ABSTRACT
Only a minority of kidney transplant recipients (KTRs) develop protective neutralizing titers of anti-receptor binding domain of spike protein (RBD) IgG after two doses of mRNA COVID-19 vaccine. Administration of a third dose of mRNA vaccine to KTRs with sub-optimal response increase anti-RBD IgG titers but with high inter-individual variability. Patients with the higher response rate to the third dose of vaccine can be identified by the presence of low anti-RBD IgG titers and spike-specific CD4+ T cells in their circulation 14 days after the second dose.
ABSTRACT
Transplant recipients, which receive therapeutic immunosuppression to prevent graft rejection, are characterized by high COVID-19-related mortality and defective response to vaccines. Having observed that previous infection by SARS-CoV-2 but not the standard "2 doses" scheme of vaccination, provided complete protection against COVID-19 to transplant recipients, we undertook this translational study to compare the cellular and humoral immune responses of these 2 groups of patients. Neutralizing anti-Receptor Binding Domain (RBD) IgG were identified as the critical immune effectors associated with protection. Generation of anti-RBD IgG was dependent upon spike-specific T follicular helper (Tfh) CD4+ T cells, which acted as limiting checkpoint. Tfh generation was impeded by high dose mycophenolate mofetil in non-responders to vaccine but not in infected patients, suggesting that increasing immunogenicity of vaccine could improve response rate to mRNA vaccine. This theory was validated in two independent prospective cohorts, in which administration of a 3rd dose of vaccine resulted in the generation of anti-RBD IgG in half of non-responders to 2 doses. One sentence summaryThe generation of neutralizing IgG, which protects kidney transplant recipients from COVID-19, requires T follicular helper cells.
