Possible effects of sirolimus treatment on the long­term efficacy of COVID­19 vaccination in patients with ß­thalassemia: A theoretical perspective.

The pandemic caused by the severe acute respiratory syndrome coronavirus (SARS­CoV­2), responsible for coronavirus disease 2019 (COVID­19) has posed a major challenge for global health. In order to successfully combat SARS­CoV­2, the development of effective COVID­19 vaccines is crucial. In this context, recent studies have highlighted a high COVID­19 mortality rate in patients affected by ß­thalassemia, probably due to their co­existent immune deficiencies. In addition to a role in the severity of SARS­CoV­2 infection and in the mortality rate of COVID­19­infected patients with thalassemia, immunosuppression is expected to deeply affect the effectivity of anti­COVID­19 vaccines. In the context of the interplay between thalassemia­associated immunosuppression and the effectiveness of COVID­19 vaccines, the employment of immunomodulatory molecules is hypothesized. For instance, short­term treatment with mammalian target of rapamycin inhibitors (such as everolimus and sirolimus) has been found to improve responses to influenza vaccination in adults, with benefits possibly persisting for a year following treatment. Recently, sirolimus has been considered for the therapy of hemoglobinopathies (including ß­thalassemia). Sirolimus induces the expression of fetal hemoglobin (and this may contribute to the amelioration of the clinical parameters of patients with ß­thalassemia) and induces autophagy (thereby reducing the excessive levels of α­globin). It may also finally contribute to the mobilization of erythroid cells from the bone marrow (thereby reducing anemia). In the present study, the authors present the hypothesis that sirolimus treatment, in addition to its beneficial effects on erythroid­related parameters, may play a crucial role in sustaining the effects of COVID­19 vaccination in patients with ß­thalassemia. This hypothesis is based on several publications demonstrating the effects of sirolimus treatment on the immune system.