Cellular responses to SARS-CoV-2 vaccination after B-cell depletion: conflicting results from studies – Authors' reply

We thank Pavan Bhargava for pointing out an error in the Methods section of our Article. For the interferon γ (IFNγ) release assay, cells were indeed stimulated for 16 h, not 1 h. The original Article1Moor MB Suter-Riniker F Horn MP et al.Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigator-initiated, single-centre, open-label study.Lancet Rheumatol. 2021; 3: e789-e797Summary Full Text Full Text PDF PubMed Scopus (76) Google Scholar has now been formally corrected. Bhargava then raises several points that we find difficult to agree with. First, Bhargava appears to question the merit of studying a mixed population of patients that have different disease aetiologies and that are predominantly under co-treatment with additional immunosuppressives. We believe we have addressed this point, however. In the appendix of our Article, we present subanalyses for the different disease subpopulations and co-treatments. Next, our analysis included only four patients with multiple sclerosis that were treated with ocrelizumab. The study by Gadani and colleagues2Gadani SP Reyes-Mantilla M Jank L et al.Discordant humoral and T-cell immune responses to SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy.EBioMedicine. 2021; 73103636Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar—one of the key studies Bhargava cited to support their argument—exclusively focused on patients with multiple sclerosis, the majority of whom were treated with ocrelizumab monotherapy, and hence the results of these two studies cannot be compared. As stated in the appendix of our Article (appendix p 7), ten (56%) of 18 participants on anti-CD20 monotherapy mounted a positive IFNγ release (table). Since our Article was published, we have completed analyses in more patients; the full dataset shows a positive IFNγ release in 41 (44%) of 93 patients. Furthermore, the results of different measures of cell-mediated immunity are not interchangeable and methodological differences might yield different results—as perhaps Bhargava was also alluding to. For example, previous literature on tuberculosis showed differences between the whole-blood-based quantitative IFNγ release assays and the more sensitive, but only semiquantitative, ELISpot analyses from peripheral blood mononuclear cells.3Adetifa IMO Lugos MD Hammond A et al.Comparison of two interferon gamma release assays in the diagnosis of Mycobacterium tuberculosis infection and disease in The Gambia.BMC Infect Dis. 2007; 7: 122Crossref PubMed Scopus (77) Google Scholar Most of the published studies on SARS-CoV-2-specific T-cell responses so far have used ELISpot assays. This highly sensitive, yet only semiquantitative, assay measures the number of T cells that recognise a given antigen. In our study, however, we measured the total amount of IFNγ released after stimulation. This approach integrates the number of reactive T cells with the amount of IFNγ produced per cell. Increasingly, data show that anti-B-cell monotherapy also affects T cells.4Hardeman P Mann M Hughes S Greenberg B Does rituximab cause depletion of T-cells in multiple sclerosis and neuromyelitis optica? (P2.158).https://n.neurology.org/content/86/16_Supplement/P2.158Date: April 5, 2016Date accessed: February 8, 2022Google Scholar A recent study by Apostolidis and colleagues5Apostolidis SA Kakara M Painter MM et al.Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.Nat Med. 2021; 27: 1990-2001Crossref PubMed Scopus (148) Google Scholar reported a detectable, but altered, CD4+ T-cell response in patients on anti-CD20 therapies but also found a higher CD8+ T-cell response. Thus, it seems possible that, overall, B-cell depleting therapies impair the functional quality of T cells rather than their quantity. This finding is poorly understood for now, but points towards a key role of B cells in the promotion of cellular immunity. Finally, as age is an important influencing factor regarding the strength of immune responses, it is worth considering that our anti-CD20-depleted patient population had a median age of 67 years, whereas the anti-CD20 treated population in the study from Gadani and colleagues was considerably younger (median age of 48 years). In addition, Gadani and colleagues’ regression analysis was based on 30 patients and 12 controls and included four independent parameters. A model with such few participants and relatively many parameters may be at risk of overfitting, and thus might fail to correctly adjust for the age difference. Moreover, of the 38 patients, none of the 30 in whom cellular responses were analysed had been subjected to a serological assessment of previous SARS-CoV-2 exposure, as far as reported in Gadani and colleagues’ paper. We declare no competing interests. Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigator-initiated, single-centre, open-label studyThis study provides further evidence of blunted humoral and cell-mediated immune responses elicited by SARS-CoV-2 mRNA vaccines in patients with a history of CD20 B-cell-depleting treatment. Lymphocyte subpopulation counts were associated with vaccine response in this highly vulnerable population. On validation, these results could help guide both the administration of SARS-CoV-2 vaccines and B-cell-depleting agents in this population. Full-Text PDF Cellular responses to SARS-CoV-2 vaccination after B-cell depletion: conflicting results from studiesI read with interest the Article by Matthias Moor and colleagues evaluating humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination in patients with a history of B-cell depletion.1 They described blunted humoral responses to vaccination in individuals with a variety of diseases treated with B-cell depletion, as reported now in numerous other studies. In addition, the authors reported blunted cellular responses in their study population and concluded that B-cell depletion impacts both the B-cell and T-cell response to SARS-CoV-2 vaccination. Full-Text PDF