1061343 research-article20212021 MSJ0010.1177/13524585211061343Multiple Sclerosis JournalJA Cohen, RA Bermel MULTIPLE SCLEROSIS MSJ JOURNAL Short Report Immunoglobulin G immune response to Multiple Sclerosis Journal 2022, Vol. 28(7) 1131­–1137 SARS-CoV-2 vaccination in people living with DOI: 10.1177/ https://doi.org/10.1177/13524585211061343 13524585211061343 https://doi.org/10.1177/13524585211061343 multiple sclerosis within Multiple Sclerosis © The Author(s), 2022. Partners Advancing Technology and Health Article reuse guidelines: sagepub.com/journals- permissions Solutions Jeffrey A Cohen , Robert A Bermel , Cynthia I Grossman, Carrie M Hersh , Megan Correspondence to: Hyland, Ellen M Mowry, Robert Naismith , Maria L Naylor* , Jacqueline Nicholas, JA Cohen Mellen Center, Neurological Rajani Rajbhandar*, Carol M Singh, Mar Tintorè , Ana Zabalza , Tjalf Ziemssen , Institute, Cleveland Clinic, James R Williams and Xavier Montalban; on behalf of the MS PATHS Investigators 9500 Euclid Avenue, Cleveland, OH 44195, USA. cohenj@ccf.org Jeffrey A Cohen Abstract Robert A Bermel Background: The impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on SARS- Mellen Center, Neurological Institute, Cleveland Clinic, CoV-2 vaccination response is uncertain. Cleveland, OH, USA Methods: Post-SARS-CoV-2 vaccination blood samples across multiple DMTs were tested for SARS- Cynthia I Grossman Maria L Naylor CoV-2 immunoglobulin G (IgG) response. Rajani Rajbhandari Results: Three hundred twenty-two people with MS were included; 91.9% received an mRNA vaccine. Carol M Singh James R Williams Post-vaccination reactive IgG rates (IgG index > 1) were 40% for anti-CD20 (32/80 patients); 41% for Biogen, Cambridge, MA, USA sphingosine 1-phosphate receptor modulators (S1PRM, 16/39); and 100% for all other classes, including Carrie M Hersh the no DMT group. Lou Ruvo Center for Brain Conclusion: Anti-CD20 therapies and S1PRMs reduce IgG response to SARS-CoV-2 vaccination; IgG Health, Cleveland Clinic, Las Vegas, NV, USA response is preserved with other DMTs. Megan Hyland Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA Keywords: Multiple sclerosis, disease-modifying therapy, SARS-COV-2 vaccination, humoral immune Ellen M Mowry response, MS PATHS, optimal management Department of Neurology, Johns Hopkins University School of Medicine, Date received: 20 July 2021; revised: 13 October 2021; accepted: 26 October 2021 Baltimore, MD, USA Robert Naismith Department of Neurology, Introduction Limited data relating to the efficacy of COVID-19 Washington University in St. Louis, St. Louis, MO, USA Coronavirus disease 2019 (COVID-19) has resulted vaccines in DMT-treated PwMS have led to varying Jacqueline Nicholas in millions of deaths worldwide.1 Vaccination against vaccination guidelines from MS organizations.4 An OhioHealth Multiple SARS-CoV-2, the virus that causes COVID-19, is the initial study suggested that immunoglobulin G (IgG) Sclerosis Center, Riverside Methodist Hospital, most effective means of protecting populations, antibody responses to SARS-CoV-2 vaccination are Columbus, OH, USA including people with multiple sclerosis (PwMS),2 attenuated in PwMS treated with the anti-CD20 ther- Mar Tintorè and ending the COVID-19 pandemic.3 However, as a apy ocrelizumab or the sphingosine 1-phosphate Ana Zabalza Xavier Montalban result of immunomodulatory effects or depletion of receptor modulator (S1PRM) fingolimod.5 This Centre d’Esclerosi Múltiple circulating lymphocytes, MS disease-modifying ther- observation is consistent with previous studies of de Catalunya, Department of Neurology and apies (DMTs) may reduce humoral or cellular immune non-COVID vaccine responses in PwMS treated with Neuroimmunology, Hospital responses to vaccines, including against SARS- these DMTs.6,7 Thus, robust data on immune responses Universitari Vall d’Hebron, Universitat Autònoma de CoV-2.1,4,5 Although the clinical significance of these to COVID-19 vaccines across multiple DMTs are Barcelona, Barcelona, Spain varying responses, including the impact on risk of needed to support evidence-based COVID-19 vacci- Tjalf Ziemssen Multiple Sclerosis Center infection, is not fully understood, the COVID-19 pan- nation recommendations. We report initial results Dresden, Center of Clinical demic makes better characterization of how MS from a large real-world study of the impact of differ- Neuroscience, Department of Neurology, University Clinic DMTs influence vaccine effectiveness critically ent DMT classes on IgG responses to SARS-CoV-2 Carl-Gustav Carus, Dresden, important.1,4,5 vaccines. Germany journals.sagepub.com/home/msj 1131 Multiple Sclerosis Journal 28(7) *M.L.N. and R.R. were employees of Biogen at Methods fumarate n = 5), GA (n = 33), IFNs (n = 23; IM IFN the time the analysis was beta-1a n = 16, pegylated IFN beta-1a n = 6, IFN beta- conducted. Study design 1b, n = 1), natalizumab (n = 44), S1PRMs (n = 39; fin- Participants with MS enrolled in the Multiple golimod n = 32, ozanimod n = 4, siponimod n = 3), Sclerosis Partners Advancing Technology and Health teriflunomide (n = 15), and no DMT (n = 28). Post- Solutions (MS PATHS) network in the United States, vaccination samples were collected 47.4 (16.2) days Germany, and Spain were recruited to voluntarily pro- after the last vaccine dose; 296/322 (91.9%) were fol- vide pre- and post-vaccination blood serum samples. lowing an mRNA vaccine. No pre-vaccination sam- MS PATHS comprises 10 MS centers that collect ples were available for these participants. standardized data during routine office visits with the aim of improving outcomes for PwMS. Sample col- Baseline demographics and disease characteristics by lection is ongoing; initial post-vaccination data from DMT class are shown in Table 1. Reactive IgG rates DMT classes (with minimum ⩾10 patients) are (IgG index >1) from initial post-vaccination testing reported here. DMTs included in the preliminary anal- were 32/80 participants (40%) for anti-CD20, 16/39 ysis were grouped by mechanisms of action: alemtu- (41%) for S1PRMs, and 100% for all other classes, zumab, anti-CD20, fumarates, glatiramer acetate including alemtuzumab (n = 23), fumarates (n = 37), (GA), interferons (IFNs), natalizumab, S1PRMs, teri- GA (n = 33), IFNs (n = 23), natalizumab (n = 44), terif- flunomide, and no DMT. lunomide (n = 15), and no DMT (n = 28). SARS- CoV-2 IgG index value by DMT is shown in Figure 1. For this study, serum samples could be collected up to IgG response was not correlated with time of last dose 30 days pre-vaccination relative to the first injection of anti-CD20 therapies (Figure 2). In the anti-CD20 of the vaccine and 28–90 days after the final vaccine and S1PRM groups, for 1 year increase in the duration dose. Post-vaccination blood samples, collected with of therapy, odds of a reactive IgG results are: or without a corresponding pre-vaccination sample, ORanti-CD20 = 0.53, 95% confidence interval were taken after two injections for the AstraZeneca, (CI) = (0.34, 0.83) and ORS1PRM = 0.70, 95% CI = (0.53, Pfizer, and Moderna vaccines, and one injection for 0.93). There was no association between probability the Johnson & Johnson vaccine. The Siemens of a reactive IgG result and patient characteristics, Healthineers Atellica® IM* SARS-CoV-2 IgG assay and no association between reactive IgG status and was used to measure semi-quantitative (index value) MS subtype (Figure 1). IgG response to the SARS-CoV-2 spike protein.8 Univariate logistic regression analyses assessed the For the anti-CD20 group, the percent of patients with relationship between post-vaccination IgG response a reactive anti-SARS-CoV-2 response of >1.0 was: (reactive/non-reactive) and demographic, disease, Pfizer (45% (14/31)), Moderna (38% (16/42)), and and vaccine characteristics. These analyses were Johnson & Johnson (29% (2/7)). For the S1PRM restricted to participants on anti-CD20 or S1PRM group, the percent of patients with a reactive anti- therapy since there was no heterogeneity in IgG SARS-CoV-2 response of >1.0 was: Pfizer (33% response in other DMT categories. Univariate linear (9/27)), Moderna (60% (6/10)), Johnson & Johnson regression was used to assess the relationship between (100% (1/1)), and AstraZeneca (0% (0/1)). time of last anti-CD20 dose and IgG index value. The study was approved by central and local ethics Discussion committees and conducted in accordance with the Our preliminary results suggest that anti-CD20 and International Council on Harmonization guidelines S1PRM DMTs reduce the IgG response to SARS- for Good Clinical Practice and the Declaration of CoV-2 vaccination in PwMS, consistent with other Helsinki. All patients provided written, informed studies.5,9,10 We also report an association between consent. duration anti-CD20 and S1PRM treatment and reduced odds of an SARS-CoV-2 vaccination IgG response. Conversely, the IgG response to SARS- Results CoV-2 vaccination appears to be preserved in PwMS As of 24 August, 2021, post-vaccination serum sam- treated with other DMTs, including alemtuzumab ples were obtained from 322 participants: alemtu- (n = 23), fumarates (n = 37), GA (n = 33), IFNs (n = 23), zumab (n = 23), anti-CD20 (n = 80; ocrelizumab natalizumab (n = 44), teriflunomide (n = 15), and no n = 57, rituximab n = 22, ofatumumab n = 1), fuma- DMT (n = 28). SARS-CoV-2 IgG index value by rates (n = 37; dimethyl fumarate n = 32, diroximel DMT is shown in Figure 1. 1132 journals.sagepub.com/home/msj Table 1. Clinical and demographic characteristics of DMT-treated and DMT-untreated participants with MS who received SARS-CoV-2 vaccination. All DMT-treated patients (n = 294) No DMT participants (n = 28) (n = 322) Alemtuzumab Anti-CD20 Fumarates Glatiramer Interferons Natalizumab S1PRMs Teriflunomide (n = 23) (n = 80) (n = 37) acetate (n = 23) (n = 44) (n = 39) (n = 15) (n = 33) Age (years), mean (SD) 49.2 (12.2) 41.5 (8.6) 46.8 (12.5) 47.4 (11.1) 49.9 (11.4) 50.8 (6.2) 46.2 (11.5) 47.8 (9.0) 60.8 (8.2) 63.1 (13.3) journals.sagepub.com/home/msj Sex, n (%) Male 80 (24.8) 7 (30.4) 25 (31.3) 8 (21.6) 5 (15.2) 5 (21.7) 10 (22.7) 13 (33.3) 3 (20.0) 4 (14.3) Female 242 (75) 16 (69.6) 55 (68.8) 29 (78.4) 28 (84.8) 18 (78.3) 34 (77.3) 26 (66.7) 12 (80.0) 24 (86) Race/area of origin, n (%) White 205 (63.7) 7 (30.4) 46 (57.5) 27 (73.0) 21 (63.6) 17 (73.9) 38 (86.4) 21 (53.8) 7 (46.7) 21 (75.0) Western Europe (EU only) 53 (16.5) 13 (56.5) 11 (13.8) 3 (8.1) 4 (12.1) 4 (17.4) 1 (2.3) 13 (33.3) 2 (13.3) 2 (7.1) Eastern Europe 6 (1.9) 2 (8.7) 1 (1.3) 0 (0.0) 1 (3.0) 0 (0.0) 0 (0.0) 1 (2.6) 0 (0.0) 1 (3.6) Black or African American 12 (3.7) 0 (0.0) 5 (6.3) 3 (8.1) 1 (3.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (6.7) 2 (7.1) Asian 2 (0.6) 0 (0.0) 1 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.6) 0 (0.0) 0 (0.0) American Indian or Alaska Native 1 (0.3) 0 (0.0) 1 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Multiple 7 (2.2) 1 (4.3) 3 (3.8) 0 (0.0) 1 (3.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (6.7) 1 (3.6) Other/unknown 6 (1.9) 0 (0.0) 1 (1.3) 0 (0.0) 1 (3.0) 0 (0.0) 2 (4.5) 1 (2.6) 1 (6.7) 0 (0.0) Missing 29 (9.0) 0 (0.0) 11 (13.8) 4 (10.8) 4 (12.1) 1 (4.3) 3 (6.8) 2 (5.1) 3 (20.0) 1 (3.6) Ethnicity (US only),a n (%) Hispanic or Latino 11 (4.3) 0 (0.0) 4 (6.0) 1 (3.0) 1 (3.6) 3 (15.8) 2 (4.8) 0 (0.0) 0 (0.0) 0 (0.0) Not Hispanic or Latino 205 (80.1) 6 (75.0) 51 (76.1) 26 (78.8) 23 (82.1) 14 (73.7) 34 (81.0) 19 (86.4) 8 (66.7) 24 (96.0) Chose not to report 7 (2.7) 1 (12.5) 1 (1.5) 2 (6.1) 0 (0.0) 1 (5.3) 0 (0.0) 0 (0.0) 2 (16.7) 0 (0.0) Unknown 11 (4.3) 1 (12.5) 3 (4.5) 1 (3.0) 0 (0.0) 0 (0.0) 3 (7.1) 3 (13.6) 0 (0.0) 0 (0.0) Missing 22 (8.6) 0 (0.0) 8 (11.9) 3 (9.1) 4 (14.3) 1 (5.3) 3 (7.1) 0 (0.0) 2 (16.7) 1 (4.0) PDDS, mean (SD) 1.6 (2.0) 2.0 (2.1) 2.2 (2.0) 0.9 (1.4) 0.6 (1.3) 1.0 (1.5) 1.4 (1.9) 1.5 (2.1) 1.4 (2.1) 2.8 (2.6) MS subtype, n (%) Clinically isolated syndrome 87 (27.0) 4 (17.4) 18 (22.5) 10 (27.0) 12 (36.4) 12 (52.2) 12 (27.3) 10 (25.6) 5 (33.3) 4 (14.3) Primary progressive 33 (10.2) 4 (17.4) 15 (18.8) 0 (0.0) 0 (0.0) 1 (4.3) 3 (6.8) 2 (5.1) 2 (13.3) 6 (21.4) Relapsing remitting 154 (47.8) 11 (47.8) 33 (41.3) 25 (67.6) 16 (48.5) 7 (30.4) 23 (52.3) 20 (51.3) 5 (33.3) 14 (50.0) Secondary progressive 45 (14.0) 4 (17.4) 14 (17.5) 2 (5.4) 4 (12.1) 2 (8.7) 6 (13.6) 7 (17.9) 2 (13.3) 4 (14.3) Missing 3 (0.9) 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.0) 1 (4.3) 0 (0.0) 0 (0.0) 1 (6.7) 0 (0.0) Time since first symptom onset (years), mean 17.0 (11.5) 15.0 (7.4) 14.0 (9.5) 16.5 (10.4) 15.4 (10.0) 18.9 (13.4) 16.4 (11.3) 18.0 (9.7) 23.7 (20.1) 25.4 (14.4) (SD) Time since MS diagnosis (years), mean (SD) 14.2 (9.5) 14.0 (7.1) 11.5 (8.0) 13.8 (9.3) 12.2 (7.0) 14.4 (7.3) 14.3 (8.4) 15.5 (8.1) 20.2 (19.7) 20.6 (12.7) Time on current DMT (years), mean (SD) 4.2 (4.0) 3.6 (1.6) 2.2 (1.4) 3.6 (2.6) 6.7 (6.6) 7.7 (5.6) 5.7 (4.0) 4.0 (2.8) 2.2 (1.7) NA Time since last infusion or discontinuation of N/A N/A 6.1 (11.7) N/A N/A N/A 0.7 (0.6) N/A N/A 51.1 (46.8)b DMT for no DMT (months), mean (SD) Time since last vaccine dose (days), mean (SD) 47.4 (16.2) 42.2 (15.7) 46.9 (15.9) 49.9 (14.2) 53.1 (15.5) 44.3 (17.6) 50.5 (16.6) 46.6 (16.0) 55.8 (21.6) 37.1 (8.9) Vaccine AstraZeneca 7 (2.2) 0 (0.0) 0 (0.0) 1 (2.7) 1 (3.0) 1 (4.3) 0 (0.0) 1 (2.6) 2 (13.3) 1 (3.6) Johnson & Johnson 19 (5.9) 0 (0.0) 7 (8.8) 2 (5.4) 0 (0.0) 2 (8.7) 4 (9.1) 1 (2.6) 0 (0.0) 3 (10.7) Moderna 129 (40.1) 6 (26.1) 42 (52.5) 13 (35.1) 15 (45.5) 8 (34.8) 15 (34.1) 10 (25.6) 5 (33.3) 15 (53.6) Pfizer 167 (52) 17 (74) 31 (39) 21 (57) 17 (52) 12 (52) 25 (57) 27 (69) 8 (53) 9 (32) (Continued) 1133 JA Cohen, RA Bermel et al. Multiple Sclerosis Journal 28(7) Based on the mechanism of action, the failure to 153.8 (175.5) mount a humoral response to SARS-CoV-2 vaccina- 28 (100) Anti-CD20: n = 57 (71%) ocrelizumab, n = 22 (28%) rituximab, n = 1 (1%) ofatumumab; fumarates: n = 32 (86%) dimethyl fumarate, n = 5 (14%) diroximel fumarate; interferons: n = 16 (70%) interferon beta-1a, n = 6 (26%) No DMT 1.8, 743 tion with anti-CD20 therapy is likely due to depletion (n = 28) to their vaccination, and 90% (18/20) reported their last dose was ≥ 6 months since their vaccination. Among the 2 patients who reported their last dose within 6 months of vaccination, 1 patient discontinued treatment with bA prior history of DMT use was reported for (71%) 20/28 patients who did not report currently taking a DMT at the time of vaccination. Within this subset, 10% (2/20) reported their last dose was less than 6 months prior of naive and memory B lymphocytes.5 The mecha- nism underlying reduced vaccine response in the Teriflunomide S1PRM class is not clear even though reduced influ- 49.2 (41.2) 15 (100) enza vaccine response has also been observed in fin- 1.6, 128 (n = 15) golimod treatment.11 Although the number of DMT: disease-modifying therapy; MS: multiple sclerosis; NA: not applicable; PDSS: Patient Determined Disease Steps; SD: standard deviation, S1PRM: sphingosine 1-phosphate receptor modulator. circulating lymphocytes is reduced with S1PRM treatment, cells are sequestered in lymphoid organs 21.2 (74.7) but not killed. However, besides inhibiting lympho- 16 (41) S1PRMs 0.5, 430 (n = 39) cyte egress from lymph nodes, fingolimod has a vari- ety of effects on T-cell and B-cell mediated immune responses that might be expected to quantitatively or 123.1 (184.3) Natalizumab qualitatively affect antibody responses to vaccines.12 44 (100) 2.3, 750 (n = 44) glatiramer acetate 25 days prior to their second vaccine dose and another patient discontinued treatment with teriflunomide 11 days prior to their first vaccine dose. Limitations include the relatively small number of participants in some DMT groups. A larger cohort, 199.0 (183.3) including additional DMT classes, is being accrued in 23 (100) Interferons an ongoing study. A further limitation is the lack of 2.8, 750 (n = 23) pre-vaccination samples or cross-testing post-vacci- nation samples using nucleocapsid-based assay to screen out patients previously infected with SARS- 33 (100) Glatiramer peginterferon beta-1a, n = 1 (4%) interferon beta-1b; S1PRM: n = 32 (82%) fingolimod, n=4 (10%) ozanimod, n = 3 (8%) siponimod. CoV-2; both are being tested in the ongoing study. 6.7, 750 (n = 33) (199.5) acetate 176.4 This study used a commercially available assay to semi-quantitatively assess the SARS-CoV-2 IgG response to spike protein as a measure for SARS- 37 (100) Fumarates CoV-2 immunity.13 We did not directly measure neu- 7.6, 750 (n = 37) (192.9) 136.9 tralizing activity; however, the test manufacturer has reported a 0.81 correlation between IgG index and neutralization titers.14 We also did not assess T-cell 23.3 (61.5) DMT-treated patients (n = 294) Anti-CD20 32 (40) response to SARS-CoV-2. The relative importance of 0.5, 371 (n = 80) both humoral and cell-mediated mechanisms in pro- tective immunity to SARS-CoV-2 in the context of DMTs has not been fully elucidated and will be cru- Alemtuzumab 217.0 (242.8) 23 (100) cial to understand long term. 24.2, 750 (n = 23) This study highlights the complexity of post-vaccina- tion IgG responses across DMTs, knowledge of which 104.4 (168.5) participants is necessary to optimize MS management and to pro- 251 (78) (n = 322) 0.5, 750 vide guidance to PwMS around recommended behav- All iors and precautions given their likelihood of cMin value of 0.5 and max value of 750 for detection. protection after vaccination. Additional studies are needed to further evaluate humoral and especially cel- lular responses to SARS-CoV-2 vaccination in DMT- treated PwMS. Vaccinations should be discussed as Anti-SARS-CoV-2 serological response an integral part of MS care, particularly in relation to how some DMTs may impact effective immune responses to routine vaccines, as well as the SARS- Table 1. (Continued) Mean IgG index (SD) IgG index >1, n (%) CoV-2 vaccine. IgG min, maxc Acknowledgements an = 256. This study was sponsored by Biogen (Cambridge, MA, USA). Karen Spach, PhD, of Excel Scientific Solutions (Fairfield, CT, USA) provided initial 1134 journals.sagepub.com/home/msj JA Cohen, RA Bermel et al. SARS-CoV-2 IgG Levels 4 Relapsing-remitting MS Primary progressive MS Secondary progressive MS IgG Antibody Titer (AU/mL) 3 Clinically Isolated syndrome Log Anti-SARS-CoV-2 2 1 0 >0 = log reactive IgG titer -1 ab 20 es e ns ab s e T M at id M at ro m D m m PR et D C ar rfe zu izu no Ac o ti- S1 m tu N te al lu An Fu er em In at rif am N Te Al tir la G Figure 1. Unadjusted post-vaccination SARS-CoV-2 IgG levels by DMT class. Post-vaccination blood serum samples, collected 28–90 days after the final vaccine dose, were assessed for SARS-CoV-2 immunoglobulin G (IgG) response to the spike protein using Siemens Healthineers Atellica® IM* SARS-CoV-2 IgG assay. Unadjusted log-transformed anti- SARS-CoV-2 IgG index values are presented. Log-transformed IgG index values >0 are interpreted as reactive. DMT: disease-modifying therapy; S1PRM: sphingosine 1-phosphate receptor modulator. Black symbols = relapsing-remitting MS; green symbols = primary progressive MS; blue symbols = secondary progressive MS; red symbols = clinically isolated syndrome. editing support based on a draft from authors and receiving research support from Biogen, Genentech, incorporated author comments during revisions, and and Teva and royalties from UpTo Date (editorial Nathaniel Hoover from Excel Scientific Solutions duties). R.N. reports being on the scientific advisory copyedited and styled the manuscript per journal board and/or doing consulting for Avidea, Biogen, requirements. Bristol Myers Squibb, Genentech, Genzyme, GW Therapeutics, Horizon Therapeutics, Janssen, Declaration of Conflicting Interests Lundbeck, Nervgen, TG Therapeutics, Third Rock The author(s) declared the following potential con- Ventures, and Viela Bio. J.N. reports receiving flicts of interest with respect to the research, author- research grants from ADAMAS, Biogen, Genzyme, ship, and/or publication of this article: J.A.C. reports Novartis, and PCORI and consulting and/or speaking receiving personal compensation for consulting from fees from Alexion, Bristol Myers Squib, EMD Biogen, Bristol Myers Squibb, Convelo, Genentech, Serono, Genetech, Greenwich Biosciences, Novartis, Janssen, NervGen, Novartis, and PSI; speaking for and Viela Bio. M.T. has received compensation for H3 Communications; and serving as an Editor of consulting services and speaking honoraria from Multiple Sclerosis Journal. R.A.B. reports being on Almirall, Bayer Schering Pharma, Biogen, Genzyme, the scientific advisory board and/or doing consulting Janssen, Merck-Serono, Novartis, Roche, Sanofi- for Biogen, EMD Serono, Genentech/Roche, Aventis, Viela Bio, and Teva Pharmaceuticals and is Novartis, Sanofi/Genzyme, and Viela Bio and receiv- the co-editor of Multiple Sclerosis Journal-ETC. ing research support from Biogen, Novartis, and A.Z. has received travel expenses for scientific meet- Roche. C.M.H. reports receiving speaking and con- ings from Biogen and Novartis, speaking honoraria sulting fees from Biogen, Bristol Myers Squibb, from Eisai, and a study grant from Novartis. T.Z. EMD Serono, Genentech, Genzyme, and Novartis reports being on the scientific advisory board and/or and grants/research support from Biogen, Genentech, doing consulting for Biogen, Celgene, Merck, NIH–NINDS 1U01NS111678-01A1 sub-award, Novartis, and Roche; receiving compensation for Novartis, and Patient-Centered Outcomes Research serving on speakers bureaus for Biogen, Celgene, Institute (PCORI). M.H. reports receiving research Merck, Novartis, Roche, and Sanofi; and receiving support from Biogen and PCORI. E.M.M. reports research support from Biogen, Celgene, Merck, journals.sagepub.com/home/msj 1135 Multiple Sclerosis Journal 28(7) 400 M.L.N. are shareholder/stockholders and former Anti-SARS-CoV-2 IgG Antibody Titer (AU/mL) Post-vaccination SARS-Cov-2 IgG employees of Biogen. Anti-CD20 IgG+ (reactive) Anti-CD20 IgG- (non-reactive) Funding 300 The author(s) disclosed receipt of the following finan- cial support for the research, authorship, and/or publi- cation of this article: This study was sponsored by 200 Biogen (Cambridge, MA, USA). Funding for writing and editorial support was provided by Biogen. 100 ORCID iDs Jeffrey A Cohen https://orcid.org/0000-0001-9245 -9772 0 Robert A Bermel https://orcid.org/0000-0003 0 5 10 15 20 -2334-6883 Time since last dose (months) Carrie M Hersh https://orcid.org/0000-0002 (a) -5716-5645 110 Robert Naismith https://orcid.org/0000-0003 Median (Q1, Q3) time since -0520-4283 last infusion (months) 90 15 Maria L Naylor https://orcid.org/0000-0003-3844 -6035 10 Mar Tintorè https://orcid.org/0000-0001-9999-5359 5 Ana Zabalza https://orcid.org/0000-0003-3860-5251 Tjalf Ziemssen https://orcid.org/0000-0001-8799 0 -8202 Anti-CD20 IgG- Anti-CD20 IgG+ (Non-reactive) (Reactive) (b) References 1. 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