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Sphingosine-1-phosphate receptor modulators and anti-CD20 treatment are widely used disease-modifying treatments for multiple sclerosis. Unfortunately, they may impair the patient’s ability to mount sufficient humoral and T-cellular responses to vaccination, which is of special relevance in the context of the SARS-CoV-2 pandemic. We present here a case series of six multiple sclerosis patients on treatment with sphingosine-1-phosphate receptor modulators who failed to develop SARS-CoV-2-specific antibodies and T-cells after three doses of vaccination. Due to their ongoing immunotherapy, lacking vaccination response, and additional risk factors, we offered them pre-exposure prophylactic treatment with monoclonal SARS-CoV-2-neutralizing antibodies. Initially, treatment was conducted with the antibody cocktail casirivimab/imdevimab. When the SARS-CoV-2 Omicron variant became predominant, we switched treatment to monoclonal antibody sotrovimab due to its sustained neutralizing ability also against the Omicron strain. Since sotrovimab was approved only for the treatment of COVID-19 infection and not for pre-exposure prophylaxis, we switched treatment to tixagevimab/cilgavimab as soon as it was granted marketing authorization in the European Union. This antibody cocktail has retained, albeit reduced, neutralizing activity against the Omicron variant and is approved for pre-exposure prophylaxis. No severe adverse events were recorded for our patients. One patient had a positive RT-PCR for SARS-CoV-2 under treatment with sotrovimab, but was asymptomatic. The other five patients did not develop symptoms of an upper respiratory tract infection or evidence of a SARS-CoV-2 infection during the time of treatment up until the finalization of this report. SARS-CoV-2-neutralizing antibody treatment should be considered individually for multiple sclerosis patients lacking adequate vaccination responses on account of their immunomodulatory treatment, especially in times of high incidences of SARS-CoV-2 infection.

Background and ObjectivesOur objective was to investigate cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in a cohort of people with multiple sclerosis (pwMS) on pulsed B-cell–depleting treatment (BCDT). In particular, we intended to evaluate a possible association between immune responses and the timing of vaccination under BCDT.MethodsWe conducted a cross-sectional study among pwMS on pulsed BCDT or without disease-modifying treatment after completed SARS-CoV-2 vaccination. Samples were collected during routine clinical visits at the Multiple Sclerosis Center Dresden, Germany, between June 2021 and September 2021. Blood was analyzed for SARS-CoV-2 spike protein–specific antibodies and interferon-γ release of CD4 and CD8 T cells on stimulation with spike protein peptide pools. Lymphocyte subpopulations and total immunoglobulin levels in the blood were measured as part of clinical routine.ResultsWe included 160 pwMS in our analysis, comprising 133 pwMS on BCDT (n = 132 on ocrelizumab and n = 1 on rituximab) and 27 without disease-modifying treatment. Humoral and cellular anti–SARS-CoV-2 responses were reciprocally regulated by the time between the last BCDT cycle and vaccination. Although antibody responses increased with prolonged intervals between the last BCDT cycle and vaccination, CD4 and CD8 T-cell responses were higher in pwMS vaccinated at early time points after the last BCDT cycle compared with untreated pwMS. T-cellular vaccination responses correlated with total, CD3 CD4, and partly with CD3 CD8 lymphocyte counts. Humoral responses correlated with CD19 lymphocyte counts. Status post coronavirus disease 2019 infection led to significantly increased SARS-CoV-2–specific T-cell and antibody responses.DiscussionDelaying BCDT is currently discussed as a strategy to optimize humoral responses to SARS-CoV-2 vaccination. However, T cells represent an important line of defense against SARS-CoV-2 infection as well, especially in light of emerging variants of concern. We observed enhanced CD4 and CD8 T-cellular responses in pwMS receiving vaccination at early time points after their last BCDT cycle. These data may influence clinical decision making with respect to vaccination strategies in patients receiving BCDT.

For more than a year now, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing the coronavirus disease (COVID-19) pandemic with high mortality and detrimental effects on society, economy, and individual lives. Great hopes are being placed on vaccination as one of the most potent escape strategies from the pandemic and multiple vaccines are already in clinical use. However, there is still a lot of insecurity about the safety and efficacy of vaccines in patients with autoimmune diseases like multiple sclerosis (MS), especially under treatment with immunomodulatory or immunosuppressive drugs. We propose strategic approaches to SARS-CoV-2 vaccination management in MS patients and encourage fellow physicians to measure the immune response in their patients. Notably, both humoral and cellular responses should be considered since the immunological equivalent for protection from SARS-CoV-2 after infection or vaccination still remains undefined and will most likely involve antiviral cellular immunity. It is important to gain insights into the vaccine response of immunocompromised patients in order to be able to deduce sensible strategies for vaccination in the future.

Cytotoxic T lymphocytes (CTLs) play a key role in the control of lymphocytic choriomeningitis virus (LCMV) infection. In C57BL/6 mice (H-2 b ), the CTL response is mainly directed against epitopes from the LCMV glycoprotein (GP) and the nucleoprotein (NP) which represent the two major viral proteins. The role of GP-versus NP-derived epitopes for viralclearance was examined using transgenic (tg) mice ubiquitously expressing LCMV GP and NP, respectively. These mice lack GP-or NP-specific CTLs and show decreased levels of GP-or NP-specific antibodies as a result of tolerance induction. During acute LCMV infection, CTLs specific for GP-and NP-derived epitopes are generated with similar frequencies. Nonetheless, we found that lack of GP-but not of NP-specific CTLs abolished control of acute LCMV infection. In contrast, after high-dose or chronic LCMV infection, virus elimination was delayed to a similar extent in GP-and NP-tg mice. Thus, immunological tolerance to LCMV antigens differently affects virus clearance in acute and chronic infection settings. In addition, our data reveal that immunodominance of H-2 b -restricted LCMV-specific CTL epitopes and their antiviral activity do not strictly correlate.Keywords: Epitopes r Immunodominance r LCMV r T cells r Tolerance Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionInfection of mice with lymphocytic choriomeningitis virus (LCMV) is frequently used to study acute and chronic viral infections. In this model, cytotoxic T lymphocytes (CTLs) play a key role in virus clearance. In C57BL/6 (B6) mice, the CTL response is predominantly directed against LCMV glycoprotein (GP)-and nucleoprotein (NP)-derived epitopes [1]. Inoculation of mice with the LCMV Correspondence: Prof. Hanspeter Pircher e-mail: hanspeter.pircher@uniklinik-freiburg.de strain Armstrong (Arm) or WE (at a low virus dose) induces a potent CTL response followed by rapid virus clearance. Here, the response is dominated by NP 396 -and GP 33 -specific CTLs [2,3]. Infection with LCMV Clone 13 (Cl13) or LCMV-WE at a high dose leads to a decreased CTL response and prolonged viremia. Here, CTLs specific for GP 33 and GP 276 epitopes become immunodominant and frequencies of NP 396 -specific CTLs strongly decrease [4]. This shift in immunodominance is thought to be due to high NP antigen levels that lead to preferential deletion of the NP 396 -specific CTLs.www.eji-journal.eu Eur. J. Immunol. 2018. 48: 120-127 Immunity to infection 121Studies addressing the relative importance of LCMV GP-and NP-derived epitopes for viral clearance are scarce. Gallimore et al. reported that NP 396 -CTL lines were more efficient than GP 33 -specific CTLs in lowering viral titers upon adoptive transfer [5]. Schildknecht et al. used transgenic (tg) mice ubiquitously expressing LCMV GP or NP [6]. Due to tolerance induction, these mice lack GP-and NP-specific CTLs, respectively. Infection of NP-tg mice with a high dose of LCMV-WE resulted in heavily impaired viru...