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

Area of Science:

• Immunology
• Vaccinology
• Transplantation

Background:

• Kidney transplant recipients (KTRs) often have diminished responses to SARS-CoV-2 mRNA vaccines.
• The impact of a third vaccine dose on immune responses and mechanistic drivers in KTRs remains incompletely understood.

Purpose of the Study:

• To evaluate the immune response patterns following a third monovalent mRNA vaccine dose in KTRs with varying baseline antibody titers.
• To investigate the mechanistic drivers of vaccine response, including neutralization, T cell responses, and T cell receptor repertoires in KTRs compared to healthy controls.

Main Methods:

• Eighty-one KTRs (anti-RBD negative or low-titer) and 19 healthy controls (HCs) received a third mRNA vaccine dose.
• Assessed anti-receptor binding domain (RBD) antibodies, Omicron neutralization capacity, spike-specific CD8+ T cell percentages, and SARS-CoV-2-reactive T cell receptor (TCR) repertoires at day 30.
• Correlated immune responses with clinical outcomes, including breakthrough infections.

Main Results:

• 44% of anti-RBD negative KTRs remained seronegative by day 30; only 5% achieved BA.5 neutralization (vs. 68% of HCs).
• 91% of KTRs had negative spike-specific CD8+ T cell responses, and CD8+ TCR depth was significantly lower (7.6-fold) compared to HCs.
• 16% of KTRs experienced breakthrough infections, with poor pre-infection neutralization, underscoring continued vulnerability.

Conclusions:

• A third mRNA vaccine dose provides inadequate neutralizing and CD8+ T cell responses in many KTRs, indicating persistent vulnerability to COVID-19.
• The lack of neutralization despite CD4+ T cell expansion suggests potential B cell dysfunction or ineffective T cell help in KTRs.
• Novel and more effective vaccine strategies are critically needed for KTRs to achieve robust and protective immunity.