T cell responses to SARS-CoV-2 vaccination in people with multiple sclerosis differ between disease-modifying therapies

Immune responses in people with multiple sclerosis (pwMS) on disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators attenuate antibody responses after vaccination. Evaluation of cellular responses after vaccination is therefore of particular importance in these populations. In this study, we analysed CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy controls and pwMS on five different DMTs by flow cytometry. Although pwMS on anti-CD20 and S1PR therapies had low antibody responses after both 2 and 3 vaccine doses, T cell responses in pwMS on anti-CD20 therapies were preserved after a third vaccination, even when additional anti-CD20 treatment was administered between vaccine doses 2 and 3. PwMS taking S1PR modulators had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that even in the absence of robust antibody responses vaccination can generate immune responses in pwMS. ### Competing Interest Statement MK reported receiving speaker honoraria from Novartis, Biogen, Merck and Sanofi outside the submitted work. TH has received speaker honoraria from Biogen, Merck, Novartis, Sanofi, Bristol Myers Squibb and Roche, and participated in clinical trials organized by Roche, Merck and Biogen EAH received honoraria for lecturing and advisory board activity from Biogen, Merck and Sanofi-Genzyme and unrestricted research grant from Merck. EGC has participated in advisory boards and received speaker honoraria from Biogen, Janssen, Merck, Novartis, Teva, Roche, Sanofi and Bristol Myers Squibb. KKJ has received speaker bureaus from Bristol Myers Squibb and Roche. ### Funding Statement This study was funded by the Norwegian Institute of Public Health, the Norwegian Ministry of Health through a program for corona vaccination surveillance, the Odd Fellows Foundation, the Sanofi Research Fund for MS, the Norwegian MS Society, and the Research Council of Norway (RCN) Covid (312693), LAM, SM; a KG Jebsen Foundation (grant 19), LAM; the Coalition for Epidemic Preparedness Innovations (CEPI), LAM, SM, JTV, FL-J; and the University of Oslo and Oslo University Hospital, LAM, FL-J, JTV. ### 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: The Norwegian South-Eastern Regional Ethical Committee gave ethical approval for this work(Reference numbers 200631, 235424, 135924, and 204104). The Norwegian Medicines Agency gave ethical approval for this work (EudraCT Number: 2021- 003618-37). 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors