ABSTRACT
Introduction: Prevention of COVID by vaccination is important in allogeneic HSCT recipients but impaired humoral and cellular responses have been reported. To gain further insights into the immune defects leading to impaired immune, we performed a high-throughput T cell receptor (TCR) repertoire profiling of cells recovered from allogeneic HSCT recipients or healthy controls after SARS-CoV2 natural infection or mRNA-based vaccination. Method(s): Peripheral blood samples were obtained from allogeneic HSCT recipients after a median of 3 months after COVID- 19 infection (n = 11) or 44 days after vaccination with 3 doses of mRNA-based SARS-CoV-2 vaccines (n = 13). 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-MAPTM COVID, Adaptive). SARS-CoV-2-specific T cell responses were quantified based on IFN-gamma release against a range of peptides from the SARS-CoV-2 proteins using an ELISpot assay. Result(s): HSCT recipients displayed significantly reduced SARS-CoV-2-specific T cell clonotypes compared with HC (p = 0.0037;Figure 1 A-B)as well as a less diverse TCR repertoire as revealed by higher Simpson clonality (p = 0.0079). We also observed significantly lower numbers of IFN-gamma 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-gamma spot forming units in HSCT recipients compared with HC (p = 0.019), confirming the results obtained by TCR-seq. Conclusion(s): Allogeneic HSCT recipients display a quantitative and qualitative defect in cellular SARS-CoV-2-specific responses asscociated with a reduced TCR repertoire after COVID-19 infection and vaccination. (Figure Presented).
ABSTRACT
Allogeneic hematopoietic stem cell transplantation recipients have a higher risk of developing severe forms of COVID-19. Induction of protective immunity through prophylactic vaccination is therefore important. We analyzed humoral responses to two doses of mRNA-based SARS-Cov-2 vaccines in 63 patients transplanted at Geneva University Hospitals, following our institutional priority vaccination program whose inclusion criteria were: minimum 3 months and maximum 3 year since allogeneic HSCT;or at more than 3 years post-transplant with GvHD requiring immunosuppressive drugs;absence of Rituximab in the previous 3 months;absence of steroid treatment with Prednisone ≥ 10 mg/day. Vaccine-induced antibody responses against the SARS-CoV-2 spike protein (anti-S) were assessed in serum using the semi-quantitative El-ecsys® Anti-SARS-CoV-2 immunoassay (Roche).Median age was 54 (18-78) years. The first vaccine dose was administered at a median of 14 (3-150) months after transplantation. Forty-six out of 63 (73%) patients received mRNA-1273 and 17/63 (27%) received BNT162b2 vaccines. Forty-eight out of 63 (76%) allogeneic HSCT recipients showed some degree of humoral response to vaccination based on anti-S IgG. Median levels of anti-S IgG were 815 U/ml. We observed significantly lower anti-S IgG responses in patients receiving the first vaccine dose within 6 months since transplantation (6/13, 46%;median 0.88 U/ml) compared with patients vaccinated after 6 months post-HSCT (42/50, 84%;median 2500 U/ml;p = 0.0016) and lower anti-S IgG responses in patients having received ATG as part of their conditioning (27/41, 66%;median 183 U/ml) compared with patients who did not receive ATG (21/22, 95%;median 2500 U/ml;p = 0.004).