Longitudinal study of immunity to SARS-CoV2 in Ocrelizumab-treated multiple sclerosis patients up to 2 years after COVID-19 vaccination

Objectives 1 To plot the trajectory of humoral and cellular immune responses to the primary (two-dose) COVID-19 mRNA series and the third/booster dose in B-cell-depleted multiple sclerosis (MS) patients up to 2 years post-vaccination; 2. to identify predictors of immune responses to vaccination; and 3. to assess the impact of intercurrent COVID-19 infections on SARS CoV-2-specific immunity. Methods 60 Ocrelizumab-treated MS patients were enrolled from NYU (New York) and University of Colorado (Anschutz) MS Centers. Samples were collected pre-vaccination, and then 4, 12, 24, and 48 weeks post-primary series, and 4, 12, 24, and 48 weeks post-booster. Binding anti-Spike antibody responses were assessed with multiplex bead-based immunoassay (MBI) and electrochemiluminescence (Elecsys®, Roche Diagnostics), and neutralizing antibody responses with live-virus immunofluorescence-based microneutralization assay. Spike-specific cellular responses were assessed with IFNγ/IL-2 ELISpot (Invitrogen) and, in a subset, by sequencing complementary determining regions (CDR)-3 within T-cell receptors (Adaptive Biotechnologies). A linear mixed effect model was used to compare antibody and cytokine levels across time points. Multivariate analyses identified predictors of immune responses. Results The primary vaccination induced an 11-208-fold increase in binding and neutralizing antibody levels and a 3-4-fold increase in IFNγ/IL-2 responses, followed by a modest decline in antibody but not cytokine responses. Booster dose induced a further 3-5-fold increase in binding antibodies and 4-5-fold increase in IFNγ/IL-2, which were maintained for up to 1 year. Infections had a variable impact on immunity. Interpretation Humoral and cellular benefits of COVID-19 vaccination in B-cell-depleted MS patients were sustained for up to 2 years when booster doses were administered. ### Competing Interest Statement This work was supported by an unrestricted investigator-initiated grant from Genentech. IK served on the scientific advisory board for Biogen Idec, Genentech, Alexion, EMDSerono; received consulting fees from Roche; and received research support from Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen Idec, Serono, Genzyme, and Genentech/Roche; he receives royalties from Wolters Kluwer for 'Top 100 Diagnosis in Neurology' (co-written with Jose Biller). GJS received honoraria from BMS, Eli Lilly and Human Biosciences, and research support from BMS, Genentech, Biogen, Lupus Research Alliance, NIH-NIAMS, NIH-NIAID and the Colton Center at NYU. MK is on the scientific advisory board for Merck, NexImmune and Genentech and received research support from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Genentech, the Mark Foundation, NIH-NIGMS and NIH-NCI. BLB receives salary and owns stock from Adaptive Biotechnologies. MJM reported potential competing interests: laboratory research and clinical trials contracts for vaccines or MAB vs SARS-CoV-2 with Lilly, Pfizer, and Sanofi; research grant funding from USG/HHS/NIH for vaccine and MAB clinical trials; personal fees for Scientific Advisory Board service from Merck, Meissa Vaccines, Inc. and Pfizer. ALP reports research grants from the University of Colorado, Rocky Mountain MS Center, and the Foundation for Sarcoidosis; consulting fees from Genentech/Roche, UCB, EMD Serono and Alexion; and honorarium from MedLink and publication royalties from Springer as co-editor of a medical textbook. All others declare no conflicts of interest. ### Funding Statement Editorial assistance with tables and figures was provided by Emma Bouck, PhD, of Nucleus Global and funded by Genentech, Inc. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of NYU Grossman School of Medicine (New York) has approved this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymized data are available in Table S2 .