• Citer

Predictors and determinants of the immune response to COVID-19 mRNA vaccination in hemodialysis and kidney transplant recipients

par Gemander, Nicolas
Président du jury Corazza, Francis
Promoteur Marchant, Arnaud
Co-Promoteur Le Moine, Alain
Publication Non publié, 2025-09-16

Thèse de doctorat

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

End-stage renal disease (ESRD) is associated with profound immune dysregulation, affecting both innate and adaptive compartments. Although renal replacement therapies (RRT), including hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KT), prolong survival, they fail to restore immune competence and may even exacerbate immunological alterations. The resulting immune profile of these patients contributes to increased susceptibility to severe infections, malignancies, and suboptimal vaccine responses.During the COVID-19 pandemic, hemodialysis recipients (HDRs) and kidney transplant recipients (KTRs) experienced severe outcomes, largely attributable to underlying immune impairment. While SARS-CoV-2-naïve individuals within these groups demonstrated attenuated responses to COVID-19 mRNA vaccines such as BNT162b2, particularly among KTRs under immunosuppressive regimens, prior SARS-CoV-2 infection markedly enhanced vaccine-induced immunity. This hybrid immunity, defined as infection followed by vaccination, elicited robust humoral and cellular responses, comparable to those observed in healthy individuals. Preliminary studies have identified baseline immune correlates, including transitional B cell frequencies, associated with vaccine responsiveness in SARS-CoV-2-naïve KTRs. However, the immunological mechanisms underlying deficient vaccine responses and the extent to which these mechanisms affect hybrid immunity in these immunocompromised patients remain poorly characterized. Moreover, systems-level analyses to predict vaccine efficacy in immunocompromised patients are lacking. The NEPHRO-VAC study was designed to address these knowledge gaps by assessing both clinical risk factors and cellular determinants of BNT162b2 vaccine response in SARS-CoV-2-naïve and SARS-CoV-2-experienced HDRs and KTRs, with the perspective of informing precision vaccination strategies in vulnerable populations.Initial data from our study confirmed that SARS-CoV-2-naïve HDRs and KTRs mounted weaker humoral responses following primary BNT162b2 vaccination than healthy adults, while SARS-CoV-2-experienced patients developed high levels of RBD-specific antibodies. We then conduced two complementary studies to perform an in-depth characterization of humoral and cellular immune responses post-primary BNT162b2 vaccination across these groups and to evaluate the impact of demographic and clinical factors on immunogenicity. SARS-CoV-2-naïve patients exhibited reduced neutralizing and non-neutralizing antibody responses, although CD4⁺ and CD8⁺ T cell responses were generally preserved when compared to healthy controls. These impaired antibody responses correlated with known risk factors, such as hypoalbuminemia and lymphopenia in HDRs and immunosuppressive therapy in KTRs. In contrast, SARS-CoV-2-experienced individuals generated polyfunctional antibody responses that included Fc-mediated effector functions and showed elevated CD4⁺ T cell frequencies post-vaccination, reaching levels of healthy adults. Importantly, these enhanced immune responses were largely unaffected by the risk factors that limited vaccine efficacy in SARS-CoV-2-naïve individuals, supporting the hypothesis that immune priming through infection enables effective vaccination even in immunocompromised hosts.To further investigate determinants of vaccine responsiveness, high-dimensional immune profiling using multiparametric flow cytometry was performed in a cohort comprising both KTRs and lung transplant recipients (LTRs). This analysis revealed a baseline immunophenotype predictive of humoral responses to both primary and booster doses of BNT162b2 vaccination. Notably, solid organ transplant (SOT) recipients who mounted efficient responses to the third vaccine dose displayed baseline profiles enriched in activated B cell subsets and specific activated innate immune cells, resembling the immune phenotype of healthy individuals. These findings underscore the utility of systems vaccinology in identifying mechanistic pathways and immune signatures associated with vaccine responsiveness in immunocompromised populations.In conclusion, this work supports the notion that robust and polyfunctional immune responses can be achieved in immunocompromised individuals through immune priming with SARS-CoV-2 infection followed by COVID-19 vaccination, partially overcoming the effects of immune suppression. Moreover, baseline immune profiling may help identify patients at highest risk of vaccine non-responsiveness, even after multiple vaccine doses. These findings have important implications for understanding vaccine-induced immunity in vulnerable populations and highlight the value of systems-level approaches to uncover cellular and molecular determinants of immune response. Such insights are essential to guide the development of tailored vaccination strategies aimed at improving protection in high-risk, immunocompromised individuals.