

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBD(NEG); n = 42 anti-RBD(LO)), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8(+)%, and SARS-CoV-2–reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBD(NEG) remained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P < .001). Day 30 spike-specific CD8(+)% was negative in 91% KTRs (vs 20% HCs; P = .07), without correlation to anti-RBD (r(s) = 0.17). Day 30 SARS-CoV-2–reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P = .11). Spike-specific CD4(+) TCR expansion was similar between KTRs and HCs, yet KTR CD8(+) TCR depth was 7.6-fold lower (P = .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P = .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8(+) responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4(+) expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263)