Humoral and T Cell Immune Responses to Sars-Cov-2 Vaccination in Hematopoietic Cell Transplant Recipients
Authors: Gavriilaki Eleni , Papadopoulou Anastasia , Touloumenidou Tasoula , Stavridou Fani , Koravou Evdoxia , Giannaki Maria , Papalexandri Apostolia , Karavalakis Georgios , Batsis Ioannis , Kourelis Andreas , Chatzopoulou Fani , Chatzidimitriou Dimitrios , Sotiropoulos Damianos , Yannaki Evangelia , Sakellari Ioanna , Anagnostopoulos Achilles 
Published: November 2021

Abstract
Background. Hematopoietic cell transplant (HCT) recipients who develop coronavirus disease 2019 (COVID-19), have dismal prognosis with approximately 20% mortality. Given the lack of a specific and effective therapy, the availability of various vaccination platforms against SARS-CοV-2 has generated optimism towards the development of a robust herd immunity. Notwithstanding the prioritization of HCT recipients to COVID-19 vaccination, limited information is available on whether and to what extent, they mount an immune response to SARS-CοV-2 vaccination as they were generally excluded from vaccination trials.
Aim. To gain insights in the immune responses developed to SARS-CoV-2 vaccines under immunosuppression, we studied the humoral and cellular immune responses to SARS-CoV-2 vaccination in HCT recipients.
Methods. We prospectively studied (April-July 2021), adult patients who had undergone HCT in our Unit and received two doses of a SARS-CoV-2 vaccine (as per international guidelines) after providing written informed consent. Responses were studied before each vaccination dose and 12-51 days later after the second dose. Neutralizing antibodies against SARS-CoV-2 (CoV-2-NAbs) were measured using an FDA approved methodology for diagnostic use (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA; cut-off value for a positive result set at ≥30%) and SARS-CoV-2 spike-specific T cells (spike-STs) by interferon-γ Elispot after pulsing peripheral blood mononuclear cells with spike pepmixes.
Results. Humoral responses were studied on 65 patients, (50 allo-HCT/15 auto-HCT, Figure A). T cell responses were measured on 38/65 vaccinated patients (32 allo-HCT/6 auto-HCT) with a median of 3 (0.17-31) and 2 years (1.25-8) post allo- and auto-HCT respectively, and 19 healthy, unexposed vaccinees. One patient with prior COVID-19, was excluded from analysis. All patients were vaccinated with the Pfizer-BioNTech, except for 2 vaccinated with the AstraZeneca vaccine. Both CoV-2-NAbs and spike-STs were barely detectable before vaccination but could be detected in both allo- and auto-HCT patients after the first vaccination dose, reaching statistically significant increase after the second vaccination dose (p&lt;0.001 and p=0.036, respectively). Circulating spike-STs in allo-HCT recipients, although present, were lower over their counterparts in healthy volunteers (p&lt;0.001) and auto-HCT patients (p=0.080). In the latter patient cohort, the rather long period post auto-HCT (≥1.25 years for all patients) might have generated unintended bias towards elevated immune responses. The longer time post HCT in all patients was associated with increased CoV-2-NAbs and spike-STs (p=0.004 and p=0.030). Allo-HCT recipients under immunosuppression had lower levels of CoV-2-NAbs and spike-STs after the booster dose compared to patients off-treatment (Figure B and C, p&lt;0.001 and p=0.021 respectively). In particular, only 50% and 40% of patients on systemic immunosuppression reached adequate CoV-2-Nab and spike-ST levels after the second dose, as compared to 98% and 94% of immunosuppression-free patients. One allo-HCT recipient with failure to mount any immune response post booster vaccination, developed 40 days later COVID-19 infection and succumbed. The one allo-HCT recipient off treatment who did not elicit protective immune response after vaccination, was suffering from metabolic syndrome, a potentially immunosuppressive entity. Overall, there was a good correlation between humoral and T-cellular responses (p=0.013), although few cases were observed with sufficient T-cell response but no humoral reactivity and vice versa.
Conclusion . Herein, we report for first time humoral and T cell responses post SARS-CoV-2 vaccination in HCT recipients. Transplant recipients not under active and intense immunosuppression at the time of vaccination may benefit significantly from COVID-19 vaccination even though these responses are blunted compared to healthy individuals. However, for the severely immunocompromised patients it seems highly unlikely that they could be protected by vaccination and for this vulnerable population, different vaccination schemes or therapeutic platforms should be developed along with collateral measures including minimal exposure and immunization of caregivers and health care providers.
Figure 1 Figure 1.

Disclosures
Gavriilaki: Alexion, Omeros, Sanofi Corporation: Consultancy; Pfizer Corporation: Research Funding; Gilead Corporation: Honoraria. Yannaki: SANDOZ: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Speakers Bureau; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Anagnostopoulos: Abbvie: Other: clinical trials; Sanofi: Other: clinical trials ; Ocopeptides: Other: clinical trials ; GSK: Other: clinical trials; Incyte: Other: clinical trials ; Takeda: Other: clinical trials ; Amgen: Other: clinical trials ; Janssen: Other: clinical trials; novartis: Other: clinical trials; Celgene: Other: clinical trials; Roche: Other: clinical trials; Astellas: Other: clinical trials .