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

Abstract

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).

Keywords: SARS-CoV-2; antibody; clinical trial; immunogenicity; kidney transplant; vaccination.

Graphical abstract

Figure 1

(A) Anti-receptor binding domain (anti-RBD) titers in KTRs following a third mRNA vaccine dose, stratified by day 0 anti-RBD level. Blue trajectories represent anti-RBD^NEG (n = 39) and yellow trajectories represent anti-RBD^LO low-titer (n = 42). Anti-RBD titers are represented in units/mL on the logarithmic scale. Triangles represent participants who developed incident COVID-19 (n = 4), and circles represent participants receiving monoclonal antibody (mAb) (n = 1). Squares represent participants with a history of COVID-19 prior to third vaccination. (B) Comparison of anti-receptor binding domain (anti-RBD) titers between KTRs and HCs before and 30 days after a third mRNA vaccine dose. Anti-RBD titers are represented in units/mL on the logarithmic scale. Triangles represent participants who developed incident COVID-19 (n = 1), and circles represent participants receiving monoclonal antibody (mAb) (n = 1) before day 30. Squares (n = 6) represent participants with a history of COVID-19 prior to third vaccination. HC, healthy control; KTR, kidney transplant recipient; RBD, receptor binding domain.

Figure 2

Neutralizing capacity against SARS-CoV-2 variants before and 30 days after a third mRNA dose in KTRs and HCs. The Y axis represents percent ACE2 inhibition, ranging 0% to 100% with ≥25% consistent with neutralizing inhibition (dashed orange line). Triangles denote participants with incident COVID-19 (n = 4) and open circles denote participants receiving mAb (n = 1). Squares indicate participants with a prior history of COVID-19 (n = 4 KTRs, n = 2 HCs). HC, healthy control; KTR, kidney transplant recipient.

Figure 3

SARS-CoV-2 spike-specific CD8⁺ memory T cell responses before and after a third mRNA vaccine dose in KTRs and HCs. Flow cytometric data (epitope staining) are presented for HLA-A∗02 participants. The dashed orange line represents background staining threshold (<0.03%). Triangles denote participants who developed COVID-19 (n = 1) and squares indicate participants with prior history of COVID-19 (n = 3). HC, healthy control; KTR, kidney transplant recipient.

Figure 4

Response patterns following third mRNA vaccine doses: correlation of SARS-CoV-2 antibody and T cell responses. Scatterplot of anti-receptor binding domain (RBD) level and dimensions of SARS-CoV-2 T cell receptor expansion (spike-specific CD4+ and CD8+ breadth and depth) on the logarithmic scale at day 30 post vaccination among kidney transplant recipients (A, n = 55) and healthy controls (B, n = 19). Data points are colorized by response pattern, (+)/(-) anti- RBD and (+)/(-)T-MAP (SARS-CoV-2-reactive T cell repertoire). Trend lines visualize correlation between vaccine responses in participants with detectable signatures (i.e., (+)anti-RBD and categorizable T cell receptor repertoire).