ABSTRACT
Background: Patients with neuroimmunological disorders on anti-CD20 therapy are at increased risk of severe COVID-19. However, little is known about SARS-CoV-2 vaccine efficacy in this cohort. In particular, the impact of B cell depletion on humoral and cellular immune responses to SARS-CoV-2 vaccination remains poorly defined. No study has addressed vaccine responses to the SARS-CoV-2 delta variant in immunocompromised individuals so far.Methods: In this prospective cohort study we investigated humoral and cellular responses in serial samples from 164 individuals after SARS-CoV-2 mRNA vaccination (82 patients with neuroimmunological disorders on anti-CD20 therapy and 82 healthy controls). Antibodies were quantified using the Elecsys anti-SARS-CoV-2 S immunoassay against the receptor-binding (RBD) domain. T cell responses against the SARS-CoV-2 Wuhan strain and the delta variant were assessed by IFN-g enzyme-linked immunosorbent spot assays. Findings: Following vaccination, SARS-CoV-2 –specific antibodies were detected in 57/82 (70%) patients compared to 82/82 (100%) healthy controls (p<0·001). Seroconversion rates and antibody levels were lower in B cell-depleted (<1 B cell/mcl) patients compared to non-depleted (≥ 1 B cell/mcl) patients (p<0·001). B cell levels ≥ 1 cell/mcl were sufficient to induce anti-SARS-CoV-2-S antibody responses. In contrast to the antibody response, most B cell-depleted patients generated a T-cell response against the SARS-CoV-2 Wuhan strain and the delta variant that was more robust in frequency (p<0·05) and magnitude (p<0·01) compared to non-depleted patients and persisted for at least six weeks.Interpretation: Humoral immunity following SARS-CoV-2 mRNA vaccination can be achieved in patients on anti-CD20 therapy once B cells start to repopulate. In the absence of B cells, a robust and stable T cell response is generated which may provide a potent defense against severe COVID-19 in this high-risk patient population. Funding Information: Funded partly by a Medical-Scientific fund of the Major of the federal capital of Vienna (grant Covid003).Declaration of Interests: BK has received honoraria for speaking and for consulting from Biogen, BMS-Celgene, Johnson&Johnson, Merck, Novartis, Roche, Teva and Sanofi-Genzyme outside of the submitted work. No conflict of interest with respect to the present study. FL has received honoraria for speaking and consulting from Almirall, Biogen-Idec, Celgene BMS, MedDay, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Genzyme, Santhera; Schering, Teva-Ratiopharm. There are no conflicts of interest with respect to the present study, PR has received honoraria for speaking and for consulting from Alexion, Almirall, Amicus, Biogen, Merck, Novartis, Roche, Teva, Sandoz, and Sanofi Genzyme outside of the submitted work. He has received research grants from Amicus, Biogen, Merck and Roche outside the submitted work. GZ recieved speaking honoria from biogen and has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. No conflict of interest regarding this study, GB has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene/BMS, Lilly, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Novartis, Roche, Sanofi-Genzyme and Teva. He has received financial support in the past 12 months by unrestricted research grants (Celgene/BMS, Novartis). No conflict of interest with respect to the present study, ADB declares no conflict of interest related to the content of this article. Independent of this study, ADB has participated in meetings sponsored by or received speaker honoraria or travel funding from Biogen, Merck, Novartis, Roche, Celgene (BMS), and Sanofi. She has received an unrestricted grant from Merck GmbH, an affiliate of Merck KGaA and is currently supported by a research grant from Biogen. TB has no particular conflicts of interest regarding the present study. In general, he has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Bayer, Biogen, Biologix, Bionorica, Genzyme, GSK, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi/Genzyme, TG Pharmaceuticals, TEVA ratiopharm and UCB. His institution has received financial support in the last 12 months by unrestricted research grants (Biogen, Bayer, Merck, Novartis, Sanofi/Genzyme, and TEVA ratiopharm) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi/Genzyme, and TEVA. LS, HH, RT, FZ, WR, KZ, IW, AS, MG, MM, KR, SW, JHA, ST report no conflicts of interest.Ethics Approval Statement: Subjects gave written informed consent. The study was approved by the ethics committee of the Medical University of Vienna, Austria, EK Nr. 1073/2021.
Subject(s)
Leigh Disease , Multiple Sclerosis , Genetic Diseases, Inborn , Nervous System Diseases , COVID-19ABSTRACT
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) has led to exponentially rising mortality, particularly in immunosuppressed patients, who inadequately respond to conventional COVID-19 vaccination. In this blinded randomized clinical trial (EudraCT 2021-002348-57) we compare the efficacy and safety of an additional booster vaccination with a vector versus mRNA vaccine in non-seroconverted patients. We assigned 60 patients under rituximab treatment, who did not seroconvert after their primary mRNA vaccination with either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), to receive a third dose, either using the same mRNA or the vector vaccine ChAdOx1 nCoV-19 (Oxford-AstraZeneca). Patients were stratified according to the presence of peripheral B-cells. The primary efficacy endpoint was the difference in the SARS-CoV-2 antibody seroconversion rate between vector (heterologous) and mRNA (homologous) vaccinated patients by week four. Key secondary endpoints included the overall seroconversion and cellular immune response; safety was assessed at weeks one and four. Seroconversion rates at week four were comparable between vector (6/27 patients, 22%) and mRNA (9/28, 32%) vaccine (p=0.6). Overall, 27% of patients seroconverted; specific T-cell responses were observed in 20/20 (100%) vector versus 13/16 (81%) mRNA vaccinated patients. Newly induced humoral and/or cellular responses occurred in 9/11 (82%) patients. No serious adverse events, related to immunization, were observed. This enhanced humoral and/or cellular immune response supports an additional booster vaccination in non-seroconverted patients irrespective of a heterologous or homologous vaccination regimen.