Predictive factors of response to 3rd dose of COVID-19 mRNA vaccine in kidney transplant recipients (preprint)

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.

Comparison of infected and vaccinated transplant recipients highlights the role of Tfh and neutralizing IgG in COVID-19 protection (preprint)

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 3 rd dose of vaccine resulted in the generation of anti-RBD IgG in half of non-responders to 2 doses. One sentence summary The generation of neutralizing IgG, which protects kidney transplant recipients from COVID-19, requires T follicular helper cells.

Justification, safety, and efficacy of a third dose of mRNA vaccine in maintenance hemodialysis patients: a prospective observational study (preprint)

Background Patients on maintenance hemodialysis (MHD) are at high risk of infection with SARS-Cov-2 and death due to COVID-19. This vulnerable population has been prioritized for vaccination, but the level of protection achieved in these immunocompromised patients is unclear. Objectives To evaluate the protection of MHD patients against COVID-19 after 2 doses (2D) of BNT162b2, and the safety and impact on immune responses of a 3 rd dose (3D). Design Prospective observational. Setting, Patients, intervention and measurements REIN national registry was used to compare the severity of 1474 cases of COVID-19 diagnosed in MHD patients after 0, 1 or 2 doses of mRNA vaccine. Anti-spike receptor binding domain (RBD) IgG and interferon gamma-producing CD4+ and CD8+ specific-T cells were measured after 2D and 3D of BNT162b2 in a monocentric cohort of 75 MHD patients. Results Vaccination reduced disease severity but 11% of MHD patients infected after 2D still died. Tolerance to 3D of BNT162b2 was excellent. MHD patients with humoral response similar to healthy volunteers after 2D did not generate more immune effectors after 3D and had more side effects. In contrast, 2/3 of MHD patients with suboptimal response after 2D reached optimal titer of anti-RBD IgG and/or developed spike-specific CD8+ T cells after 3D. Presence of spike-specific CD4+ T cells after 2D was associated with response to 3D in multivariate analysis (OR=4.80 [1.23−21.54]; p=0.029). Limitations Limited number of patients injected with 3D. Conclusion Standard scheme of vaccination provides insufficient protection to some MHD patients. Anti-RBD IgG and specific CD4+ T cells should be measured after 2D. Among patients with suboptimal humoral response, those with specific CD4+ T cells could benefit of a 3 rd dose of vaccine. Registration NCT04881396 Funding Source None