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Persistent SARS-CoV-2-specific immune defects in kidney transplant recipients following third mRNA vaccine dose. 2023
William A Werbel, and
Andrew H Karaba, and
Teresa Po-Yu Chiang, and
Allan B Massie, and
Diane M Brown, and
Natasha Watson, and
Maggie Chahoud, and
Elizabeth A Thompson, and
Aileen C Johnson, and
Robin K Avery, and
Willa V Cochran, and
Daniel Warren, and
Tao Liang, and
Miguel Fribourg, and
Christopher Huerta, and
Hady Samaha, and
Sabra L Klein, and
Maria P Bettinotti, and
William A Clarke, and
Ioannis Sitaras, and
Nadine Rouphael, and
Andrea L Cox, and
Justin R Bailey, and
Andrew Pekosz, and
Aaron A R Tobian, and
Christine M Durand, and
Nancy D Bridges, and
Christian P Larsen, and
Peter S Heeger, and
Dorry L Segev, and
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address: wwerbel1@jhmi.edu.
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-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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