4.6 Article

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

Journal

AMERICAN JOURNAL OF TRANSPLANTATION
Volume 23, Issue 6, Pages 744-758

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajt.2023.03.014

Keywords

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

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Kidney transplant recipients (KTRs) show poor response to SARS-CoV-2 mRNA vaccination, with a significant number remaining seronegative and lacking neutralizing antibodies. Third doses of mRNA vaccine in KTRs did not improve the response and showed low levels of spike-specific CD8+ T cells. B cell dysfunction and ineffective T cell help may contribute to the lack of neutralizing response. Developing more effective vaccine strategies for KTRs is crucial.
Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vacci-nation, 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-RBDNEG; n = 42 anti-RBDLO), 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-RBDNEG 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 (rs = 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)

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