key: cord-0973493-szq9iknn authors: Cohen, Jeffrey A; Bermel, Robert A; Grossman, Cynthia I; Hersh, Carrie M; Hyland, Megan; Mowry, Ellen M; Naismith, Robert; Naylor, Maria L; Nicholas, Jacqueline; Rajbhandar, Rajani; Singh, Carol M; Tintorè, Mar; Zabalza, Ana; Ziemssen, Tjalf; Williams, James R; Montalban, Xavier title: Immunoglobulin G immune response to SARS-CoV-2 vaccination in people living with multiple sclerosis within Multiple Sclerosis Partners Advancing Technology and Health Solutions date: 2022-01-07 journal: Mult Scler DOI: 10.1177/13524585211061343 sha: d5c793dd86fd35da99b34f0ad36840612fe6336e doc_id: 973493 cord_uid: szq9iknn BACKGROUND: The impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on SARS-CoV-2 vaccination response is uncertain. METHODS: Post-SARS-CoV-2 vaccination blood samples across multiple DMTs were tested for SARS-CoV-2 immunoglobulin G (IgG) response. RESULTS: Three hundred twenty-two people with MS were included; 91.9% received an mRNA vaccine. Post-vaccination reactive IgG rates (IgG index > 1) were 40% for anti-CD20 (32/80 patients); 41% for sphingosine 1-phosphate receptor modulators (S1PRM, 16/39); and 100% for all other classes, including the no DMT group. CONCLUSION: Anti-CD20 therapies and S1PRMs reduce IgG response to SARS-CoV-2 vaccination; IgG response is preserved with other DMTs. Coronavirus disease 2019 (COVID-19) has resulted in millions of deaths worldwide. 1 Vaccination against SARS-CoV-2, the virus that causes COVID-19, is the most effective means of protecting populations, including people with multiple sclerosis (PwMS), 2 and ending the COVID-19 pandemic. 3 However, as a result of immunomodulatory effects or depletion of circulating lymphocytes, MS disease-modifying therapies (DMTs) may reduce humoral or cellular immune responses to vaccines, including against SARS-CoV-2. 1, 4, 5 Although the clinical significance of these varying responses, including the impact on risk of infection, is not fully understood, the COVID-19 pandemic makes better characterization of how MS DMTs influence vaccine effectiveness critically important. 1, 4, 5 Limited data relating to the efficacy of COVID-19 vaccines in DMT-treated PwMS have led to varying vaccination guidelines from MS organizations. 4 An initial study suggested that immunoglobulin G (IgG) antibody responses to SARS-CoV-2 vaccination are attenuated in PwMS treated with the anti-CD20 therapy ocrelizumab or the sphingosine 1-phosphate receptor modulator (S1PRM) fingolimod. 5 This observation is consistent with previous studies of non-COVID vaccine responses in PwMS treated with these DMTs. 6,7 Thus, robust data on immune responses to COVID-19 vaccines across multiple DMTs are needed to support evidence-based COVID-19 vaccination recommendations. We report initial results from a large real-world study of the impact of different DMT classes on IgG responses to SARS-CoV-2 vaccines. Participants with MS enrolled in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network in the United States, Germany, and Spain were recruited to voluntarily provide pre-and post-vaccination blood serum samples. MS PATHS comprises 10 MS centers that collect standardized data during routine office visits with the aim of improving outcomes for PwMS. Sample collection is ongoing; initial post-vaccination data from DMT classes (with minimum ⩾10 patients) are reported here. DMTs included in the preliminary analysis were grouped by mechanisms of action: alemtuzumab, anti-CD20, fumarates, glatiramer acetate (GA), interferons (IFNs), natalizumab, S1PRMs, teriflunomide, and no DMT. For this study, serum samples could be collected up to 30 days pre-vaccination relative to the first injection of the vaccine and 28-90 days after the final vaccine dose. Post-vaccination blood samples, collected with or without a corresponding pre-vaccination sample, were taken after two injections for the AstraZeneca, Pfizer, and Moderna vaccines, and one injection for the Johnson & Johnson vaccine. The Siemens Healthineers Atellica ® IM* SARS-CoV-2 IgG assay was used to measure semi-quantitative (index value) IgG response to the SARS-CoV-2 spike protein. 8 Univariate logistic regression analyses assessed the relationship between post-vaccination IgG response (reactive/non-reactive) and demographic, disease, and vaccine characteristics. These analyses were restricted to participants on anti-CD20 or S1PRM therapy since there was no heterogeneity in IgG response in other DMT categories. Univariate linear regression was used to assess the relationship between time of last anti-CD20 dose and IgG index value. The study was approved by central and local ethics committees and conducted in accordance with the International Council on Harmonization guidelines for Good Clinical Practice and the Declaration of Helsinki. All patients provided written, informed consent. As of 24 August, 2021, post-vaccination serum samples were obtained from 322 participants: alemtuzumab (n = 23), anti-CD20 (n = 80; ocrelizumab n = 57, rituximab n = 22, ofatumumab n = 1), fumarates (n = 37; dimethyl fumarate n = 32, diroximel fumarate n = 5), GA (n = 33), IFNs (n = 23; IM IFN beta-1a n = 16, pegylated IFN beta-1a n = 6, IFN beta-1b, n = 1), natalizumab (n = 44), S1PRMs (n = 39; fingolimod n = 32, ozanimod n = 4, siponimod n = 3), teriflunomide (n = 15), and no DMT (n = 28). Postvaccination samples were collected 47.4 (16.2) days after the last vaccine dose; 296/322 (91.9%) were following an mRNA vaccine. No pre-vaccination samples were available for these participants. Baseline demographics and disease characteristics by DMT class are shown in Table 1 . Reactive IgG rates (IgG index >1) from initial post-vaccination testing were 32/80 participants (40%) for anti-CD20, 16/39 (41%) for S1PRMs, and 100% for all other classes, including alemtuzumab (n = 23), fumarates (n = 37), GA (n = 33), IFNs (n = 23), natalizumab (n = 44), teriflunomide (n = 15), and no DMT (n = 28). SARS-CoV-2 IgG index value by DMT is shown in Figure 1 . IgG response was not correlated with time of last dose of anti-CD20 therapies ( Figure 2 ). In the anti-CD20 and S1PRM groups, for 1 year increase in the duration of therapy, odds of a reactive IgG results are: OR anti-CD20 = 0.53, 95% confidence interval (CI) = (0.34, 0.83) and OR S1PRM = 0.70, 95% CI = (0.53, 0.93). There was no association between probability of a reactive IgG result and patient characteristics, and no association between reactive IgG status and MS subtype ( Figure 1 ). For the anti-CD20 group, the percent of patients with a reactive anti-SARS-CoV-2 response of >1.0 was: Pfizer (45% (14/31)), Moderna (38% (16/42)), and Johnson & Johnson (29% (2/7)). For the S1PRM group, the percent of patients with a reactive anti-SARS-CoV-2 response of >1.0 was: Pfizer (33% (9/27)), Moderna (60% (6/10)), Johnson & Johnson (100% (1/1)), and AstraZeneca (0% (0/1)). Our preliminary results suggest that anti-CD20 and S1PRM DMTs reduce the IgG response to SARS-CoV-2 vaccination in PwMS, consistent with other studies. 5, 9, 10 We also report an association between duration anti-CD20 and S1PRM treatment and reduced odds of an SARS-CoV-2 vaccination IgG response. Conversely, the IgG response to SARS-CoV-2 vaccination appears to be preserved in PwMS treated with other DMTs, including alemtuzumab (n = 23), fumarates (n = 37), GA (n = 33), IFNs (n = 23), natalizumab (n = 44), teriflunomide (n = 15), and no DMT (n = 28). SARS-CoV-2 IgG index value by DMT is shown in Figure 1 . Black or African American Based on the mechanism of action, the failure to mount a humoral response to SARS-CoV-2 vaccination with anti-CD20 therapy is likely due to depletion of naive and memory B lymphocytes. 5 The mechanism underlying reduced vaccine response in the S1PRM class is not clear even though reduced influenza vaccine response has also been observed in fingolimod treatment. 11 Although the number of circulating lymphocytes is reduced with S1PRM treatment, cells are sequestered in lymphoid organs but not killed. However, besides inhibiting lymphocyte egress from lymph nodes, fingolimod has a variety of effects on T-cell and B-cell mediated immune responses that might be expected to quantitatively or qualitatively affect antibody responses to vaccines. 12 Limitations include the relatively small number of participants in some DMT groups. A larger cohort, including additional DMT classes, is being accrued in an ongoing study. A further limitation is the lack of pre-vaccination samples or cross-testing post-vaccination samples using nucleocapsid-based assay to screen out patients previously infected with SARS-CoV-2; both are being tested in the ongoing study. 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-CoV-2 immunity. 13 We did not directly measure neutralizing 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 response to SARS-CoV-2. The relative importance of both humoral and cell-mediated mechanisms in protective immunity to SARS-CoV-2 in the context of DMTs has not been fully elucidated and will be crucial to understand long term. This study highlights the complexity of post-vaccination IgG responses across DMTs, knowledge of which is necessary to optimize MS management and to provide guidance to PwMS around recommended behaviors and precautions given their likelihood of protection after vaccination. Additional studies are needed to further evaluate humoral and especially cellular responses to SARS-CoV-2 vaccination in DMTtreated PwMS. Vaccinations should be discussed as 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-CoV-2 vaccine. editing support based on a draft from authors and incorporated author comments during revisions, and Nathaniel Hoover from Excel Scientific Solutions copyedited and styled the manuscript per journal requirements. The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J. Black symbols indicate the IgG positivity (reactive) and green symbols indicate the IgG response below the threshold of >1 AU/ mL (non-reactive). reports receiving speaking honoraria and/or travel expenses for participation in scientific meetings, and/or has been a steering committee member of clinical trials and/or participated in advisory boards of clinical trials in the past years with Actelion, Alexion are employees of and shareholders/stockholders of Biogen. R.R. and M.L.N. are shareholder/stockholders and former employees of Biogen Approach to SARS-CoV-2 vaccination in patients with multiple sclerosis MS International Federation. Global COVID-19 advice for people with MS Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine Vaccine considerations for multiple sclerosis in the COVID-19 era Atellica IM SARS-CoV-2 IgG (sCOVG) instructions for use Association of disease-modifying treatment and anti-CD20 infusion timing with humoral response to 2 SARS-CoV-2 vaccines in patients with multiple sclerosis Serological response to SARS-CoV-2 vaccination in multiple sclerosis patients treated with fingolimod or ocrelizumab: An initial real-life experience Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis Fingolimod leads to immediate immunological changes within 6 h after first administration SARS-CoV-2 serology status detected by commercialized platforms distinguishes previous infection and vaccination adaptive immune responses. medRxiv. Epub ahead of print 12 SARS-CoV-2 IgG (sCOVG) assay Visit SAGE journals online journals.sagepub.com/ home/msj SAGE journals The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Biogen (Cambridge, MA, USA). Funding for writing and editorial support was provided by Biogen.