Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster III
Hematology Disease Topics & Pathways:
Research, adult, Translational Research, Diseases, SARS-CoV-2/COVID-19, Infectious Diseases, immunology, Biological Processes, Study Population, Human
Methods: Peripheral blood samples were obtained from allogeneic HSCT recipients after a median of 3 months (range 2-7) after COVID-19 infection (n=11) or 44 days (range 24-166) after vaccination with 3 doses of mRNA-based SARS-CoV-2 vaccines in SARS-CoV2 infection-naive patients (n=13). Median time since HSCT to SARS-CoV-2 infection was 24 months (range 11-79) and to last vaccination was 22.5 months (range 7-174). Healthy controls at 1 to 3 months after SARS-CoV-2 infection (n=10) or vaccination served as controls (n=10). SARS-CoV-2- specific T cell clonotypes were identified by genomic DNA T-cell receptor (TCR) sequencing (immunoSEQ® T-MAP™ COVID, Adaptive). SARS-CoV-2-specific T cell responses were quantified based on IFN-γ release against a range of peptides from the SARS-CoV-2 Spike protein (S) as well as from the membrane glycoprotein (M) and the nucleocapside phosphoprotein (N) using an Enzyme-Linked ImmunoSpot (ELISpot) assay.
Results: SARS-CoV-2- specific T cell clonotypes were detectable in both HC and HSCT recipients after COVID-19 infection (Figure 1A). After adjusting for recovered T cell numbers, HSCT recipients displayed significantly reduced SARS-CoV-2-specific T cell clonotypes compared with HC (p=0.0037; Figure 1B). Such a difference was maintained when T cell clonotypes specific for the S protein (p=0.0011) or the N and M proteins (p=0.036) were analyzed. As predicted, HSCT recipients displayed a less diverse TCR repertoire compared with HC as revealed by higher Simpson clonality (p= 0.0079). Interestingly, the Simpson clonality negatively correlated with the number of different SARS-CoV-2-specific T cell clonotypes (r2=0.86, p=4.8e−06; Figure 1C). According to the TCR-seq results, we observed significantly lower numbers of IFN-γ spot forming units after stimulation of PBMCs from HSCT recipients with peptides from both the S protein (p=0.0068) and the M plus N proteins (p=0.0067) compared with HC. Performing the same analysis after SARS-CoV-2 mRNA vaccination, we observed a significant reduction in S-protein-specific T cell clonotypes in allogeneic HSCT recipient compared to HC (p=0.0003; Figure 1D-E). We detected a significantly negative correlation between the Simpson clonality and the number of different S-protein specific T cell clonotypes after vaccination (r2=0.55, p=7.8e-05; Figure 1F). ELISpot analysis of PBMCs recovered after vaccination and stimulated with S-protein peptides revealed significantly lower numbers of IFN-γ spot forming units in HSCT recipients compared with HC (p= 0.019), confirming the results obtained by TCR-seq.
Conclusions: Our results indicate that allogeneic HSCT recipients display a defect in cellular SARS-CoV-2-specific responses after COVID-19 infection and vaccination. Such impairment was both quantitative, as revealed by reduced IFN-γ release upon stimulation with SARS-CoV-2 peptides, and qualitative as demonstrated by the reduced breadth of SARS-CoV-2-specific T cell clonotypes. Such impairment was associated with increased T-cell clonality after HSCT, pointing to the reduced diversity of the TCR repertoire as a mechanism leading to impaired cellular responses against SARS-CoV-2 in HSCT recipients. SARS-CoV-2 infection represents an unprecedented opportunity to study the immune responses established in allogeneic HSCT recipients against a new pathogen that either the donor or the HSCT recipient have never been exposed to. Our findings provide insights into our understanding of immune-dysfunction after allogeneic HSCT.
Disclosures: Neofytos: Basilea: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Eberhardt: Pfizer: Research Funding. Chalandon: Incyte: Other: consulting fees + travel support; Jazz: Other: consulting fees+ travel support; Pfizer: Other: consulting fees; MSD: Other: consulting fees+ travel support; Novartis: Other: consulting fees; Servier: Other: consulting fees; Abbvie: Other: consulting fees + travel support; Roche: Other: consulting fees + travel support; Gilead: Other: consulting fees + travel support; Amgen: Other: consulting fees + travel support; BMS: Other: consulting fees; Astra-Zeneca: Other: consulting fees + travel support; Janssen: Other: Travel support. Simonetta: AstraZeneca: Other: Travel support; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel support.
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