P1461: INFLAMMATORY AND SENESCENCE-ASSOCIATED MEDIATORS AFFECT THE PERSISTENCE OF HUMORAL RESPONSE TO COVID-19 MRNA VACCINATION IN TRANSFUSION-DEPENDENT BETA-THALASSEMIC PATIENTS (2023)

Topic: 27. Thalassemias Background: Patients with Transfusion-Dependent β-thalassemia (TDT) are characterized by an impaired innate and adaptive immune response, mainly due to chronic transfusions and iron overload. We recently reported an early antibody response to SARS-CoV-2 vaccination in TDT patients comparable to that observed in a control group of health-care workers (HCW). Nevertheless, the vaccine-induced anti-RBD antibodies declined more rapidly in TDT patients respect to HCW, similarly to healthy elderly subjects, suggesting a premature aging of the immune system in these patients. Aims: The aim of this study was to identify inflammatory/senescence factors before mRNA SARS-CoV-2 vaccination associated with a reduced persistence of anti-RBD antibody overtime. Methods: A total of 64 TDT patients within the clinical trial (NCT05157256) were included in this study, selected according to the availability of serum samples before vaccination (T0) and of data about anti-RBD response after 2 (T1) and 12 (T2) weeks from the second dose of vaccine. There were no significant differences in compliance to iron-chelating therapy and iron overload among the patients studied. Senescent-Associated Secretory Phenotype (SASPs), including inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), TIMP-1 and MMP-9, were quantified in sera of TDT and HCW before vaccination (T0) by an automated ELISA assay. TDT patients were divided in four different groups on the basis of the extent of anti-RBD reduction over time (T1/T2 ratio): i) slow decrease (T1/T2 between 0-25th percentile); ii) slow/middle decrease (T1/T2 between 25 th-50th percentile); iii) middle/fast decrease (T1/T2 between 50 th-75th percentile) and iv) fast decrease (T1/T2 between 75 th-100th percentile). Principal component analysis (PCA) and the ROC curve were performed to evaluate the impact of SASP on the durability of antibody response. Results: A higher expression of SASP (IL1-β, TNF-α, IL-6, IL-8, MMP-9 and TIMP-1) before vaccination was observed in TDT patients respect to HCW (p<0.0001), with the highest levels of IL-6, IL-8 and TIMP-1 observed in splenectomized patients (p<0.01). PCA of SASP was able to efficiently segregate the first and the fourth group of TDT patients, characterized respectively by the slowest and the fastest reduction of anti-RBD Abs overtime (Figure, left). The factors mainly responsible for this segregation were the inflammatory cytokines (IL-1β, IL-8) and MMP-9. The correlation analysis (Figure, middle) showed that: i) IL-1β, IL-8 and MMP-9 correlated with each other, suggesting a strict relationship between inflammation and cell senescence; ii) IL-1β and IL-8 correlated with the anti-RBD fold decrease (T1/T2), confirming their impact on the durability of anti-RBD response overtime. Finally, the ROC analysis (Figure, right) demonstrated that IL-1β and IL-8 before vaccination are the best factors able to distinguish between TDT patients with a T1/T2 ratio below (slow + slow/middle) or above (middle/fast + fast) the median (IL-1β- AUC: 0.78, p=0.0002; IL-8-AUC: 0.74, p=0.0009). Summary/Conclusion: Our data identify inflammatory and senescence-associated soluble mediators before vaccination able to predict the durability of the humoral response to SARS-CoV2 mRNA vaccination. A similar observation helps characterize the specific immune deficit in patients with TD and highlights the key role of the plasmatic environment in modulating the effectiveness of the immune response to vaccination, opening new interesting perspectives for studies and interventions.Keywords: Inflammation, beta thalassemia, Vaccination, Senescence